Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[N:11]/[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]>CO.O>[NH2:18][C:15]1[CH:14]=[CH:13][C:12](/[N:11]=[N:10]/[C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1
Reactant: CCN(CC)c1ccc(/N=N/c2ccc([N+](=O)[O-])cc2)cc1
Solvent: CO
Solvent: O
Product: CCN(CC)c1ccc(/N=N/c2ccc(N)cc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
56.7 g of N,N-diethyl-4-[(E)-(4-nitrophenyl)diazenyl]aniline (0.19 M) were slurried in 270 ml of methanol at 60° C. and a solution of 147 g of sodium hydrogen sulfide-1-hydrate (1.98 M) in 150 ml of water was added cautiously. Upon addition, the former thick suspension became more liquid and the reaction mixture boiled heavily. When addition was complete, it was stirred for 0.5 h at 60° C., then cooled to room temperature and 400 ml of ice-water were added. The resulting suspension was stirred for 10 min., thereafter the solids were filtered off and washed several times with warm water, giving almost pure N-{4-[(E)-(4-aminophenyl)diazenyl]phenyl}-N,N-diethylamine as red-orange solid, used without drying in the next step.
Reaction SMILES: O[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[Cl:23][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1C1(O)c2ccccc2-c2sccc21
Solvent: c1ccccc1
Product: Cc1ccccc1C1(Cl)c2ccccc2-c2sccc21

Procedure:
5.6 g (20 mmoles) of 4-hydroxy-4-(2-methyl-phenyl)-4H-indeno[1,2-b]thiophene were dissolved in 40 ml of absolute benzene, and 34 ml of thionyl chloride were added. The mixture was heated under reflux for 5 hours. The reaction solution was then evaporated in vacuo, the oily residue was taken up in cyclohexane, the insoluble material was filtered off and the clear filtrate was evaporated again in vacuo. 6.1 g of crude 4-chloro-4-(2-methyl-phenyl)-4H-indeno[1,2-b]thiophene were obtained as a viscous oil, which was further reacted directly. ##STR11##
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH:15]=[O:16].[CH3:17][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH:15]([OH:16])[CH3:17]
Reactant: O=Cc1cccc2cc(-c3nccs3)[nH]c12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 2-(1,3-thiazol-2-yl)-1H-indole-7-carbaldehyde (0.446 g) in anhydrous tetrahydrofuran (10 mL) was added 1.0 M methylmagnesium bromide (4 mL) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. Under ice-cooling, 1.0 M methylmagnesium bromide (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was ice-cooled, 1.0 M methylmagnesium bromide (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (0.090 g, yield 19%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34]([NH:36][C@@H:37]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:44][CH:43]=3)[C:38](O)=[O:39])=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>>[C:49]([O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C@H:37]([NH:36][C:34](=[O:35])[O:33][CH2:32][CH:30]2[C:31]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:38]([N:5]([CH2:6][CH:7]([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:4][C:3]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:2]=2[F:1])=[O:39])=[CH:47][CH:46]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(CNCc1ccc(F)cc1F)OCC
Product: CCOC(CN(Cc1ccc(F)cc1F)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Reaction time: 8 h
Yield: 36.8 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1 with the modification that the reaction was carried out overnight, N-(2,4-difluorobenzyl)-2,2-diethoxyethanamine (Compound IX-17) (49.3 g, 190 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (128.6 g, 280 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1) to obtain the title compound (49.0 g, 36%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:20][CH3:21].[Cl-].[Na+]>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:20][CH3:21])=[CH:13][C:12]=1[F:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCI
Reactant: Oc1ccc(OCc2ccccc2)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccccc2)c(F)c1
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
Sodium hydride (60% dispersion; 55 mg, 1.38 mmol) was added to a mixture of 4-benzyloxy-3-fluoro-phenol (Bionet Research, Camelford, Cornwall, UK; 250 mg, 1.15 mmol) in dimethylformamide (4 mL). After stirring for 15 min, iodoethane (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 215 mg, 1.38 mmol) was added and the reaction mixture was stirred overnight. Saturated sodium chloride was added to quench the reaction and the aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated ammonium chloride and saturated sodium carbonate, and then dried over sodium sulfate. The mixture was filtered, concentrated and purified by flash chromatography on silica gel, eluting with 5% ethyl acetate/hexane to give 1-benzyloxy-4-ethoxy-2-fluoro-benzene (270 mg, 96%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.26 (t, 3H, J=7.0 Hz), 3.93 (q, 2H, J=7.0 Hz), 5.07 (s, 2H), 6.62-6.67 (m, 1H), 6.82-6.87 (m, 1H), 7.11 (t, 1H, J=9.0 Hz), 7.31-7.42 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=1>CC(N(C)C)=O.O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: CSc1nccc(Cl)n1
Reactant: Nc1cc(O)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CSc1nccc(Oc2ccc(F)c(N)c2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
In DMA (10 mL) was placed 3-amino-4-fluorophenol (500 mg, 3.93 mmol), potassium t-butoxide (441 mg, 3.93 mmol) and 4-chloro-2-(methylthio)pyrimidine (632 mg, 3.93 mmol). The mixture was warmed to 50° C. and stirred overnight. The mixture was cooled to RT and diluted with water (30 mL), extracted with ethyl acetate (2×25 mL) and the combined organic phases washed with brine, dried (Na2SO4) and concentrated to yield a dark oil. The oil was purified by column chromatography to yield 2-fluoro-5-(2-(methylthio)pyrimidin-4-yloxy)benzenamine (841 mg, 85% yield) as an oil which was used without further purification. MS (ESI) m/z: 252.0 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][NH:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[CH2:31][C:32]3[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=3)[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(CBr)c1
Reactant: O[C@H]1CN[C@@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(CN2C[C@H](O)C[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a mixture of (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-4-ol (229 mg) and potassium carbonate (155 mg) in DMF (5 mL) was added ethyl 3-(bromomethyl)phenoxyacetate (245 mg) at 5° C. and stirred at the same temperature for 30 minutes then at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc, 1:2) to give ethyl 3-{[(2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidin-1-yl]methyl}phenoxyacetate (359.7 mg).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: Nc1cnc(C2=CCC3(CC2)OCCO3)cn1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(C2CCC3(CC2)OCCO3)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-amine (645 mg, 2.77 mmol) in a round bottom flask that was flushed with argon was added Pd—C 10% degaussa (294 mg, 0.277 mmol). Then under argon with syringe was added MeOH (10 mL) and then last a hydrogen balloon was added. The flask was evacuated and refilled with hydrogen (6 X). The reaction was stirred at room temperature for total of 16 h, under the hydrogen balloon, followed by LCMS. The reaction was flushed with argon and 25 mL of DCM was added. The crude mixture was filtered through a Celite plug, and concentrated to constant mass to give 635 mg of the desired product as free base, used as is (98% yield). LCMS (m/z): 236.2 (MH+), 0.41 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (d, J=1.2 Hz, 1H), 7.74 (d, J=1.2 Hz, 1H), 6.09 (s, 2H), 3.85 (s, 4H), 2.52-2.60 (m, 1H), 1.65-1.78 (m, 6H), 1.49-1.61 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:25](=[O:26])[CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: Cc1nc(-c2sc(NC(=O)Cc3cccs3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and thiophen-2-yl-acetyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:16][O:17][CH3:18])[C:9]([N:11]1[CH2:14][CH:13]([F:15])[CH2:12]1)=[O:10])(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:7][C@H:8]([CH2:16][O:17][CH3:18])[C:9]([N:11]1[CH2:14][CH:13]([F:15])[CH2:12]1)=[O:10]
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@@H](N)C(=O)N1CC(F)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 25 mL round-bottomed flask, [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (265 mg, 0.96 mmol) was dissolved in dichloromethane (5 ml). The reaction was cooled to 0° C. and trifluoroacetic acid (1.5 ml, 19.5 mmol) was slowly added. The reaction mixture was stirred at room temperature for 3 h then concentrated to provide (R)-2-amino-1-(3-fluoro-azetidin-1-yl)-3-methoxy-propan-1-one trifluoroacetate as a colorless viscous oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:24])=[O:23]
Reactant: OCCCc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCCc1ccc(Br)cc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirred solution of 3-(4-Bromophenyl)propan-1-ol (500 g, 2.30 mol) and diisopropylethylamine (312 g, 2.40 mol) in anhydrous dichloromethane (4 L) at 0˜5° C. was added dropwise methanesulphonyl chloride (280 g, 2.40 mol) slowly. After addition, the reaction mixture was stirred for 1 hour at 0˜5° C. The reaction mixture was washed with brine (1 L) twice. The organic phase was concentrated in vacuo to afford the subtitle compound (i) (667 g). HPLC Retention Time=1.353 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][O:13][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[CH2:35](O)[CH3:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][O:13][CH:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:15]([O:17][CH2:35][CH3:36])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-2-phenylacetic acid (8.0 g.) in ethanol (200 ml.) containing concentrated sulphuric acid (1 ml.) was heated under reflux for 90 minutes, then cooled to room temperature, and carefully neutralised by addition of an excess of saturated aqueous bicarbonate solution. The mixture obtained was evaporated and the residue extracted thoroughly with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and evaporated to give ethyl 2-[4-(4-chlorophenyl)benzyloxy]-2-phenylacetate (6.65 g.), m.p. 50°-51° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[OH:30][CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: CN(Cc1cc(-c2ccccc2)c(Br)s1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2ccccc2)c(C(O)c2ccccc2)s1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
A solution of tert-butyl [(5-bromo-4-phenyl-2-thienyl)methyl]methylcarbamate (1.0 g) in tetrahydrofuran was cooled to −78° C., and 1.6 mol/L n-butyllithium-hexane solution (1.96 mL) was added dropwise. After stirring at the same temperature for 1 hr, benzaldehyde (334 mg) in tetrahydrofuran (3 mL) was added dropwise. The mixture was gradually warmed to room temperature, and stirred for 2 hr. The reaction mixture was treated with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→9:1) to give the title compound as a pale-yellow oil (yield 607 mg, yield 57%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:14]1([S:20]([O:5][C:4]2[C:6]([O:7][CH3:8])=[CH:9][CH:10]=[CH:11][C:3]=2[CH:2]=[O:1])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc(C=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C=O)c1OS(=O)(=O)c1ccccc1
Yield: 76 %

Procedure:
o-Vanillin (350 g, 2.3 mols) was added to a solution of NaOH (166 g, 4.15 mols) in 2 l water. Benzenesulfonyl chloride (485 g, 2.74 mols) was added to the slurry at 20°-25° C. over 1 hour. The solid which formed was collected on a filter, washed with 2 l water, and redissolved in CH2Cl2. That solution was dried (MgSO4) and evaporated to a slurry. The solid was collected on a filter, the filtrate was further evaporated and filtered. The solid was washed with MeOH and dried in vacuo to afford the desired product, (511 g, 81.4%), mp 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.Cl.[NH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2g; 3.47 mmol) in THF (100 ml) was treated with tert-butyl 3-aminopropanoate hydrochloride (800 mg; 4.4 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11][NH2:12])[CH3:8]>C1C=CC=CC=1>[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11][NH:12][C:2]1[S:3][CH:4]=[N:5][N:6]=1)[CH3:8]
Reactant: Brc1nncs1
Reactant: CCOC(CN)OCC
Solvent: c1ccccc1
Product: CCOC(CNc1nncs1)OCC
Yield: 79.8 %

Procedure:
A solution of 2-bromo-1,3,4-thiadiazole (3.14 g.) and aminoacetaldehyde diethyl acetal (5.1 g.) in benzene (75 ml) was refluxed for 20 hours. After cooling, the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give oil (6.3 g.). The oil was purified by column chromatography on silica gel (120 g.) using benzene and then ethyl acetate as developing solvent to give (1,3,4-thiadiazol-2-yl)aminoacetaldehyde diethyl acetal (3.3 g.), mp 108° to 112° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][OH:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.Cl[Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35].O>CN(C)C=O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][O:20][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2cc(CO)ccc21
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1ccc2c(c1)cc(-c1ccccc1)n2S(=O)(=O)c1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-benzenesulfonyl-5-hydroxymethyl-2-phenylindole (171 mg) in N,N-dimethylformamide (2.4 mL) were added imidazole (128 mg) and chlorotriisopropylsilane (0.150 mL) under cooling with ice, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (221 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8](OS(C)(=O)=O)[C@@H:7]([NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:6]1)=[O:4].[C:24](#[N:26])C>[C-]#N.C([N+](CC)(CC)CC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([C:24]#[N:26])[CH:7]([NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:6]1)=[O:4]
Reactant: CC#N
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@H](OS(C)(=O)=O)C1
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Product: COC(=O)C1CC(C#N)C(NC(=O)c2ccc(Cl)s2)C1

Procedure:
A solution of (1R,3S,4R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methanesulfonyloxy-cyclopentanecarboxylic acid methyl ester (150 mg) in acetonitrile (5 ml) was treated with tetraethylammonium cyanide (74 mg) and heated to reflux for 4 hrs. The reaction mixture was concentrated. The crude product was isolated by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 95:5) to give 3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-cyano-cyclopentanecarboxylic acid methyl ester (100 mg) as light brown oil.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[O:8].[CH3:9][Mg]Br.C1COCC1>C(OCC)C>[CH3:9][C:2]1([OH:8])[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2
Reactant: C[Mg]Br
Reactant: O=C1CC2CCC1C2
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CC2CCC1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of bicyclo[2.2.1]heptan-2-one (25 g, 0.23 mol) in diethyl ether (250 mL) was added a solution of methylmagnesium bromide in THF (3 mol/L, 90 mL, 0.27 mol) over 1 h at 0° C. The reaction mixture was stirred for an additional 30 min as it was warmed to room temperature. Then the reaction was quenched with 40 mL saturated aqueous ammonium chloride solution. The resulting mixture was extracted with diethyl ether (3×80 mL). The organic layers were combined and concentrated to give the desired product (26 g, 0.205 mol, yield: 90%). 1H NMR (400 MHz, CDCl3) δ ppm 2.20 (s, 1H), 2.01 (s, 1H), 1.94 (s, 1H), 1.61-1.49 (m, 3H), 1.34-1.20 (m, 7H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: Nc1c(F)cccc1Cl
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3c(F)cccc3Cl)c2c2ccccc12
Yield: 69.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2-chloro-6-fluoroaniline (82 mg, 0.56 mmol) to provide 207 (101 mg, 69% yield) as a white solid. LC-MS (M+H=340, obsd.=340).