Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([O:13]CC)=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C(O)C.O.O1CCOCC1.O.CCOCC>[C:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1c(C(=O)O)cnn1C(C)(C)C
Temperature: 40 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
In a mixture of ethanol:water:dioxane (1:1:1, 21 mL) was placed ethyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate (1.48 g, 7.04 mmol) and lithium hydroxide hydrate (886 mg, 21.12 mmol). The reaction was stirred at 40° C. for 3 hrs and then at RT overnight. The reaction was diluted with water (25 mL) and ether (25 mL). The ether layer was discarded and the aqueous phase made acidic (pH˜=4) with 1N HCl. The acidic phase was then extracted with ethyl acetate (2×25 mL) and the combined ethyl acetate layers were washed with brine, dried (Na2SO4), and evaporated at reduced pressure to give 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid as a white solid (1.12 g, 87% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.56 (s, 9 H), 2.67 (s, 3 H), 7.65 (s, 1 H), 12.13 (s, 1 H); MS (ESI) m/z: 183.0 (M++).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22].O>C(Cl)(Cl)Cl>[C:21]([NH:2][CH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9]1)(=[O:23])[CH3:22]
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](CNC(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl trans-4-(aminomethyl)cyclohexanecarboxylate hydrochloride (5.86 g) and triethylamine (12 mL) in chloroform (100 mL) is added dropwise acetyl chloride (2.69 g) under ice-cooling and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into water and the mixture is extracted with chloroform (×2). The combined extracts are washed successively with 10% HCl, saturated brine, a saturated sodium hydrogencarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=1:1→0:1) to give methyl trans-4-(acetylaminomethyl)cyclohexanecarboxylate (5.92 g, yield; 98%) as an amorphous powder. MS (APCI) m/z; 214 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:24])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5](O)=[O:6].S(Cl)([Cl:27])=O>C(OCC)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:24])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]([Cl:27])=[O:6]
Reactant: CCCCCCCCCCCCOc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1c(Cl)cc(C(=O)Cl)cc1Cl
Temperature: 60 °C

Procedure:
3,5-Dichloro-4-dodecyloxybenzoic acid (200 g, 0.533 mol) was suspended/dissolved in ethyl acetate (1000 mL) with DMF (0.5 mL) and thionyl chloride (194 mL, 2.66 mol). The mixture was then heated to 60° C. for 2.5 hrs. After this period the solution was cooled, concentrated under reduced pressure and co-evaporated with ethyl acetate (×1). The resulting oil was used as such in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1.C([O-])(=[O:12])C.[Na+]>C(O)(=O)C>[OH:12][C:2]1[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: CSc1ccc(Cl)nn1
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1ccc(O)nn1
Yield: 65.4 %

Procedure:
A solution of 96 g (0.6 mol) of 3-chloro-6-methylthiopyridazine and 98.4 g (1.2 mols) of sodium acetate in 500 ml of glacial acetic acid was boiled for 2 hours under reflux. The solvent was then distilled off in vacuo, the residue was triturated with water and the reaction product was filtered off. In this way, 55.8 g (65% of theory) of 3-hydroxy-6-methylthiopyridazine were obtained in the form of a beige powder of melting point 119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15](S(C)(=O)=O)[N:14]=[C:13]([C:21]([NH2:23])=[O:22])[CH:12]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].CN1CCOCC1>CS(C)=O>[CH2:24]([N:26]([CH2:27][CH3:28])[C:15]1[N:14]=[C:13]([C:21]([NH2:23])=[O:22])[CH:12]=[C:11]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH3:10])[N:16]=1)[CH3:25]
Reactant: COc1cccc(OC)c1-c1cc(C(N)=O)nc(S(C)(=O)=O)n1
Reactant: CCNCC
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: CCN(CC)c1nc(C(N)=O)cc(-c2c(OC)cccc2OC)n1
Temperature: 75 °C
Yield: 18 %

Procedure:
A 4 mL screw-cap vial was charged with a solution of 6-(2,6-dimethoxy-phenyl)-2-methanesulfonyl-pyrimidine-4-carboxylic acid amide (assumed 0.3 mmol) in DMSO (0.9 mL). A solution of diethylamine and N-methyl-morpholine (NMM) in DMSO (0.3 mL, 3 M in both, 0.9 mmol, 3 eq.) was added, and the sealed vial was heated at 75° C. for 22 hours. The mixture was then submitted for purification by preparative HPLC to afford 18 mg (18%) of the 2-diethylamino-6-(2,6-dimethoxy-phenyl)-pyrimidine-4-carboxylic acid amide. 1H NMR (300 MHz, CDCl3) □ 7.79 (br s, 1H), 7.30 (t, J=8.3 Hz, 1H), 7.26 (s, 1H), 6.61 (d, J=8.3 Hz, 2H), 6.16 (brs, 1H), 3.74 (s, 6H), 3.66 (q, J=6.9 Hz, 4H), 1.22 (t, J=6.9 Hz, 6H); HPLC ret. time 2.85 min., 10-100% CH3CN, 5 min gradient; ESI-MS m/z 330.2 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([N+:19]1[C:23](=[O:24])[C:22](=[C:25]2[N:29]([CH3:30])[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][S:26]2)[S:21][C:20]=1SC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:39][C:40]1[CH:49]=[CH:48][C:43]([NH:44][C:45](=[O:47])[CH3:46])=[CH:42][CH:41]=1>>[CH2:12]([N:19]1[C:23](=[O:24])[C:22](=[C:25]2[N:29]([CH3:30])[C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][S:26]2)[S:21][C:20]1=[N:39][C:40]1[CH:41]=[CH:42][C:43]([NH:44][C:45](=[O:47])[CH3:46])=[CH:48][CH:49]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CSC1=[N+](Cc2ccccc2)C(=O)C(=C2SC=C(c3ccccc3)N2C)S1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)Nc1ccc(N=C2SC(=C3SC=C(c4ccccc4)N3C)C(=O)N2Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 3′-benzyl-3-methyl-2′-methylthio-4′-oxo-4-phenyl-3H,4′H-[2,5′]bithiazolyliden-3′-ium p-toluenesulfonate and 4′-aminoacetanilide in a manner similar to that described in Example 1. 1H-NMR (CDCl3): δ 7.56 (2H, d), 7.42–7.47 (5H, m), 7.24–7.34 (5H, m), 7.12 (1H, s), 6.97 (2H, d), 6.30 (1H, s), 5.15 (2H, s), 3.49 (3H, s), 2.17 (3H, s); MS(ESI): 513 (MH+).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(=[O:18])C1C=CC=CC=1>[Pt]>[C:1]([OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Pt]
Agent: OO
Product: O=C(O)c1ccccc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 0.7 %

Procedure:
Platinum black (19.5 mg, 0.100 mmol) and benzyl alcohol (1.0 ml, 10 mmol) were mixed and stirred at 90° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (1.3 ml, 12 mmol) was gradually added dropwise to the mixed solution, followed by stirring at 90° C. for 15 hours, and then the reaction solution was cooled to room temperature. As a result of measurement by GLC, it was found that benzaldehyde was obtained in yield of 85%. Benzoic acid was obtained in yield of 0.7%.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]2[N:16]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:26]1[CH2:28][C@H:27]1[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>C(Cl)(Cl)Cl.CO>[CH:1]1([CH2:6][CH2:7][C:8]2[N:16]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH:23][CH2:28][CH:27]([OH:26])[CH2:29][O:30][C:31]4[C:39]5[NH:38][C:37](=[O:40])[NH:36][C:35]=5[CH:34]=[CH:33][CH:32]=4)=[CH:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]c2cccc(OC[C@@H]3CO3)c2[nH]1
Reactant: NCCc1ccc(-n2c(CCC3CCCC3)nc3cccnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1[nH]c2cccc(OCC(O)CNCCc3ccc(-n4c(CCC5CCCC5)nc5cccnc54)cc3)c2[nH]1
Yield: 8.7 %

Procedure:
4-[2-(2-Cyclopentylethyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethylamine (0.229 g, 0.68 mmol) was reacted with 4-[(2S)oxiranylmethoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.141 g, 0.68 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.032 g, 0.059 mmol).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Br:16])[CH:9]=2)=[O:4].[Na+].[NH2:19][CH2:20][C:21]([O-:23])=[O:22]>COCCO>[Br:16][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:4])[C:6](=[O:17])[O:7]2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2oc1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2ccc(Br)cc2oc1=O
Yield: 99.1 %

Procedure:
A mixture of 7-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (example 11-b) (2.835 g, 9.47 mmol) and glycine sodium salt (13.8 g, 142.12 mmol) in 2-methoxyethanol (100 mL) was refluxed for 6 h; then cooled, solvent was evaporated, the residue was dissolved in water and acidified with 2 M HCl solution; the precipitates were collected via filtration, washed with water and air dried to give the desired title product (3.209 g). 1H NMR (200 MHz, DMSO-d6): δ (ppm)=18-12 (br, 2H), 9.79 (br, 1H), 7.85 (d, 1H, J=8.4 Hz), 7.7-7.5 (m, 2H), 4.05 (d, 2H, J=5.6 Hz).
Reaction SMILES: [O:1]=[S:2]1(=[O:40])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:30][CH:29]([NH:31]C(OC(C)(C)C)=O)[C:25]4([CH2:28][O:27][CH2:26]4)[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:39])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[O:40]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:30][CH:29]([NH2:31])[C:25]4([CH2:26][O:27][CH2:28]4)[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:39])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC(NC(=O)OC(C)(C)C)C4(COC4)C3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC(N)C4(COC4)C3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
To a solution of tert-butyl 6-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-6-methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-carbamate (700 mg, 1.24 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL) at 0° C. The resulting mixture was stirred at room temperature for further 30 minutes. The reaction was quenched with a saturated aqueous solution of sodium carbonate, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 80 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=7.6 Hz, 1 H), 7.83 (d, J=7.6 Hz, 1 H), 7.79 (s, 1 H), 7.63 (m, 1 H), 7.52 (d, J=8.4 Hz, 1 H), 7.44 (m, 1 H), 7.35 (m, 1 H), 6.10 (s, 1 H), 5.17 (s, 2 H), 4.95 (d, J=6.8 Hz, 1 H), 4.68-4.62 (m, 3 H), 4.50 (brs, 2 H), 4.10 (d, J=8.8 Hz, 1 H), 3.91-3.81 (m, 3 H), 3.60 (m, 2 H), 3.45 (m 1 H), 2.41 (s, 3 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:17][O:18][CH2:19][CH2:20][NH:21][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: COCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COCCNc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 200 °C
Yield: 71 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 23 mg of 2-methoxyethanamine and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc:EtOH:NEt3=10:1:0.5 solvent mixture. N4-(2-Methoxyethyl)-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[CH2:11]=[O:12]>CS(C)=O.[OH-].[K+]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][OH:12])([O-:3])=[O:2]
Reactant: C=O
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1CCO
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 55.8 %

Procedure:
KOH (21 mg, 0.37 mmol) was added to a mixture of o-nitrotoluene (9.2 g, 67 mmol) and paraformaldehyde (0.8 g, 25 mmol) in DMSO (10 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å) which was then stirred for 2.5 h at 95° C. The solvent was removed and the residue purified by column chromatography (SiO2, 20×3 cm, solvent: toluene 750 ml, toluene/EtOAc 10:1 500 ml, 7:1 500 ml, 5:1 500 ml). 2-(2-nitrophenyl)ethanol (2.33 g, 21%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4](=[O:20])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([CH3:19])=[C:14]([C:16]([OH:18])=O)[S:15][C:9]=2[N:8]=[CH:7]1)[CH3:2].CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][N:43]([C:16]([C:14]3[S:15][C:9]4[N:8]=[CH:7][N:6]([CH2:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:21][CH3:22])=[O:20])[C:11](=[O:12])[C:10]=4[C:13]=3[CH3:19])=[O:18])[CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CCN(CC)C(=O)Cn1cnc2sc(C(=O)O)c(C)c2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)Cn1cnc2sc(C(=O)N3CCN(c4ccc(Cl)c(Cl)c4)CC3)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a mixture of 3-(2-(diethylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (0.12 g, 0.37 mmol) in DCM (5 mL) was added DIEA (0.2 mL, 1.1 mmol), 4(3,4-dichlorophenyl)piperazine (0.073 g, 0.37 mmol), and HATU (0.182 g, 0.48 mmol). The reaction mixture was stirred at RT overnight. The organic layer was diluted with CH2Cl2 and then washed with sat. NaHCO3 aq. (20 mL), dried over Na2SO4, and concentrated to give crude product as a gummy solid. Purification by flash column chromatography using a mixture of Et2O: DCM (1:1) as the eluant afforded the 0.092 g of 2-(6-(4-(3,4-dichlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxo thieno[2,3-d]pyrimidin-3(4H)-yl)-N,N-diethylacetamide, (yield: 50%).
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:8]=1)=[O:6])C.[Li+].[OH-].Cl>C1COCC1>[F:37][C:34]([F:35])([F:36])[O:33][C:30]1[CH:31]=[CH:32][C:27]([N:9]2[C:10]3[C:15](=[CH:14][C:13]([C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]([C:5](=[O:6])[C:4]([OH:38])=[O:3])=[CH:8]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(=O)c1cn(-c2ccc(OC(F)(F)F)cc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(-c2ccc(OC(F)(F)F)cc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reaction time: 5 h
Yield: 60.9 %

Procedure:
To a solution of 0.142 g [1,5-bis-(4-trifluoromethoxy-phenyl)-1H-indol-3-yl]-oxo-acetic acid ethyl ester from Step 3 in 1 mL THF was added 2 ml 0.5M aqueous LiOH. The reaction was mixed using orbital shaking for 5 hr, at which time TLC indicated that the reaction was complete. The solution was acidified by the dropwise addition of 2N aqueous HCl and extracted with dichloromethane. The organic phase was dried by filtration through a ChemElute column (Varian Inc., Palo Alto, Calif.) and the solvent was evaporated to afford 82 mg [1,5-Bis-(4-trifluoromethoxy-phenyl)-1H-indol-3-yl]-oxo-acetic acid as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 9.13 (s, 1H), 8.64 (s, 1H), 7.70 (d, J=6.6 Hz, 2H), 7.57-7.68 (m, 3H), 7.46-7.56 (m, 3H), 7.33 (d, J=8 Hz, 2H), MS: m/z (ESI) 508.2 (M−H);
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=O)=[C:4]([F:24])[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>N1C=CC=CC=1>[Cl:27][C:13]1[N:12]([C:5]2[CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=2[F:24])[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with phosphorus oxychloride and pyridine within 20 minutes at 30°-35° C. and thereafter for 1 hour at 70° C. there is obtained 2-chloro-1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 101°-103° C.;
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]1[S:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]#[N:14].N>>[NH2:6][C:7]1[S:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]([NH2:14])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: Cc1nsc(N)c1C#N
Agent: N
Product: Cc1nsc(N)c1C(N)=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a chilled solution of sulfuric acid (7.2 volumes, 12.9 equivs) was charged 5-amino-3-methylisothiazole-4-carbonitrile (method 4) (1.0 equiv). The temperature was maintained below 55° C. The reaction mixture was heated to 70° C. and held for 1 hour until TLC showed disappearance of starting material. The mixture was cooled to 60-65° C. before the ammonia (21 volumes) was charged to pH 10. The mixture was cooled to 20° C., aged overnight and filtered. The resulting solid was washed with dilute ammonia (3.6 volumes) and dried at 40° C. to give a pale brown solid (typical yield 80%).1H NMR (300 MHz, DMSO-d6) δ 2.46(s, 3H), 6.28 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.8 %

Procedure:
To a solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1 g, 4.29 mmol) in dichloromethane (50 ml) was added phenyl boronic acid (1.05 g, 8.6 mmol), pyridine (680 mg, 8.6 mmol) and copper(II) acetate (1.18 g, 6.5 mmol). The reaction mixture was stirred for 16 h at room temperature. Then, the reaction mixture was filtered through celite, concentrated and the residue was purified by flash chromatography (9:1 Hexane/EtOAc) to obtain 435 mg (33%) of 5-Phenyl-3-phenylamino-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.38 ppm (dd, 2H, Haro); 7.35-7.26 ppm (m, 5H, Haro); 7.19 ppm (s, 1H, Haro); 7.15 ppm (dd, 2H, Haro); 7.02 ppm (ddt, 1H, Haro); 3.82 ppm (s, 3H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[Br:18].Cl[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([C:2]([F:26])([F:1])[F:27])[CH:21]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[Br:18])[C:29](=[O:30])[O:31][CH3:32]
Reactant: COC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,5-bis(trifluoromethyl)benzyl](2-bromo-5-nitrobenzyl)amine from Step C (0.47 g, 1.0 mmol) in methylene chloride (20 ml) at room temperature, methyl chloroformate (0.12 ml, 1.54 mmol) and triethylamine (0.29 ml, 2.05 mmol) were added. The solution was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using 1:9 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 8.11 (m, 1H), 8.02 (dd, J=9.0, 2.5 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 4.67 (m, 4H), 3.89 (s, 3H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[Cl:10][S:11]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([OH:9])=[O:8])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1
Product: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 127.5 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Solid benzoic acid (50 g, 0.41 mol) in portions was added to chlorosulfonic acid (348.7 g, 200 mL, 3 mol) at room temperature. The reaction mixture was heated to 125-130° C. for 2 hr and was then poured into vigorously stirred crushed-ice (1000 g). After 30 min, the white solid was collected, washed with water (1 L) and air dried to give 72.5 g (80%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([CH2:49][CH2:50][O:51][CH3:52])(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[F:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([CH2:49][CH2:50][O:51][CH3:52])(=[O:47])=[O:48])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: COCCS(=O)(=O)Nc1cc(F)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COCCS(=O)(=O)Nc1cc(F)cc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 75.7 %

Procedure:
(S)—N-(3-Fluoro-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-methoxyethanesulfonamide (30 mg, 0.03 mmol, 78% purity) was treated with trifluoroacetic acid (600 μl, 7.79 mmol) and a solution of ammonia (7N in methanol, 600 μl, 4.20 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 14 mg (73% yield) of the title compound.