Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[C:14]1([C:24]2[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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.O1CCCC1>[CH3:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:27]2[CH:28]=[CH:29][C:24]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)=[CH:25][CH:26]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc(-c2cccc3ccccc23)cc1
Reactant: COc1ccc(Br)c2ccccc12
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: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(-c3cccc4ccccc34)cc2)c2ccccc12
Temperature: 25 °C
Yield: 52.4 %

Procedure:
1-Bromo-4-methoxynaphthalene (25 g, 0.105 mol), 4-(naphthalen-1-yl)phenylboronic acid (30.4 g, 0.137 mol), potassium carbonate (21.9 g, 0.16 mol), tetrakis(triphenylphosphine)palladium(0) (2.4 g, 0.01 mol), water (25 mL), tetrahydrofuran (75 mL) and toluene (75 mL) were stirred in a 250 mL round-bottom flask for 12 hours under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (300 mL) and water (1000 mL). The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to obtain a solid. The solid was dissolved in hot toluene (400 mL) and then filtered. The filtrate was recrystallized in methanol (800 mL). The resultant solid was filtered and washed with hexane (300 mL) to obtain a product (20 g, 0.055 mol, 52.6%).
Reaction SMILES: [C:1]([CH:5]1[CH2:9][S:8][CH2:7][C:6]1=O)(OC)=[O:2].C(O)(=O)C.[CH:15]([NH2:17])=[NH:16].[O-]CC.[Na+]>CCO>[N:16]1[C:6]2[CH2:7][S:8][CH2:9][C:5]=2[C:1](=[O:2])[NH:17][CH:15]=1
Reactant: N=CN
Reactant: COC(=O)C1CSCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1CSC2
Temperature: 90 °C

Procedure:
Commercially available 4-carbomethoxytetrahydro-3-thiophenone (5 g, 31.2 mmol) is dissolved in EtOH (284 mL). Formamidine acetate (22 g, 211 mmol) is then added followed by sodium ethoxide (45 mL, 121 mmol, 21% w/w) and the mixture is heated at 90° C. for 14 hours. Reaction is cooled to room temperature and concentrated to a residue which is absorbed onto silica and separated via FCC (0-10% Methanol:CH2Cl2) to give the title compound as a solid. MS (EST) m/z 155.14 (M+1).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cccnc1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: S=C(NN=Cc1cccnc1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 3-pyridine carboxaldehyde (53 μL, 0.56 mmol) similar to Example 3 and isolated as a white solid (59 mg, 39%). 1H NMR (CDCl3): 9.51 (s, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.64 (dd, J=1.7, 5.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.82 (s, 1H), 7.46 (d, J=6.3 Hz, 1H), 7.38-7.34 (m, 1H), 6.24-6.14 (m, 2H), 4.30-4.25 (m, 1H), 3.06 (s, 1H), 2.97 (s, 1H), 1.95-1.87 (m, 1H), 1.67 (d, J=8.7 Hz, 1H), 1.5 (d, J=9.0 Hz, 1H), 1.45-1.39 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])[N:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:44])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[N:26][C:27]([O:33]CC3C=CC(OC)=CC=3)=[CH:28][C:29]=2[O:30][CH2:31][CH3:32])=[CH:20][C:19]=1[F:43].C(Cl)[Cl:46]>[Pd]>[ClH:46].[CH2:31]([O:30][C:29]1[C:24]([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C:16]([NH:15][C:3]3[CH:4]=[N:5][C:6]([C:8]([CH3:14])([CH3:13])[C:9]([F:11])([F:12])[F:10])=[CH:7][CH:2]=3)=[O:44])=[C:19]([F:43])[CH:20]=2)=[CH:25][NH:26][C:27](=[O:33])[CH:28]=1)[CH3:32]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cnc(C(C)(C)C(F)(F)F)cc2Br)c(F)c1
Reactant: ClCCl
Agent: [Pd]
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2ccc(C(C)(C)C(F)(F)F)nc2)c(F)c1
Product: Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.6 %

Procedure:
To a mixture of N-(4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (30 mg, 0.044 mmol) in DCM (10 mL) was added Pd/C (4 mg, 0.038 mmol). The mixture was stirred at 25° C. for 72 h under H2. The mixture was filtered and concentrated. The crude material was purified by preparative HPLC (Column: ASB C18 150*25 mm; Mobile phase A: Water+0.1% HCl; Mobile phaseB: MeCN; Flowrate: 25 mL/min; Gradient Profile Description: 45-75 (B %)) to yield an off-white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)acetamide hydrochloride (7.91 mg, 0.015 mmol, 34.6% yield). TLC (DCM/MeOH=9:1, Rf=0.2): 1H NMR (400 MHz, CD3OD): δ 9.08 (d, J=2.0 Hz, 1H), 8.32 (dd, J=2.4, 8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.34-7.27 (m, 2H), 6.39 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 3.89 (s, 2H), 1.69 (s, 6H), 1.41 (t, J=7.2 Hz, 3H). ES-LCMS m/z 478.1 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]([S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH2:11][C@H:12]([NH:20][C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])[C:13]([O:15][C:16](C)(C)[CH3:17])=[O:14].C([N:36](C(C)C)C(C)C)C.O>ClCCl.BrCC#N>[O:8]=[C:9]([S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH2:11][C@H:12]([NH:20][C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])[C:13]([O:15][CH2:16][C:17]#[N:36])=[O:14]
Reactant: C=CCCC(=O)N[C@@H](CCC(=O)Sc1ccccc1)C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=CCCC(=O)N[C@@H](CCC(=O)Sc1ccccc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
Trifluoroacetic acid (3.85 ml, 51.8 mmol) was added to a solution of (S)-tert-butyl 5-oxo-2-(pent-4-enamido)-5-(phenylthio)pentanoate (Compound 1e-IIF) (978 mg, 2.59 mmol) in dichloromethane (6.74 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure. N-Ethyl-N-isopropylpropan-2-amine (1.30 ml, 7.47 mmol) was added to a solution of the resulting residue in 2-bromoacetonitrile (8 ml), and the mixture was stirred at room temperature for 30 minutes. After adding water to the reaction mixture, purification by reverse phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=60/40→20/80) afforded (S)-cyanomethyl 5-oxo-2-(pent-4-enamido)-5-(phenylthio)pentanoate (Compound 1g-IIF) (722 mg, 64%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[C:17]([C:21]([O-])=[O:22])=[N:18][N:19]([CH3:20])[C:10]=4[C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[K+].C([N:27](C(C)C)C(C)C)C.N1(C([O-])=O)C2C=CC=CC=2N=N1.[NH4+]>CN(C)C=O.O1CCCC1.O>[CH:1]1([NH:6][C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[C:17]([C:21]([NH2:27])=[O:22])=[N:18][N:19]([CH3:20])[C:10]=4[C:9]=3[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1nc(C(=O)[O-])c2c1-c1nc(NC3CCCC3)ncc1CC2
Agent: O=C([O-])n1nnc2ccccc21
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCCC3)ncc1CC2
Temperature: 0 °C
Yield: 90 %

Procedure:
A suspension of potassium 8-(cyclopentylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (180 mg, 0.51 mmol) in anhydrous dimethylformamide (3.0 mL) and anhydrous tetrahydrofuran (3.0 mL) was treated with N-ethyl-N,N-diisopropylamine (0.175 mL, 2 eq.) and N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (195 mg, 2 eq). The mixture was then cooled to 0° C. and treated with ammonium 1H-1,2,3-benzotriazol-1-ate (137 mg, 2 eq). After 5 minutes the reaction was warmed to room temperature and kept at this temperature overnight. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (143 mg, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([O:24]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:23])=O)=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8].[S:36]1[CH:40]=[N:39][N:38]=[C:37]1[NH2:41].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:41][C:37]4[S:36][CH:40]=[N:39][N:38]=4)(=[O:24])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8]
Reactant: Nc1nncs1
Reactant: COc1nc(Cl)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1nc(Cl)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A vial was charged with perfluorophenyl 1-(5,6-dichloro-2-methoxypyridin-3-yl)isoquinoline-6-sulfonate (0.042 g, 0.076 mmol), 1,3,4-thiadiazol-2-amine (8.48 mg, 0.084 mmol), and cesium carbonate (0.074 g, 0.229 mmol). The vial was flushed with Ar (g), then acetonitrile (0.381 ml) was added. The reaction was stirred for four hours at room temperature. The mixture was diluted with EtOAc and 1 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford crude 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide as a yellow solid. (ESI) 470.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[CH:4][N:3]1[CH2:15][CH2:16][CH:17]=O.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:26]=[CH:25][C:24]([C@:27]23[CH2:32][C@H:31]2[CH2:30][NH:29][CH2:28]3)=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CO.CC(O)=O>[N:10]1[CH:11]=[CH:12][N:13]=[CH:14][C:9]=1[C:5]1[C:6](=[O:8])[NH:7][C:2](=[O:1])[N:3]([CH2:15][CH2:16][CH2:17][N:29]2[CH2:30][C@H:31]3[C@:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:34])[F:33])=[CH:26][CH:25]=4)([CH2:32]3)[CH2:28]2)[CH:4]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: O=CCCn1cc(-c2cnccn2)c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(Cl)Cl
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1cnccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A solution of 3-(2,4-dioxo-5-pyrazin-2-yl-3,4-dihydro-2H-pyrimidin-1-yl)-propionaldehyde (Prep127, 0.38 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 86 mg, 0.38 mmol), and AcOH (26 μl) in dichloroethane-MeOH (10-0.5, 4 ml) was cooled to 0° C. NaBH(AcO)3 (84 mg, 0.40 mmol) was added portionwise. The mixture was stirred at 0° C. for further one hour and then basified with 1N NaOH. The product was extracted with DCM. The organic phase was dried (Na2SO4) and evaporated. The residue was redissolved in DCM and stirred overnight in the presence of PS-isocyanate. The mixture was filtered and the solvent evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98-2-0.2) to give 78 mg of the title compound (45% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].[CH2:10]([OH:15])[C:11]([F:14])([F:13])[F:12].O.[OH-].[Li+]>CS(C)=O.O>[Cl:9][C:5]1[N:4]=[N:3][C:2]([O:15][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:7]([NH2:8])[CH:6]=1
Reactant: Nc1cc(Cl)nnc1Cl
Reactant: OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Cl)nnc1OCC(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 3.28 g 3,6-dichloro-pyridazin-4-ylamine in 30 mL dimethylsulfoxide and 4.0 g trifluoroethanol was added 1.84 g lithium hydroxide hydrate and 3 mL water and the mixture was heated to 80° C. for 18 h. The reaction mixture was diluted with 100 mL water and stirred at ambient temperature for 2 h. The resulting solid was collected by filtration washed with water and dried to constant weight under high vacuum to yield 3.84 g of the title compound as off white crystals, MS 228.1 and 230.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1.[C:11]([NH:14][C:15](=[CH2:20])[C:16]([O:18][CH3:19])=[O:17])(=[O:13])[CH3:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]([NH:14][C:15](=[CH:20][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1)[C:16]([O:18][CH3:19])=[O:17])(=[O:13])[CH3:12]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: Cc1cc(Br)cc(C)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(=Cc1cc(C)c(Cl)c(C)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere 30.0 g (136.7 mmol) 5-bromo-2-chloro-1,3-dimethylbenzene, 24.0 g (164.0 mmol) methyl 2-acetylamino-acrylate in 420 mL triethylamine and 200 mL acetonitrile were combined with 3.4 g (10.9 mmol) tri-o-tolyl-phosphane and 2.4 g (10.9 mmol) Pd(OAc)2 and stirred for 18 h at 80° C. The precipitate was suction filtered, the filtrate was evaporated down i. vac., combined with 800 mL DCM and 800 mL water, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was stirred with EtOAc, suction filtered and dried i. vac.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:19][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1.O.N1(O)C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:19][N:14]3[CH2:15][CH2:16][N:17]([C:29](=[O:30])[CH2:28][C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:32])([F:20])[F:33])[CH:23]=4)[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CNCCN3C2)cn1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(C(=O)Cc4cccc(C(F)(F)F)c4)CCN3C2)cn1
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
The product from Example 152C (102 mg, 0.392 mmol) was dissolved in dichloromethane (1 mL) followed by addition of 3-trifluoromethylphenylacetic acid (88 mg, 0.431 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (66.0 mg, 0.431 mmol). The mixture was stirred for 5 minutes and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (76 μL, 0.431 mmol) was added. After stirring for 18 hours at ambient temperature, the mixture was partitioned between water and dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on a 24 g silica gel column, eluting with 2.5% methanol (containing 2 N ammonia) in dichloromethane for 3 minutes and then a gradient to 10% methanol (2 N ammonia) in dichloromethane to afford the title compound as a viscous colorless oil (101 mg, 57.7%). 1H NMR (300 MHz, CDCl3) δ ppm 1.76-2.15 (m, 2H), 2.18 (s, 3H), 2.19-2.37 (m, 2H), 2.37-2.53 (m, 1H), 2.69-2.91 (m, 1H), 2.91-3.05 (m, 1H), 3.14-3.29 (m, 1H), 3.65-3.78 (m, 1H), 3.80 (d, J=3.3 Hz, 2H), 3.93 (dd, J=12.5, 2.0 Hz, 1H), 4.64 (ddd, J=10.3, 5.9, 4.5 Hz, 1H), 4.74-4.83 (m, 1H), 5.23 (d, J=1.4 Hz, 1H), 5.39 (tdd, J=7.2, 5.2, 1.9 Hz, 1H), 5.80 (s, 1H), 7.49 (ddd, J=16.3, 4.6, 2.8 Hz, 3H), 8.14 (t, J=1.4 Hz, 1H), 8.18-8.23 (m, 1H); MS (ESI) m/z 447 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH:23]1([CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O.O>[Cl:1][C:2]1[C:3]([NH:36][C@@H:32]2[CH2:33][CH2:34][CH2:35][N:30]([CH2:29][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:31]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH2:13][CH3:14])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: N[C@@H]1CCCN(CC2CCCCC2)C1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
A mixture of 5,6-dichloronicotinic acid (356 mg), iodoethane (318 mg) and potassium carbonate (308 mg) in N,N-dimethylformamide (3 mL) was heated at eighty degree for fourteen hours. The mixture was allowed to cool to ambient temperature and to this was added (3R)-1-(cyclohexylmethyl)-3-piperidinamine dihydrochloride (549 mg) and potassium carbonate (898 mg) and heated at eighty degree for thirtyeight hours. The mixture was allowed to cool to ambient temperature and was added water. The mixture was extracted with ethyl acetate (100 mL) and aqueous phase was separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was filtered and evaporated in vacuo to give an amorphous solid. The crude solid was purified by a flash chromatography eluting with 3% methanol-chloroform (v/v) to give ethyl 5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}nicotinate (154 mg) as a pale yellow amorphous solid.
Reaction SMILES: C12CCC(CC1)CN(C(CN1C3C=CC=CC=3C(C3C=CC=CC=3F)=NC([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=3)=[O:33])C1=O)=O)C2.Cl.C([N:47](CC)CC)C.C(OCC)(=O)C.[OH2:58]>CS(C)=O>[NH2:47][C:41]([C:37]1[CH:36]=[C:35]([NH:34][C:32](=[O:33])[NH2:31])[CH:40]=[CH:39][CH:38]=1)=[N:42][OH:58]
Reactant: N#Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Reactant: CCN(CC)CC
Reactant: O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)Nc1cccc(C(N)=NO)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-cyanophenyl)urea, hydroxyamie hydrochloride and triethylamine in dimethylsulfoxide was stirred at 70° C. overnight. Ethyl acetate and water weretadded to the reaction mixture and the organic layer was separated, washed with water and brion, dried over magnesium sulfate, and evaporated to dryness. The crude powder was purified by column chromatography on silica gel to afford N-[(3RS)-1-(3-azabicyclol[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-{3-[1-amino-1-hydroxyiminomethyl]-phenyl}urea.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[N:10]=NC1C=CC(Cl)=CC=1>C(O)C.O.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10]
Reactant: Nc1nc(N)c(N=Nc2ccc(Cl)cc2)c(Cl)n1
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1nc(N)c(N)c(Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.7 %

Procedure:
A suspension of 6-chloro-5-[(4-chlorophenyl)azo]-2,4-pyrimidinediamine (24.55 g, 0.0906 mol) in ethanol (640 ml), water (640 ml) and acetic acid (64 ml) was heated to 70° under nitrogen. Zinc dust (75 g) was added slowly over 1 hour, and then the reaction was stirred an additional hour at 70°. Then the reaction was cooled to room temperature and filtered under nitrogen. The filtrate was cooled to 0° and the pH was raised to 10 with 10% sodium hydroxide (400 ml). The precipitated zinc hydroxide was removed by filtration through Celite, and the dark red filtrate was neutralized to pH 7 with glacial acetic acid and concentrated to 300 ml. Water (50 ml) was added, the reaction was cooled to 0°, and the pH raised to 9 with 10% NaOH. The solution was allowed to stand at 5° for 3 days. The crystals were collected, washed with water (50 ml) and then ether (50 ml), and dried at 35° for 16 hours in vacuo to give 10.94 g of desired product.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:16]2[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:23][C:24](=[O:26])[CH3:25])[CH:17]=2)[O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])(=O)[CH3:2].C[N:28]([CH:30](OC)OC)C.O.[NH2:36]N>C1(C)C=CC=CC=1>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]1[O:7][C:6]([C:16]2[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:23][C:24](=[O:26])[CH3:25])[CH:17]=2)=[N:5][C:4]=1[C:1]1[CH:2]=[CH:30][NH:28][N:36]=1
Reactant: NN
Reactant: CC(=O)Nc1cc(-c2nc(C(C)=O)c(-c3ccccc3Cl)o2)c(C)cn1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(-c2nc(-c3cc[nH]n3)c(-c3ccccc3Cl)o2)c(C)cn1
Temperature: 100 °C
Reaction time: 96 h
Yield: 359.7 %

Procedure:
A solution of N-{4-[4-acetyl-5-(2-chlorophenyl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (0.12 g, 0.24 mmol) and DMF-DMA (0.84 mL, 0.63 mmol) in toluene (0.5 mL) was allowed to stir at 100° C. for 5 days, during which time several additional portions of DMF-DMA were added. The reaction mixture was concentrated and the residue was redissolved in AcOH (2 mL). Hydrazine hydrate (0.13 mL, 2.63 mmol) was added and the reaction mixture was allowed to stir at 100° C. for 4 days. The reaction mixture was concentrated and the residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(1H-pyrazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (Compound I-30) (0.34 g, 35%). LCMS (FA): m/z=394 (M+H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1ccsc1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1
Yield: 55.7 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (100 mg, 0.24 mmols), 3-thienylboronic acid (92 mg, 0.72 mmols), potassium carbonate (197 mg), and Pd(PPh3)4 (28 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (57 mg, 55%)
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][C:5]#[N:6].[N:9]1([CH2:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[O:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C>[C:5]([N:4]=[C:3]([S:2][CH3:1])[NH:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:23]=[CH:24][CH:25]=[C:15]([CH2:14][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:16]=1)#[N:6]
Reactant: CSC(=NC#N)SC
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Solvent: CCOC(C)=O
Product: CSC(=NC#N)NCCCOc1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-cyano-carbonimidodithioic acid dimethyl ester (5 g) in ethyl acetate (50 ml) was added to a solution of 3-[3-(1-pyrrolidinylmethyl)phenoxy]propanamine in ethyl acetate (60 ml). The reaction mixture was stirred at room temperature for 1 hr to give the title compound as an off-white solid m.p. 107°-108.5° (7.45 g). TLC silica; ethyl acetate: isopropanol:water:0.88 ammonia (25:15:8:2) single spot Rf 0.7.