Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][NH:24][C:25]([NH2:27])=[S:26]>O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1](=[N:23][NH:24][C:25]([NH2:27])=[S:26])([C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc(C(O)c2ccccc2)c1
Reactant: NNC(N)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: NC(=S)NN=C(c1ccccc1)c1cccc(C(O)c2ccccc2)c1
Reaction time: 48 h
Yield: 57.9 %

Procedure:
p-toluenesulfonic acid (0.007 g, 0.03 mmol) was added to a solution of 3-benzoyl benzhydrol 5 (0.396 g, 1.09 mmol) in anhydrous tetrahydrofuran (10 mL). After stirring at reflux for 10 min, thiosemicarbazide (0.199 g, 2.19 mmol) was added to the reaction mixture and stirred for 2 days under an inert atmosphere of nitrogen gas. After 2 days, tetrahydrofuran was removed under reduced pressure and water (50 mL) was added. The products were extracted with ethyl acetate (2×20 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 88:12 to 0:100) afforded 3-benzoyl benzhydrol thiosemicarbazone 6 (0.228 g, 0.631 mmol) as a white solid in a 57% yield. HRMS (ESI) calculated for C21H19N3OSH+ (M+H)+ 362.1321, found 362.1336.
Reaction SMILES: [Br:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5]CC)=O.[NH2:13][C:14]1[N:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O>[BrH:1].[CH2:11]([O:10][C:8]([C:2]1[N:24]2[CH:23]=[CH:22][CH:21]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]2=[N:13][C:3]=1[OH:5])=[O:9])[CH3:12]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CCOC(=O)c1cccnc1N
Solvent: CC(C)=O
Product: Br
Product: CCOC(=O)c1cccn2c(C(=O)OCC)c(O)nc12
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A mixture of diethyl bromomalonate (26 ml) and ethyl 2-aminonicotinate (13.3 g) was allowed to react at 80°-90° C. for 6 hours under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, and acetone (100 ml) was added thereto. The precipitated crystals were collected by filtration, affording 3,8-diethoxycarbonyl-2-hydroxy-imidazo[1,2-a]pyridine hydrobromide (9.98 g, yield 34.8%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:37]=[CH:36][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:35])[N:21]([N:30]=[C:31]4[CH2:34][CH2:33][CH2:32]4)[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Li+]>O1CCCC1.Cl>[CH2:1]([O:8][C:9]1[CH:37]=[CH:36][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:35])[N:21]([NH:30][CH:31]4[CH2:32][CH2:33][CH2:34]4)[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1N=C1CCC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1NC1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
The product of Example 304G (0.178 g, 0.35 mmol) in tetrahydrofuran (3 mL) at 0° C. was treated with methanol (0.025 mL, 0.70 mmol), followed by dropwise addition of a 2.0 M solution of lithium borohydride in tetrahydrofuran (0.260 mL, 0.52 mmol), stirred at 25° C. for one hour, and diluted with 1 N HCl. The resulting precipitate was filtered and dried. The solid was dissolved in tetrahydrofuran and absorbed onto silica gel by evaporating to dryness. The resulting silica was loaded onto a 2 g Alltech sep pack and eluted with dichloromethane to give the title compound (0.059 g, 33%). MS (ESI−) m/z 515 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55 (m, 1 H) 1.71 (m, 1 H) 2.04 (m, 4 H) 3.77 (m, 1 H) 5.26 (s, 2 H) 6.57 (d, J=5.15 Hz, 1 H) 7.45 (m, 8 H) 7.64 (d, J=9.56 Hz, 1 H) 7.88 (m, 1 H) 8.05 (d, J=8.46 Hz, 1 H) 8.17 (m, 1 H).
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[O:32]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][N:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]3[NH:24][C:25]4[CH2:30][CH2:29][N:28]([C:43]([C:42]5[CH:41]=[N:40][C:39]([O:32][C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=6)=[CH:47][CH:46]=5)=[O:44])[CH2:27][C:26]=4[N:31]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1)[CH3:5]
Reactant: O=C(O)c1ccc(Oc2ccccc2)nc1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(Oc5ccccc5)nc3)C4)n[nH]c2c1
Yield: 6.7 %

Procedure:
The title compound was prepared from 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) and 6-phenoxy-nicotinic acid (17 mg, 80 μmol) using the method of Example 1. The crude material was purified by HPLC Method A to afford 3.1 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[C:40]([O:42][C:43]([F:46])([F:45])[F:44])[CH:39]=[CH:38][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([O:31][CH3:32])[C:13]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]([O:28]CC)=[O:27])[CH2:22][CH2:21]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH2:33][C:34]([F:37])([F:36])[F:35])[CH:9]=1)=[O:7].[OH-].[Li+].Cl.CS(C)=O>O1CCOCC1>[Cl:1][C:2]1[CH:41]=[C:40]([O:42][C:43]([F:46])([F:44])[F:45])[CH:39]=[CH:38][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([O:31][CH3:32])[C:13]([N:20]3[CH2:21][CH2:22][CH:23]([C:26]([OH:28])=[O:27])[CH2:24][CH2:25]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH2:33][C:34]([F:37])([F:36])[F:35])[CH:9]=1)=[O:7]
Reactant: CCOC(=O)C1CCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4Cl)cn(CC(F)(F)F)c3c2OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3Cl)cn(CC(F)(F)F)c12
Temperature: 25 °C

Procedure:
40 mg (0.059 mmol) of the compound of Example 3 are dissolved in 2 ml of dioxane, and 293 μl (5 eq.) of a 1M solution of lithium hydroxide are added, and the mixture is stirred at RT until the reaction is complete (2 days). The reaction mixture is acidified with 1N hydrochloric acid, a little DMSO is added, and the entire crude solution is separated by preparative HPLC (method 5). 25 mg (65% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[C:5]=2/[C:16](/Cl)=N/O)[CH2:3][CH2:2]1.[CH3:20][O-:21].[Na+].C[OH:24]>C(OCC)(=O)C.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[C:5]=2[C:16]([O:21][CH3:20])=[O:24])[CH2:3][CH2:2]1
Reactant: C[O-]
Reactant: CO
Reactant: Cc1ccccc1-c1noc(C2CC2)c1/C(Cl)=N/O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(-c2ccccc2C)noc1C1CC1
Temperature: 0 °C

Procedure:
Methyl 3-cyclopropropyl-3-oxopropanoate (5.23 g, 36.8 mmol) and (Z)-5-cyclopropyl-N-hydroxy-3-(o-tolyl)isoxazole-4-carbimidoyl chloride (6.23 g, 36.8 mmol) were combined in anhydrous methanol (50 mL) and cooled to 0° C. under a nitrogen atmosphere. Sodium methoxide (25% in methanol, 11.0 mL, 44.2 mmol, 1.2 eq) was added dropwise and the mixture was allowed to warm to RT over 1 hour. The mixture was diluted with ethyl acetate (120 mL) and water (100 mL). The organic layer was separated and washed with brine (75 mL) then dried over magnesium sulfate and concentrated under vacuum. The oil was purified by column chromatography (SiO2, linear gradient, 0-100% ethyl acetate in hexanes) to afford the desired product. MS m/z 258.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH:10]([OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][O:14][S:17]([CH3:16])(=[O:19])=[O:18])[CH:10]([OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CN(Cc2ccccc2)CC1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CN(Cc2ccccc2)CC1O
Yield: 53.5 %

Procedure:
The known compound, 1-benzyl-3-hydroxy-4-hydroxymethylpyrrolidine [see J. Org. Chem., 30, 740 (1965)] (110 g) was allowed to react in chloroform with methanesulfonyl chloride (60.9 g) in the presence of triethylamine to yield 1-benzyl-3-hydroxy-4-methanesulfonyloxymethylpyrrolidine (81 g) as an oil.
Reaction SMILES: CS[CH:3]1[CH2:12][CH:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH2:10]2)[C:5](=O)[C:4]1=[CH:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[CH3:28][NH:29][NH2:30].O>C(O)C>[C:24]([O:23][C:21]([N:18]1[CH2:17][CH2:16][N:15]([C:14]2[C:4]3[CH2:3][CH2:12][C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]=3[N:29]([CH3:28])[N:30]=2)[CH2:20][CH2:19]1)=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: CSC1CC2CC=CC=C2C(=O)C1=CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CNN
Solvent: O
Solvent: CCO
Product: Cn1nc(N2CCN(C(=O)OC(C)(C)C)CC2)c2c1-c1ccccc1CC2
Yield: 11 %

Procedure:
2-(Methylthio(4-(tert-butyloxycarbonyl)piperazin 1-yl)methylene-4,5-dihydro-2H-naphthalen-1-one (3.2 g, 8.2 mmol) and methylhydrazine (5 ml) were kept in ethanol (30 ml) for four days. Water (150 ml) was added, and the mixture extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine, dried (MgSO4), evaporated in vacuo, and purified by flash chromatography, eluting with hexane:ethyl acetate (4:1 v/v) to give 3-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-4,5-dihydro-1-methyl-1H-benzo[g]indazole (342 mg, 11%) as a colourless oil; 1H NMR (360 MHz, CDCl3) δ 1.52 (9H, s, tBu), 2.67 (2H, t, J=7.3 Hz, CCH2CH2C), 2.94 (2H, t, J=7.3 Hz, CCH2CH2C), 3.15 (4H, t, J=5.1 Hz, NCH2), 3.61 (4H, t, J=5.1 Hz, NCH2), 4.15 (3H, s, Me), 7.22-7.34 (3H, m, ArH), 7.55 (1H, d, J=7.7 Hz, H-9). Iradiation at δ 4.15 gave a positive nOe to the doublet at δ 7.55, and the reverse; and 3-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-4,5-dihydro-2-methyl-2H-benzo[g]indazole (561 mg, 19%) as a white solid δ (360 MHz, CDCl3) 1.54 (9H, s, tBu), 2.86 (2H, t, J=7.8 Hz, CCH2CH2C), 2.95 (2H, t, J=7.8 Hz, CCH2CH2C), 3.08 (4H, t, J=4.9 Hz, NCH2), 3.60 (4H, t, J=4.9 Hz, NCH2), 7.20-7.30 (3H, m, ArH), 7.83 (1H, d, J=7.5 Hz, H-9).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]([Cl:25])=[CH:22][CH2:23]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:23][CH:22]=[C:21]([Cl:25])[Cl:20])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOc1c(C)cc(O)cc1Cl
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1c(C)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a mixture of 10 g of 3-chloro-4-methoxymethoxy-5-methylphenol, 7 g of potassium carbonate and 100 ml of N,N-dimethylformamide was added dropwise a solution of 8 g of 1,1,3-trichloro-1-propene dissolved in 30 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 200 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography, which afforded 14.1 g of 3-chloro-4-methoxymethoxy-5-methyl-1-(3,3-dichloro-2propenyloxy)benzene (91% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14](O)(=O)[CH2:15][CH3:16].Cl.C>O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:14]([CH2:15][CH3:16])=[N:1][C:2]=2[CH:7]=1
Reactant: CCC(=O)O
Reactant: Nc1cc(Cl)ccc1NCCCO
Agent: Cl
Solvent: O
Product: CCc1nc2cc(Cl)ccc2n1CCCO

Procedure:
A mixture of 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol, 20 parts of propanoic acid and 200 parts of a hydrochloric acid solution 4 N is stirred and refluxed for 3 hours. The reaction mixture is cooled, water and crushed ice are added and the whole is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with ammonium hydroxide. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 5-chloro-2-ethyl-1H-benzimidazole-1-propanol.
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[O:4].[NH2:6][C:7]1[C:8]([F:35])=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:30])=[C:21]([N:24]4[CH2:28]C[C@H:26](N)[CH2:25]4)[N:22]=3)[C:17](=[O:31])[C:16]([C:32]([OH:34])=[O:33])=[CH:15]2)[CH:10]=[CH:11][C:12]=1[F:13].[CH:36]([O:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]>C(O)=O>[CH:36]([O:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37].[NH2:6][C:7]1[C:8]([F:35])=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:30])=[C:21]([N:24]4[CH2:25][CH2:26][C@H:1]([NH:2][CH:3]=[O:4])[CH2:28]4)[N:22]=3)[C:17](=[O:31])[C:16]([C:32]([OH:34])=[O:33])=[CH:15]2)[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: Nc1c(F)ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N)C4)nc32)c1F
Reactant: CN(C)C=O
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: Nc1c(F)ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](NC=O)C4)nc32)c1F
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To 600 mg of N,N-dimethylformamide were added 210 mg of 1-(3-amino-2,4-difluorophenyl)-7-[(3S)-3-aminopyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 40 mg of formic acid. The solution was stirred at 120° C. for 1 hour. After 8 ml of diisopropyl ether was added and stirred, the solution was allowed to stand. The supernatant was decanted off. Then 2 ml of ethanol was added, and the solution was heated at reflux for 20 minutes and allowed to cool down. The precipitate was collected by filtration and washed with ethanol and then diisopropyl ether to give 180 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[N+:15]([O-])=O.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH3:1][O:2][C:3]1[C:4]([NH2:15])=[CH:5][CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:8]=1
Reactant: COc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1nc(N2CCOCC2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 4-(6-methoxy-5-nitropyridin-2-yl)morpholine (Preparation 81, 280 mg, 1.170 mmol) in EtOAc/EtOH (1:1, 10 ml) was added palladium on charcoal (10%, 100 mg). The flask was charged with hydrogen and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo to give the title compound (245 mg, 99%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C@@H:43]([CH2:51][CH3:52])[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:45])(=O)=O.O>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C@H:43]([CH2:51][CH3:52])[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:45])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Reactant: CCCCOC(=O)[C@H](CC)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCOC(=O)[C@@H](CC)Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1
Reaction time: 0.17 h
Yield: 104.4 %

Procedure:
To a solution of N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydrox ybenzylamine (530 mg) in acetonitrile (10 mL), potassium carbonate (272 mg) in a powder form was added at room temperature, and the resulting mixture was stirred for 10 minutes. The solution of n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate (587 mg) in acetonitrile (10 mL) prepared in Preparative Example 6 was added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, the mixture was extracted with toluene, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain a colorless oil (748 mg, 100%).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:13](=[C:14]2[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19]2)[C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCC(=O)O)cc2)CC(C)(C)C1
Yield: 76.8 %

Procedure:
The hydrolysis procedure described for 191 was followed. A solution of ethyl({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetate (220) (0.280 g, 0.66 mmol) in THF/EtOH (1:1, 10 mL) was treated with 1 N NaOH (5 ml, excess) at 70° C. for 1 h. Acid work-up and purification afforded 0.20 g (77%) of the title compound 221. mp 163-164° C. 1H NMR (300 MHz, CD3OD): δ 7.05 (d, J=8.1 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 2H), 4.46 (s, 2H), 2.99 (d, J=4.8 Hz, 4H), 1.30 (s, 2H), 0.94 (s, 12H). LCMS (ESI): m/z 393 (M−H)−.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][N:12]2[S:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])(=[O:17])=[O:16])=[CH:7][CH:6]=1)=[O:4].[OH-].[K+].O>CO.O1CCCC1>[CH3:26][O:25][C:19]1[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[S:15]([N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=2)[CH2:9][CH2:10][CH2:11]1)(=[O:16])=[O:17]
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(C)ccc1OC)CCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (35.09 g, 0.09 mol) in methanol (0.27 L) and tetrahydrofuran (95.00 mL) was treated with a 3N solution of KOH in water (93.00 mL, 0.28 mol) and stirred at room temperature for 18 hours, then at 45° C. for 2 hours. The organic solvents were evaporated and the residual aqueous slurry diluted with water (0.45 L) and cooled to 0° C. The mixture was set to pH 1 with HCl 3N (85.00 mL) and the precipitated solid was filtered and dried under vacuum. 1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was obtained as an off-white solid, 34.08 g (100%), MS (ISP): m/e=360.1 (M−H).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C(#N)C>[CH2:18]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:3][CH2:4]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=C1Cc2cc(N3CCNCC3)ccc2N1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C1Cc2cc(N3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.9 %

Procedure:
A mixture of 5-(1-piperazinyl)oxindol.hydrobromide (1.0 g), 1.2 g of benzyl chloride and 1.1 g of triethylamine in 20 ml of acetonitrile was stirred at room temperature for 6 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate and chloroform was removed. The residue was recrystallized from isopropyl alcohol to give 0.7 g of 5-(4-benzyl-1-piperazinyl)oxindol.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH2:12][CH:11]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=1.Cl.[CH3:24][C:25]1[N:26]=[C:27]([N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[C:28]2[CH:33]=[CH:32][S:31][C:29]=2[N:30]=1>CC(O)C.CS(C)=O>[OH:22][CH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][CH:11]([OH:10])[CH2:12][NH:40][CH:37]1[CH2:36][CH2:35][N:34]([C:27]2[C:28]3[CH:33]=[CH:32][S:31][C:29]=3[N:30]=[C:25]([CH3:24])[N:26]=2)[CH2:39][CH2:38]1
Reactant: Cc1nc(N2CCC(N)CC2)c2ccsc2n1
Reactant: OCc1cccc(OCC2CO2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1nc(N2CCC(NCC(O)COc3cccc(CO)c3)CC2)c2ccsc2n1
Yield: 20 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 1.2 eq. DIEA, 120° C., 90 h), using 150 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine HCl-salt to give the title compound with 20% yield upon purification by prep. HPLC (reversed phase) and subsequent by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:39]=[CH:38][C:30]([CH2:31][NH:32][C:33](=O)[CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:27]2[CH:39]=[CH:38][C:30]([CH2:31][NH:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COCCNCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
To a solution of N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzyl]-2-methoxy-acetamide (200 mg, 0.38 mmol) in anhydrous THF (10 mL) was added borane-methyl sulfide complex (2.0 M solution in THF, 1 mL, 2 mmol), and the reaction was stirred at reflux for 7 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc (50 mL) and water (50 mL), and then the organic layer was separated and washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (90:10 CH2Cl2/MeOH) to give 30 mg (15%) of the desired product. 1H-NMR (DMSO-d6) δ 8.79 (s, 1H), 8.42 (d, J=4.8 Hz, 2H), 7.61 to 7.46 (m, 7H), 7.06 (d, J=6.6 Hz, 2H), 6.84 (d, J=4.5 Hz, 2H), 6.44 (s, 1H), 3.85 (s, 2H), 3.49 (t, J=5.7 HZ, 2H), 3.29 (s, 3H), 2.81 (t, J=5.7 Hz, 2H), 1.31 (s, 9H); MS LC-MS [M+H]+=515, RT=2.02 min.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[C:3]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Sc1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: Clc1ncc(Br)c(Sc2ccccc2)n1

Procedure:
Using an analogous method to that described in Method 1, but starting from 5-bromo-2,4-dichloropyrimidine and thiophenol, the product was obtained. NMR: 7.6 (m, 5H), 8.8 (s, 1H).