Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O:18][C:19]1([CH3:34])[C:23]2=[N+:24]([O-:33])[C:25]3[C:30]([N+:31]([O-:32])=[C:22]2[CH2:21][O:20]1)=[CH:29][CH:28]=[CH:27][CH:26]=3>O>[OH:18][C:19]1([CH3:34])[C:23]2=[N+:24]([O-:33])[C:25]3[C:30]([N+:31]([O-:32])=[C:22]2[CH2:21][O:20]1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: COC1(C)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(O)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Temperature: 25 °C
Yield: 68 %

Procedure:
To a mixture of 1,500 ml. of acetone and 75 ml. of water, containing 3.78 g. (0.02 mol.) of 4-toluenesulfonic acid monohydrate, was added 63.6 g. (0.26 mol.) of 1-methoxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide. The reaction mixture was heated under reflux for 4.5 hours and then allowed to cool to ambient temperature. The solvent was removed by evaporation in vacuo, and the residue was washed with ether. This afforded 58.7 g. (98% yield) of crude product. The crude product was recrystallized from water with the aid of activated carbon, to give a 68% yield of product having m.p. 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][O:14][C:15]2[N:16]([CH3:28])[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)[CH:19]=2)[CH3:11])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][O:14][C:15]2[N:16]([CH3:28])[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[CH:19]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(OCCN(C)CCc3ccc(Cl)cc3)n(C)n2)cc1
Agent: BrB(Br)Br
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Solvent: ClCCl
Product: CN(CCOc1cc(-c2ccc(O)cc2)nn1C)CCc1ccc(Cl)cc1
Reaction time: 12 h
Yield: 66.2 %

Procedure:
1.8 g of 3-(2-[N-(2-(4-chlorophenyl)-ethyl)-N-methylamino]-ethyloxy}-5-(-4-methoxyphenyl)-2-methylpyrazole (see Example 24) were dissolved in 100 ml of dichloromethane. 10 ml of a 1 molar solution of boron tribromide in dichloromethane were added to the solution. The reaction mixture was allowed to stand for 12 hours and then placed in water and extracted with dichloromethane. The aqueous phase was separated, rendered alkaline and extracted three times with a mixture of dichloromethane and methanol, and the combined organic phases were dried and concentrated. The crude title compound obtained as an oil was purified by chromatography on silica gel using dichloromethane/methanol. The purified title compound was reacted in accordance with the method described in Example 4C) with an equimolar quantity of L-(+)-tartaric acid to form a salt, and the resulting salt was crystallized from a mixture of diethyl ether and isopropanol. 1.15 g of 3-{2-[N-(2-(4-chlorophenyl)-ethyl)-N-methylamino]-ethyloxy}-5-(4-hydroxyphenyl)-2-methylpyrazole x 1.3 hydrogen tartrate were obtained having a melting point of 90° to 91° C.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14](O)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:24]1([N:30]=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.Cl.CN.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH:30][CH3:24])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CN
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 10 h
Yield: 58.6 %

Procedure:
Boc-Asp(OBzl) (6.4 g) was dissolved in tetrahydrofuran (30 ml), added with dicyclohexylcarbodiimide (4.1 g), hydroxybenzotriazole (3.0 g), methylamine hydrochloride (2.0 g) and diisopropylethylamine (3.9 g) under ice cooling and stirred for 10 hours. Insolubles were removed from the mixture by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed with 10% aqueous solution of citric acid and saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. Then the ethyl acetate was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give Boc-Asp(OBzl)-NHMe (3.9 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:24][CH:23]=3)[C@H:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46]>O1CCCC1>[CH3:43][C:44]([CH3:49])([CH3:48])[C:45]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:24][CH:23]=3)[C@H:7]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1)=[O:46]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of (±)-cis-7-hydroxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-(4-(trifluoromethyl)-phenyl)chromane (2.41 g, 4.98 mmol), triethylamine (3.40 ml, 24.4 mmol), 2,2-dimethylpropanoyl chloride (3.0 ml, 24.4 mmol) and tetrahydrofuran (150 ml) was stirred at room temperature for 4 days. The mixture was filtered to remove inorganic solids, the filter plug being washed with a little extra tetrahydrofuran. The solvents were then evaporated to give a colourless amorphous solid, which was recrystallised from 4:1 ethanol/water (20 ml) to give the product as colourless needles.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH2:27][C:28](O)=[O:29]>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:29]
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)ccc1F)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.90-7.93 (m, 1H), 7.36 (ddd, J=9.0, 5.8, 3.2 Hz, 1H), 7.12-7.29 (m, 2H), 3.82-3.84 (m, 4H), 3.75 (s, 2H), 3.09-3.11 (m, 4H); MS (ESI+) M/Z 401 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][N:12]2[CH2:14][C@@H:15]([OH:18])[CH2:16][CH2:17][C@@H:11]2[CH2:10][N:9]1[C:19]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH2:1]([C@@H:8]1[CH2:13][N:12]2[CH2:14][C@@H:15]([O:18][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:16][CH2:17][C@@H:11]2[CH2:10][N:9]1[C:19](=[O:20])[C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](O)CN2C[C@H]1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CC[C@@H]2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccccc3)CN2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (3R,7S,9aR)-(3-benzyl-7-hydroxy-octahydropyrido[1,2-a]pyrazin-2-yl)-(3,5-bis(trifluoromethyl)phenyl)-methanone (3.3 g, prepared analogous to example 3 steps 1–8) in dichloromethane (100 mL) was added diisopropylethylamine (2.4 mL) and methanesulfonyl chloride (0.8 mL), at 5° C. The resulting mixture was stirred at room temperature for 15 min. and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 95:5) to afford methanesulfonic acid (3R,7S,9aR)-3-benzyl-2-(3,5-bis(trifluoromethyl)benzoyl)-octahydropyrido[1,2-a]pyrazin-7-yl ester (3.8 g). Rf 0.67 (CH2Cl2/MeOH 95:5) (intermediate 18).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:34][CH2:35][CH3:36])=[C:4]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:13]2[CH2:14][CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[O:17][C:12]=2[C:11]=1[CH2:24][CH2:25][CH3:26].S(OC)(O[CH3:41])(=O)=O.[OH-].[K+]>C1COCC1>[CH3:41][O:1][C:2]1[C:3]([CH2:34][CH2:35][CH3:36])=[C:4]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:13]2[CH2:14][CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[O:17][C:12]=2[C:11]=1[CH2:24][CH2:25][CH3:26]
Reactant: COS(=O)(=O)OC
Reactant: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(=O)NC)c1O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 33 (100 mg, 0.2 mmol), dimethyl sulfate (76 mg, 0.6 mmol), and potassium hydroxide (22 mg, 0.4 mmol) were added to about 15 ml of THF. The reaction mixture was stirred overnight at room temperature then washed with water and thoroughly extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Chromatography of the crude material on silica gel using 50/50 ethyl acetate/hexane as eluant gave the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C#N)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-cyanophenylboronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.78 min; Mass spectrum (ESI+): m/z=406 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH3:20][O:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH:25]3[CH2:32][C:33](O)=[O:34])[CH2:23]1)[CH2:29]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:20][O:21][C:22]12[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH:25]3[CH2:32][C:33]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:34])[CH2:31]1)[CH2:29]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: COC12CC3CC(C1)C(CC(=O)O)C(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC12CC3CC(C1)C(CC(=O)N1CC4CC[C@](C)(C1)C4(C)C)C(C3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 29.3 μl was added to a methylene chloride 1 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 33.7 mg and stirred at 0° C. for 30 min. 5-methoxy-2-adamantyl acetic acid 36.2 mg and WSC 40.3 mg were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 20.5 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(5-methoxy-2-adamantylacetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 3 ml solution of lithium aluminum hydride 7.4 mg and refluxed under heating for 1.5 hours. The reaction mixture was cooled, then water was added thereto and then insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=20:1-10:1) to obtain the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:26]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27]1.CCN=C=NCCCN(C)C>>[S:26]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:33])=[CH:27]1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)Cc1ccsc1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccsc4)c3)c2c1
Yield: 4.7 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with 3-thiopheneacetic acid (0.13 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 13 mg (5% yield) of the title compound. 1H NMR (DMSOd6) δ 13.4 (br s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.92 (d, 1H), 7.8-7.7 (m, 2H), 7.6 (d, 1H), 7.54-7.44 (m, 2H), 7.35 (m, 2H), 7.14 (m, 1H), 3.7 (s, 2H); ES-MS (m/z) 377 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:24][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.CC(N(C)C)=O.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[NH:16][C:15]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:33][CH2:31][CH3:32])=[O:35])=[CH:3][CH:4]=3)[NH:24][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Nc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Reactant: CCN=C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
300 mg (0.89 mmol) of 6-(4-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (see Stage 19.5), dissolved in 20 ml of abs. THF and 2 ml (3.56 mmol) of DMA are treated with 0.29 ml of ethyl isocyanate (FLUKA) with exclusion of moisture and heated under reflux until starting material is no longer present in the TLC (24 h). The reaction mixture is evaporated to dryness in vacuo and the crude product is chromatographed on silica gel, ethyl acetate/methanol being used as the eluent. Fractions which contain the desired product are combined and evaporated to dryness. The residue is dissolved in a little THF. The target compound is precipitated/crystallized by addition of n-hexane. Colorless crystals of 4-(3-chloroanilino)-6-(4-[N3-ethylureido]phenyl)-7H-pyrrolo[2,3-d]pyrimidine are obtained; m.p.>290° C., FAB-MS: (M+H)+=407.
Reaction SMILES: C1C=CC(C([S+]([O-])CC(N)=[O:17])C2C=CC=CC=2)=CC=1.[CH:20]([S:33][C:34]([OH:36])=[O:35])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:20]([S@@:33]([C:34]([OH:36])=[O:35])=[O:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)SC(c1ccccc1)c1ccccc1
Reactant: NC(=O)C[S+]([O-])C(c1ccccc1)c1ccccc1
Product: O=C(O)[S@@](=O)C(c1ccccc1)c1ccccc1

Procedure:
In another aspect, a method of preparing an (+)-(S)-enantiomer of modafinil is disclosed. The method includes subjecting benzhydrylsulfanyl carboxylic acid to an oxidation reaction using Beauveria bassiana to obtain (S)-benzhydrylsulfinyl carboxylic acid and subjecting the (S)-benzhydrylsulfinyl carboxylic acid to an amidation reaction using Bacillus subtilis to obtain (+)-(S)-modafinil.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]([C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:30](F)[CH:29]=4)[C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)#[N:8]>CS(C)=O.O>[C:7]([C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:30]([NH:20][C@H:19]5[CH2:27][CH2:26][C@H:1]([OH:4])[CH2:17][CH2:18]5)[CH:29]=4)[C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)#[N:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1N[C@H]1CC[C@H](O)CC1
Temperature: 90 °C

Procedure:
0.3 g of potassium carbonate and 1.68 g of 4-trans-aminocyclohexanol are successively added to a solution of 0.34 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate in 6 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 2 hours in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (75/25 by volume), so as to give 0.15 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzoate in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.CCCCCC.[CH3:33][O:34][C:35]1[C:40]([CH:41]=O)=[CH:39][N:38]=[C:37]2[N:43]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:44]=[CH:45][C:36]=12>C1COCC1>[CH3:33][O:34][C:35]1[C:40]([CH:41]=[CH2:2])=[CH:39][N:38]=[C:37]2[N:43]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:44]=[CH:45][C:36]=12
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1cnc2c(ccn2COCC[Si](C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
To a solution methyltriphenylphosphonium iodide (782 mg, 1.93 mmol) in dried THF (5 mL) was added 2.5 M n-BuLi in Hexane (0.74 mL, 1.85 mmol) at −78° C. After 10 minutes, 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (493 mg, 1.61 mmol) was added to the reaction mixture. The reaction mixture was warmed to room temperature spontaneously. After 2 hours, the reaction mixture was quenched with water and was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (5% to 15% Ethyl acetate/Hexane) as a solvent to afford title compound (371 mg, 76% yield). 1H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H), 7.27 (d, J=3.6 Hz, 1H), 7.07 (dd, J=11.4, 18 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 5.78 (d, J=18 Hz, 1H), 5.70 (s, 2H), 5.30 (d, J=11.4 Hz, 1H), 4.38 (s, 3H), 3.60 (t, J=8.4 Hz, 2H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H). MS m/z: 305 [M+1].
Reaction SMILES: [CH:1](=[C:3]1[C:7]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[O:17][CH2:18][C:19](O)=[O:20])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([CH3:25])[N:4]1[CH3:26])[CH3:2].[C:27]([NH:34][CH2:35][CH2:36][NH2:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[CH:1](=[C:3]1[C:7]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[O:17][CH2:18][C:19]([NH:37][CH2:36][CH2:35][NH:34][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:20])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([CH3:25])[N:4]1[CH3:26])[CH3:2]
Reactant: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(OCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(OCC(=O)NCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Product of Step 11 (0.11 g) was dissolved in acetonitrile (10 mL). To this, N-boc-ethylene diamine (0.1 g), HBTU (0.4 g), HOBT (0.15 g), and DIPEA (1 mL) were added. The reaction mixture was stirred at 25° C. for 1 hr and was evaporated under vacuum. Residue was dissolved in dichloromethane (300 mL) and was extracted with water (twice at 200 mL each). The organic layer was dried on anhydrous magnesium sulfate and was filtered and was evaporated. Crude product was loaded on a SNAP cartridge containing 100 g silica gel and eluted with a gradient of chloroform and methanol using the BIOTAGE® AB ISOLERA™ flash chromatography system. Fractions containing product were pooled and evaporated under vacuum to obtain Step 12 (0.13 g). 1H NMR (CDCl3): 1.25 δ (—CH—CH3 of isopropyl), 1.5 δ (9H, —(CH3)3 of N-boc) 1.8 δ (3H, ═CH—CH3 of ethylidene) 2.9 δ (3H, —N—(CH3)), 2.2, 2.3, 3.1 δ (1H, 1H, 1H —CH2-CH—CH3 of isopropyl), 3.3, 3.5 δ (2H, 2H, —N—CH2-CH2-N—), 4.4 δ (1H, ═CH—CH3 of ethylidene), 4.5 (2H, —O—CH2-C(O)—), 6.8-7.5 δ (9H, phenyl rings). Mass spectrometry: m/z=494 (M+H).