Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([O-:19])(=[O:18])=[O:17])([CH3:3])[CH3:2].[OH:20][C:21]1[CH:26]=[CH:25][C:24]([S+:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)CCN(C)C.[CH:54]([O:56][CH2:57][CH2:58]Cl)=[CH2:55]>CS(C)=O>[CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[S:16]([O-:19])(=[O:17])=[O:18])([CH3:14])[CH3:15].[CH:54]([O:56][CH2:57][CH2:58][O:20][C:21]1[CH:26]=[CH:25][C:24]([S+:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[CH2:55]
Reactant: C=COCCCl
Reactant: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)[O-])c(C(C)C)c1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: C=COCCOc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
4-Hydroxyphenyldiphenylsulfonium 2,4,6-triisopropylbenzenesulfonate (8.00 g), potassium carbonate (2.46 g), and N,N,N′,N′-tetramethylethylenediamine (0.16 g) were dissolved in dimethyl sulfoxide (24.00 g). Subsequently, chloroethyl vinyl ether (1.59 g) was added to the resultant solution, followed by heating to 80° C. and stirring for 15 hours. The resultant reaction mixture was cooled to 30° C. or lower. After removal of solid matter through filtration, water (160 g) and dichloromethane (64 g) were added to the filtrate for extraction of a target substance into the dichloromethane layer. The organic layer was repeatedly washed with distilled water until the pH of the separated aqueous layer became 7. The solvent was removed by means of a rotary evaporator, and the thus-obtained oily substance was dissolved in acetonitrile (32 g). The acetonitrile layer was washed five times with hexane (24 g). The solvent was removed by means of a rotary evaporator, to thereby yield 9.84 g of a brown oily substance. Through 1H-NMR analysis and ion chromatography, this substance was identified to be 4-vinyloxyethoxyphenyldiphenylsulfonium 2,4,6-triisopropylbenzenesulfonate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.N#N.CN(CCN(C)C)C.[BH4-].[Na+]>C1COCC1.[Cl-].[Na+].O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: CN(C)CCN(C)C
Agent: N#N
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
4,7 Dichloroquinoline (10 g, 50 mmol) in THF (100 ml) was degassed with N2 for 5 min. PdCl2dppf (1.2 g, 2 mmol), TMEDA (9.97 g, 86 mmol), and NaBH4 (3.24 g, 86 mmol) were added and the mixture was stirred at room temperature for 5 h. Brine (20 ml) was added dropwise and the solvent was removed in vacuo. The residue dissolved in EtOAc (200 ml), dried (MgSO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAC (4:1-1:1 gradient) as the eluent to give the title compound (5.4 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:37])[C:20]([C:22]1[N:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:25]2[N:26]=[C:27](Cl)[N:28]=[CH:29][C:24]=2[CH:23]=1)=[O:21]>>[CH3:18][N:19]([CH3:37])[C:20]([C:22]1[N:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:25]2[N:26]=[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]4)=[CH:6][N:7]=3)[N:28]=[CH:29][C:24]=2[CH:23]=1)=[O:21]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: N#CCCN1CCN(c2ccc(N)nc2)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCC#N)CC4)cn3)nc2n1C1CCCC1
Yield: 10.2 %

Procedure:
Following Buchwald Procedure A, 3-[4-(6-amino-pyridin-3-yl)-piperazin-1-yl]-propionitrile (173 mg, 0.751 mmol) and 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.683 mmol) gave 2-{5-[4-(2-cyano-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (34 mg, 10%) [following purification by preparative LCMS]. MS (ESI) m/z 488.2 (M+H)+ (method B).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH:4]=O.C([BH3-])#N.[Na+].[NH2:11][C@@H:12]1[CH2:29][C@@:27]2([CH3:28])[C@@H:23]([CH2:24][CH2:25][C@@H:26]2[C:30]([O:32][CH3:33])=[O:31])[C@H:22]2[C@H:13]1[C@:14]1([CH3:35])[C@@H:19]([CH2:20][CH2:21]2)[CH2:18][C@H:17]([OH:34])[CH2:16][CH2:15]1.[BH4-].[Na+].[ClH:38]>C(O)C.C(OCC)(=O)C.CCOCC.O>[ClH:38].[OH:34][C@@H:17]1[CH2:16][CH2:15][C@@:14]2([CH3:35])[C@@H:19]([CH2:20][CH2:21][C@@H:22]3[C@@H:13]2[C@H:12]([NH:11][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[C:30]([O:32][CH3:33])=[O:31])[CH2:18]1
Reactant: CC(C)CC=O
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Agent: Cl
Agent: [BH3-]C#N
Agent: [BH4-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reaction time: 0.5 h

Procedure:
3-Methylbutanal (2.62 ml) and sodium cyanoborohydride (306 mg) were added to a solution of methyl 11α-amino-3α-hydroxy-5α-androstane-17β-carboxylate (5.77 g) in ethanol (130 ml) and after 18 h sodium borohydride (0.7 g) was added. After a further 15 minutes water (350 ml) was added and the mixture was extracted with ether (×2). The extract was washed with water, dried (Na2SO4) and evaporated to leave a foam which was dissolved in ethyl acetate (200 ml). Concentrated hydrochloric acid solution (4 ml) was added to the stirred solution and the mixture was diluted with ether (200 ml). The solid formed was collected by filtration, dried and stirred with ethyl acetate (100 ml) for 0.5 h. The solid was collected and dried to give the title compound (4.82 g) m.p. dec 230°-300° C., [α]D +30°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[O:20]=[C:21]1[CH2:30][CH:29]2[CH2:31][N:32]([CH2:33][C:34]([O-])=[O:35])[C:27]3[C:28]2=[C:23]([CH:24]=[CH:25][CH:26]=3)[NH:22]1.[Li+].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:20]=[C:21]1[CH2:30][CH:29]2[CH2:31][N:32]([CH2:33][C:34]([NH:1][C:2]3[CH:3]=[C:4]4[C:17](=[CH:18][CH:19]=3)[CH2:16][C:6]3([C:14]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]3=[O:15])[CH2:5]4)=[O:35])[C:27]3[C:28]2=[C:23]([CH:24]=[CH:25][CH:26]=3)[NH:22]1
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C([O-])CN1CC2CC(=O)Nc3cccc1c32
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CN1CC2CC(=O)Nc3cccc1c32)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A mixture of (−)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (108 mg, 0.431 mmol, described in Intermediate 3), lithium (4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer B (100 mg, 0.431 mmol, described in Intermediate 12), EDC (107 mg, 0.560 mmol), HOBT (86 mg, 0.560 mmol), and N,N-diisopropylethylamine (0.113 mL, 0.646 mmol) was stirred in DMF (3 mL) at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated in vacuo. The residue was added to saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=466 (M+1). HRMS: m/z=466.1913; calculated m/z=466.1874 for C27H24N5O3.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[C:9]([N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=1)=[N:10][CH:11]=[CH:12][N:13]=2)=[O:5])C.C1(C2C=CC=CC=2)C=CC=CC=1CN1C2C(=NC=CC=2)C(=O)C(C(O)=O)=C1>>[C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:14]1[C:9]2=[N:10][CH:11]=[CH:12][N:13]=[C:8]2[C:7](=[O:29])[C:6]([C:4]([OH:5])=[O:3])=[CH:15]1
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2nccnc2c1=O
Agent: O=C(O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Product: O=C(O)c1cn(Cc2ccccc2-c2ccccc2)c2nccnc2c1=O
Yield: 53.9 %

Procedure:
5-Biphenyl-2-ylmethyl-8-oxo-5,8-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid (15) (300 mg, 54%) was synthesized as a light yellow solid from 600 mg of 5-biphenyl-2-ylmethyl-8-oxo-5,8-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid ethyl ester (14) following the procedure described for 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid (7).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:38][O:39][CH:40]1[CH2:43][CH2:42][CH2:41]1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29])(C(C)(C)C)(C)C>O1CCCC1>[CH:40]1([O:39][CH2:38][C@H:27]([OH:26])[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=2)=[O:29])[CH2:41][CH2:42][CH2:43]1
Reactant: Cc1ccc(NC(=O)[C@H](COC2CCC2)O[Si](C)(C)C(C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@@H](O)COC2CCC2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (0.439 mL, 0.44 mmol) was added to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-cyclobutoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate R5) (80 mg, 0.22 mmol) in tetrahydrofuran (5 mL). The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated and diluted with ethyl acetate (20 mL) and washed sequentially with water (5 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 60% ethyl acetate in isohexane to afford the product (46.0 mg, 84%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>ClCCl>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: COC1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Product: COC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4.2 g 4-methoxycyclohexanol in 30 ml dichloromethane is added to a suspension of 52.6 g pyridinium chlorochromate on basic aluminium oxide in 90 ml dichloromethane. The suspension is stirred for 3 h at ambient temperature. Then the mixture is filtered through silica gel (dichloromethane) and the solvent is eliminated.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[C:5](=[CH:10][C:11]([NH:14][CH2:15][C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[CH:20]=2)=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=[C:16]1[CH2:15][NH:14][C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4](=[CH:13][CH:12]=1)[C:3]([OH:25])=[O:2]
Reactant: COC(=O)c1ccc(NCc2cc3ccccc3o2)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NCc2cc3ccccc3o2)cc1C(=O)O
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A mixture of 4-[(benzofuran-2-ylmethyl)-amino]-phthalic acid dimethyl ester (0.89 g, 3.30 mmol) and 3N sodium hydroxide (50 mL) in ethanol (100 mL) was refluxed for one hour. The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with CH2Cl2 (2×100 mL), and acidified (HCl). The resulting mixture was extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with water (2×100 mL), dried (MgSO4), and evaporated, providing 0.80 g of 4-[(benzofuran-2-ylmethyl)amino]-phthalic acid, in 98% yield; 1H NMR (DMSO-d6) δ 4.54 (d, J=4.5 Hz, 2H), 6.71-6.77 (m, 3H), 7.18-7.29 (m, 3H), 7.51-7.61 (m, 3H), 12.52 (br, 2H).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[S:19])[CH:14]=[CH:15][CH:16]=1)#[N:10]>ClCCl>[O:8]=[C:2]1[C:3](=[O:5])[N:17]([C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[C:9]#[N:10])[C:18](=[S:19])[N:20]1[CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(NC(=S)Nc1cccc(C#N)c1)C(C)(C)C
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2cccc(C#N)c2)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Ethyl chlorooxoacetate (1.03 mL, 9.17 mmol) was added to a stirring solution of the above thiourea (1.19 g, 4.59 mmol) in dichloromethane (30 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and filtration afforded 1.167 g (81%) of 3-[4,5-dioxo-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidin-1-yl]-benzonitrile as a yellow solid: mp 168.1–168.7° C.; 1H NMR (DMSO-d6): δ8.00 (d, 1H), 7.84 (s, 1H), 7.75 (m, 2H), 4.83 (q, 1H), 1.47 (d, 3H), 1.01 (s, 9H); IR (KBr): 3500, 2970, 2230, 1765, 1600 cm−1; MS (m/z) 315 (M+).
Reaction SMILES: O[CH2:2][CH2:3][C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])([CH3:6])[CH3:5].[NH:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:38]([O:37][C:35]([N:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:2][CH2:3][C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])([CH3:6])[CH3:5])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(CCO)Nc1cc(C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Nc1cc(C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 45.5 %

Procedure:
To a stirred solution of benzyl 3-[(4-hydroxy-2-methylbutan-2-yl)amino]-4-nitrobenzoate (395 mg, 1.10 mmol), di-tert-butyl iminodicarboxylate (367 mg, 1.65 mmol), and triphenylphosphine (430 mg, 1.65 mmol) in THF (5 mL) is added diisopropyl azodicarboxylate (0.34 mL, 1.65 mmol). After 16 h at room temperature the solvent is evaporated and the residue is purified by flash chromatography on silica eluting with a heptane/EtOAc gradient to afford the title compound (280 mg, 0.50 mmol, 46%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:15][NH:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].O.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>C1COCC1.CCOC(C)=O>[CH2:36]([O:35][C:33]([N:14]1[CH2:15][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:11][C@H:12]([C:22]([O:24][CH3:25])=[O:23])[C@@H:13]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)[C@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)CN[C@H]1c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Yield: 105.6 %

Procedure:
To a stirred and ice-cooled mixture of (2R*,3S*,5S*)-5-(tert-butyldimethylsilyloxy)methyl-3-methoxycarbonyl-2-phenylpiperidine (11.46 g, 31.52 mmol), NaHCO3 (3.97 g, 47.3 mmol), H2O (80.0 ml), and THF (10.0 ml) was added a solution of benzyl chloroformate (Cbz-Cl, 5.92 g, 34.67 mmol) in THF (15.0 ml). A precipitated gummy material was dispersed by adding AcOEt (40.0 ml). After the resultant milky suspension was stirred with ice-cooling for 2.5 hours, the organic layer was separated from the mixture, and the aqueous layer was extracted with AcOEt (40 ml×4). The combined organic layer and AcOEt extracts were washed with sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a yellow oil (16.56 g). This was flash chromatographed over Sir (Merck Kieselgel 60, 200 g). Elution with n-hexane-AcOEt (60:1/30:1/20:1) gave title compound (13.88 g, 88.5%) as a pale yellow oil. IRmax (film): 1735(s), 1700(s), 1498(m), 1290(s), 1253(s), 1100(s), 775(s), 740(m), 700(s) cm-1 ; 1H-NMR δ: 7.42-7.28(m, 6H), 7.28-7.16(m, 4H), 5.98-5.87(m, 1H), 5.31-5.10(m, 2H), 3.92(dm, J=13.6 Hz, 1H), 3.63(dd, J=10.1, 9.7 Hz, 1H), 3.60(s, 3H), 3.53(dd, J=10.1, 7.9 Hz, 1H), 3.09(ddd, J=11.2, 5.6, 5.6 Hz, 1H), 3.12-2.95(m, 1H), 2.24-2.06(m, 1H), 2.06-1.93(m, 1H), 0.87(s, 9H), 0.02(s, 6H) ppm.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10]([Cl:14])=[CH:11][C:12](Cl)=[C:7]2[C:6]([CH3:15])=[CH:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1.C(OCC)(=O)C>CS(C)=O>[Cl:14][C:10]1[N:9]=[C:8]2[NH:4][CH:5]=[C:6]([CH3:15])[C:7]2=[C:12]([O:29][C:26]2[CH:27]=[CH:28][C:23]([NH2:22])=[CH:24][C:25]=2[F:30])[CH:11]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: CC(=O)n1cc(C)c2c(Cl)cc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2nc(Cl)cc(Oc3ccc(N)cc3F)c12
Temperature: 120 °C

Procedure:
300 mg (1.16 mmol) of 1-acetyl-4,6-dichloro-3-methyl-1H-pyrrolo[2,3-b]pyridine (from example XL) and 320 mg (2.32 mmol) of powdered potassium carbonate are suspended in 9 ml of DMSO. The mixture is degassed, and 442 mg (3.48 mmol) of 4-amino-2-fluorophenol are added. The mixture is heated at 120° C. for 4 hours. After addition of ethyl acetate, the mixture is filtered off with suction through CELITE (diatomaceous earth) and the filtercake is washed with ethyl acetate. The filtrate is extracted three times with sat. sodium bicarbonate solution and with sat. sodium chloride solution. The filtrate is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel 60, mobile phase: DCM:methanol=50:1).
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[CH:10]=[C:9]([NH:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[N:8]=2)[CH2:3]1.O1CCOCC1.Cl.C([O-])(O)=O.[Na+]>>[NH:15]1[CH2:14][CH:13]([C:11]2[CH:12]=[C:7]([N:4]3[CH2:5][CH2:6][C:2]([F:35])([F:1])[CH2:3]3)[N:8]=[C:9]([NH:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=3)[CH:10]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Nc3cc(C(F)(F)F)ccn3)nc(N3CCC(F)(F)C3)c2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: FC1(F)CCN(c2cc(C3CNC3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 3-[2-(3,3-difluoropyrrolidin-1-yl)-6-[[4-(trifluoromethyl)-2-pyridyl]amino]-4-pyridyl]azetidine-1-carboxylate (1-c, 918 mg, 1.562 mmol) in dioxane (6.0 ml, 70.30 mmol) was added hydrogen chloride (4.0 mol/l) in dioxane (16.0 mL, 40 equiv., 62.49 mmol), and the reaction was kept at 25° C. for 4 h. The reaction was neutralized by NaHCO3 to pH 9, and the aqueous layer was extracted by EtOAc. After evaporation of the organic layer, the crude was used without further purification. LCMS: m/z 400 (M+H).
Reaction SMILES: [CH2:1]([O:4][N:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH:32]O.[OH-].[Na+]>O1CCCC1>[OH:32][CH2:3][CH2:2][CH2:1][O:4][N:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1
Reactant: C=CCON=Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: OO
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCCON=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 1-benzyl-1H-indole-3-carbaldehyde O-allyl-oxime (2.965 g, 10.2 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. was added 9-BBN (0.5 M in THF)(50.0 mL, 25.0 mmol). The reaction was stirred at 0° C. for 1 hour and then warmed to room temperature over 30 minutes. Hydrogen peroxide (12 mL) was carefully added followed by a 10% NaOH solution (20 mL) and stirring continued at room temperature for 25 minutes. The reaction was quenched by the addition of saturated sodium bisulfite and extracted with ethyl acetate. The combined organic were washed with saturated sodium bisulfite and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography through silica gel using ethyl acetate/hexanes (10/90 to 40/60) to give 1-benzyl-1H-indole-3-carbaldehyde O-(3-hydroxy-propyl)-oxime (1.298 g, 41%) as a white solid. mp=76.4-77.7° C.; mass spectrum (+ES, M+H) m/z 309. 1H NMR (400 MHz, CDCl3); δ 8.33 (s, 1H), 8.01 (d, 1H), 7.92 (s, 1H), 7.49 (d, 1H), 7.22 (m, 7H), 5.44 (s, 2H), 4.47 (t, 1H), 4.13 (t, 2H), 3.52 (q, 2H), 1.82 (m, 2H). Elemental analysis: Calcd. for C19H20N2O2: C, 74.0; H, 6.54; N, 9.08. Found: C, 73.74; H, 6.46; N, 8.95.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[C:20]([F:23])[CH:19]=[CH:18][CH:17]=3)=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH2:28].[Li+].[Cl-]>C1COCC1.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>[CH2:28]([C:7]1[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[C:20]([F:23])[CH:19]=[CH:18][CH:17]=3)=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH:27]=[CH2:26]
Reactant: O=S(=O)(Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a mixture of 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (2 g, 5.1 mmol), allyltributylstannane (2 g, 6.1 mmol) and anhydrous LiCl (256 mg, 6.1 mmol) in THF (30 mL), Pd(PPh3)4 (588 mg, 0.51 mmol) was added under N2 protection. The reaction mixture was stirred at 60° C. overnight. After it was concentrated in vacuo, the residue was purified by column chromatography (PE:EA=400:1˜100:1) to give the product of 2-(3-allyl-6-chloropyridin-2-yl)-4-fluoro-1H-indole (1 g, yield: 68%). 1H-NMR (CDCl3, 400 MHz) δ 9.72 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.12˜7.24 (m, 3H), 7.02 (s, 1H), 6.77 (t, J=8.0 Hz, 1H), 6.04˜6.12 (m, 1H), 5.25 (d, J=10.0 Hz, 1H), 5.13 (d, J=17.2 Hz, 1H), 3.74 (d, J=6.0 Hz, 2H). MS (M+H)+: 287/289.