Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]5[O:34][CH:33]=[N:32][CH:31]=5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.C1C=CC2N(O)N=NC=2C=1.[S:50]1[CH:54]=[CH:53][C:52]([CH2:55][C:56](O)=[O:57])=[CH:51]1>CC(N(C)C)=O>[O:34]1[C:30]([C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:56](=[O:57])[CH2:55][C:52]6[CH:53]=[CH:54][S:50][CH:51]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:31][N:32]=[CH:33]1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: O=C(O)Cc1ccsc1
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[3-(1,3-oxazol-5-yl)phenyl]-2-pyrimidinamine (50 mg, 0.112 mmol) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and 3-thienylacetic acid (48 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by mass-guided prep LC (C18, 15% H20 (with 0.1% formic acid)/CH3OH to 100% CH3OH gradient) to afford the title compound (30 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ 3.65 (s, 2H), 6.51 (d, 1H, J=5.37 Hz), 7.07-7.12 (m, 2H), 7.23-7.48 (m, 7H), 7.55 (s, 1H), 7.68-7.76 (m, 2H), 7.89 (s, 1H), 8.20 (s, 1H), 8.27 (d, 1H, J=5.37 Hz), 8.38 (s, 1H), 8.50-8.51 (m, 1H), 8.81 (d, 1H, J=6.84 Hz), 9.73 (s, 1H), 10.28 (s, 1H). ES-LC/MS m/z=570 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[NH:10][N:9]=1)=[O:7])[CH3:4].[F:23][C:24]([F:35])([F:34])[CH2:25]OS(C(F)(F)F)(=O)=O.ClCCl>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:25][C:24]([F:35])([F:34])[F:23])[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])[CH3:4]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 56.8 %

Procedure:
Sodium hydride (55% dispersion in mineral oil, 203 mg, 5 mmol) was added to an ice cooled solution of 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1 g, 4 mmol; PCT Int. Appl. (2003), WO 2004000785 A2) in DMF (60 ml) under an argon atmosphere. The solution was stirred for 10 min at 0° C. and for 40 min at ambient temperature. Trifluoroethyltriflate (1.07 g, 5 mmol) was added and the mixture was stirred for 3 h at ambient temperature. The solution was cooled to 0° C., 1 N HCl/ice water 1/2 and dichloromethane were added. The aqueous layer was extracted two times with dichloromethane, the combined extracts were washed with brine/ice water 1/1 and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave yellow crystals which were purified by column chromatography (silica gel, n-heptane/AcOEt) to yield 833 mg (2.27 mmol, 65%) of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[C:37]([O:45][C:46](=[O:48])[CH3:47])=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](O)=[O:40])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39](=[O:40])[C:38]2[CH:42]=[CH:43][CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[C:37]=2[O:45][C:46](=[O:48])[CH3:47])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3cccnc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.5 %

Procedure:
3-Aminopyridine (0.076 g, 0.802 mmol), triethylamine (0.081 g, 0.802 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.136 g, 0.802 mmol) were added to a methylene chloride solution (100 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.100 g, 0.222 mmol, 41%).
Reaction SMILES: [CH3:1][C:2]([CH:5]([NH2:10])[C:6]([O:8][CH3:9])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[N:30]=[C:31]=[O:32])[CH2:27]2>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C@@H:5]([NH:10][C:31]([NH:30][CH:21]1[CH:20]2[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]1[CH2:23]3)[CH2:27]2)=[O:32])[C:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: COC(=O)C(N)C(C)(C)C
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)NC1C2CC3CC(C2)CC1C3)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
L-(+)-Methyl-tert-leucinate hydrochloride (564 mg) was dissolved in abs. DMF and then N-ethyl-diisopropylamine (0.68 mL) was added drop by drop. The mixture was allowed to stir for 30 minutes at RT and then 2-adamantyl isocyanate (500 mg) was added in one portion. Stirring was continued over night at RT. The reaction mixture was evaporated to dryness and residual DMF was removed by co-evaporation with toluene. The residue was purified by flash chromatography using 5% methanol in DCM as an eluent to give (S)-2-(3-adamantan-2-yl-ureido)-3,3-dimethyl-butyric acid methyl ester (834 mg) as a white solid. MS (EI): 322.4 (M+).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7].[CH3:28][O:29][CH2:30][CH2:31][CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][CH2:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:23][C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7]
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(O)ccc1F
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(OCCCOC)ccc1F
Yield: 94 %

Procedure:
This compound was prepared from (R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2-fluoro-5-hydroxy-benzyl) ester and toluene-4-sulfonic acid 3-methoxy-propyl ester according to the procedure described in Example 187 to give the product as a colorless oil (342 mg; 94%); MS (ISP): 472.4 (M+NH4)+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[N:13]([C:17]2[CH:41]=[CH:40][C:20]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:30]4=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:15][N:16]=1)([O-])=O.O.[OH-].[Na+]>C(O)C>[NH2:2][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[N:13]([C:17]2[CH:41]=[CH:40][C:20]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:30]4=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:15][N:16]=1
Reactant: O=C(c1ccc(-n2ccnc2Sc2ccccc2[N+](=O)[O-])cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1Sc1nccn1-c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To the mixture of conc. hydrochloric acid (3.2 ml) and ethanol (2 ml) is added 1-[1-{4-[2-(2-nitrophenyl)thio-1-imidazolyl]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (2.0 g), and thereto is added dropwise a solution of stannous chloride dihydrate (2.7 g) in ethanol (4 ml) at a temperature below 25° C. with water-cooling, and the mixture is stirred at room temperature for two hours. The mixture is poured into ice-water and basified with aqueous sodium hydroxide solution, extracted with chloroform, washed with water, and dried over sodium sulfate. After concentrated under reduced pressure, the resulting residue is purified by silica gel column chromatography (eluent; chloroform: methanol=50:1-25:1), and further dissolved in methanol. The mixture is added dropwise with stirring into water (about 40 ml) and the resulting precipitates are collected by filtration and dried to give 1-[1-{4-[2-(2-aminophenyl)thio-1-imidazolyl]benzoyl}-4-piperidinyl}-3,4-dihydrocarbostyril (1.6 g) as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:3]=1[N+:18]([O-:20])=[O:19].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(N2CCOCC2)n1
Reactant: Nc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCCSc1nc(Nc2ccccc2Cl)c([N+](=O)[O-])c(N2CCOCC2)n1
Temperature: 55 °C

Procedure:
A mixture of the product from step (i) (1 g), 2-chloroaniline (0.4 g) and N,N-diisopropylethylamine (0.404 g) in isopropylalcohol (12ml) was heated at 55° C. for 14 h. The mixture was cooled and the isopropylalcohol decanted off. Yield 0.82 g
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(CC)CC)C.[CH:65]1([C:68](Cl)=[O:69])[CH2:67][CH2:66]1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:68]([CH:65]3[CH2:67][CH2:66]3)=[O:69])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC(=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 32 mg of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added triethylamine (10 μl) followed by a solution of cyclopropane carbonyl chloride (5 mg) in methylene chloride (0.1 ml). The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:13]=2[C:24](=[O:41])[NH:25][C:26]2[CH:30]=[CH:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[N:27]=2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:42][NH:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9]([C:7]3[N:8]=[C:3]([CH2:2][N:43]([CH3:42])[CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:60])([CH3:59])[CH3:61])=[O:56])[CH:4]=[CH:5][CH:6]=3)=[O:10])=[C:13]([C:24](=[O:41])[NH:25][C:26]3[CH:30]=[CH:29][N:28]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)[N:27]=3)[CH:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)n1
Reactant: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)n1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 6-(chloromethyl)-N-(4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)picolinamide (170 mg, 0.29 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)-propanoate (255 mg, 0.88 mmol, 3.00 equiv), potassium iodide (24.2 mg, 0.15 mmol, 0.50 equiv), and potassium carbonate (79.5 mg, 0.58 mmol, 1.97 equiv). The resulting solution was stirred for 2.5 h at 70° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(Br)[CH:14]=[C:13]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[NH:6]1)=[O:4].[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2[C:7](=[C:8]([N:31]3[CH2:32][CH2:33][CH2:34][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: CN1CCCNCC1
Reactant: COC(=O)C1(Br)C=C(OCOCC[Si](C)(C)C)c2cc(OC)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(N3CCCN(C)CC3)c2n1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a clear, light brown solution of 2-bromo-6-methoxy-4-(2-trimethylsilanyl -ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (1.01 g, 2.28 mmol), N-methylhomopiperazine (0.32 mL, 2.57 mmol), and 4 Å sieves in 30 mL anhydrous toluene was added Pd2 (dba)2 (43.8 mg, 0.048 mmol) and BINAP (169.8 mg, 0.27 mmol). The resulting wine colored solution was treated with cesium carbonate (1.124 g, 3.45 mmol). The reaction mixture was heated at reflux under nitrogen for 21 hours. The pea green reaction mixture was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using a gradient of 95:5 to 40:60 methylene chloride: methanol to afford the desired product as a yellow foam (1.004 g, 92%). 1H NMR (300 MHz, DMSO, d6) δ 7.67 (s, 1 H, ArH3), 6.94 (d, 1 H, Jm=2.4 Hz, ArH5), 6.66 (d, 1 H, Jm=2.4 Hz, ArH7), 5.60 (s, 2 H, OCH2O), 3.94 (s, 3 H, CO2CH3), 3.88 (s, 3 H, OCH3), 3.82 (t, 2 H, J=8.0 Hz, OCH2CH2Si), 3.75 (bs, 4 H, ArNCH2CH2CH2NCH3 & ArNCH2CH2N—CH3), 3.45 (bs, 2H, ArNCH2CH2NCH3), 3.31 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.83 (s, 3 H, NCH3), 2.28 (bs, 2 H ArNCH2CH2 CH2NCH3), 0.92 (t, 2 H, J=8.0 Hz, OCH2CH2Si), −0.04 (s, 9 H, Si(CH3)3; Mass Spec.: calc. for [C24H37N3O5Si+H]+ Theor. m/z=476; Obs. 476.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][C:3](=O)[CH2:2]1.S([CH2:23][N+:24]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CCO.CC([O-])(C)C.[K+]>COCCOC>[CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([C:23]#[N:24])[CH2:2]1
Reactant: O=C1CCC2(CCCCC2)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CCC2(CCCCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a solution of spiro[5.5]undecan-3-one (1.66 g, 10 mmol) and tosylmethylisocyanide (2.54 g, 13 mmol) in DME (50 ml) and abs. EtOH (1 ml) was added KOtBu (2.69 g, 24 mmol) portionwise during 0.5 hr at −10° C. After addition, the reaction mixture was stirred at 0° C. for 1 hr then 2 hr at ambient temperature. Solvent was removed in vacuo and the resulting residue was extracted with diethyl ether (50 ml×3) and the combined organic layer was washed with water (50 ml×3). The organic layer was dried with anhydrous MgSO4, concentrated under reduced pressure and purified by flash column chromatography (50%-100% CH2Cl2/Hexane) to give the nitrile as colorless solid (1.28 g, 72% Yield). 1H-NMR (360 MHz, CDCl3) δ 2.58-2.53 (m, 1H), 1.83-1.70 (m, 4H), 1.63-1.58 (m, 2H), 1.40-1.26 (m, 8H), 1.28-1.20 (m, 4H); 13C-NMR (90 MHz, CDCl3) δ 122.79, 34.41, 31.88, 28.37, 26.88, 24.73, 21.64, 21.55; ESI-MS: Calculated for C12H19N (M+H)+178.3. Found: 178.2.
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.CC1(C)C(C)(C)OB([C:46]2[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]3[C:56](=[O:70])[N:57]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=4)[CH:58]=[CH:59][CH:60]=3)=[O:54])=[CH:48][CH:47]=2)O1.[B].[Cl:73][C:74]1[CH:75]=[C:76]2[C:82](I)=[CH:81][NH:80][C:77]2=[N:78][CH:79]=1>>[Cl:73][C:74]1[CH:75]=[C:76]2[C:82]([C:46]3[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]4[C:56](=[O:70])[N:57]([CH2:61][C:62]5[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=5)[CH:58]=[CH:59][CH:60]=4)=[O:54])=[CH:48][CH:47]=3)=[CH:81][NH:80][C:77]2=[N:78][CH:79]=1
Reactant: CC1(C)OB(c2ccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)s2)OC1(C)C
Reactant: Clc1cnc2[nH]cc(I)c2c1
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1ccc(-c2c[nH]c3ncc(Cl)cc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-ylmethyl]-amide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophen-2-ylmethyl]-amide as activated boron species and 5-Chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine as substituted bicyclic heterocycle, to yield the product. 1H NMR (300 MHz, CDCl3-MeOH-d4) d ppm 8.533 (dd, J=7.4, 2.2 Hz, 1H) 8.413 (d, J=1.7 Hz, 1H) 8.262 (s, 1H) 7.594 (s, 1H) 7.550 (dd, J=6.7, 2.3 Hz, 1H) 7.198-6.950 (m, 5H) 6.458 (t, J=6.9 Hz, 1H) 5.114 (s, 2H), 4.758 (s, 2H); MS m/z=511.13 M+H.
Reaction SMILES: [BH4-].[Na+].[OH:3][C@H:4]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5](OCC)=[O:6].O>CO>[C:12]1([CH2:11][CH2:10][C@@H:4]([OH:3])[CH2:5][OH:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](O)CCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC[C@H](O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 102.1 %

Procedure:
NaBH4 (1.82 g) was added portionwise to an ice cooled solution of ethyl (R)-2-hydroxy-4-phenylbutyrate (2.0 g) in methanol (40 ml). After the addition was completed, the reaction mixture was stirred at room temperature for 45 minutes. Water (20 ml) was added, and the resulting mixture was stirred for several minutes and then evaporated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave (R)-4-phenylbutane-1,2-diol (1.63 g) as a colorless oil. This material was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B(O)O.Br[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][C:42]3[C:47]([Cl:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:43]=3[Cl:50])=[CH:34][CH:33]=2)[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:17]([CH3:51])[CH:16]=1>>[Cl:48][C:47]1[CH:46]=[C:45]([CH3:49])[CH:44]=[C:43]([Cl:50])[C:42]=1[O:41][CH2:40][CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[CH2:4][CH2:3][O:2][CH3:1])=[CH:16][C:17]=2[CH3:51])[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:33][CH:34]=1
Reactant: COCCc1ccccc1B(O)O
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(Br)cc3C)cc2)c(Cl)c1
Product: COCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 1 using [2-(2-methoxyethyl)phenyl]boronic acid from step 3 and tert-butyl (2-(4-bromo-2-methylphenyl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from step 2 as starting materials.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]Br.C(OCC)C.[NH4+].[Cl-]>O1CCCC1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([OH:19])[CH3:27])[NH:15][C:12]2=[CH:13][N:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (Example 139) (2.89 g, 8.46 mmol) in tetrahydrofuran (42 mL) was added 3.0 M methylmagnesium bromide in diethyl ether (7.05 mL, 21.2 mmol). The reaction mixture was stirred overnight (16 h) under a nitrogen atmosphere at room temperature. The reaction mixture was poured into a stirring saturated NH4Cl solution. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4. After filtration and concentration, a small amount of the desired product was obtained by trituration with CH2Cl2. Additional material was obtained by purification using Biotage chromatography on silica (eluting with Hex/EtOAc 90:10 to 0:100) to provide 1-[5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]ethanol (1.74 g, 57%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ1.53 (3H, d, J=6.6 Hz), 4.69 (4H, s), 4.90-4.99 (1H, m), 6.08 (1H, s), 6.58 (1H, s), 7.17-7.29 (10H, m), 8.26 (1H, s); ESI MS m/z 358 [C23H23N3O+H]+; HPLC (Method A) 98.5% (AUC), tR=18.2 min.