Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:4]=1)=[O:28]
Reactant: CSc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
2-[4-(Methylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.28 g, 1.00 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.23 g, 77%) as pale yellow crystals.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:20][CH2:21][C@H:22]1[CH2:24][C@H:23]1[CH2:25][OH:26])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:13]([NH:20][CH2:21][C@H:22]1[CH2:24][C@H:23]1[CH2:25][O:26][N:28]1[C:32](=[O:33])[C:31]2[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]1=[O:38])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@H]1CON1C(=O)c2ccccc2C1=O

Procedure:
A solution of 2.61 ml (0.0157 mol) of diethyl azodicarboxylate (93%) in 15 ml of benzene is added dropwise to a mixture of 3 g (0.0149 mol) of cis-2-(N-BOC-aminomethyl)-cyclopropanemethanol, 2.43 g (0.0149 mol) of N-hydroxyphthalimide, 3.9 g (0.0149 mol) of triphenylphosphine and 120 ml of benzene at 20°-30° C., while stirring. The reaction mixture is stirred at room temperature for 16 hours and filtered, the crystalline residue is washed with benzene and the filtrate is evaporated in vacuo. The residue is purified by means of flash chromatography on silica gel using hexane and hexane/ethyl acetate (2:1). After evaporation of the product-containing fractions and crystallization of the residue from methanol/hexane, the title compound is obtained, m.p. 96°-97° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][N:4]=1.[H-].[Na+].[I-].[K+].Cl[CH2:19][CH2:20][C:21]([NH:23][C:24]1[S:28][C:27]2[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=2[C:25]=1[C:33]([NH2:35])=[O:34])=[O:22]>CN(C=O)C.O>[F:13][C:2]([F:1])([F:12])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH:20]([CH3:19])[C:21]([NH:23][C:24]2[S:28][C:27]3[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=3[C:25]=2[C:33]([NH2:35])=[O:34])=[O:22])[N:4]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: NC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)Nc1sc2c(c1C(N)=O)CCCC2)n1nc(C(F)(F)F)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole (50 mg, 0.263 mmol) was dissolved in DMF (2 mL). NaH (60% [w/w] suspension in oil, 11 mg, 0.275 mmol) was added followed by potassium iodide (2 mg, catalyst) and the reaction mixture stirred at RT for 30 min. 2-(3-chloropropanamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (75 mg, 0.262 mmol) was then added and the reaction mixture heated at 120° C. for 400 sec in a Biotage SmithCreator microwave. Water was added followed by EtOAc (3×10 mL) extraction. The EtOAc layers were washed with water (5×5 mL), brine, dried over MgSO4, filtered and the solvent removed in vacuo to give a yellow gum. Purification by preparative reverse phase HPLC gave desired product (22.7 mg, 0.052 mmol, 20%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[CH2:11]([C:14]1[N:19]2[N:20]=[CH:21][C:22]([C:23](OCC)=[O:24])=[C:18]2[CH:17]=[CH:16][CH:15]=1)[CH2:12][CH3:13]>C1C=CC=CC=1>[CH2:11]([C:14]1[N:19]2[N:20]=[CH:21][C:22]([C:23]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:24])=[C:18]2[CH:17]=[CH:16][CH:15]=1)[CH2:12][CH3:13]
Reactant: OC1CN2CCC1CC2
Reactant: CCCc1cccc2c(C(=O)OCC)cnn12
Agent: [Na]
Solvent: c1ccccc1
Product: CCCc1cccc2c(C(=O)OC3CN4CCC3CC4)cnn12
Reaction time: 2 h
Yield: 84.9 %

Procedure:
After a suspension of 330 mg (2.60 mmol) of 3-quinuclidinol in 30 ml of benzene was refluxed for 0.5 hour by using a Dean-Stark apparatus, 0.1 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 2 hours. Unreacted sodium was removed and 200 mg (0.86 mmol) of ethyl 7-propylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 20 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform: methanol=10:1), whereby 230 mg (0.73 mmol) of the title compound were obtained as an oily substance (yield: 85%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[OH:15]O>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N+:3]=1[O-:15]
Reactant: OO
Reactant: CCOc1nc(N)nc2nccnc12
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nc(N)[n+]([O-])c2nccnc12
Reaction time: 48 h
Yield: 32 %

Procedure:
To a cooled (0° C.) solution of the compound of example 60 (2.47 g, 12.9 mmoles) in trifluoroacetic acid (53 ml) was added dropwise 2.53 ml of a 35% aqueous H2O2 solution. The reaction mixture was kept at 4° C. for two days in the refrigerator, whereby another 1.25 ml of the same H2O2 solution was added after 1 day. The solution was concentrated in vacuo. The residue was suspended in water and neutralized by the addition of a concentrated ammonia solution. Evaporation of the solvent in vacuo and purification of the residue by flash chromatography (silica, using a CH3OH/CH2Cl2 mixture (6:94) as the eluent) provided the title compound as a yellow powder (861 mg, yield: 32%). Mass spectrum data are as follows: m/z (%): 230 ([M+Na]+, 30), 208 ([M+H]+, 100), 180 [(M+H-ethene)+, 10].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[C:19]2[O:18][C:17]2[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:16]3=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C.C(O)C>[F:29][C:28]1[C:16]2[C:15]3([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[C:19]3[O:18][C:17]=2[CH:25]=[CH:26][CH:27]=1
Reactant: Fc1cccc2c1C1(c3ccc(OCc4ccccc4)cc3)CCCCC=C1O2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc(C23CCCCC=C2Oc2cccc(F)c23)cc1
Yield: 69.6 %

Procedure:
10% Palladium on activated carbon (few mg) was added to a solution of 22 (15 mg) in ethyl acetate (2 mL) and ethanol (2 mL). A balloon filled with H2 was fitted and H2 was bubbled through the solution for 15 s. The mixture was filtered after 15 min, TLC indicated 50% conversion of 22. Work-up by flash chromatography (eluent: dichloromethane ->5% ethyl acetate in dichloromethane) afforded 8 mg of the title product. Starting material (5 mg) was recovered. LC-MS confirmed m/z=295 (M−1). 1H-NMR (400 MHz, CDCl3): δ ppm 7.49-7.46 (m, 2H), 7.05-7.00 (m, 1H), 6.81-6.79 (m, 2H), 6.61-6.59 (m, 1H), 6.53-6.48 (m, 1H), 5.73 (dd, J=4.8, 9.2 Hz, 1H), 3.07-3.02 (m, 1H), 2.00-1.20 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:23])[C:13](=[O:22])[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:23])[CH:13]([OH:22])[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)C(C)(C)C(O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A solution of ethyl(4S)-4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-oxopentanoate (905 mg) in methanol (30 mL) was cooled to 0° C., 90% sodium borohydride (180 mg) was added, and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give ethyl(4S)-4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-hydroxypentanoate as a colorless oil (yield: 720 mg, 79%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[C:12]([CH3:19])[CH:11]=1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].[NH4+].[Cl-]>C1COCC1.O>[CH3:25][O:24][C:22](=[O:23])[CH2:21][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][C:12]=1[CH3:19])[C:17]#[N:18]
Reactant: Cc1cc(Br)ccc1CC#N
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(C#N)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
Lithium diisopropylamide (2 M in THF, 110 mL) was added dropwise at −78° C. to a solution of (4-bromo-2-methyl-phenyl)-acetonitrile (38.55 g, 0.1835 mol) in THF (400 mL). The reaction mixture was stirred for 10 minutes and methyl bromoacetate (16.87 mL, 0.1835 mol) was added. The resulting mixture was stirred at −78° C. for 2 hours. A saturated solution of NH4Cl was then added at −78° C. and the resulting mixture was warmed to room temperature. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine; dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 9/1) to give 43.09 g of 3-(4-bromo-2-methyl-phenyl)-3-cyano-propionic acid methyl ester (83% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.O.[NH2:25][NH2:26].[C:27]([OH:30])(=[O:29])[CH3:28]>COC(OC)(N(C)C)C>[C:27]([OH:30])(=[O:29])[CH3:28].[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]3[NH:23][C:27]([CH3:28])=[N:26][N:25]=3)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Reactant: NN
Agent: COC(C)(OC)N(C)C
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(-c2sc(-c3c(C)nn4ccsc34)nc2-c2ccccc2)[nH]1
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
2-(6-Methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxamide (79 mg, about 0.23 mmol) produced in the same manner as in Example 35-B(ix) was suspended in N,N-dimethylacetamide dimethyl acetal (2 mL), and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, hydrazine monohydrate (0.017 mL, 0.35 mmol) and acetic acid (2 mL) were added to the residue, and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and the resulting solid was collected by filtration and washed with ethyl acetate to give the title compound (72 mg, 70%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:26]1[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[C:28](Cl)[N:27]=1>C(#N)C>[NH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:26]2[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][N:27]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccnc(NCC2CCNCC2)n1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was prepared as follows: A 40 mL round-bottomed vial was charged with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.76 mmol, 1.1 equiv.), acetonitrile (4 mL), DiPEA (2.37 mmol, 1.5 equiv.), methyl 2,6-dichloropyrimidine-4-carboxylate (1.58 mmol, 1 equiv.), and then shaken at 85° C. for 72 h. The reaction mixture was concentrated under reduced pressure and purified on SiO2 using a Biotage and a 10-50% EtOAc/hexanes gradient to provide the desired protected amine (233 mg, 552 mg theoretical, 42%). Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was prepared using the general TFA de-protection procedure and used directly in the general displacement procedure to provide the title compound (4 mg, 73.4 mg theoretical, 5%). LC-MS m/z 456.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]Br.O>C(Cl)(Cl)Cl>[Br:11][C:5]1[O:4][C:3]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: COC(=O)c1occc1C
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1oc(Br)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of methyl 3-methylfuran-2-carboxylate (5.6 g) in chloroform (40 mL) was added dropwise bromine (2.3 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 30 min, at room temperature for 1 hr, and at 50° C. overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 10% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (5.3 g, 60%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:19].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][I:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Reactant: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Temperature: 62 °C
Yield: 84.5 %

Procedure:
A solution of 2-(S)-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (compound (3) obtained from above, 30 g, 0.10 mol) in anhydrous tetrahydrofuran (600 mL) was cooled to 0° C. Lithium iodide (144 g, 1 mol) was added to the cold reaction mixture as a solid in portions while maintaining the reaction temperature at below 30° C. The reaction mixture was warmed to 62° C. until HPLC showed less than 2% starting material. The reaction mixture was quenched with 10% aqueous sodium thiosulfate (300 mL). Ethyl acetate (600 mL) was added to reaction mixture. The organic layer was separated. The aqueous layer was re-extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (2×100 mL), dried over MgSO4, filtered, and concentrated to leave an oily residual product (26.3 g, 78.6% yield). 1H NMR (CDCl3): δ 1.46 (d, 3H, CH3), 1.48 (d, 6H, 2×CH3), 1.792.14 (m, 4H, 2×CH2), 3.14–3.52 (m, 4H, 2×CH2) and 3.88 (m, 1H, CH); [M+H]+ at m/z 312.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]([CH3:18])[C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:10]=1)[C:5]([OH:7])=O.[CH3:19][C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]([CH3:18])[C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:10]=1)[C:5]([NH:25][C:22]1[S:23][CH:24]=[C:20]([CH3:19])[N:21]=1)=[O:7]
Reactant: Cc1csc(N)n1
Reactant: CN(c1cncnc1)c1cc(F)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cc(F)cc(N(C)c3cncnc3)c2)n1
Yield: 58.1 %

Procedure:
Compound 13 (0.727 g, 2.94 mmol, 1.00 eq), 4-methylthiazol-2-amine (369 mg, 3.23 mmol, 1.10 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.23 g, 3.23 mmol, 1.10 eq), and DIEA (563 μL, 3.23 mmol, 1.10 eq) were dissolved in CH2Cl2 (15 mL) and DMF (3 mL) and stirred rt for 48 h. The reaction was diluted with CH2Cl2 and washed with water (1×). The organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 587 mg (58%) of the title compound as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.68 (s, 2H), 7.58 (m, 1H), 7.45 (m, 1H), 7.18 (m, 1H), 6.81 (s, 1H), 3.39 (s, 3H), 2.28 (s, 3H); [M+1]+: 344.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:9]=1)[C:5]#[N:6].[Cl:19][C:20]1[C:21](B(O)O)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=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>[Cl:19][C:20]1[C:21]([C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:9]=2)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1
Reactant: N#Cc1cc(Cl)nc(NCc2cccc(F)c2)c1
Reactant: OB(O)c1cc(F)ncc1Cl
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(F)ncc2Cl)c1
Temperature: 110 °C
Yield: 46.5 %

Procedure:
To a degassed suspension of 2-chloro-6-(3-fluorobenzylamino) isonicotinonitrile (150 mg, 0.573 mmol) and 5-chloro-2-fluoropyridin-4-ylboronic acid (151 mg, 0.860 mmol) in DME (5 ml) was added Na2CO3 (1.433 ml, 2M, 2.87 mmol) and Pd(Ph3P)4 (66.2 mg, 0.057 mmol). The reaction mixture was capped and heated to 110° C. in an oil bath for 2 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified purified by column chromatography on silica gel (0-20% EtOAc/Hexane) to give 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (95 mg, 47%). LCMS (m/z): 357.0 (MH+), retention time=1.09 min
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:29]4[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]4)=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Reactant: O=C(O)C1CNC1
Product: O=C(Nc1ccc(CN2CC(C(=O)O)C2)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and azetidine-3-carboxylic acid (Apollo), the title compound was obtained as a yellow solid after precipitation from DCM/MeOH.
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])=[CH:3][CH2:4][CH2:5][Mg]Br.BrCCC=C(C)CCC1C(C)(C)CCCC=1C.[Mg].BrCCBr.[CH3:41][Si:42]([CH3:51])([CH3:50])[C:43]1[O:47][CH:46]=[C:45]([CH:48]=[O:49])[CH:44]=1.Cl>C(OCC)C>[OH:49][CH:48]([C:45]1[CH:44]=[C:43]([Si:42]([CH3:51])([CH3:50])[CH3:41])[O:47][CH:46]=1)[CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CC(=CCC[Mg]Br)CCC1=C(C)CCCC1(C)C
Agent: CC(=CCCBr)CCC1=C(C)CCCC1(C)C
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: BrCCBr
Product: CC(=CCCC(O)c1coc([Si](C)(C)C)c1)CCC1=C(C)CCCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)-3-hexenylmagnesium bromide (0.70 mmol, prepared from 0.21 g., 0.70 mmol 1-bromo-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)-3-hexene and 2.1 mmol magnesium, with a catalytic amount of 1,2-dibromoethane as initiator), in one ml ethyl ether at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.13 g., 0.77 mmol) in one ml ether. This solution was allowed to warm to room temperature, stirred for 30 minutes, and then poured over crushed ice containing several drops of hydrochloric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. This material was purified by flash chromatography (silica, 20% ethyl ether/hexane) to give the desired alcohol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[Cl-].[NH4+:37]>CO>[NH2:32][C:31](=[NH:37])[C:27]1[CH:26]=[C:25]([O:24][C:18]2[CH:17]=[C:16]3[C:21]([CH2:22][CH2:23][CH:14]([C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=4)=[O:13])[CH2:15]3)=[CH:20][CH:19]=2)[CH:30]=[CH:29][N:28]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(C#N)c4)cc3C2)c1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(C(=N)N)c4)cc3C2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-(3-tert-butylphenyl)-7-[(2-cyanopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (1.5 g, 3.5 mmol) in MeOH (20 mL) was added sodium methoxide (28 mg, 0.52 mmol). The solution was allowed to stir at rt for 3 days and then ammonium chloride (0.28 g, 5.3 mmol) was added. The reaction mixture was allowed to stir overnight and then concentrated to give 7-({2-[amino(imino)methyl]pyridin-4-yl}oxy)-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-422 as a white solid, which was directly used into the next step. LCMS: (FA) ES+ 443.3.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]#[N:18])=[C:15]([N:19]=[CH:20][N:21](C)C)[NH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)N>CO>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:16]3[C:15](=[N:19][CH:20]=[N:21][C:17]=3[NH:18][C:31]3[CH:30]=[CH:28][CH:27]=[C:26]([Cl:25])[CH:32]=3)[NH:14][N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Nc2n[nH]c(N=CN(C)C)c2C#N)cc1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6.32 g (20.3 mmol) of 3-(4-acetylamino-phenylamino)-4-cyano-5-(dimethylamino-methyleneamino)-pyrazole and 4 g (24.4 mmol) of 3-chloro-aniline hydrochloride in 50 ml of methanol is heated under reflux for 96 hours and then cooled to room temperature. The reaction mixture is filtered and the filter residue is digested for 1/2 hour in 50 ml of 1N sodium hydroxide solution. Filtering and washing with water yield the title compound; m.p. 290-291° C. (decomp.).