Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)=[C:4]([CH2:13][CH3:14])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22]CC)=[CH2:21])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:13]([C:4]1[CH:3]=[C:2]([C:20](=[O:22])[CH3:21])[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)[CH3:14]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCc1cc(Br)ccc1-c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1cc(C(C)=O)ccc1-c1cscn1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a stirred solution of 4-(4-bromo-2-ethylphenyl)-1,3-thiazole (2.35 g, 8.76 mmol) in dioxane (45 ml) was added tributyl(1-ethoxyvinyl)tin (3.48 g, 9.64 mmol), tetrakis(triphenylphosphine)palladium (1010 mg, 0.876 mmol), lithium chloride (928 mg, 21.9 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was concentrated in vacuo. To the residue was added THF (15 ml), 2N HCl aqueous solution (15 ml), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, made neutral by addition of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (1.51 g, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:15]([C:14]2[CH:20]=[CH:21][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2cccc(Cl)n2)cc1
Temperature: 45 °C
Yield: 85.8 %

Procedure:
To a cold (0° C.) solution of 6-chloro-2-picoline (18.3 mL 166.5 mmol) and ethyl 4-methoxybenzoate (30.0 g, 166.5 mmol) in tetrahydrofuran (300 mL) was added lithium bis(trimethylsilyl)amide (333 mL, 1.0 M in tetrahydrofuran, 332.7 mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon complete addition, the cold bath was removed and the resulting solution was heated at 45 ° C. for 15 hours. The mixture was cooled to room temperature, and the solution was concentrated. Methanol was added to quench the reaction, resulting in the formation of a yellow precipitate. The precipitate was collected by filtration and dried to give 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone (37.4 g, 86%) as a yellow solid. 1H NMR (CDCl3): δ 7.99 (d, 2 H), 7.57 (t, 1 H), 7.22–7.19 (m, 2 H), 6.90 (d, 2H), 4.39 (s, 2H), 3.83 (s, 3 H); MS m/z 262 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=[O:14].[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](Cl)=[O:19])[CH3:16]>C1COCC1>[CH2:15]([N:17]([CH2:21][CH3:22])[C:18]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[C:7]([CH:13]=[O:14])=[CH:8]1)=[O:19])[CH3:16]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)n1cc(C=O)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.6 %

Procedure:
To a suspension of sodium hydride (0.93 g, 37 mmol) in anhydrous THF (75 mL) was added dropwise a solution of 5-bromo-1H-indole-3-carbaldehyde (7.5 g, 34 mmol) in anhydrous THF (60 ml) at 0° C. After stirring at 0° C. for 15 min, N,N-diethylcarbamyl chloride (5.0 g, 37 mmol) was added dropwise into the reaction mixture. The mixture was warmed to room temperature and stirred overnight. The reaction was then quenched with water and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from ether/hexane to give the title compound (8.75 g, 80%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=5)=[C:36]([O:49][CH3:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:60])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:60])=[C:36]([O:49][CH3:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:51]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methylpyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1 g) was dissolved in dichloromethane (30 ml), and to the solution was added 3-chloroperbenzoic acid (0.46 g) under ice-cooling and the mixture was stirred at room temperature for 4 hours. An aqueous solution of sodium thiosulfate was added to the mixture, the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.77 g) as colorless amorphous.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1)#[CH:2].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>C(N(CC)CC)C.C(OCC)C.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.[Cu]I>[CH3:13][O:12][C:11]1[C:4]2[C:3]([C:1]#[C:2][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[CH:7][S:6][C:5]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(Br)cc1
Reactant: C#Cc1csc2cccc(OC)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cccc2scc(C#Cc3ccc(C)cc3)c12

Procedure:
3-Ethynyl-4-methoxybenzo[b]thiophene (0.15 g) was dissolved in triethylamine (10 mL). To the solution were added 4-bromotoluene (0.11 mL), tetrakis(triphenylphosphine)palladium (0) (92 mg) and copper (I) iodide (30 mg), and the mixture was heated for ref lux under an argon atmosphere for 10 hours. The reaction mixture was diluted with diethyl ether, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=50/1) to give 4-methoxy-3-[2-(4-methylphenyl)ethynyl]benzo[b]thiophene (27 mg). This material was dissolved in ethanol (1.5 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-methoxy-3-[2-(4-methylphenyl)ethyl]-benzo[b]thiophene (27 mg). This material was dissolved in dichloromethane (1.5 mL). To the solution was added boron tribromide (0.011 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hour. Then the mixture was stirred under ice-cooling for 1 hour. The reaction mixture poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=15/1) to give the title compound (10 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: COc1cccc(CC(=O)O)c1
Product: CCC(NC(=O)Cc1cccc(OC)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3-methoxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH2:56]([O:58][C:59](=[O:68])[CH2:60][N:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH2:67])[CH2:62]1)[CH3:57]>CN(C=O)C>[CH2:56]([O:58][C:59](=[O:68])[CH2:60][N:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH:67][C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:62]1)[CH3:57]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)CN1CCCC(N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6 mmol) in DMF (10 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (569 mg, 1.8 mmol), N,N-diisopropyl ethyl amine (1.38 mL, 8.1 mmol) and (3-amino-piperidin-1-yl)-acetic acid ethyl ester hydrochloride (459 mg, 1.8 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1 and then dichloromethane:methanol=9:1) afforded the title compound (622 mg, 81%) as a light brown gum. MS: m/e=479.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C(NCCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(NCCCN1CCC(O)(c2ccccc2)CC1)OCc1ccccc1

Procedure:
A mixture of 4-hydroxy-4-phenylpiperidine (5 g, 0.0282 mol), N-benzyloxycarbonyl-3-bromopropylamine (8.445 g, 0.031 mol), and potassium carbonate (7.795 g, 0.0564 mole) in acetone (200 mL) was stirred and refluxed for 12 hours. Acetone was evaporated at reduced pressure, the residue was treated with ice-cold water (400 mL) and extracted with CH2Cl2 (4×120 mL). Solvent was evaporated from the combined dried (sodium sulfate) extracts and the residue was found to be almost pure desired product (9.5 g, 91%) by tlc and 1H-NMR and was used as such without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:15]1C=CN[N:16]=1)=[CH:11][N:12]([CH3:14])[CH3:13].ClC1C=C(Cl)C=CC=1C(=O)CC1N[CH:33]=[C:34]([CH3:36])[N:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:15]1[NH:16][CH:33]=[C:34]([CH3:36])[N:35]=1)=[CH:11][N:12]([CH3:13])[CH3:14]
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1cc[nH]n1
Reactant: Cc1c[nH]c(CC(=O)c2ccc(Cl)cc2Cl)n1
Product: Cc1c[nH]c(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)n1

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-pyrazolylprop-2-en-1-one except that 1-(2,4-dichlorophenyl)-2-(4-methylimidazolyl)ethan-1-one (II, 1.0 g, 3.7 mmol) was used. The crude residue was used without purification.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>COCCO>[C:4]([C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: C1CNCCN1
Solvent: COCCO
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCNCC1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
A mixture of 2-chloro-5-nitrobenzonitrile (1 g) and piperazine (2.12 g) in ethylene glycol monomethyl ether (5 mL) was heated at 60° C. for 30 minutes. After cooling to room temperature, H2O was added (50 mL) and the solution extracted with CH2Cl2 (3×25 mL). The combined organic layers were washed with H2O, dried over Na2SO4 and evaporated to dryness to give 1.27 g (99%) of the desired compound.
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:13]2([CH3:30])[CH:14]([OH:29])[CH2:15][CH:16]3[C:21]4([CH3:27])[CH2:22][CH2:23][CH:24]([OH:26])[CH2:25][CH:20]4[CH2:19][CH:18]([OH:28])[CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCOC(C)=O>N1C=CC=CC=1>[OH:28][C@@H:18]1[CH2:19][C@H:20]2[C@:21]([CH3:27])([CH2:22][CH2:23][C@@H:24]([O:26][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:25]2)[C@@H:16]2[C@@H:17]1[C@H:12]1[C@:13]([CH3:30])([C@@H:14]([OH:29])[CH2:15]2)[C@@H:9]([C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:10][CH2:11]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
To a solution of cholic acid methyl ester (25 g, 59.2 mmol) in pyridine (75 mL), stirring at 0° C., was added methanesulfonyl chloride (5.04 mL, 65.1 mmol) dropwise over 30 minutes. The reaction was allowed to warm to room temperature and stir for 6 hours. The reaction mixture was poured into a mixture of EtOAc (200 mL), 1 N HCI (200 mL), and ice. The layers were separated, and the organic layer was washed with 1N HCI (2×50 mL), dried (Na2SO4) and concentrated to provide a light yellow oil. The crude material was passed through a plug of silica eluting with 50% EtOAc/hexanes to provide 24.5 g (83%) of the title compound as a light yellow oil that foamed into a white, sticky foam when placed on the high vacuum pump.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19](=[O:31])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH2:14][CH2:13]3)[C:7]=1[C:8]#[N:9].O.[NH2:33][NH2:34]>C(O)C>[F:28][C:27]([F:29])([F:30])[C:23]1[CH:22]=[C:21]([CH2:20][C:19]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]5[NH:33][N:34]=[C:8]([NH2:9])[C:7]=45)=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[O:31])[CH:26]=[CH:25][CH:24]=1
Reactant: NN
Reactant: N#Cc1c(Cl)cncc1-c1ccc2c(c1)CCN2C(=O)Cc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2cncc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To 3-chloro-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile (80 mg, 0.181 mmol) was added hydrazine monohydrate (0.266 mL, 5.43 mmol) to a 5 mL sealable vial with Ethanol (3 mL). The reaction was then capped and heated at 100° C. overnight. Observed 80% product and 20% SM. Additional hydrazine monohydrate (0.266 mL, 5.43 mmol) was added and heating was continued overnight. The reaction was concentrated then dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 17% ACN/H2O, 0.1% TFA to 42% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and it was extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The residue was then transferred into a 40 mL vial with MeCN, water was added and the solution was freeze-dried to afford 4-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-amine (20 mg, 25.3% yield) as a white solid. LC/MS (ES) m/z=438.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.74 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.56-7.67 (m, 3H), 7.44 (s, 1H), 7.33 (d, J=8.34 Hz, 1H), 4.61 (br. s., 2H), 4.30 (t, J=8.46 Hz, 2H), 4.05 (s, 2H), 3.26-3.30 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:15])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([Cl:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(CC(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cccc(CC(=O)Cl)c1
Reaction time: 16 h

Procedure:
A mixture of 3-methoxyphenylacetic acid (47.7 g, 0.287 m), thionyl chloride (50 ml) and N,N-dimethylformamide (6 drops) in toluene (500 ml) was stirred for 16 hours at 25° and concentrated in vacuo to afford 3-methoxyphenylacetyl chloride. The acetyl chloride was dissolved in chloroform (100 ml) and added to a solution of aminoacetaldehyde dimethyl acetal (32.1 g, 0.306 m) and triethylamine (32.4 g, 0.320 m) in chloroform (500 ml) stirred at 5°. The mixture was stirred at 25° for 16 hours, washed with water, 1.5N hydrochloric acid and water, dried with magnesium sulfate and concentrated in vacuo to give N-(2,2-dimethoxyethyl)-3-methoxybenzeneacetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH:9](=O)[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[CH2:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[CH3:10]
Reactant: CC=O
Reactant: Cc1cccc(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNc1cccc(C)n1
Reaction time: 4 h
Yield: 50.5 %

Procedure:
2-Amino-6-methylpyridine (1.00 g, 9.25 mmol) and acetaldehyde (0.52 mL, 9.34 mmol) were stirred together in anhydrous methyl alcohol for 1 hour at room temperature under a nitrogen atmosphere. The mixture was then treated with sodium triacetoxyborohydride (7.84 g, 37.0 mmol) and five drops of acetic acid and all was allowed to continue stirring for 4 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM, and the separated aqueous phase was extracted twice with DCM. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give a mobile oil which was purified by flash column chromatography, eluting with 2% MeOH/DCM, to give 2-ethylamino-6-methylpyridine (636 mg, 51%).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16].O>ClCCl>[CH:1]([NH:14][C:15]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C(NC(c1ccccc1)c1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzhydrylamine (1.83 g) was dissolved in dichloromethane (3.0 ml). Carbonyldiimidazole (1.78 g) was added to the solution. The mixture was stirred at room temperature overnight. Water and dichloromethane were added thereto. The mixture was stirred, and then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation is to give imidazole-1-carboxylic acid benzhydrylamide.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:35][CH2:36][C:37]1[CH:61]=[CH:60][C:40]([CH2:41][NH:42][C:43](=[O:59])[C:44]2[CH:49]=[C:48](F)[CH:47]=[N:46][C:45]=2[O:51][C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[CH:39][CH:38]=1.CN1CCOCC1>CN(C)C=O>[F:58][C:55]1[CH:54]=[CH:53][C:52]([O:51][C:45]2[N:46]=[CH:47][CH:48]=[CH:49][C:44]=2[C:43]([NH:42][CH2:41][C:40]2[CH:60]=[CH:61][C:37]([CH2:36][NH:35][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=3[OH:1])=[CH:38][CH:39]=2)=[O:59])=[CH:57][CH:56]=1
Reactant: NCc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Reactant: Cc1cccc(C(=O)O)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cccc(C(=O)NCc2ccc(CNC(=O)c3cccnc3Oc3ccc(F)cc3)cc2)c1O
Yield: 21.3 %

Procedure:
A solution of 2-Hydroxy-3-methylbenzoic acid (118 mg, 0.773 mmol), 1-hydroxybenzotriazole (157 mg, 1.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (193 mg, 1.01 mmol), N-(4-aminomethyl-benzyl)-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide hydrochloride (300 mg, 0.773 mmol) (see Preparation 3) and N-methyl morpholine (0.17 ml, 1.55 mmol) in N,N-dimethylformamide (6 ml) was stirred under nitrogen at room temperature for 18 hours. The mixture was then partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (10 ml) and dried over anhydrous magnesium sulphate. The solvent was then removed in vacuo and the residue was triturated with diethylether (3-fold 10 ml) giving 2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-3-methyl-benzoylamino)-methyl]-benzyl}-nicotinamide (80 mg) as an off-white foam.