Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCO.C([Li])CCC.[C:12]1([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Br)(Br)(Br)[Br:25]>CCCCCC.O>[Br:25][C:22]1[CH:23]=[C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=[CH:20][N:21]=1
Reactant: c1ccc(-c2ccncc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: Brc1cc(-c2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 2-dimethylaminoethanol (5.60 g, 62.8 mmol) in hexane (80 ml) was added dropwise 1.6N hexane solution of n-butyl lithium (78.5 ml, 125 mmol) under ice-cooling, and stirred at 0° C. for 30 minutes. Then, 4-phenylpyridine (3.24 g, 20.8 mmol) was added thereto, and stirred at 0° C. for 1 hour. After cooling the reaction solution to −78° C., a solution of carbon tetrabromide (25.0 g, 75.4 mmol) in hexane (40 ml) was added thereto, and stirred at −78° C. for 1 hour, then at room temperature for 1 hour. To the reaction solution was added water under ice-cooling, and extracted with ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the titled compound 2.21 g (45.4%) as solid product.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][O:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][N:32]=1>>[CH3:29][O:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:3]=2)[N:32]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: COc1n[nH]c2ccccc12
Product: COc1nn(-c2nc(N3CCOCC3)c3nc(CN4CCC(C(C)(C)O)CC4)n(C)c3n2)c2ccccc12

Procedure:
2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.2 g) was reacted with 3-methoxy-1H-indazole via General Procedure I for Buchwald coupling to give 119.5 mg 235 following reverse phase purification. MS (Q1) 521.3 (M)+
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:9][C:7]2[C:6]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[CH:5][N:4]=[C:3]([CH2:2][OH:1])[CH:8]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cnc(CO)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 2-(hydroxymethyl)-5-(4-methoxybenzyloxy)pyridin-4(1H)-one (Intermediate 62, 3.48 g, 13.32 mmol) in DMF (100 mL) at room temperature was added 4-methoxybenzyl chloride (1.987 mL, 14.65 mmol) followed by potassium carbonate (2.273 mL, 39.96 mmol). The reaction mixture was stirred for 1 hour at room temperature then heated at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine. The ethyl acetate layer was concentrated to afford an oil. To the oil was added 1N HCl and a light brown solid crashed out. This was collected by filtration. The solid was taken up in ethyl acetate and washed with saturated sodium bicarbonate. The organics were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a brown solid (2.62 g, 52%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C@@H:4]2[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>ClCCl>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C@@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:9][C@@H:4]3[CH2:3]2)=[O:30])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](N)C[C@H]2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](NC(=O)c3ccc(F)cc3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (7S,8aS)-tert-butyl 7-aminohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (0.241 g, 1 mmol) in dichloromethane (6 mL) was added sodium carbonate (0.127 g, 1.2 mmol) and 4-fluorobenzoyl chloride (0.174 g, 1.1 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol=10:1) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.40 (m, 1H), 1.47 (s, 9H), 1.63 (m, 2H), 2.05-2.20 (m, 2H), 2.50-2.65 (m, 2H), 3.00 (m, 2H), 4.20 (m, 2H), 4.70 (m, 1H), 6.68 (m, 1H), 7.10 (m, 2H), 7.80 (m, 2H); MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:6]2[C:13]([I:14])=[CH:12][N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=2[N:8]=[CH:9][N:10]=1>CO.O>[I:14][C:13]1[C:6]2[C:5]([NH2:3])=[N:10][CH:9]=[N:8][C:7]=2[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: N
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(I)c2c(N)ncnc21
Temperature: 120 °C
Reaction time: 1 h

Procedure:
An 8 N ammonia methanol solution (120 ml) was added to the 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (20.0 g) obtained in Step 1, and the mixture was stirred in a microwave reactor at 120° C. for 1 hour. After being cooled, the reaction mixture was diluted with methanol (65 ml) and water (185 ml). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (15.2 g) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:27]([C:29]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:30])[N:28]=1
Reactant: Nc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CC(C)C[C@H]2CN1C(=O)c1nc(N)sc1-c1ccccc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-amino-5-phenyl-thiazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]=[C:15]2[C:10]([NH:11][C:12]([CH3:26])=[C:13]([C:24]#[N:25])[CH:14]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:27][CH2:26][C:12]1[NH:11][C:10]2=[N:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:16]=[C:15]2[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:13]=1[C:24]#[N:25]
Reactant: CC1=C(C#N)C(c2ccccc2Cl)c2cn(C(=O)OC(C)(C)C)nc2N1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)n1cc2c(n1)NC(CBr)=C(C#N)C2c1ccccc1Cl
Reaction time: 1 h

Procedure:
A solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (22.9 g), di-t-butyl dicarbonate (19.4 g) and dimethylaminopyridine (0.5 g) in tetrahydrofuran (200 ml) was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (21.8 g) as white crystals. 2-(t-Butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (5.0 g), N-bromosuccinimide (2.5 g) and azobisisobutyronitrile (66 mg) were suspended in benzene (50 ml) and the suspension was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (2:1)) and crystallized from ethyl acetate to give 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine as white crystals. To a suspension of sodium hydride (32 mg) in DMF (10 ml) was added morpholine (70 μl) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.36 g) and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water, and the precipitated crystals were collected by filtration and washed with hexane to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (450 mg) as white crystals. A solution of 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (440 mg) in trifluoroacetic acid (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and 4M hydrochloric acid-dioxane solution was added. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (250 mg) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1([C:26](Cl)=[O:27])[C:21]([CH3:23])([CH3:22])[C:20]1([Cl:25])[Cl:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH:8][C:26]([C:19]2([Cl:18])[C:21]([CH3:23])([CH3:22])[C:20]2([Cl:25])[Cl:24])=[O:27])[CH3:7])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: CC1(C)C(Cl)(Cl)C1(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(NC(=O)C1(Cl)C(C)(C)C1(Cl)Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 90.1 %

Procedure:
4-Chloro-α-methylbenzylamine (15.6 g) and triethylamine (10.1 g) were dissolved in toluene (150 ml). With stirring, a solution of 1,2,2-trichloro-3,3-dimethylcyclopropanecarboxylic acid chloride (23.6 g) in toluene (30 ml) was added dropwise to the solution at 0° to 10° C. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and the aqueous layer was extracted with toluene. The toluene layers were combined, washed with a 1% aqueous solution of hydrochloric acid, a 1% aqueous solution of sodium hydroxide and water in this order, and then dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give the desired N-(4-chloro-α-methylbenzyl)-1,2,2-trichloro-3,3-dimethylcyclopropanecarboxamide (32 g) represented by the following formula as colorless crystals. mp. 138°-139° C. ##STR35##
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44].O>CN(C)C=O>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: CN(C)C(=O)CCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Rac-cis-(3,5-Bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone (200 mg, 0.41 mmol) was dissolved in N,N-dimethylforamide (5 mL). Potassium carbonate (171 mg, 1.24 mmol) and 2-chloro-N,N-dimethylacetamide (0.042 mL, 0.41 mmol) were added and the reaction mixture was stirred at room temperature overnight. Water (50 mL) was added and the mixture was extracted twice with 100 mL ethyl acetate. Organic phases were pooled, dried with magnesium sulfate and evaporated. Chromatography on silica gel with methylen chloride/methanol/triethyl amine 90:10:1 gave the desired product (200 mg, 85%) as an off-white solid, MS: m/e=571.1 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:29][C:30]([NH:32][CH3:33])=[O:31])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:61])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([NH:29][C:30]([NH:32][CH3:33])=[O:31])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:61])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)NC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)NC(=O)NC

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-(3-methylureido)propane IIIf2 is allowed to react and worked up by the same procedure as described in (5). m.p. 70°-71° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: C1COCC1.C[O:7][C:8](=[O:36])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:17]=[CH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:22]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:20]=3[N:21]=2)=[N:11][CH:10]=1.[Li+].[OH-].Cl>CO.O>[CH:30]1([N:22]2[C:20]3[N:21]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([C:8]([OH:36])=[O:7])=[CH:10][N:11]=4)[N:17]=[CH:18][C:19]=3[CH:24]=[C:23]2[C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCCC4)c3n2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCC1
Temperature: 50 °C
Yield: 96.6 %

Procedure:
To a 25 mL solution of THF, water and MeOH (2:2:1) containing 6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid methyl ester (860 mg, 2.04 mmol) was added solid LiOH (244 mg, 10.2 mmol). After stirring at 50° C. for 90 m, reaction was acidified to pH 6 with 1M HCl and then partitioned into two phases with a mixture of water, isopropyl alcohol and chloroform. The organic layer was removed and concentrated to yield 6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (805 mg, 1.97 mmol) in 97% yield. MS m/z 409.6 (M÷H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH2:22][C:23]4[N:27]([CH3:28])[C:26]5[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=5[N:24]=4)=[CH:15][C:14]=3[F:33])O)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C(#N)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:13]3[C:14]([F:33])=[CH:15][C:16]([O:21][CH2:22][C:23]4[N:27]([CH3:28])[C:26]5[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=5[N:24]=4)=[C:17]([O:19][CH3:20])[CH:18]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(Cl)cc23)c(F)cc1OCc1nc2ccccc2n1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(Cc2c[nH]c3ncc(Cl)cc23)c(F)cc1OCc1nc2ccccc2n1C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
(5-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-5-methoxy-4-(1-methyl-1H-benzimidazol-2-ylmethoxy)-phenyl]-methanol (145) (0.140 g, 0.225 mmol) was suspended in acetonitrile (5 ml, 100 mmol). Triethylsilane (1.0 mL, 6.3 mmol) was added followed by trifluoroacetic acid (0.500 mL, 6.4 mmol). After the reaction was stirred at 60-80° C. for 1.5 hours the solvent was evaporated to dryness. Ethyl acetate was added and the organic portion was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. Purification with silica gel flash chromatography eluting with a gradient of ethyl acetate (20 to 100%) in hexanes gave the desired compound as a white powder (P-2106, 0.034 g, 34%). MS (ESI) [M+H+]+=451.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:10][C:11]1[C:12](Cl)=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([C:12]2[C:11]([CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[CH2:8][CH3:9])=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:29]=1)[CH3:24]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc2ccccc2nc1Cl)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2nc3ccccc3cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
(2-Chloro-quinolin-3-ylmethyl)-ethyl-carbamic acid tert-butyl ester (1.0 g, 3.11 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (1.07 g, 3.34 mmol), potassium carbonate (1.08 g, 7.8 mmol), and catalytic tetrakis(triphenylphosphine)palladium(0) were combined in 2:1 DME:H2O (18 mL), and stirred at 80° C. for 6 hours. After standard work-up, the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:17]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27][Br:28])[CH:24]=[C:23]([CH2:29]Br)[CH:22]=1)[CH3:18]>>[Br:28][CH2:27][C:25]1[CH:24]=[C:23]([CH2:29][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:22]=[C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:31])[CH:26]=1
Reactant: CCOC(=O)c1cc(CBr)cc(CBr)c1
Reactant: COCCOc1cc(O)cc(C(=O)OC)c1
Product: CCOC(=O)c1cc(CBr)cc(COc2cc(OCCOC)cc(C(=O)OC)c2)c1

Procedure:
The subtitle compound was prepared from the product of step (iii) (1.5 g) and 3,5-bis(bromomethyl)benzoic acid ethyl ester (4.9g) by the method of example 11 step (i). Purification was by chromatography eluting with 30% ethyl acetate in isohexane. Yield 1.6 g. Used directly in the next step
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19]CC)=O)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:17]([OH:19])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:14](=[O:15])[C:8]32[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2cccc(Cl)c2)CCOCC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(Cl)cc2C2(CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
Diethyl 2-(4-(3-chlorophenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (10.66 g, 27.8 mmol) was added to H2SO4 (50 mL, 591 mmol), and the mixture was stirred at room temperature for 1 hour. Ice (H2O) was added, and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with water (2×) and brine, dried (MgSO4), and concentrated in vacuo to give the crude compound as an orange oil. The crude oil was purified by silica flash chromatography (0-100% DCM/hexane) to give the desired compound as a yellow solid (4.93 g). MS (m/e)=337.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH2:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4=[C:14]([CH2:17][CH2:18][CH2:19][C:20](=[O:22])/[C:21]/4=[CH:39]/[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccccn1
Reactant: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc2/C1=C\c1ccccn1
Temperature: -60 °C
Yield: 79.7 %

Procedure:
A 3 neck round bottom flask with stir bar, nitrogen line and thermometer was charged with 1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6 (1H)-one (6, R1=4-Fluorophenyl) (0.500 g, 1.699 mmol) and THF (15 mL). The solution was cooled to about −60° C. then LiHMDS (1M in THF, 2.0 mL, 2.0 mmol) was added. After complete addition the mixture was removed from the cold bath and allowed to warm to about 0° C. The mixture was cooled to about −65° C. then picolinaldehyde (0.546 g, 5.10 mmol) was added and the temperature of the mixture was raised to about −5° C. After about 15 min the reaction was quenched with AcOH (1 mL) and stirred for about 15 min. The mixture was transferred to a separatory funnel with the aid of EtOAc (25 mL) and sat. aq. NaHCO3 (25 mL). The layers were separated then the aq. layer was extracted with EtOAc (25 mL). The combined organic layers were washed with brine (15 mL) then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-40% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield (E)-1-(4-fluorophenyl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (0.519 g, 80%); LC/MS, method 3, Rt=2.54 min, MS m/z 384 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.56-8.54 (m, 1H), 8.23 (d, J=0.8 Hz, 1H), 7.89-7.83 (m, 3H), 7.69 (s, 1H), 7.59-7.51 (m, 1H), 7.53 (s, 1H), 7.51-7.41 (m, 2H), 7.22-7.20 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 2.99 (t, J=7.0 Hz, 2H), 2.38 (t, J=6.9 Hz, 2H), 2.09-1.95 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][Cl:15])[C:6]#[N:7].[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:8]1[CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH2:14][Cl:15])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]#[N:7])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C#N)ccc1OCCCCl
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCCCCl
Temperature: 30 °C

Procedure:
3-methoxy-4-chloropropoxybenzonitrile (1.350 g, 6 mmol) and nitric acid (6 mL) were added into a round bottom flask. The solution was heated to 30° C. while stirring to react for 2 h, then poured into ice-water, filtered, washed with water and air-dried to yield light yellow solid product (1.555 g) with a recovery rate of 96%.