Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:62])[CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][NH:40][C:41](=[O:60])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]4[C:53]5=[N:54][O:55][N:56]=[C:52]5[C:51]([N+:57]([O-:59])=[O:58])=[CH:50][CH:49]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:62])[CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][NH:40][C:41](=[O:60])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]4[C:53]5=[N:54][O:55][N:56]=[C:52]5[C:51]([N+:57]([O-:59])=[O:58])=[CH:50][CH:49]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
To a slurry of N-[3-({3-[(3-{(3β)-cholest-5-en-3-yl [(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}amino)-3-oxopropyl]-6-(7-nitrobenzofurazan-4-ylamino)hexanamide (24, 29 mg, 0.028 mmol) and K2CO3 (76 mg, 0.552 mmol) in N,N-dimethylformamide (6 mL) and tetrahydrofuran (2 mL) was added thiophenol (40 μL, 0.389 mmol). After 18 h at 23° C., the suspension was filtered and solvent removed in vacuo. Purification by preparative reverse-phase HPLC (gradient: 59.9% MeCN, 40% H2O, and 0.1% TFA to 99.9% MeCN, 0% H2O, and 0.1% TFA over 14 min; retention time=10.6 min) afforded 6 (15 mg, 52%) mp 170-171° C.; 1H NMR (500 MHz, CDCl3) δ 9.54 (br s, 1H), 8.68 (br s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.07 (t, J=5.35, 1H), 7.92 (t, J=5.4 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 6.40 (d, J=8.9 Hz, 1H), 5.36 (m, 1H), 3.43 (m, 1H), 3.24-3.17 (m, 4H), 3.10 (m, 2H), 2.88 (br s, 3H), 2.35 (d, J=7.2 Hz, 2H), 2.23 (t, J=6.9 Hz, 2H), 2.18 (t, J=7.1 Hz, 2H), 2.04 (t, J=7.2 Hz, 2H), 1.94-0.96 (m, 35H), 0.93 (s, 3H), 0.86 (d, J=6.2 Hz, 3H), 0.84 (d, J=2.1 Hz, 3H), 0.82 (d, J=2.1 Hz, 3H), 0.62 (s, 3H); 13C NMR (125.8 MHz, DMSO d6) δ 171.9, 170.8, 170.3, 145.1, 144.4, 144.2, 138.6, 137.9 122.3, 120.5, 99.1, 56.6, 56.1, 55.5, 49.3 (×2), 45.5, 43.3, 41.8 (×2), 41.5, 36.4, 36.2, 35.6 (×2), 35.5 (×2), 35.3 (×2), 35.2, 35.1, 34.3, 31.2, 27.7, 27.4, 27.3, 26.2, 26.0, 24.9, 24.3, 23.8, 23.2, 22.6, 22.4, 20.5, 18.8, 18.5, 11.6; IR (film) νmax 3173, 3075, 2919, 2848, 1634, 1538, 1331 cm−1; CI m/z 861.5965 (MH+, C48H77N8O6 requires 861.5966).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@H:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:6].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[I:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[O:37][C@@H:36]([C:41](O)=[O:42])[CH2:35][CH2:34]2>ClCCl>[OH:6][C@H:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][NH:3][C:41]([C@H:36]1[CH2:35][CH2:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([I:30])[CH:32]=2)[O:37]1)=[O:42]
Reactant: NC[C@H](O)c1cccnc1
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC[C@H](O)c1cccnc1)[C@H]1CCc2cc(I)ccc2O1
Reaction time: 18 h
Yield: 74 %

Procedure:
(1R)-2-Amino-1-(3-pyridinyl)ethanol dihydrochloride (U.S. Pat. No. 6,051,586) (5.73 g, 27.1 mmol), 1-hydroxybenzotriazole (6.67 g, 49.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcabodiimide hydrochloride (9.46 g, 49.3 mmol), and triethylamine (13.8 mL, 9.98 g, 98.7 mmol) were added successively to a stirred solution of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, Method A, 7.50 g, 24.7 mmol) in dichloromethane (100 mL). The reaction was stirred for 18 hours and then diluted with dichloromethane (300 mL). The solution was washed with saturated aqueous sodium bicarbonate (300 mL) and then the aqueous layer was back-extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 5-10% methanol/ethyl acetate gave the product (7.80 g, 74%) as a white solid: 1H NMR (acetone-d6, δ): 8.55 (d, J=1.6 Hz, 1 H), 8.44 (dd, J=4.7, 1.6 Hz, 1 H), 7.71 (ddd, J=7.9, 1.8, 1.8 Hz, 1 H), 7.59 (s, 1 H), 7.35-7.42 (m, 2 H), 7.27 (dd, J=7.9, 4.7 Hz, 1 H), 6.63 (d, 9.6 Hz, 1 H), 4.98 (d, J=4.2 Hz, 1 H), 4.85-4.93 (m, 1 H), 4.53 (dd, J=8.8, 3.4 Hz, 1 H), 3.38-3.70 (m, 2 H), 2.61-2.91 (m, 4 H), 2.16-2.28 (m, 2 H), 1.85-1.99 (m, 1 H); mass spectroscopy gave m/z=425.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]1[C:12]([C:13](=[O:29])[NH:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:23]=3)[CH:20]=2)=[C:11]([C:30](O)=[O:31])[CH:10]=[N:9]1>>[N:24]1([C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:13]([C:12]4[N:8]([CH3:7])[N:9]=[CH:10][C:11]=4[C:30]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:31])=[O:29])=[CH:20][N:19]3[N:21]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1

Procedure:
Using morpholine and 1-Methyl-5-(2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (68 mg,95%). MS: m/z=425 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13]C(=O)C)=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[S:18]([CH3:21])(=[O:20])=[O:19].NC(N)=S>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[S:18]([CH3:21])(=[O:19])=[O:20]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(Cl)c(S(C)(=O)=O)c2)s1
Agent: NC(N)=S
Product: Cc1nc(N)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1

Procedure:
This compound is made via an analogous procedure to N-[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Ex. 48) by replacing N-acetylthiourea with thiourea.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyl]-1H-pyrazol-4-yl]propionate (561 mg), 1 N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (2.5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyl]-1H-pyrazol-4-yl]propionic acid (506 mg, yield: 96%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 133–134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1>>[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][S:21]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)(=[O:22])=[O:23])=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:36])=[CH:33][N:32]=1
Reactant: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Reactant: Nc1ccc(C(=O)O)cn1
Product: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(NC(=O)c1ccc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 7-methoxy-8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 1) and 6-aminonicotinic acid. High vacuum drying gave the title compound (122 mg, 63%): HPLC MS RT=1.96 min, MH+=544.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.22-2.27 (2H, m), 3.15-3.18 (4H, m), 3.24-3.29 (2H, m), 3.61-3.65 (4H, m), 3.99 (3H, s), 4.24-4.27 (2H, m), 4.38 (2H, t), 4.48-4.52 (2H, m), 7.05 (1H, d), 7.47 (1H, d), 8.04 (1H, d), 8.49 (1H, dd), 8.78 (1H, d).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:19]1([CH:23]=O)[CH2:22][CH2:21][CH2:20]1.O>C1COCC1.CN(C=O)C>[CH:19]1(/[CH:23]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:22][CH2:21][CH2:20]1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=CC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/C1CCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
6.4 ml (27.3 mmol) of tert-butyl (diethoxyphosphoryl)acetate were added dropwise to a suspension, cooled to 0° C., of 1.05 g (60% in mineral oil, 26.2 mmol) of sodium hydride in a mixture of 22 ml of THF and 22 ml of DMF. After 30 min, the mixture was cooled to −10° C., and 2.0 g (crude, about 23.8 mmol) of cyclobutanecarbaldehyde were added in several portions. The reaction mixture was stirred at 0° C. for 5 h and then slowly warmed to RT overnight, subsequently added to water and extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 1.21 g of the target product (about 28% of theory).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[Na+]>C(O)(=O)C>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)c1cnc2ccnn2c1O

Procedure:
A mixture of ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (0.50g., 2.4mM) and 10% sodium hydroxide solution (5ml) was heated on a steam bath for 3 hours. The reaction mixture was cooled and acidified with acetic acid to give the required product as white crystals in 76.3% weight yield (0.33%), m.p. 319°-320° C (decomposition), νmax (nujol) 1740 (acid C=O) and 1675 (lactam C=O)cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34](=[O:37])[NH:35][CH3:36])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:19][CH2:20][O:21]C(=O)C)[CH2:16][CH2:15][N:14]([CH3:25])[C:13]=3[CH:26]=2)=[N:6][CH:7]=1.ClC1C(NC2C=CC=CC=2C(NC)=O)=NC(NC2C=CC3CNCCN(C)C=3C=2)=NC=1.C(OCCBr)(=O)C.C(N(CC)CC)C>CO.ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([NH:35][CH3:36])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:15][N:14]([CH3:25])[C:13]=3[CH:26]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)N(C)CCN(CCOC(C)=O)C3)ncc1Cl
Agent: CC(=O)OCCBr
Agent: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)N(C)CCNC3)ncc1Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)N(C)CCN(CCO)C3)ncc1Cl
Yield: 10 %

Procedure:
Synthesis of Acetic acid 2-{8-[5-chloro-4-(2-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-1-methyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-ethyl ester: To 40 ml sure-seal reaction vial, 2-[5-chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (105 mg, 0.19 mmole), 2-bromoethyl acetate (36 mg, 0.21 mmole), triethylamine (0.3 ml, 2.1 mmoles), KI (10 mg, catalytic), and DMF (5 ml) were added. The reaction was heated to 700 C for 18 hours. The solvent was removed under vacuum to afford a brown solid. The desired product (10 mg, 10%) was isolated via column chromatography with dichloromethane and methanol as eluant. LCMS (ESI+) 524.42 (M+H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:8]1
Reactant: C1CNCCN1
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1cnc(N2CCNCC2)cn1

Procedure:
A mixture of 3 g of piperazine, 1.04 ml of 2-chloropyrazine and 1.85 g of K2CO3 in 100 ml of EtOH is heated at reflux for 48 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in water, the system is rendered alkaline to pH=10 by addition of 10% NaOH and subjected to extraction with chloroform, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 1.8 g of the expected product following recrystallization from hexane.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[S:11])[CH:7]=[CH:8][N:9]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=O>C(O)C>[CH3:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[S:11][CH:14]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[N:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CCCc1cc(C(N)=S)ccn1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: CCCc1cc(-c2nc(-c3ccc(C)cc3)cs2)ccn1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
A mixture of prothionamide (1.03 g, 5.70 mmol) and 2-bromo-4′-methylacetophenone (1.22 g, 5.70 mmol) in ethanol (20 ml) was heated at 70° C. with stirring for 0.5 h, and then cooled to 0° C. A yellow precipitate formed was filtered, washed with cold ethanol, and dried to give 2-propyl-4-(4-p-tolylthiazol-2-yl)pyridine (fatostatin) 1 HBr salt (1.78 g, 83%) as yellow needles. mp: 190-193° C.; 1H NMR (600 MHz, DMSO-d6): δ 8.88 (d, J=6.2 Hz, 1H), 8.54 (s, 1H), 8.46 (d, J=1.4 Hz, 1H), 8.36 (dd, J=1.4, 6.2 Hz, 1H), 7.99 (d, J=7.6 Hz, 2H), 7.31 (d, J=7.6 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H), 2.35 (s, 3H), 1.80 (m, 2H), 0.96 (t, J=7.6 Hz, 3H); 13C NMR (150 MHz, DMSO-d6): δ 161.3, 158.5, 156.9, 146.2, 143.2, 138.4, 130.4, 129.5, 126.3, 122.3, 120.3, 119.5, 35.0, 22.4, 20.9, 13.4; HRMS (m/z): [M+H]+ calcd for C18H19N2S, 295.1269; found, 295.1269.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:16][C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[CH2:18][C@H:17]([NH:16][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][S:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:26][CH2:25]3)[CH2:28][CH2:29]1
Reactant: O=C(O)c1ccc(N2CCSCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCSCC4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Thiomorpholinobenzoic acid (0.25 g, 1.1 mmol) was dissolved in thionyl chloride (25 mL). The excess of thionyl chloride was immediately evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (107 mg, 0.44 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (104 mg, 0.42 mmol) and triethylamine (68 μL, 0.87 mmol) in methylene chloride (35 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. Yield: 58 mg (31%) of the title compound as white crystals: mp 190-191° C.; [α]21D -86° (c 0.25, chloroform); EIMS (70 eV) m/z (relative intensity) 450 (2, M+).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO>[NH2:1][C:2]1[C:7]([O:11][CH3:10])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Cc1cnc(N)c(Br)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cnc1N
Temperature: 25 °C
Yield: 75 %

Procedure:
2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml)). The reaction was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75%), m.p. 67°-69° C.; mass spectrum (+ve CI): 140 (M+H)+.
Reaction SMILES: O1CCC[CH2:2]1.C([Li])CCC.Cl[C:12]1[N:13]=[N:14][C:15]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:17]=[C:12]([CH3:2])[N:13]=[N:14][C:15]=2[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(-c2nnc(Cl)nc2-c2ccc(OC)cc2)cc1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: COc1ccc(-c2nnc(C)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 11.7 g. (0.33 mole) of methyltriphenylphosphonium bromide in 150 ml. of dry tetrahydrofuran at -35° C. was added, over a 15-minute period, 20 ml. (0.033 mole) of n-butyl lithium. The reaction mixture was stirred for one hour. To the reaction mixture at -35° to -40° C. was added over a 10-minute period a solution of 5.7 g. (0.0165 mole) of 3-chloro-5,6-bis(4-methoxyphenyl)-1,2,4-triazine in 50 ml. of tetrahydrofuran. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. A solution of 1.05 g. (0.0165 mole) of sodium carbonate in 50 ml. of water was added dropwise to the reaction mixture which then was heated at reflux for three hours. The reaction mixture was cooled, poured over ice, and extracted with diethyl ether. The diethyl ether extract was washed with water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was chromatographed over silica gel, with three fractions being collected. After evaporation of solvent, the third fraction solidified, m.p. about 109°-113° C. The solid was identified as 5,6-bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine by nuclear magnetic resonance analysis, mass spectrographic analysis, and elemental microanalysis.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:46])[CH:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]([C:30]([C:32]3[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[O:34][C:33]=3[CH2:41][CH2:42][CH2:43][CH3:44])=[O:31])[CH3:29])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[Br:45])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CO>[Br:45][C:16]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]([C:30]([C:32]3[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[O:34][C:33]=3[CH2:41][CH2:42][CH2:43][CH3:44])=[O:31])[CH3:29])=[CH:23][CH:22]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:46])=[O:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)OC)c(Br)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)O)c(Br)c2)cc1
Yield: 92.4 %

Procedure:
1 N NaOH (2.28 mL, 2.28 mmol) was added under nitrogen to a solution of methyl2-[(3-bromo-4′-{[[(2-butyl-1-benzofuran-3-yl)carbonyl](methyl)amino]methyl}-1,1′-biphenyl-4-yl)oxy]-3-phenylpropanoate (995 mg, 1.52 mmol), prepared in the previous step, in 100 mL of methanol plus 10 mL of water. After the addition the reaction was refluxed for 5 h. The reaction was filtered, acidified with 2.5 mL of 1 N HCl and concentrated under reduced pressure to remove the methanol. The solid that was present was collected by filtration and dried under reduced pressure to give the title compound (900 mg, 92%) as a white solid, mp 79-86° C. Elemental Analysis for C36H34BrNO5Calc'd: C, 67.50; H, 5.35; N, 2.19. Found: C, 6 7.16; H, 5.42; N, 2.09
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@H:29]([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@H:29]([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: C[C@@H](N)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.54 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 257-2 (5.50 mmol, crude form) as starting materials, respectively 0.76 g (Isomer A, colorless powder) and 0.60 g (Isomer B, colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH2:26][OH:27])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.Br[CH2:29][C:30]([OH:32])=[O:31].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=2)[CH2:26][O:27][CH2:29][C:30]([OH:32])=[O:31])[CH:13]=1
Reactant: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(CO)c2)n1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(COCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 530.1 %

Procedure:
A solution of (3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-methanol (640 mg, 1.65 mmol) and bromo-acetic acid (0.25 g, 1.82 mmol) in N,N′-dimethylformamide (5 mL) is treated with sodium hydride (60%, 0.28 g, 6.94 mmol) at −30° C. The mixture is allowed to warm to room temperature over 1 hour, stirred for an additional 1 hour and quenched with water. The mixture is diluted with water, and washed with ether. The aqueous phase is acidified to pH 3.8 and the resulting solid is filtered and dried to give (3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzyloxy)-acetic acid [3.9 g, 53%, Example 56]. The filtrate is extracted with ethyl acetate, and the combined extracts are washed with water, dried over magnesium sulfate, and concentrated to afford additional quantity of (3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzyloxy)-acetic acid (0.43 g, Example 56). LCMS: RT=2.43 minutes, MS: 446 (M+H). IC50=0.6 nM