Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:15]1([C@@H:21]2CCC[C@H:22]2[NH2:26])[CH:20]=[CH:19][CH:18]=CC=1>>[ClH:1].[C:2]1([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:22]2[CH2:21][CH2:15][CH2:20][CH2:19][CH2:18][NH:26]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCC[C@H]1c1ccccc1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Product: c1ccc([C@@H]2CCC[C@H]2N=C2CCCCCN2)cc1

Procedure:
Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride the appropriate molar equivalent amount of trans-2-phenylcyclopentylamine hydrochloride, M.P. 147°-149° C., the desired product was obtained, M.P. 192°-195° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[Si](C)(C)[CH3:13]>CO>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1cccc(I)c1
Solvent: CO
Product: COC(=O)c1cccc(I)c1
Temperature: 65 °C
Yield: 100.4 %

Procedure:
3-Iodobenzoic acid (10.0 g, 40.3 mmol) was placed in dry methanol (50 mL) under an argon atmosphere and was treated with chlorotrimethylsilane (15.4 mL, 0.12 mol). After heating at 65° C. for 4 h, the mixture was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water, the organic phase was washed twice with water, was dried (Na2SO4) and was evaporated to provide the titled compound as a white solid (10.6 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:15][CH:16]([CH3:25])[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1)=[O:18].[Cl-].[NH4+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:17]([OH:18])([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:16]([CH3:25])[CH3:15])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC(C)C(=O)c1cncnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O)(C#Cc1ccc(Cl)cc1)c1cncnc1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
1(4'-Chlorophenyl)ethyne (1.43g:0.01 mole) was dissolved in tetrahydrofuran (10 ml) under nitrogen and cooled to -35° C. Butyllithium was added (6.5 ml of 1.6M solution:0.0104 mole) causing the colour to change. The mixture was stirred for 1/2 hour during which time it thickened and the colour changed to pink (from purple). Addition of a solution of chlorotanium triisopropoxide (10.6 ml or a 1 molar solution:0.0106 mole) caused the colour to change to yellow and the mixture was stirred for 20 minutes. The mixture was cooled to -60° C. and a solution of 2-methyl 1(pyrimidin-5-yl)propan-1-one in tetrahydrofuran (10 ml) was added and the reaction mixture allowed to warm up to room temperature within the cold bath. A solution of ammonium chloride in water (20%) was added and the mixture filtered. The aqueous was extracted with ethyl acetate (×3), washed (with water then brine), dried and the solvent removed in vacuo. The product was passed through silica (in ether) and then titurated with pentane and ether (0.467g: off white solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.I[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)=[CH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cccs2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(-c3ccc(Cl)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution (15 ml) of 2-(4-chlorophenyl)thiophene (2.63 g) in tetrahydrofuran was added dropwise n-butyl lithium (1.6 M solution in hexane, 9.00 ml) under an argon atmosphere at −78° C. This mixed solution was heated to room temperature, and a solution (30 ml) of zinc chloride (2.04 g) in tetrahydrofuran was added. This mixture was stirred for 1 hr., and ethyl 4-iodobenzoate (1.16 ml) and tetrakis(triphenylphosphine)palladium (0.202 g) were added. This mixture was stirred overnight under an argon atmosphere, and poured into 0.5 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Ethanol (200 ml) was added to the residue, and the mixture was heated under reflux for 10 min. Insoluble materials were filtered off, and the filtrate was concentrated to give ethyl 4-[5-(4-chlorophenyl)-2-thienyl]benzoate (2.42 g, yield 45%) as a pale-green crystalline powder. melting point: 167–168° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-n2ccc3ccccc32)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 3.0 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added 1H-indole 48 mq, tripotassium phosphate 0.12 g, tris(dibenzylideneacetone)dipalladium(0) 8.0 mg, tri-tert-butylphosphine tetrafluoroborate 2.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.0 mg at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, tris(dibenzylideneacetone)dipalladium(0) 8.0 mg, tri-tert-butylphosphine tetrafluoroborate 2.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.0 mg were added to it, and it was heated and refluxed for 3 hours. After the reaction mixture was cooled to room temperature, tris(dibenzylideneacetone)dipalladium(0) 8.0 mg, tri-tert-butylphosphine tetrafluoroborate 2.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.0 mg were added to it, and it was heated and refluxed for 7 hours. After the reaction mixture was cooled to room temperature, toluene and 10% citric acid aqueous solution were added. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=5:1] to give tert-butyl 2-(4-fluoroanilino)-4-(1H-indol-1-yl)benzoate.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:33])=[C:22]([O:24]C(=O)C3C=CC=CC=3)[CH:23]=2)[N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:7][CH:6]=1)#[N:4]>O.CO>[F:33][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:11]([N:12]2[CH:13]=[N:14][N:15]=[CH:16]2)[C:8]2[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=2)=[CH:23][C:22]=1[OH:24]
Reactant: N#Cc1ccc(N(Cc2ccc(F)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(F)c(O)c2)n2cnnc2)cc1

Procedure:
A solution of sodium hydroxide (250 mg, 6.25 mmol) in water (5 mL) was added to a solution of benzoic acid 5-{[(4-cyano-phenyl)-[1,2,4]triazol-4-yl-amino]methyl}-2-fluoro-phenyl ester (CAB02147, 958 mg, 2.32 mmol) in methanol (10 mL). The solution was heated to reflux for 5 minutes and concentrated under reduced pressure. Water (10 mL) was added and the milky suspension was neutralised (pH 7-8) with 2N hydrochloric acid. The white precipitate was filtered off, washed with a small amount of water (5 mL) and dried under high vacuum. Yield: 476 mg (66%). 1H-NMR (400 MHz, d6-DMSO) δ=4.95 (s, 2H), 6.70 (ddd, J=11.4, 8.4, 2.4 Hz, 1H), 6.75 (d, J=9.0 Hz, 2H), 6.84 (dd, J=8.4, 2.4 Hz, 1H), 7.06 (dd, J=11.3, 8.4 Hz, 1H), 7.76 (d, J=9.0 Hz, 2H), 8.75 (s, 2H), 9.90 (s, 1H, —OH). LRMS (FAB+): 310.1 (100, [M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH3:12][O:13][C:14](=[O:18])[C@H:15](Cl)[CH3:16].[Cl-].[NH4+]>CN(C)C=O>[CH3:12][O:13][C:14](=[O:18])[C@@H:15]([O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=1)[CH3:16]
Reactant: COC(=O)[C@@H](C)Cl
Reactant: Nc1cc(O)ccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)Oc1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-4-fluorophenol (4.1 g) in N,N-dimethylformamide (15 mL) was added dropwise to a stirred suspension of sodium hydride (60% in oil, 1.3 g) in N,N-dimethylformamide (35 mL) at 0° C. The mixture was stirred a room temperature for 30 minutes, cooled 0° C. and then (R)-2-chloropropionic acid methyl ester (4.0 g) was added in one portion. The resulting mixture was stirred at room temperature overnight and then treated with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the combined extracts, washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 3:2 by volume) to give the mixture of title compounds as golden oil, 2.5 g.
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:17][CH2:18][CH3:19].[F:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1>O1CCCC1>[CH2:18]([CH:17]([C:29]([C:28]1[CH:38]=[CH:39][C:25]([F:24])=[CH:26][CH:27]=1)([C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[OH:30])[C:16]([O:21][CH2:22][CH3:23])=[O:20])[CH3:19]
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCCC(=O)OCC
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
Butyl lithium (65.7 mL of 2.1M solution, 138 mmol) was added to a solution of N-isopropylcyclohexylamine in 100 mL tetrahydrofuran at -20° C. After stirring for 1 hour and cooling to -40° C., ethyl butyrate (16.0 g, 138 mmol) was added. After stiring for an additional hour and further cooling to -70° C., 4,4'-difluorobenzophenone (15 g, 68.8 mmol) was added. The solution was stirred for 3 hours at -70° C., allowed to warm to 20° C. during the next 5 hours and stirred at 20° C. for 8 hours. The reaction was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried and concentrated in vacuo. The residue was crystallized from hexane to give 11.7 g of the title compound; m.p. =99°-101° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:35]=[CH:34][C:33]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26](=[O:36])[C:25]=3[CH:24]=2)[O:21][CH:22]=1>>[CH:24]1[C:25]2[C:26](=[O:36])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][C:23]=1[C:20]1[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:19]=1
Reactant: O=C1c2ccccc2-c2ccc(-c3nc(CCl)co3)cc21
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: O=C1c2ccccc2-c2ccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc21
Yield: 86 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(9-fluorenone-2-yl)oxazole to give 2-(9-fluorenone-2-yl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 86%. Recrystallization from ethanol gave yellow needles, mp 153-154° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([O:16][CH2:17][CH2:18][O:19][CH3:20])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].N1CCCCC1.C(O)(=O)C>C(O)(C)C>[C:12]([C:11](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])[C:10]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15])(=[O:13])[CH3:14]
Reactant: O=Cc1ccccc1F
Reactant: COCCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COCCOC(=O)C(=Cc1ccccc1F)C(C)=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
10 g (80 mmol) of 2-fluorobenzaldehyde are dissolved in 200 ml of isopropanol with 13 g (80 mmol) of 2-methoxyethyl acetoacetate. A freshly prepared solution of 1.0 ml of piperidine and 0.5 ml of glacial acetic acid in 10 ml of isopropanol is added to this solution and it is stirred overnight at 40° C. The mixture is concentrated, the residue is taken up in toluene, the solution is concentrated again and the residue is purified by filtration on 300 ml of silica gel (eluent: toluene/ethyl acetate 100:1-10:1) to give 15 g of the target compound as a yellow oil which is immediately reacted further.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[S:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)(=[O:22])=[O:21])(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21])=[CH:12]2
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1)N1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Temperature: 80 °C

Procedure:
The requisite 1-(5-chloroindol-2-ylsulphonyl)piperazine starting material was prepared as follows 1-(1-Benzenesulphonyl-5-chloroindol-2-ylsulphonyl)piperazine (4.15 g, 9.44 mmol) was treated with sodium hydroxide solution (32 ml of 2.5M), giving a yellow suspension. This was warmed to 80° C. with vigorous stirring and stirred for 45 mins, giving complete solution. The solution was cooled to ambient temperature and carefully treated with concentrated hydrochloric acid to pH 8; the resultant precipitate was filtered off, washed with water and dried to give 1-(5-chloroindol-2-ylsulphonyl)piperazine as a pale yellow solid, 1H NMR (d6DMSO) 2.75 ppm (m, 4H), 2.9 ppm (m, 4H), 7.0 ppm (s, 1H), 7.3 ppm (dd, 1H), 7.5 ppm (d, 1H), 7.8 ppm (d, 1H); MS (M+H)+ 300/302.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[CH3:21][O:20][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(=O)c1ccc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccccc2c1OCCO[Si](C)(C)C(C)(C)C
Yield: 94.6 %

Procedure:
To 5.2 g cesium carbonate and 1.6 g methyl 1-hydroxy-2-naphthoate in 10 ml abs. DMF was added 1.9 g (2-bromethoxy)-tert.butyldimethylsilane and the mixture was reacted for 4 h at 60-80° C. The reaction was poured unto ice and extracted with ethyl acetate twice. The combined organic layers were washed with aqueous sat. sodium hydrogen carbonate solution and brine, dried over magnesium sulphate and concentrated in vacuo to yield 2.7 g of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-naphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Al](C)C.[Cl:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C@H:32]1[CH2:36][CH2:35][O:34][C:33]1=[O:37].Cl>ClCCCl>[Cl:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C@@H:32]([CH2:36][CH2:35][OH:34])[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:6][N:7]=1)=[O:37]
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cn1
Reactant: O=C1OCC[C@@H]1N1CCc2c1ccc(F)c2Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cn1)[C@H](CCO)N1CCc2c1ccc(F)c2Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
Prepared using General Procedure 2. To a stirring suspension of the 6-amino-N-(thiazol-2-yl)pyridine-3-sulfonamide (92 mg, 0.36 mmol) and DCE (2.0 mL) under N2, at RT, was added 2 M trimethylaluminum in hexanes (0.18 mL, 0.36 mmol) dropwise over 5 minutes. The solution was stirred at ambient temperature for 30 minutes. To this solution was added, a solution of (S)-3-(4-chloro-5-fluoroindolin-1-yl)dihydrofuran-2(3H)-one (92 mg, 0.36 mmol) in DCE (1.0 mL) over 5 minutes. The solution was stirred at 70° C. for 19 hours. The solution was cooled to 0° C. and aqueous 1.0 M HCl was added dropwise. The organic portion was washed with 1.0 N aqueous HCl (2×5.0 mL) and evaporated to dryness under reduced pressure. The residue was purified via silica gel chromatography using 5%-10% MeOH in CH2Cl2 to obtain (S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-(5-(N-thiazol-2-ylsulfamoyl)pyridine-2-yl)butanamide (47 mg, 26%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][S:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20](=[O:25])[CH:19]4SC)[N:9]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][S:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20](=[O:25])[CH2:19]4)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CSC1C(=O)Nc2ccc(CN3N=C(c4ccc(Cl)cc4)CSC3=O)cc21
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Cc2cc(CN3N=C(c4ccc(Cl)cc4)CSC3=O)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Powdered zinc (18.09 mmoles) is added to a solution of the compound obtained in Step D (27.68 mmoles) in glacial acetic acid (350 ml). The reaction mixture is stirred overnight at ambient temperature and then filtered. The filtrate is concentrated and then brought to pH 8-9 with saturated aqueous sodium bicarbonate solution and sonicated for 5 minutes. The solid formed is filtered off and then recrystallised from ethanol to yield the title product.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:15]1=[O:23])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1C(C)C
Reactant: O=C1Cc2ccccc2N1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1C(C)C

Procedure:
2-Isopropylphenol was methylated and then formylated to give 3-isopropyl-4-methoxybenzaldehyde. 3-Isopropyl-4-methoxybenzaldehyde was condensed with 2-oxindole to give 0.3 g of 3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[N:22]=2)=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH:3][C:4]3[CH:5]=[CH:6][C:7]4[S:11][C:10]([CH3:12])=[N:9][C:8]=4[CH:13]=3)=[O:26])=[C:23]([CH3:30])[N:22]=2)=[CH:17][CH:16]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc2cc(NC(=O)c3ccc(-c4ccc(F)cc4)nc3C)ccc2s1

Procedure:
5-Amino-2-methylbenzothiazole dihydrochloride (98 mg, 0.41 mmol), 6-(4-fluorophenyl)-2-methylnicotinic acid (D3) (96 mg, 0.42 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (119 mg, 0.62 mmol) and 4-dimethylaminopyridine (25 mg, 0.21 mmol) in DCM (2 ml) were stirred at room temperature overnight. The reaction mixture was purified directly by column chromatography, eluting with a 0-10% MeOH/DCM gradient to give the title compound as a white solid. 1H NMR (400 MHz, DMSO) δ (ppm): 8.42 (d, 1H), 8.21 (dd, 2H), 8.02 (d, 1H), 7.98 (d, 1H), 7.94 (d, 1H), 7.71 (dd, 1H), 7.34 (t, 2H), 2.80 (s, 3H), 2.67 (s, 3H). MS(ES): MH+ 378, M−H+ 376.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][CH:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][NH:21]3)=[CH:16][CH:15]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[C:31]([N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([CH:12]([NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:13])[CH:23]=2)[CH2:18][CH2:19][CH2:20]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(NC(=O)C=Cc1ccccc1)c1ccc2c(c1)NCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2ccc(C(C)NC(=O)C=Cc3ccccc3)cc21

Procedure:
To a solution of 3-phenyl-N-[1-(1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]-acrylamide (Example 233) in CH2Cl2 at 0° C. was added triethylamine followed by acetyl chloride. Work up and flash chromatography provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([SH:14])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].I[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:18])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Sc1nccc(-c2ccc(Cl)cc2)n1
Agent: [K+]
Agent: [OH-]
Product: CSc1nccc(-c2ccc(Cl)cc2)n1
Reaction time: 0.5 h

Procedure:
4-(4-Chlorophenyl)pyrimidine-2-thiol (1.2 g, 5.39 mmol) was taken in 10 ml of an aqueous potassium hydroxide (0.453 g, 5.39 mmol) solution. Iodomethane (503 μl, 5.39 mmol) was added at ambient temperature and the reaction mixture was allowed to stir for 30 minutes. The resulting white solid was collected via filtration and washed with minimal water and hexanes to provide the title compound: EI-MS (m/z) 237 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[C:12]([CH3:19])[CH:13]=C(C#N)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([OH:23])(=[O:22])[CH3:21].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[C:12]([CH3:19])[CH:13]=[C:21]([C:20]([OH:23])=[O:22])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1cc(C#N)cc2c(-c3cccc(F)c3)n[nH]c12
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C(=O)O)cc2c(-c3cccc(F)c3)n[nH]c12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To 430 mg of 3-(3-fluorophenyl)-7-methyl-1H-indazole-5-carbonitrile were sequentially added 6.0 ml of glacial acetic acid, 2.0 ml of water and 2.0 ml of concentrated sulfuric acid, followed by stirring at 100° C. for one day. After standing to cool, the reaction mixture was diluted with 20 ml of water, and the resulting crystals were collected by filtration. The crystals were sequentially washed with water and diethyl ether, to give 360 mg of the title compound as colorless crystals.