Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[BrH:10].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:10][CH:2]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5])[OH:1]
Reactant: OCC(CO)(CO)CO
Reactant: Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: OCC(CO)(CO)C(O)Br
Yield: 70 %

Procedure:
In a 2 liter, three-necked flask equipped with a reflux condenser and an addition funnel are placed 200 g pentaerythritol (1.47 mole) and 16 ml 48% hydrobromic acid in about 500 ml glacial acetic acid. The mixture is refluxed for about one-half hour until all pentaerythritol is dissolved. Then 170 ml 48% hydrobromic acid are added, followed by 310 ml acetic anhydride and the mixture is refluxed for 3 hours. Then, 94 ml 48% hydrobromic acid followed by 150 ml acetic anhydride are added and the mixture is refluxed for an additional 3 hours. The acetic acid is then removed as completely as possible on a rotary evaporator. Ethanol (95%, 750 ml) and 17 ml 48% hydrobromic acid are then added to the residue. The flask is equipped with 1 m Vigreux column and the azeotrope ethyl acetate/ethanol is slowly distilled off. When 500 ml distillate has been collected, an additional 750 ml 95% ethanol is added and the distillation is continued until about 400 ml is left over. After cooling, the precipitated pentaerythritol is filtered off. The solvent is evaporated and the residue is dissolved in water. The aqueous phase is extracted twice with carbon tetrachloride and twice with ether. The water is evaporated on the rotary evaporator and the last traces of water are removed by azeotropic distillation with toluene using a Dean-Stark trap. The solid is recrystalized from chloroform containing 10% acetonitrile. The first crop yielded 190 g monobromopentaerythritol. The total yield is 70%.
Reaction SMILES: [CH:1](O)([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.N[C:16](N)=[S:17].ClC[C:21]([OH:23])=[O:22].Br>>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:17][CH2:16][C:21]([OH:23])=[O:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: O=C(O)CCl
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Br
Product: O=C(O)CSC(c1ccccc1)c1ccccc1

Procedure:
U.S. Pat. No. 4,177,290 discloses an alternative process for the application on an industrial scale (scheme 2). Benzhydrol (5), thiourea (6) and 2-chloroacetic acid (7) are reacted in the presence of hydrobromic acid to obtain 2-[(diphenylmethyl)sulfenyl]acetic acid (8), which is oxidized with hydrogen peroxide to afford 2-[2-[(diphenylmethyl)sulfinyl]acetic acid (9). This is reacted with NaHCO3 and dimethyl sulfate and the resulting methyl ester (10) is converted to modafinil by treatment with ammonia.
Reaction SMILES: [NH2:1][C:2]([NH:4][C@H:5]([C:9]([N:11]1[CH2:19][C@H:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([CH:31]=[CH2:32])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:6]([CH3:8])[CH3:7])=[S:3].Br[CH2:34][C:35](=O)[CH2:36][CH2:37][CH:38]=[CH2:39]>O1CCOCC1>[CH2:36]([C:35]1[N:1]=[C:2]([NH:4][C@H:5]([C:9]([N:11]2[CH2:19][C@H:18]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([CH:31]=[CH2:32])[CH:29]=4)[CH:24]=[CH:23][N:22]=3)[CH2:17][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:6]([CH3:8])[CH3:7])[S:3][CH:34]=1)[CH2:37][CH:38]=[CH2:39]
Reactant: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(N)=S)C(C)C)C3)c2c1
Reactant: C=CCCC(=O)CBr
Solvent: C1COCCO1
Product: C=CCCc1csc(N[C@H](C(=O)N2C[C@H](Oc3nccc4ccc(C=C)cc34)C[C@H]2C(=O)OC)C(C)C)n1

Procedure:
A solution of thiourea from Step 3 and Intermediate 3 (1.5 eq) in dioxane was stirred at 65° C. for 1 h. The volatiles were then removed under reduced pressure and the residue was purified by SiO2 gel chromatography (DCM/MeOH=98/2) to give the title compound as a pale brown oil. MS (ES+) C29H34N4O4S requires: 534. Found: 535 (M+H+).
Reaction SMILES: [C:1]1([C@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Cl:15][C:16]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Cl:15][C:16]1[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:9][CH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10]
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: C[C@H](CN)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Yield: 45.4 %

Procedure:
To a solution of (S)-2-phenyl propylamine (0.5 g, 3.7 mmol) in dry dichloromethane was added acetic acid followed by 2-chloro-3-trifluoromethylbenzaldehyde (1.1 g, 5.5 mmol) and sodium triacetoxyborohydride (1.5 g, 7.4 mmol). After the resulting mixture was stirred for 1.5 h at RT water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified by column chromatograph (Ethyl acetate:Hexane/25:75) to give the title compound as an oil (0.55 g, 45%). MS (ESI) 327.6 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1.[CH3:20][NH:21][CH2:22][CH2:23][OH:24]>>[ClH:1].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:21]([CH3:20])[CH2:22][CH2:23][OH:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: CNCCO
Product: COc1ccc(-c2cc(N(C)CCO)c3ccccc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 201-204° C., and MS: m/e=309.2 (M+H+), was prepared from 4-chloro-2-(4-methoxy-phenyl)-quinoline and 2-(Methylamino)-ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:16](N)[CH2:17][NH2:18].[S]>>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[CH:8]([C:9]1[NH:18][CH2:17][CH2:16][N:10]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NCCN
Reactant: N#CC(c1ccc(Cl)cc1)c1nccs1
Agent: [S]
Product: Clc1ccc(C(C2=NCCN2)c2nccs2)cc1

Procedure:
Under a nitrogen atmosphere, heat (110°-115° C), under reflux conditions, a mixture containing 23.5 g. of α-p-chlorphenyl-2-thiazolylacetonitrile, 7 g. of ethylene diamine and 0.2 g. of sulphur for 3 hrs. Extract the black tarry product with 200 ml. of hot benzene, cool and wash the extract with 50 ml. of water. Treat the benzene extract with a cooled solution of 4 ml. of concentrated hydrochloric acid in 25 ml. of water and separate the dark aqueous phase from the benzene. Basify the water extract with sodium carbonate and extract the precipitated oil with two 100 ml. portions of ether. Dry the ether extract and evaporate the ether to obtain 2-[α-(2-thiazolyl)-p-chlorbenzyl]-imidazoline, a viscous red product which is dissolved in acetonitrile and converted to the maleate salt which melts at 145°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=C(c1ccc2[nH]ccc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1ccc2cc(C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a stirred solution of (4-(4-chlorophenoxy)piperidin-1-yl)(1H-indol-5-yl)methanone (80 mg, 0.23 mmol, Step-1 of Example 353) and sodium hydride (60% in oil, 27 mg, 1.13 mmol) in N,N-dimethylformamide (5 mL) was added tert-butyl (2-bromoethyl)carbamate (76 mg, 0.34 mmol) at room temperature. Then the mixture was stirred at 70° C. for 3 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water (30 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica-gel column chromatography (eluting with n-hexane/ethyl acetate=2/1) to give 112 mg (>99% yield) of the title compound as brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]#[N:12])[C:7](=[O:13])[C:6]=2[CH:14]=1.C([O:18][C:19](=[O:21])[CH3:20])(=O)C.S(=O)(=O)(O)O.[C:27]([OH:30])(=[O:29])[CH3:28]>[O-2].[O-2].[O-2].[Cr+6]>[C:27]([O:30][CH:1]([O:18][C:19](=[O:21])[CH3:20])[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]#[N:12])[C:7](=[O:13])[C:6]=2[CH:14]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2occ(C#N)c(=O)c2c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: CC(=O)OC(OC(C)=O)c1ccc2occ(C#N)c(=O)c2c1
Temperature: 0 °C

Procedure:
To a solution of 9.25 parts of 6-methyl-4-oxo-4H-1-benzopyran-3-carbonitrile in a mixture of 100 parts by volume of acetic acid, 100 parts by volume of acetic anhydride and 10 parts by volume of 97% sulfuric acid kept at 5°-10° C, there was added 15.5 parts of chromium trioxide over a period of 4 hours under stirring. The reaction mixture was poured into 1500 parts by volume of ice-water to give precipitates, which were collected by filtration, washed with water and recrystallized from ethanol. The procedure yielded 8.19 parts of 6-diacetoxymethyl-4-oxo-4H-1-benzopyran-3-carbonitrile as colorless needles. Melting point: 185°-186° C
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:35][C:33](=[O:34])[NH:32][CH:23]([C:22]2[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]([OH:28])=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1ccccc1Cl
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3Cl)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 130 °C
Reaction time: 48 h
Yield: 14.3 %

Procedure:
To a solution of 1-(2-chlorophenyl)-2-phenylethanone (100 mg, 0.43 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (91 mg, 0.43 mmol), and urea (60 mg, 1.29 mmol) in 10 mL of ethanol was added 0.2 mL of concentrated HCl solution. The mixture was stirred at 130° C. for 2 days, concentrated under reduced pressure, and purified by preparative HPLC (40-70% acetonitrile+0.1% trifluoroacetic acid in water, over 15 min.) to give Compound 51 (28.7 mg, yield 14.2%). 1H NMR (CD3OD 400 MHz): δ 7.43 (s, 1H), 7.19-7.04 (m, 5H), 6.79 (d, J=6.0 Hz, 3H), 6.72 (s, 2H), 5.23 (s, 1H), 3.88-3.85 (m, 2H), 1.81 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.2 [M+1]+.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH:47]=O.O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+]>ClCCCl>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([CH2:47][C:43]5[S:42][CH:46]=[CH:45][N:44]=5)[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(Cc2nccs2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in 1,2-dichloroethane (1 mL) was added triethylamine (14 μL, 0.1 mmol), 2-thiazole-carboxaldehyde (6.6 mg, 0.05 mmol) and sodium triacetoxylborohydride (10.6 mg, 0.05 mmol). The resulting mixture was stirred for 4 hours at ambient temperature before it was quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined extracts was washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvents, the residue was brought to a flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 2-methyl-1-(8-{2-[4-phenyl-1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]ethyl}-8-azabicyclo-[3.2.1]oct-3-yl)-1H-benzimidazole (23 mg, 87%). 1H NMR (300 MHz, CDCl3) δ 7.79-7.65 (m, 2H), 7.46-7.37 (m, 2H), 7.34-7.15 (m, 7H), 5.32 (br, 1H), 3.68 (s, 2H), 3.54 (br, 2H), 2.82-2.80 (m, 2H), 2.67 (s, 3H), 2.63-2.47 (m, 4H), 2.25 (br, 4H), 2.08-1.96 (m, 8H), 1.86 (br, 2H). HRMS m/z (M+H)+ calcd: 526.3004, obsd: 526.3008.
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][CH2:13][NH:12]2)[CH2:10][O:9]1.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH:27]2[CH2:30][N:29]([C:31]([C:33]3[O:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:36][N:37]=3)=[O:32])[CH2:28]2)[CH:23]=[CH:22][C:19]=1[CH:20]=O.C(N(CC)CC)C.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:10]1[C:11]2([CH2:15][CH2:14][CH2:13][N:12]2[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:26][CH:27]3[CH2:28][N:29]([C:31]([C:33]4[O:34][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[N:36][N:37]=4)=[O:32])[CH2:30]3)=[CH:25][C:18]=2[O:17][CH3:16])[CH2:8][O:9]1
Reactant: COc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Reactant: C1CNC2(C1)COC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1CN1CCCC12COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
2-Oxa-5-azaspiro[3.4]octane TFA salt (0.111 g, ca. 70%, 0.34 mmol) and 2-methoxy-4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.13 g, 0.34 mmol) were mixed in dichloromethane (2 ml). Triethylamine (0.1 ml, 0.72 mmol) was then added, followed by sodium triacetoxyhydroborate (0.145 g, 0.69 mmol). The mixture was stirred at ambient temperature overnight. LC-MS showed some remaining starting material. An additional amount of sodium triacetoxyhydroborate (0.11 g) was added and stirring was continued for 6 hours. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a colourless residue, which was was purified by preparative reverse-phase HPLC at pH 10 to give 0.113 g (69%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 1.58-1.66 (m, 2H), 2.07-2.12 (m, 2H), 2.55-2.58 (m, 2H), 3.81 (s, 3H), 3.88 (s, 2H), 4.08-4.12 (m, 1H), 4.44 (d, 2H), 4.54-4.58 (m, 1H), 4.64 (ddd, 1H), 4.79 (d, 2H), 5.10 (ddd, 1H), 5.19 (ddd, 1H), 6.42 (dd, 1H), 6.54 (d, 1H), 7.20 (d, 1H), 7.64-7.72 (m, 3H), 8.05-8.11 (m, 2H). MS (APCI+) m/z 477.2 [M+H]+, LC purity: 93%
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reaction time: 2 h
Yield: 87.5 %

Procedure:
(Bromomethyl)cyclopentane was obtained by the following procedure. A solution of commercially available cyclopentanemethanol (20 g) in dry pyridine (220 ml) was stirred at 0° while 4-toluenesulfonyl chloride (42 g) was added. The mixture was stirred at 0° for two hours, and was then held without stirring at 4° overnight. It was then poured into water and the product was extracted into dichloromethane. The dichloromethane extract was washed with 10% (w/v) HCl solution, water, and brine in succession, and was then dried (MgSO4) and evaporated. There was thus obtained the desired intermediate compound, cyclopentylmethyl (4-methylphenyl)sulfonate (44.42 g, 87% yield) as a clear oil. Without further purification, this material was dissolved in dry DMF (175 ml). Lithium bromide (45.5 g) was then added with stirring. The mixture was heated to 45° for three hours, and then cooled to room temperature. The mixture was then diluted with pentane (800 ml), and washed with water (800 ml). The water layer was extracted with an additional portion of pentane (200 ml) and was discarded. The combined pentane layers were washed with water (1000 ml), and brine (200 ml) in succession, and then dried (MgSO4). The solvent was distilled away at atmospheric pressure, and the residue was then vacuum distilled. The desired (bromomethyl)cyclopentane (23.64 g, 83% yield) was obtained as a colorless mobile oil, distilling at 54°-55° at a pressure of 2000 Pascals (15 Torr).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:5]([S:12][CH2:13][CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.COC(=O)[C@H](N)[C@H](SCC)C1C=CC=CC=1.C(N(CC)CC)C.FC1C=CC(C2C=CC(S(Cl)(=O)=O)=CC=2)=CC=1>C(Cl)Cl>[CH2:13]([S:12][C@H:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C@@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:3]([OH:32])=[O:2])[CH3:14]
Reactant: CCS[C@H](c1ccccc1)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1)C(=O)OC
Agent: CCS[C@H](c1ccccc1)[C@@H](N)C(=O)OC
Agent: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS[C@H](c1ccccc1)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2S,3R)-3-Ethylsulfanyl-2-(4′-fluoro-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid methyl ester. To a solution of (2S,3R)-2-amino-3-ethylsulfanyl-3-phenyl-propionic acid methyl ester 4a (49 mg, 0.20 mmol) in methylene chloride (2.0 mL) is added triethylamine (0.060 mL, 0.43 mmol) and 4′-fluoro-4-biphenylsulfonyl chloride (66 mg, 0.24 mmol). This mixture is stirred under argon overnight at room temperature. The reaction is diluted with methylene chloride and washed with 1.0 N aq. HCl. The aqueous layer is extracted with methylene chloride. The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel, 20% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
The reaction mixture of 1.0 g (6.4 mmoles) of 2-chloro-4-hydroxybenzaldehyde, 4.4 g (32 mmoles) of potassium carbonate, and 1.4 g (9.6 mmoles) of methyl iodide in 10 mL of N,N-dimethylformamide was stirred at 70° C. for 2 h and poured into ice water. The precipitate was filtered, washed with water, and dried at 40° C. in vacuum oven overnight to yield 750 mg (68%) of the title compound as a light pink solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.O>ClCCl>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=3)=[CH:22][CH:23]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: CCOC(=O)Cn1nc(Cc2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cn1nc(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc21
Yield: 31.4 %

Procedure:
220 mg (0.711 mmol) ethyl 2-[3-(4-aminobenzyl)-1H-indazol-1-yl]acetate was dissolved in 20 mL dichloromethane, and triethylamine 0.15 mL (1.08 mmol) was added. The system was placed in an ice bath, and 137 mg (0.78 mmol) p-chlorobenzoyl chloride was added slowly. Upon completion of addition, the reaction was monitored to be complete by TLC. Water was added, extracted with ethyl acetate, and separated by a preparative chromatography to obtain 100 mg a white solid, at a yield of 31.4%.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:33]=[CH:32][C:16]3[N:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:19][C:15]=3[CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:38][O:39][C:40](=[O:47])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]Br.O>CN(C)C=O>[CH3:38][O:39][C:40](=[O:47])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:34])[F:35])=[CH:4][CH:5]=1)(=[O:10])=[O:11])[C:13]1[CH:33]=[CH:32][C:16]2[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:19][C:15]=2[CH:14]=1
Reactant: COC(=O)CCCCCBr
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
150 mg of 4-(trifluoromethyl)-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 11 mg of sodium hydride and stirred for 30 minutes at 20° C. 88 mg of 6-bromohexanoic acid methyl ester was added, it was allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was digested with diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12](=O)[CH2:13][C:14]#[N:15].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][NH2:22])[CH3:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([NH:22][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])=[CH:13][C:14]#[N:15]
Reactant: N#CCC(=O)c1cc(C(F)(F)F)ccc1Cl
Reactant: CCOC(CN)OCC
Solvent: Cc1ccccc1
Product: CCOC(CNC(=CC#N)c1cc(C(F)(F)F)ccc1Cl)OCC

Procedure:
A mixture of 3-[2-chloro-5-(trifluoromethyl)phenyl]-3-oxopropanenitrile (1.2 g, 4.8 mmol), 2-aminoacetaldehyde diethyl acetal (0.77 mL, 5.3 mmol) and toluene (30 mL) was stirred under reflux for 5 h under nitrogen atmosphere in the Dean-Stark apparatus. The mixture was evaporated in vacuo and used in the next step without further purification.