Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O.C(OCC)(=O)C.[CH3:18][N:19]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:18]#[N:19])[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: CN1CCCC1=O
Reactant: Brc1cnc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cnc2[nH]ccc2c1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 73 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine described in Preparation Example R-5 (90 mg, 0.46 mmol), zinc cyanide (80 mg, 0.69 mmol) and tetrakis(triphenylphosphine)palladium(0) (53 mg, 46 μmol) were dissolved in N-methyl-2-pyrrolidinone (2 mL), and the mixture was stirred for 4.5 hours at 110° C. under nitrogen atmosphere. The reaction mixture was cooled to room temperature, water and ethyl acetate were added to the reaction mixture, the organic layer was partitioned, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (48 mg, 0.34 mmol, 73%) was obtained as a white solid.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:17])=[C:12]([C:14](=O)[CH3:15])[CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:17])=[C:12]([C:14]([CH3:1])=[CH2:15])[CH:13]=1
Reactant: CC(=O)c1cc(Br)ccc1F
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (58.92 g, 162 mmol) in tetrahydrofuran (400 ml) was treated with potassium tert-butylate (18.51 g, 162 mmol), and the yellow mixture was stirred at room temperature for 20 minutes. The orange reaction mixture was cooled to 0° C., and a solution of 1-(5-bromo-2-fluoro-phenyl)-ethanone (29.33 g, 135 mmol) in tetrahydrofuran (50 ml) was added within 16 minutes. The mixture was left to warm to room temperature and stirred for 1.5 hours. For the workup, the mixture was diluted with ethyl acetate (650 ml) and extracted with water (450 ml). The organic layer separated, washed with brine (220 ml), dried and evaporated at reduced pressure. After chromatography on silica gel using a gradient of hexane/ethyl acetate=100/0 to 80/20 as the eluent, the 4-bromo-1-fluoro-2-isopropenyl-benzene was obtained as a yellow oil (28.49 g, 98% of theory).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][N:10]2[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([C:20](=[O:34])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:22]=3[N+:31]([O-:33])=[O:32])[N:12]=[N:11]2)=[CH:7][CH:6]=1.Cl>O1CCCC1.CCOCC.O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20](=[O:34])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:22]=3[N+:31]([O-:33])=[O:32])[N:12]=[N:11]2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1c(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Cn2nnc(C(=O)c3cc(OC)c(OC)cc3[N+](=O)[O-])c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A 1 N aqueous sodium hydroxide solution (13 ml) was added to a solution of ethyl 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (b-1) (3.04 g, 6.46 mmol), prepared in step (b), in tetrahydrofuran (40 ml). The mixture was stirred at room temperature for 3.5 hr. The reaction solution was diluted with ether, and water was added thereto. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate, followed by washing with water and saturated brine solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxyic acid as light yellow oil (c-1′: LP) (2.55 g, 89%). The resultant 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylic acid (c-1′:LP) (1.07 g, 2.42 mmol) was dissolved in a mixed solvent composed of ethanol (50 ml) and ethyl acetate (50 ml). 10% palladium-carbon (129 mg) was added thereto. The mixture was stirred in a hydrogen atmosphere at room temperature for 4 hr. Methylene chloride was added to the reaction solution to dissolve the precipitated crystal, followed by filtration through Celite. The filtrate was concentrated under reduced pressure to give 4-(2-amino-4,5-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylic acid (c-1: LP) (1.06 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:14][N:15]=[C:16]=[S:17]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH:13][C:16]([NH:15][CH3:14])=[S:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CN=C=S
Reactant: CCOC(=O)c1ccc(NN)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(NNC(=S)NC)cc1

Procedure:
In 100 ml of benzene were dissolved 9.3 g of 4-ethoxycarbonylphenylhydrazine and 3.6 g of methyl isothiocyanate and then the solution was refluxed with stirring. After heat-refluxing for 5 hours, the reaction mixture thus formed was cooled and crystals thus formed were collected by filtration to provide 1-(4-ethoxycarbonylphenyl)-4-methylthiosemicarbazide as colorless crystals. The product, 1-(4-ethoxycarbonylphenyl)-4-methylthiosemicarbazide thus obtained could be used for the subsequent reaction without being purified.
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][Si@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1.Br[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:2][CH2:3][C@H:4]2[CH2:9][CH2:8][Si@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]2)=[CH:17][CH:18]=1)#[N:21]
Reactant: CCCCC[Si@H]1CC[C@H](CCBr)CC1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CCc2ccc(C#N)cc2)CC1

Procedure:
250 ml of an organozinc compound (1.0M THF solution) prepared from trans-4-(2-bromoethyl)-1-n-pentyl-1-silacyclohexane was dripped into a mixture of 45.5 g (0.25 mmol) of p-bromobenzonitrile, 500 mg of tetrakis (triphenylphosphine) palladium (0) and 500 ml of THF. After a conventional after treatment, they were separated by means of chromatography to obtain 49.4 g of the target product (yield 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.N([O-])=O.[Na+].[OH-].[NH4+].[BrH:21]>O1CCOCC1.O>[Br:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: Nc1ccc(F)c(-c2cccnc2)c1
Reactant: Br
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(Br)cc1-c1cccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-(2-fluoro-5-aminophenyl)pyridine (22.4 g, 119 mmol) in 1,4-dioxane (40 ml) was treated with a solution of 48% aqueous hydrobromic acid (500 ml). The resulting suspension was cooled to 0° C. before being treated dropwise over 20 min with an aqueous solution of NaNO2 (9.5 g, 137 mmol) in water (30 ml) keeping the internal temperature <5° C. After stirring at 0° C. for 2 h, a cooled (0° C.) solution of CuBr (25.6 g, 179 mmol) in 48% aqueous hydrobromic acid (150 ml) was added to the reaction which was then stirred at 0° C. for 10 min before heating at 50° C. for 20 min. The reaction was cooled to ambient temperature, diluted with ice-cold water (500 ml), then treated with ice-cold aqueous 33% ammonium hydroxide solution until pH 8-9 (ca. 750 ml). After stirring for 20 min the product was extracted into EtOAc (600 ml), the organics were washed with water, brine (300 ml), dried over anhydrous NaSO4, filtered and pre-adsorbed onto silica. Purification by column chromatography [silica; 20-50% EtOAc/isohexane (containing 1% MeOH and 1% triethylamine)] gave 3-(5-bromo-2-fluorophenyl)pyridine as a white solid (22 g, 73% for sequence): 8H (360 MHz, CDCl3) 7.09 (1H, dd, J 9 and 1), 7.37-7.40 (1H, m), 7.46-7.51 (1H, m), 7.56-7.59 (1H, m), 7.83-7.86 (1H, m), 8.63-8.65 (1H, m), 8.77-8.79 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[CH3:14]C1(C=O)C2C(=CC=CC=2)NC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:14])[CH:7]=[C:6]2[CH:12]=[O:13]
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Reactant: CC1(C=O)CNc2ccccc21
Product: COc1ccc2c(c1)c(C=O)cn2C
Yield: 92 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 5-methoxy-1H-indole-3-carboxaldehyde for the 3-methyl-1H-indole-3-carboxaldehyde, the title compound (0.86 g, 92%) was obtained as a light tan solid: MS (ES) m/e 190.2 (M+H)+.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[Cl:9][C:10]1[CH:32]=[CH:31][C:13]2[C:14](=O)[C:15](=[CH:26]N(C)C)[CH2:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:12]=2[CH:11]=1>CO.C(Cl)Cl.O.CS(O)(=O)=O>[Cl:9][C:10]1[CH:32]=[CH:31][C:13]2[C:14]3[N:5]=[C:2]([CH3:3])[N:4]=[CH:26][C:15]=3[CH2:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:12]=2[CH:11]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Reactant: CC(=N)N
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In five equal portions 5.5 g (58 mmole) of acetamidine hydrochloride and 15 ml (62 mmole) of a 4.12M methanol solution of sodium methoxide was added over 3 hr. to a solution of 3.5 g (10 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 140 ml of methanol and 140 ml of methylene chloride. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water dried with anhydrous sodium sulfate, and concentrated at reduced pressure to give an amber oil. The amber oil was dissolved in 10 ml (10 mmole) of a 1M methanol solution of methanesulfonic acid and the resulting salt was precipitated by the addition of ether to give yellow prisms, mp 193°-197° C. Recrystallization from a mixture of methanol and ether gave yellow prisms, mp 197°-198° C.
Reaction SMILES: [OH:1][C@H:2]([CH:18]([CH3:20])[CH3:19])[C:3]([NH:5][C@H:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH3:7])=[O:4].CS(O[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)=O.[H-].[Na+]>C1COCC1>[CH3:19][CH:18]([CH3:20])[C@@H:2]([O:1][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3]([NH:5][C@H:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH3:7])=[O:4]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](O)C(C)C)cc1
Reactant: CS(=O)(=O)OCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OCCOc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of methyl 4-[(1S)-1-[[(2R)-2-hydroxy-3-methyl-butanoyl]amino]ethyl]benzoate (3.0 g, 10.7 mmol) and 2-phenoxyethyl methanesulfonate (2.32 g, 10.7 mmol) in dry THF (25 mL) is added sodium hydride (440 mg, 10.7 mmol). The mixture is stirred at room temperature overnight and partitioned between 1N HCl and EtOAc. The aqueous layer is extracted with EtOAc. The combined EtOAc layers are washed with brine, dried with MgSO4, filtered, and concentrated. The crude material (4.7 g) is purified using silica gel column chromatography (120 g cartridge; 30 to 100% ethyl acetate in heptane) to provide the title compound as a white solid (1.41 g, 33%). MS (m/z): 400.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[CH:14]([C:17]1[C:18]([CH:23]=O)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15]>>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:23][C:18]1[C:17]([CH:14]([CH3:16])[CH3:15])=[CH:22][CH:21]=[CH:20][N:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CC(C)c1cccnc1C=O
Product: CC(C)c1cccnc1CNCCCCNC(=O)OC(C)(C)C

Procedure:
A pale yellow oil prepared from (4-amino-butyl)-carbamic acid tert-butyl ester and 3-isopropyl-pyridine-2-carbaldehyde. 1H NMR (CDCl3) δ 1.23 (d, 6H, J=6.6 Hz), 1.43 (s, 9H), 1.53-1.61 (m, 4H), 2.67-2.74 (m, 2H), 3.10-3.21 (m, 3H), 3.94 (s, 2H), 4.73 (s, br. 1H), 7.11-7.17 (m, 1H), 7.54-7.58 (m, 1H), 8.37-7.40 (m, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:20])[CH2:10][C:11]1[NH:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[N:12]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:10]1[CH:26]=[CH:25][C:24](=[O:27])[N:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[NH:12][C:11]=12)=[O:20]
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccccc1F
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(c1ccccc1F)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.54 mmol) of 1-(2-Fluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example XXXXVII, 58.6 mg (1.08 mmol) of sodium methylate and 45.6 mg (0.54 mmol) methyl propiolate.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[F:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:31][CH:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1ccc(F)nc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc(F)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 54 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (6-fluoropyridin-3-yl)boronic acid to afford a white solid. LC-MS (Condition 2) tR=1.91 min, m/z=463.2-464.2 [M+H]+, m/z=461 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.78 (m, 1H) 1.79-1.89 (m, 1H) 2.89 (d, J=11.49 Hz, 1H) 3.17-3.28 (m, 2H) 3.34-3.44 (m, 1H) 4.20 (s, 1H) 4.85 (s, 1H) 7.29 (dd, J=8.44, 2.57 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.29 Hz, 2H) 7.98-8.05 (m, 2H) 8.30 (d, J=1.96 Hz, 1H) 8.77 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:10][CH2:11][CH2:12][C:13]([N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][O:17][C:16]1=[O:26])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:34][C:35]1[CH:49]=[CH:48][C:38]([CH:39]=[N:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C.C[Si](Cl)(C)C.C(O)(=O)C(C(C(O)=O)O)O.S([O-])(O)=O.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([CH:39]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH:12]([CH2:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:13]([N:15]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:48][CH:49]=1
Reactant: Fc1ccc(N=Cc2ccc(Br)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC(CCC(C(=O)N1C(=O)OCC1c1ccccc1)C(Nc1ccc(F)cc1)c1ccc(Br)cc1)c1ccc(F)cc1
Temperature: -10 °C

Procedure:
4.4 g of 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)pentanoyl]-4-phenyloxazolidin-2-one are dissolved in 40 ml of absolute dichloromethane. 5.2 g of (4-bromobenzylidene)-(4-fluorophenyl)amine and 8.6 ml of ethyldiisopropylamine are added, and the solution is then cooled to −10° C. 2.94 ml of trimethylsilyl chloride are then added dropwise, and during the addition, the temperature of the reaction-mixture is maintained below −5° C. The reaction solution is then stirred at −10° C. for half an hour and then cooled to −30° C., and 1.2 ml of titanium tetrachloride are added dropwise, the temperature being maintained between −30° C. and −15° C. This gives a black reaction solution which is stirred at −20° C. for another 3 h and then allowed to warm to 0° C. In the stated order, in intervals of 10 minutes, 10 ml of glacial acetic acid, 100 ml of 7% strength aqueous tartaric acid solution and finally 100 ml of 20% strength aqueous sodium hydrogensulfite solution are added with stirring. The mixture is then extracted twice with dichloromethane and the organic phase is washed once with saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed using a rotary evaporator and the residue is purified by column chromatography (SiO2; ethyl acetate/heptane 1:4). The product is obtained from diethyl ether/pentane as white crystals. C39H43BrF2N2O4Si (749) MS (ESI): M+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:5]2=[CH:6][N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.O.C(#N)C>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:8]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[C:5]3=[CH:6][N:7]=2)[CH:26]=[N:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cn1cc(-c2cc3c(-c4ccccc4)nn(C4CCCCO4)c3cn2)cn1
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
In a microwave vial was charged with 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (500 mg, 1.39 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (435.6 mg, 2.09 mmol), potassium acetate (205.5 mg, 2.09 mmol), sodium carbonate (221.9 mg, 2.09 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed with dichloromethane (1:1) (108.3 mg, 0.13 mmol). Degassed acetonitrile (10.5 mL) and water (2.6 mL) were added. Nitrogen was passed through the mixture for 15 minutes and the vial was capped. The reaction mixture was subjected to microwave irradiation at 125° C. for 25 min. The reaction mixture was filtered through a pad of Celite® and diluted with water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified using flash chromatography (Si-PPC gradient elution, solvent: 60-100% ethyl acetate in heptanes, followed by 0-30% methanol in ethyl acetate) to give 5-(1-methyl-1H-pyrazol-4-yl)-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine as a foam (340.0 mg, 67.8%). 1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.07-7.94 (m, 5H), 7.54 (t, J=7.6 Hz, 2H), 7.45 (t, J=7.4 Hz, 1H), 5.88 (dd, J=8.8, 2.2 Hz, 1H), 4.06 (dd, J=11.8, 4.0 Hz, 1H), 3.98 (s, 3H), 3.86-3.76 (m, 1H), 2.66-2.52 (m, 1H), 2.19 (d, J=10.8 Hz, 2H), 1.89-1.67 (m, 3H). LC/MS: m/z 378.3 [M+1]
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>C(Cl)Cl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O-:14])(=[O:35])=[O:34])=[CH:29][CH:28]=1.[C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 8 h

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.3 g, 8.6 mmoles) was dissolved in methylene chloride (2.0 ml), and pyridine (1 ml) and p-toluenesulfonyl chloride (1.8 g, 9.4 mmoles) were added. The reaction was allowed to proceed at room temperature overnight, and water (30 ml) was added, followed by extraction of the product with ethyl acetate. The organic layer was washed with water and dried and the solvent was distilled off. The resulting oily product was subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (1:1) as the eluent to give p-toluensulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (3.15 g, 88%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:18]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:30])=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCOc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 88.1 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 30.0 mg (0.131 mMol) 4-hexyloxybenzoic acid, 16.8 mg (89%) of the title compound were recovered.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)[C@H:10]1[CH3:26])(C(C)(C)C)(C)C.C1COCC1.Cl.C(=O)([O-])O.[Na+]>CO>[Cl:25][C:19]1[CH:18]=[C:17]([N:11]2[C@@H:10]([CH3:26])[C@H:9]([OH:8])[C:13]3([CH2:15][CH2:14]3)[C:12]2=[O:16])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1[C@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[(6S,7R)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-chlorobenzonitrile (65.7 mg) in a mixed solvent of THF (6 mL) and methanol (6 mL) was added 6 mol/L hydrochloric acid (4.0 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate.