Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:15]=[CH:16][C:17]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1.[CH3:32]I.[Cl-].[NH4+]>C1COCC1.O.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH:15]=[CH:16][C:17]=1[B:18]1[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19]1
Reactant: CI
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (7.79 mL, 7.79 mmol) was added to methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (Intermediate 2-7; 2.2 g, 7.08 mmol) in THF (50 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 30 minutes. Next methyl iodide (0.530 mL, 8.50 mmol) was added and the reaction stirred for 30 minutes Ammonium chloride (satd) (50 mL) was added with vigorous stirring, ethyl acetate (100 mL) and water (50 mL) were added and the organic phase separated, washed with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.290 g, 56.1%) as a colourless oil.
Reaction SMILES: [Li+].[OH-].[CH2:3]([NH:5][C:6](=[O:48])[NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][N:23]=2)[N:20]([CH2:24][C:25]2[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=2)[CH:19]=[C:18]([C:31]([O:33]CC)=[O:32])[C:17]3=[O:36])=[C:10]([C:37]2[S:38][CH:39]=[C:40]([C:42]3[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=3)[N:41]=2)[CH:9]=1)[CH3:4].C1COCC1>CO>[CH2:3]([NH:5][C:6](=[O:48])[NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][N:23]=2)[N:20]([CH2:24][C:25]2[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=2)[CH:19]=[C:18]([C:31]([OH:33])=[O:32])[C:17]3=[O:36])=[C:10]([C:37]2[S:38][CH:39]=[C:40]([C:42]3[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=3)[N:41]=2)[CH:9]=1)[CH3:4]
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(-c2cc3c(=O)c(C(=O)OCC)cn(Cc4cn(C)cn4)c3cn2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(-c2cc3c(=O)c(C(=O)O)cn(Cc4cn(C)cn4)c3cn2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2N LiOH (1 mL) was added to a mixture of ethyl 6-(6-(3-ethylureido)-4-(4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-3-yl)-1-((1-methyl-1H-imidazol-4-yl)methyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate, 86.3 mg, 0.14 mmol) in MeOH (imp and THF (1 mL). The resulting solution was stirred at room temperature for two hours. The solvent was removed and the residue was diluted with water and acidified with 1N HCl. The precipitated product was collected by filtration and washed with water and dried (60 mg).
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.[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][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:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: CCOC(=O)CCCN
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
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 ethyl 4-aminobutanoate (720 mg; 4.34 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: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.Br[C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:22][C:23]=3[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: FC(F)(F)c1ccc(-c2ccco2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1-c1ccc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution (25 ml) of 2-(4-trifluoromethylphenyl)furan (3.18 g) in tetrahydrofuran was added dropwise n-butyl lithium (1.6 M solution in hexane, 10.0 ml) under an argon atmosphere at −78° C. This mixed solution was heated to room temperature, and a solution (30 ml) of zinc chloride (2.25 g) in tetrahydrofuran was added. This mixture was stirred for 1 hr., and then ethyl 2-bromobenzoate (2.38 ml) and tetrakis (triphenylphosphine)palladium (0.433 g) were added. This mixture was stirred overnight under an argon atmosphere, and then 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. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1, volume ratio) to give ethyl 2-[5-(4-trifluoromethylphenyl)-2-furyl]benzoate (2.54 g, yield 47%) as a pale-yellow oil. NMR (CDCl3) δ: 1.12 (3H, t, J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 6.70 (1H, d, J=3.6 Hz), 6.87 (1H, d, J=3.6 Hz), 7.41 (1H, dt, J=1.4, 7.4 Hz), 7.53 (1H, dt, J=1.4, 7.4 Hz), 7.61–7.79 (6H, m).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH2:8]([O:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[SH:22])[CH2:9][CH3:10].Br[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1>O>[CH2:8]([O:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[S:22][CH:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)[CH2:28][CH2:29]1)[CH2:9][CH3:10]
Reactant: FC(F)(F)c1ccc(N2CCC(Br)CC2)nc1
Reactant: CCCOc1cc(C(F)(F)F)ccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cc(C(F)(F)F)ccc1SC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After 60% sodium hydride was added, with chilling on ice, to the DMF (7 ml) solution of the chemical compound (46) (0.62 g), it was warmed to room temperature, and was then stirred for 30 minutes. After the chemical compound (48) (0.74 g) was added to the mixture, it was heated to 100° C., and was then stirred for 1 hour. After the mixture was cooled, it was poured into water, and was then subjected to extraction with ethyl acetate. After its organic layer was washed with water, and was then dried with anhydrous magnesium sulfate, it was filtered, and was then concentrated under reduced pressure. Its residue was purified by column chromatography to produce the chemical compound mentioned in the above title (0.90 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Li]CCCC.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[C:19]([Si:16]([CH3:18])([CH3:17])[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]2[CH:10]=[CH:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1ccc2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a −78° C. solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (prepared as described in WO03/082289, 1.44 g, 9.47 mmol) in THF (75 ml) was slowly added a 1.4 M solution of n-BuLi in THF (7.4 ml). The resulting mixture was stirred for 10 minutes, and then tert-butyl-dimethylsilyl chloride (1.4 g, 9.47 mmol) was added to the mixture. The reaction mixture was warm to RT overnight and partitioned between H2O and EtOAc. The organic layer was separated, washed with brine, dried, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 1-(tert-Butyl-dimethyl-silanyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine as a clear oil (2.0 g, 62% yield).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21]>>[CH2:20]([S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21]
Reactant: CCS(=O)(=O)c1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CCS(=O)(=O)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-ethylsulfonylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-ethylsulfonylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]1[O:18][C:14]([CH3:13])=[CH:15][CH:16]=1)=[N:7]2
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1

Procedure:
5-Bromo-2-chloroquinoline (CAS 99455, 2.2 g, 9 mmol) and 5-methyl-2-furanmethanamine (2.2 g, 20 mmol) were stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). (5-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine was obtained as a light brown solid (2.67 g, 92%), MS: m/e =317.1 and 319.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[N:47]([CH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1)=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:48]([NH:47][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])[CH2:41]1)=[O:39]
Reactant: O=C=NC1CCCC1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCN(C(=O)NC2CCCC2)C1
Yield: 58 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 58% yield. LCMS for C30H35ClN7O2 (M+H)+: m/z=560.2.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([C:14](=[O:22])[CH2:15][NH:16][C:17]([CH2:20][CH3:21])([CH3:19])[CH3:18])=[CH:6][C:5]=1[Cl:23].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:7]([CH:14]([OH:22])[CH2:15][NH:16][C:17]([CH2:20][CH3:21])([CH3:19])[CH3:18])=[CH:6][C:5]=1[Cl:23]
Reactant: CCC(C)(C)NCC(=O)c1cc(Cl)c(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CCC(C)(C)NCC(O)c1cc(Cl)c(N)c(C(F)(F)F)c1

Procedure:
m.p. of the hydrochloride: 176°-178° C. (decomp.), was prepared from 4'-amino-3'-chloro-2-tert.pentylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)c1ccc(OCCCCl)cc1
Reaction time: 1.5 h
Yield: 99 %

Procedure:
A mixture of 37.6 g (0.25 mole) of 4'-hydroxypropiophenone (97%)*, 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.5 g (0.75 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 18 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure. The oily residue was dissolved in 500 ml of benzene and the solution stirred with potassium hydroxide pellets for 1.5 hr to remove unreacted phenol. The mixture was filtered and the filtrate was concentrated to give 56.1 g (99% yield) of title compound as an oil. The oil gradually crystallized and a portion of the solid was recrystallized from petroleum ether (60°-110° C.) to yield title compound as a fluffy, white solid, mp 41°-43° C.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:28])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[C:17]=2[F:27])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:27][C:17]1[C:18]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(OC(F)(F)F)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ((1R,3S,5R)-3-(2-fluoro-3-trifluoromethoxy-phenylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (2.56 g, 6.33 mmol) in CH2Cl2 (20 mL) was added TFA (10 mL, 130 mmol) and the solution was stirred at RT for 16 h. CH2Cl2 was concentrated, the residue was suspended in MeOH, concentrated again and dried under high vacuum to give the desired material which was used without further purification in the next step. MS: 305 [M+H]+; tR (HPLC conditions c): 3.55 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33]CC)[CH:27]=4)[CH2:23][CH2:22][C:21]([C:36]([O:38]C)=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl.[O:45]1CCC[CH2:46]1>CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[C:28]([O:32][CH3:33])[CH:29]=[CH:30][C:31]=4[O:45][CH3:46])[CH2:23][CH2:22][C:21]([C:36]([OH:38])=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cccc(OCCC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cc(OC)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (290 mg) in a mixture of tetrahydrofuran (21 ml) and methanol (21 ml) was added 1N sodium hydroxide solution (7 ml), and the mixture was stirred at room temperature for 4 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (237 mg) as yellow crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][CH:33]=1)[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:17]=1)=[O:15])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>CN(C)C=O>[CH2:34]([N:10]([C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][CH:33]=1)[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:14][C:13]2[CH:31]=[CH:32][CH:33]=[CH:11][CH:12]=2)=[O:29])[CH:17]=1)=[O:15])[C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)c2cn(CCCC(=O)O)c3ccccc23)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(C(=O)c2cn(CCCC(=O)OCc3ccccc3)c3ccccc23)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
60% Sodium hydride in mineral oil (0.13 g) was added to a solution of 4-[3-(3-tert-butoxycarbonylaminobenzoyl)indol-1-yl]butyric acid (0.47 g) in N,N-dimethylformamide (7 ml). The mixture was stirred at 0° C. for 1 hour. Benzyl bromide (0.95 g) was added to the mixture and the ixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and 0.5N-hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (30 g) eluting with a mixture of n-hexane and ethyl acetate (5:1) to give benzyl 4-[3-[3-(N-benzyl-N-tert-butoxycarbonylamino)benzoyl]indol-1-yl]butyrate (325 mg) as an oil.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].O.Cl>C(OCC)(=O)C.C(O)C.[OH-].[K+]>[CH2:1]([S:3][CH2:4][CH:5]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CSCC)CC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCSCC(CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101.9 %

Procedure:
650 mg of ethyl 2-ethylthiomethyl-4-methylpentanoate was dissolved in 6 ml of an ethanol/water (10/1) solution, 8.9 ml of an ethanol/water (10/1) solution of 2N potassium hydroxide was added thereto. The solution was stirred at room temperature for 2.5 hours, and then, the reaction solution was distilled off under reduced pressure to obtain a suspension. To this suspension, 40 ml of water was added, and the reaction solution was adjusted to pH2 with 2N hydrochloric acid under cooling with ice, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 577 mg of 2-ethylthiomethyl-4-methylpentanoic acid as colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2.[NH:26]1[CH:30]=[CH:29][C:28](B(O)O)=[N:27]1.C(=O)(O)[O-].[Na+].O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:22]([NH:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([N:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:30]4[CH:29]=[CH:28][NH:27][N:26]=4)[CH:3]=3)[CH2:7]2)=[O:12])=[CH:15][CH:16]=1)=[O:25])[CH2:23][CH3:24]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: OB(O)c1cc[nH]n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(-c4cc[nH]n4)cc3C2)cc1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
In a 4 mL vial, a solution of 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (50 mg, 0.12 mmol) and 1H-pyrazol-3-ylboronic acid (17 mg, 0.15 mmol) in dimethylformamide was treated with saturated aqueous sodium bicarbonate followed by bis(triphenylphosphine)palladium(II) chloride (7 mg). The vial was capped under nitrogen and the reaction heated at 85° C. for 6 hours. The reaction was cooled to ambient temperature and water was added. The resulting suspension was stirred for 5 minutes and filtered. The solid collected was washed with water and dried under vacuum; the solid was purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.39-13.18 (bs, 1H), 8.59 (s, 1H), 8.24-8.28 (m, 1H), 7.75-7.79 (m, 2H), 7.70-7.80 (m, 3H), 7.62-7.69 (m, 2H), 7.40 (d, J=7.9 Hz, 1H), 6.73 (d, J=2.2 Hz, 1H), 4.79-4.83 (m, 4H), 3.15-3.25 (m, 2H), 1.46-1.57 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 390 (M+H)+.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.Cl.C([O-])(O)=O.[Na+]>CO>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: c1ccc(-c2ccc(CN3CCNCC3)cc2)cc1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
0.35 g (1.0 mmol) of compound 51 was dissolved in 5 mL methanol and 0.5 mL 12 N HCl at room temperature. The mixture was stirred for 20 min and added to a solution of NaHCO3 and extracted 3× with EtOAc. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo to give 0.25 g (100%) of 52.