Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8]2)=[C:4]([Cl:16])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>CN(C=O)C.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8]2)=[C:4]([Cl:16])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc(Cl)c2[nH]c(C3CCCC3)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(C2CCCC2)nc2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
A mixture 2,6-dichloro-8-cyclopentyl-7H-purine (0.2 g, 0.78 mmol) and potassium carbonate (0.32 g, 2.34 mmol) was taken in DMF (2.5 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (0.38 g, 2.34 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 4 hours, diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine solution and dried over Na2SO4 and concentrated. The residue was purified by column chromatography to obtain 2,6-dichloro-8-cyclopentyl-7-(2-trimethylsilanyl-ethoxymethyl)-7H-purine (0.12 g, 40%) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:4]1
Reactant: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCNC1
Reactant: COC(=O)CBr
Product: COC(=O)CN1CCC(OC)(c2cccc(OCc3ccc4ccccc4c3)c2)C1

Procedure:
Using an analogous procedure to that described in Example 3, 3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine was reacted with methyl bromoacetate to give 3-methoxy-1-(methoxycarbonylmethyl)-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine in 33Z yield, m.p. 78°-80° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]([NH:11][C:12]1[S:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[C:15]([CH3:17])[N:16]=1)(=[O:10])[CH3:9].C(N(CC)CC)C>O1CCOCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:18]([C:14]1[S:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[N:16][C:15]=1[CH3:17])(=[O:19])=[O:20]
Reactant: OCCNCCO
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N(CCO)CCO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.2 %

Procedure:
To a stirred solution of diethanolamine (1.24 g, 11.8 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methyl-thiazole-5-sulfonyl chloride (1.0 g, 3.93 mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid bis-(2-hydroxy-ethyl)-amide (0.74 g, 58%) as a white solid. MS (ISP) 324.0 [(M+H)+]; mp 204° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH:22]1[CH2:24][CH2:23]1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2CC2)CC1

Procedure:
1-Tertbutoxycarbonylpiperazine (6a) (1.86 g, 10 mmol) was dissolved in dichloromethane (20 mL), and anhydrous potassium carbonate (829 mg, 6 mmol) was added. The dichloromethane solution of chloromethyl cyclopropane (7a) (1.1 mL, 12 mmol) was added dropwise, and reacted overnight at room temperature, after that, the reaction mixture was washed with water. The water layer was extracted with dichloromethane for twice, the organic phases were combined, washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, dried with anhydrous sodium sulfate. Column chromatography (petroleum ether:ethyl acetate 2:1) was performed to isolate white solid powder 1-tertbutoxycarbonyl-4-(cyclopropylmethyl)piperazine (7b), 2.01 g white solid (yield 79.0%). ESI-MS m/z calculated for: 240.18. found: 241.05 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])[CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:43](#[N:46])[CH:44]=[CH2:45]>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:6]1[CH:7]=[C:2]([CH:45]=[CH:44][C:43]#[N:46])[CH:3]=[N:4][CH:5]=1
Reactant: CN1CCC[C@H]1c1cncc(Br)c1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1c1cncc(C=CC#N)c1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A mixture of (S)-3-bromo-5-(1-methylpyrrolidin-2-yl)pyridine (preparation 1) (300 mg, 1.24 mmol), palladium (II) acetate (14 mg, 0.06 mmol), tri(o-tolyl)phosphine (75 mg, 0.25 mmol) and triethylamine (0.35 mL, 2.48 mmol) in MeCN (10 mL) was degassed by bubbling argon through. Acrylonitrile (0.12 mL, 1.87 mmol) was then added and the reaction mixture heated at reflux temperature for 18 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the solvents evaporated to give a brown solid. The crude product was purified by flash chromatography (2% [20% ammonia in MeOH] in DCM) to give the title compound as a red-brown oil (188 mg, 71%, mixture of cis and trans isomers).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][C:21](=[O:23])[CH3:22])[CH:3]=1.[BH4-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH:21]([OH:23])[CH3:22])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(C)O
Yield: 62.9 %

Procedure:
A mixture of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-propanon-1-yl)oxybenzamide (1.28 g, 3.7 mmoles) and sodium borohydride (80 mg, 2.1 mmoles) in absolute ethanol (15 ml) was refluxed for 30 minutes, followed by addition of another 50 mg (1.3 mmole) of sodium borohydride and reflux for 10 minutes. The mixture was acidified with 2N HCl and concentrated in vacuo. The residue was partitioned between water and ether, and the ether layer was discarded. The aqueous layer was made basic with Na2CO3 and the solid filtered off to give 0.80 g (77%) of the title compound mp 149°-150°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ 8.48 (bs, 1H); 8.16 (s, 1H); 6.28 (s, 1H); 4.4-3.4 (m, 7H); 2.64 (m, 6H); 1.26 (d, J=7.5 Hz, 3H); 1.08 (t, 3H).
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]=[C:21]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][N:22]1[CH2:38][C:39](O)=[O:40]>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([C:39](=[O:40])[CH2:38][N:22]2[CH2:23][CH2:24][C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:21]2=[O:20])[CH2:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-benzhydrylpiperidine (0.25 g, 1.00 mmol) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) under nitrogen. To the reaction was added N1-(ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (6.1 mg, 0.005 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.14-7.39 (m, 20H), 4.23-4.31 (m, 1H), 4.19 (d, J=16.5 Hz, 1H), 4.08 (d, J=16.3 Hz, 1H), 3.73-3.80 (m, 1H), 3.58 (d, J=11.0 Hz, 1H), 3.35 (t, J=6.7 Hz, 2H), 2.86-3.00 (m, 1H), 2.71 (t, J=6.5 Hz, 2H), 2.50-2.62 (m, 2H), 1.37-1.47 (m, 2H), 0.81-1.07 (m, 2H); MS (DCI+) m/z 529 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:22]([CH:23]=[CH2:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])[C:7](=[O:18])[CH:6]=1.[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]2)[CH2:28][O:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH:37][C:11](=[O:12])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]=[CH2:24])[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:33]2)[CH2:28][O:27]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 65.2 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.215 g, 0.64 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.153 g, 0.78 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.530 g, 1.20 mmol). The mixture was stirred at 0° C. and triethylamine (0.122 g, 1.21 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 10% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.214 g, 65%) as a white solid: HR-ES-MS m/z calculated for C27H33FN4O5 [M+H]+ 513.2508, observed 513.2505, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.45 (br. s., 1H), 1.49-1.67 (m, 1H), 1.67-1.84 (m, 1H), 3.73 (dd, J=8.4, 5.7 Hz, 1H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.04-4.18 (m, 2H), 4.23 (d, J=18.4 Hz, 1H), 4.35 (dq, J=6.0, 5.7 Hz, 1H), 4.60 (d, J=18.4 Hz, 1H), 4.81-4.93 (m, 1H), 4.91 (s, 1H), 5.52 (d, J=11.4 Hz, 1H), 6.00 (d, J=17.8 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 6.86 (dd, J=17.8, 11.4 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.42 (td, J=7.8, 1.2 Hz, 1H), 7.57-7.64 (m, 2H), 10.81 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][C:25]3=[O:36])[CH2:18][CH2:17]2)[CH:11]=[CH:10][C:9]=1[CH3:37])(C)(C)C.[ClH:39].C(OCC)(=O)C>>[ClH:39].[NH2:7][C:8]1[CH:13]=[C:12]([CH:11]=[CH:10][C:9]=1[CH3:37])[CH2:14][NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][C:25]2=[O:36])[CH2:18][CH2:17]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc(C)c(NC(=O)OC(C)(C)C)c4)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc(C)c(N)c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
To 0.28 g of tert-butyl(5-(((1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2-methylphenyl)carbamate, 30 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred at room temperature for 41 hours. The solvent was removed under reduced pressure, ethyl acetate was added and the resulting solid was filtered to give 0.26 g of (1-(2-(4-((3-amino-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one hydrochloride as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:21]([S:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=[O:23])[CH3:22]>O.C(OCC)(=O)C>[C:21]([S:24][CH2:25][CH2:26][C:27]([N:9]1[CH:10]([C:12]([OH:14])=[O:13])[CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)=[O:28])(=[O:23])[CH3:22]
Reactant: O=C(O)C1CC(c2ccccc2)=NN1
Reactant: CC(=O)SCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)SCCC(=O)N1N=C(c2ccccc2)CC1C(=O)O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
A suspension of 8.0 g of 4,5-dihydro-3-phenyl-1H-pyrazole-5-carboxylic acid in 200 ml of distilled water is treated slowly with 2.6 g of sodium carbonate. The solution is layered with 50 ml of ethyl acetate, cooled to 5° C. and treated with 7.0 g of 3-(acetylthio)propionyl chloride in 10 ml of ethyl acetate. The pH of the reaction mixture is maintained at 7.5-8.0 by the addition of concentrated sodium carbonate solution. The mixture is stirred at room temperature for 30 minutes. The ethyl acetate layer is then discarded and the aqueous layer is washed twice with fresh ethyl acetate. Using 6 N hydrochloric acid, the pH of the aqueous layer is adjusted to 2.5 and then it is extracted with two 100 ml portions of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to a point where precipitation begins. Cooling affords 10.6 g of the title compound, melting point 137°-139° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: COc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, white solid (55 mg, 64%), MS (ISP) m/z=346.5 [(M+H)+], mp 277° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[N:6]([CH2:13][CH2:14][CH3:15])[C:5]2=[O:16].C(Cl)([Cl:19])=O>>[Cl:19][C:7]1[N:6]([CH2:13][CH2:14][CH3:15])[C:5](=[O:16])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=1
Reactant: CCCn1c(=S)[nH]c2ccc(I)cc2c1=O
Reactant: O=C(Cl)Cl
Product: CCCn1c(Cl)nc2ccc(I)cc2c1=O

Procedure:
2,3-dihydro-6-iodo-3-propyl-2-thioxo-4(1H)-quinazolinone is reacted with phosgene to give 2-chloro-6-iodo-3-propyl-4(3H)-quinazolinone ; and
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH2:7]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2OC=1C(O)=O)[CH2:8][CH2:9][CH3:10].CN(C=O)C>C(Cl)Cl>[CH2:7]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:3][C:2]=1[C:1]([Cl:6])=[O:5])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1c(C(=O)O)oc2ccccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1c(C(=O)Cl)oc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl Chloride (3.86 mL, 44.2 mmol) was added under nitrogen at room temperature to a solution of 3-butyl-benzofuran-2-carboxylic acid (1.93 g, 8.84 mmol) in 60 mL of methylene chloride. After the addition a catalytic amount of DMF (10 μL) was added and the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. To remove the excess oxalyl chloride the residue was dissolved in benzene and the solvent removed under reduced pressure to give 3-butyl-benzofuran-2-carbonyl chloride, which was immediately used in step 2 without additional purification.
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].[CH2:6]([O:8][C:9]([C:11]1[C:12](Cl)=[N:13][C:14]2[C:18]([C:19]=1[Cl:20])=[CH:17][S:16][CH:15]=2)=[O:10])[CH3:7]>C(O)(=O)C>[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:3])[NH:13][C:14]2[C:18]([C:19]=1[Cl:20])=[CH:17][S:16][CH:15]=2)=[O:10])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1c(Cl)nc2cscc2c1Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(Cl)c2cscc2[nH]c1=O
Temperature: 140 °C
Yield: 97 %

Procedure:
Ammonium acetate (0.644 mg, 8.3 mmol) was added to a stirred solution of 5,7-dichloro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (38) (2.1 g, 7.6 mmol) in glacial acetic acid at room temperature. The solution was heated at 140° C. for 6 h. The hot solution was poured over ice. The solids formed were filtered, washed by water, and dried to yield 1.9 g (97%) of 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester as white solids. MP 157° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.2 Hz, 3H), 4.32 (q, J=7.2 Hz, 2H), 7.06 (d, J=3.6 Hz, 1H), 8.20 (d, J=3.2 Hz, 1H) ppm; MS m/z=258 amu (M++1).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:17]([C:7]1[N:8]([CH2:12][C:13]2[N:16]=[C:29]([C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=3)[O:15][N:14]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH2:18][CH3:19]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C
Yield: 41.4 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3-(trifluoromethyl)benzoyl chloride (0.256 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.061 g (41% yield) of pure product: MS (ES) m/z 478 (M+).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][Cl:27]>CC(C)=O>[Cl:27][CH:26]([O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1)[CH3:25]
Reactant: ClCCBr
Reactant: O=c1c2ccccc2sc2c(O)ccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Cl)Oc1ccc(O)c2sc3ccccc3c(=O)c12
Yield: 66.4 %

Procedure:
A solution of 120 mg of 1,4-dihydroxythioxanthone in 100 ml of acetone is stirred for 0.5 h at room temperature with 138 mg of potassium carbonate. A solution of 80 mg of 1-bromo-2-chloroethane in 5 ml of acetone is then added and the mixture refluxed for 24 h. The heterogeneous mixture is cooled, filtered, concentrated under reduced pressure and purified by silica gel column chromatography using a 1:1 mixture of hexanes and ethyl acetate to produce 100 mg of a yellow-red crystals (65%).
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH3:18])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22].CN(C)C1C=CC=CC=1>>[NH2:23][C:21]1[S:22][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH3:18])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:20]=1
Reactant: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1C)C(=O)CBr
Reactant: NC(N)=S
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1C)c1csc(N)n1
Yield: 45.9 %

Procedure:
Ethyl 4-bromo-(Z)-2-(trans-2-methylcyclohexyl-oxyimino)-3-oxobutyrate (2.5 g) was treated with thiourea (0.57 g) and N,N-dimethylaniline (0.95 ml) as described in Example 4d to give the title compound as a yellow gum (1.07 g) after silica gel chromatography. (Found: M+, 311.1297. C14H21N3O3S requires M, 311.1305); νmax (CH2Cl2) 3475, 3380, 1735, 1600 and 1525 cm-1 ; δH (CDCl3) 0.98 (3H, d, J 6 Hz), 1.35 (3H, t, J 7 Hz), ca 1.1-2.4 (9H, m), 3.84 (1H, m), 4.40 (2H, q, J 7 Hz), 5.88 (2H, broad s), 6.71 (1H, s).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16]C(=O)C)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[OH:16][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(O)c2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 18.5 g of 4-Acetoxy-naphthalene-2-carboxylic acid ethyl ester in 100 ml ethanol/water (9:1), 240 ml of a 1M NaOH was added and stirred for 2 days at RT. Then, the reaction mixture was acidified to pH 2 with diluted hydrochloric acid to precipitate the product. The product was then collected by filtration and dried reduced pressure. Yield: 13.7 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH2:8])[CH2:4][CH2:3]1.[CH2:9]([O:11][C:12]([C:14]1[C:19]([O:20][CH2:21][CH3:22])=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=[C:16]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](OC3C=CC=CC=3)=[O:37])=[CH:31][CH:30]=2)[N:15]=1)=[O:13])[CH3:10].CCN(CC)CC>O1CCOCC1>[CH2:9]([O:11][C:12]([C:14]1[C:19]([O:20][CH2:21][CH3:22])=[C:18]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:17]=[C:16]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:36]([NH:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:37])=[CH:33][CH:34]=2)[N:15]=1)=[O:13])[CH3:10]
Reactant: CN1CCN(N)CC1
Reactant: CCOC(=O)c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)NN3CCN(C)CC3)cc2)nc(N2CCOCC2)c1OCC
Yield: 45 %

Procedure:
4-methyl-piperazin-1-ylamine (0.52 ml, 2 eq.) was added to a stirred solution of 5-ethoxy-6-morpholin-4-yl-2-(4-phenoxycarbonylamino-phenyl)-pyrimidine-4-carboxylic acid ethyl ester (100 mg, 1 eq.) and Et3N (0.085 ml, 3 eq.) in dioxane (3 ml), the mixture was reacted at 80° C. overnight. The reaction mixture was concentrated, and purified by flash chromatography to give a product (49.2 mg, 45%).