Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[C:17]3[C:18](=[CH:22][N:23]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:24]=3)[N:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.[S:38](Cl)([CH3:41])(=[O:40])=[O:39]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[C:17]3[C:18](=[CH:22][N:23]([CH:25]4[CH2:26][CH2:27][N:28]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:29][CH2:30]4)[N:24]=3)[N:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(C5CCNCC5)nc34)ccn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(C5CCN(S(C)(=O)=O)CC5)nc34)ccn2)c1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a solution of N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-2-(piperidin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (49 mg, 0.122 mmol) in dichloromethane (3 mL) at 0° C. was added triethylamine (0.051 ml, 0.365 mmol) and mesyl chloride (10.41 μl, 0.134 mmol). The reaction was removed from the ice bath and briefly stirred at room temperature. The reaction mixture was concentrated and subjected to silica column chromatography eluted with 0-5% methanol in dichloromethane using a step gradient (over 24 minutes) to give N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (12 mg, 21%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.31-2.49 (m, 7H) 2.83-2.95 (m, 3H) 2.95-3.10 (m, 2H) 4.03 (d, J=12.63 Hz, 2H) 4.42-4.66 (m, 1H) 7.03-7.24 (m, 4H) 7.34 (s, 1H) 7.75 (s, 1H) 7.83 (dd, J=7.58, 2.02 Hz, 1H) 8.18 (s, 1H) 8.44 (d, J=4.80 Hz, 1H) 8.65 (d, J=5.56 Hz, 1H). MS [M+H] found 481.4.
Reaction SMILES: [CH:1]1([C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)([O:8][CH3:9])[CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2]1.ClC1C=C(C(OO)=[O:25])C=CC=1>ClCCl>[CH:1]1([C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)([O:8][CH3:9])[CH2:5][CH:6]2[CH2:7][O:25]2)[CH2:3][CH2:2]1
Reactant: C=CCC(OC)(c1ccc(F)cc1)C1CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(CC1CO1)(c1ccc(F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 100.6 parts of 1-(1-cyclopropyl-1-methoxy-3-butenyl)-4-fluorobenzene and 238 parts of dichloromethane was added a solution of 101.5 parts of 3-chlorobenzeneperoxoic acid in 952 parts of dichloromethane (exothermic reaction after 30 minutes). The whole was stirred overnight at room temperature. The precipitate was filtered off and the filtrate was washed successively with a saturate sodium carbonate solution, a saturate sodium sulfite solution, a 5% sodium hydroxide solution and water. The organic phase was dried, filtered and evaporated, yielding 106 parts of [2-cyclopropyl-2-(4-fluorophenyl)-2-methoxyethyl]oxirane as a residue (intermediate 7).
Reaction SMILES: C[Si]([NH:5][CH:6]1[C:22](=[O:23])[N:8]2[C:9]([C:15]([O:17][Si](C)(C)C)=[O:16])=[C:10]([CH2:13][I:14])[CH2:11][S:12][C@H:7]12)(C)C.[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CO>>[IH:14].[NH2:5][C@@H:6]1[C:22](=[O:23])[N:8]2[C:9]([C:15]([O-:17])=[O:16])=[C:10]([CH2:13][N+:25]3([CH3:24])[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:11][S:12][C@H:7]12
Reactant: CN1CCCC1
Reactant: C[Si](C)(C)NC1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(CI)CS[C@H]12
Solvent: CO
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)CCCC1
Product: I
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To the filtrate containing the trimethylsilyl 7-(trimethylsilyl)amino-3-iodomethylceph-3-em-4-carboxylate at 0°-5° C. under an inert atmosphere of dry nitrogen was added 3.82 ml (36.7 mmoles, 1.0 equivalent) of 97% N-methylpyrrolidine (dried over molecular sieves) dropwise by syringe at such a rate so as to maintain a reaction temperature of less than 10° C. The resulting slurry was stirred an additional 15 minutes at 0°-5° C. After this time. 5.0 ml (123 mmoles, 3.35 equivalent) of methanol was added dropwise while maintaining a reaction temperature of less than 10° C. The resulting thin slurry was stirred an additional 15 minutes at 0°-5° C. The solid was suction filtered, washed with Freon TF (1×100 ml) and partially dried under suction for 15 minutes. Further drying in vacuo at ambient temperature to constant weight afforded 10.27 g (66%) of (6R,7R)-7-amino-3-(1-methyl-1-pyrrolidinio)methylceph-3-em-4-carboxylate monohydroiodide. The 360 MHz 1H NMR spectrum of this crude material (D2O) showed a Δ3 /Δ2 isomer ratio of 5.4/1; the HPLC chromatogram of the salt showed a Δ3 /Δ2 area % ratio of 8.1/1. The activity yield for the conversion of 7-ACA to 7-amino-3-(1-methyl-1-pyrrolidinio)methylceph-3-em-4-carboxylate was 43.5% (determined by HPLC quantitation of the salt versus a reference standard of the desired Δ3 isomer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][C:13]=2[N+:19]([O-])=O)[N:4]=1.[H][H].[C:24](OCC)(=O)C>[C].[Pd]>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12]2[C:13]([NH2:19])=[CH:14][CH:15]=[C:16]([CH3:24])[CH:17]=2)[N:6]=1
Reactant: [H][H]
Reactant: CCOC(C)=O
Reactant: COc1cc(OC)nc(Nc2ccc(C)cc2[N+](=O)[O-])n1
Agent: [Pd]
Product: COc1cc(OC)nc(Nc2cc(C)ccc2N)n1

Procedure:
N-(4,6-dimethoxypyrimidin-2-yl)-4-methyl-2-nitroaniline (37.50 g) was dissolved in ethyl acetate (600 ml), and 10% palladium carbon (3.75 g) was added thereto. Stirring was carried out at room temperature under normal pressure in an atmosphere of hydrogen for 4 hours, followed by filtration. The solvent of the filtrate was distilled off to obtain 32.70 g of the desired product as a white powder (m.p. 128-129° C.)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:27])[O:13][C:14](=O)[C:15]=2[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:3]1.[NH3:28]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:27])[NH:28][C:14](=[O:13])[C:15]=2[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc4ccccc34)C(=O)OC2=O)c2ccccc21
Reactant: N
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cccc4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 130 °C

Procedure:
56 mg of 3-(1-methyl-3-indolyl)-4-(1-naphthyl)furan-2,5-dione were treated with 5 ml of DMF and 5 ml of 33% aqueous ammonia and the mixture was heated at 130° C. for 5 hours. The formed precipitate was filtered off, washed with water and dried to give 53 mg of 3-(1-methyl-3-indolyl)-4-(1-naphthyl)-1H-pyrrole-2,5-dione, m.p. 258°-260° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)[N:21]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([C:22]3[N:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:31][N:30]=2)=[O:19])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2]
Reactant: Nc1ccc(-c2cccnn2)cn1
Reactant: N#Cc1cc(CC(=O)O)ccc1-c1ccnc(F)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
Product: N#Cc1cc(CC(=O)Nc2ccc(-c3cccnn3)cn2)ccc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 206-6 (38 mg, 0.15 mmol), was dissolved in DMF (2 mL), 5-(pyridazin-3-yl)pyridin-2-amine (31 mg, 0.18 mmol) and DIEA (131 uL, 0.75 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (86 mg, 0.23 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 214. MS m/z 411.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.23 (dd, 1H), 9.13 (d, 1H), 8.56 (dd, 1H), 8.42 (d, 1H), 8.30 (dd, 1H), 8.23 (d, 1H), 8.02 (d, 1H), 7.86-7.78 (m, 2H), 7.74 (d, 1H), 7.63 (dt, 1H), 7.50 (s, 1H), 3.97 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:19]2[CH3:28])=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:19]2[CH3:28])=[N:12][C:13]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:14][C:15]=1[CH3:16]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3[C@@H]2C)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3[C@@H]2C)c1C
Product: Cl
Yield: 78.3 %

Procedure:
After 4-fluoroaniline(1 ml, 10 mmol) was added to a mixture solution of (S)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.4 g, 4.8 mmol) and dimethylformamide(10 ml), 1.50 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].ClCCCl.[CH:36](OCC)=[O:37]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([CH:36]=[O:37])[CH2:13][CH2:12]1)[C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])=[O:4]
Reactant: CCOC=O
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Solvent: ClCCCl
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C=O)CC1
Temperature: 95 °C

Procedure:
A solution of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]thiophene-2-carboxylic acid methyl ester (100 mg, 0.22 mmol) in ethyl formate (1.5 mL) under nitrogen, was placed in a bath at 65° C. for 20 h after which was added 1,2-dichloroethane (2.5 mL) and another portion of ethyl formate (2 mL). The bath temperature was raised to 95° C. and the reaction refluxed for a further 21 h. Tlc showed ca 80% conversion. The reaction was stripped off solvent and the residue purified by column chromatography using methylene chloride:acetonitrile:methanol=9:1:0.1 as eluent to give 5-Cyclohex-1-enyl-3-[(1-formyl-piperidin-4-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (42 mg, 41%)
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[CH2:41][CH3:42]>CN(C=O)C.ClCCl>[OH:26][CH2:25][CH2:24][N:23]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]1[C:16]2[CH2:22][N:21]([C:40](=[O:43])[CH2:41][CH3:42])[CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)[N:14]=1
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (85 mg, 0.20 mmol, Example 1) was dissolved in DMF (0.5 mL) and dichloromethane (4 mL). Triethylamine (0.028 mL, 0.20 mmol) was added followed by propionyl chloride (0.021 mL, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 h and the solvent was evaporated under reduced pressure. The crude was dissolved in dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propan-1-one (8.0 mg, 8.32%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.Cl.[NH2:17]O.[OH-].[Na+]>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10](=[O:11])[O:12][N:17]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccc(I)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CC(c2ccc(I)cc2)=NO1
Reaction time: 1 h
Yield: 74.1 %

Procedure:
Ethyl 3-(4-iodophenyl)-3-oxopropanoate (3.0 g, 9.4 mmol) was added slowly to a solution of hydroxylamine hydrochloride (660 mg, 9.44 mmol), NaOH (795 mg, 19.8 mmol), and water (12 mL) at 0° C. The reaction mixture was kept at 0° C. for 1 h. The precipitate was collected by filtration, rinsed with water, and dried under vacuum to afford the title compound as white solid (2.0 g, 64%). 1H NMR (CDCl3, 400 MHz): δ 7.84 (d, 2H), 7.40 (d, 2H), 3.78 (s, 2H). 13C NMR (acetone-d6, 100 MHz): δ 176.1, 164.6, 139.1, 129.2, 129.0, 98.6, 34.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([OH:22])[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.[OH-].[Na+:24].C1COCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]([C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)=[O:22])[C:11]=1[C:9]([O-:10])=[O:8].[Na+:24]
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)cccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)nc(C(=O)c2cccc(Cl)c2C(=O)[O-])n1

Procedure:
1.24 g of 7-chloro-3-hydroxy-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide, 154 mg NaOH, 25 ml THF and 25 ml water are mixed until a yellow homogenous solution is achieved. The solvents are stripped on a rotovaporator and then on a Kugelrohr at 100° C. to produce the title compound as a yellow solid, m.p. 276°-278° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][N:20](C)C=O.[Cu]C#N.Cl>[Fe](Cl)(Cl)Cl.O>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]#[N:20])=[CH:3][CH:4]=2)=[N:9][CH:10]=1)[CH2:15][CH2:16][CH:17]=[CH2:18]
Reactant: CN(C)C=O
Reactant: C=CCCCc1ccc(-c2ccc(Br)cc2)nc1
Agent: Cl[Fe](Cl)Cl
Agent: N#C[Cu]
Agent: Cl
Solvent: O
Product: C=CCCCc1ccc(-c2ccc(C#N)cc2)nc1
Temperature: 180 °C

Procedure:
A suspension of 5.59 g of 2-(p-bromophenyl)-5-(4-pentenyl)pyridine, 4 ml of dimethylformamide and 1.98 g of copper(I) cyanide was heated to 180° C. for 3 hours while stirring. The brown reaction mixture was then cooled to room temperature, subsequently poured into a mixture of 3.67 g of iron(III) chloride, 36.7 ml of water and 0.245 ml of concentrated hydrochloric acid and stirred at 55° C. for a further 1 hour. Thereafter, the mixture was cooled and partitioned between methylene chloride and water. The organic phase was washed with water, dried over sodium sulphate and filtered. The filtrate was evaporated and the residue was purified by chromatography on 250 g of silica gel with 2.5 l of methylene chloride under slight pressure. The p-[5-(4-pentenyl)-2-pyridyl]benzonitrile obtained had a m.p. (C--N) of -12° C. and could not be crystallized by cooling to below -70° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=O)=[C:4]1[CH3:23])[CH3:2].[C:24]1([C:30]2[C:31]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:32][N:33]3[C:38]=2[CH:37]=[CH:36][CH:35]=[CH:34]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([C:32]3[N:33]4[C:38]([CH:37]=[CH:36][CH:35]=[CH:34]4)=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:31]=3[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:20](=[O:21])[O:22]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Reactant: c1ccc(-c2cn3ccccc3c2-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3c(-c4ccccc4)c(-c4ccccc4)c4ccccn34)OC(=O)c3cccnc32)c2ccccc21

Procedure:
A mixture of 1.6 grams of (1-ethyl-2-methylindol-3-yl)(3-carboxypyridin-2-yl)ketone, 1.85 grams of 1,2-diphenylindolizine and 10 ml. of acetic anhydride was heated at about 40° C. for 104 minutes and then cooled in an ice bath. The reaction mixture was filtered and the product was repeatedly recrystallized from a toluene-petroleum ether mixture until a constant melting point of 206.5°-207.5° C. was obtained. A chloroform solution of the final product produced a blue color when applied to a record sheet material coated with a zinc-modified phenolic resin.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(#[N:16])C>F[B-](F)(F)F.C([N+](CCC)(CCC)CCC)CC>[CH:5]1[CH:6]=[CH:7][C:2]([NH:1][C:10]2[CH:9]=[CH:8][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: CC#N
Reactant: CCCCCC
Reactant: Nc1ccccc1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: F[B-](F)(F)F
Product: Nc1ccc(Nc2ccccc2)cc1
Reaction time: 1.11 h

Procedure:
The apparatus described in EXAMPLE 1 above was employed. Two liters of solution containing 20.0 grams (0.215 mole) of aniline, 54.4 grams (0.2 mole) of tetra-n-propylammonium tetra-fluoroborate in acetonitrile was charged to the reservoir. A similar solution (50 milliliters) but without the aniline was charged to each of first and second secondary electrode compartments (3b and 4b). The flow rate of the solution from the reservoir, as determined by the flow meter, was 30 milliliters per minute; the first face (2a) of working electrode 2 current was 180 milliamperes at +1.2 volts versus the saturated calomel electrode (with occasional cathodic pulses to restore electrode activity); and the second and opposite face (2b) of working electrode 2 current was 20 milliamperes at -0.5 volt versus the saturated calomel electrode. The electrolysis was conducted over a period of 1.11 hours. The resulting sequentially electrolyzed electrolysis medium was collected and the solvent evaporated in vacuo to yield a residue which was agitated with hexane to remove unreacted aniline. The small quantity of oil remaining after the extraction by hexane was shown to be 4-aminodiphenylamine via gas chromatographic analysis and comparison with an authentic sample.
Reaction SMILES: C([O:5][C:6](=[O:19])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[O:17][C:16](=[O:18])[NH:15][C:12]2=[N:13][CH:14]=1)(C)(C)C.[Cl:20]CCl>FC(F)(F)C(O)=O>[ClH:20].[O:18]=[C:16]1[NH:15][C:12]2=[N:13][CH:14]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:19])=[O:5])[CH:10]=[C:11]2[O:17]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]c(=O)oc2c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)/C=C/c1cnc2[nH]c(=O)oc2c1
Yield: 77 %

Procedure:
A solution of (E)-3-(2-oxo-2,3-dihydro-oxazolo[4,5-b]pyridine-6-yl)acrylic acid tert-butyl ester (274 mg, 1.04 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was stirred for 30 min, then the solvents were removed in vacuo. The residue was suspended in anhydrous HCl (5 mL of a 4 M solution in 1,4-dioxane, 20 mmol) and the mixture was sonicated for 1 min. The resulting solid was collected by filtration, washed with diethyl ether and then dried in vacuo to give the title compound (194 mg, 77%) as a light brown solid: 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.13 (s, 1H), 7.63 (d, J=16.0 Hz, 1H), 6.60 (d, J=16.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19]([C:21]2[C:26]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[F:33]C1C(N[C@H]2CCC[C@@H]2N)=NC=C(C(F)(F)F)C=1.N1N(C2C(C(O)=O)=NC=CC=2)N=CC=1>>[F:33][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19]([C:21]2[C:26]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl)c1ncccc1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Agent: Cl
Agent: O=C(O)c1ncccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 122) from (1S,2S)-1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 34; 100 mg, 0.33 mmol) and 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 66 mg, 0.35 mmol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]([C:6]([CH3:10])([CH3:9])[C:7]#[N:8])=[CH:3][C:4]#[N:5].N[OH:12].Cl>CO>[NH2:5][C:4]1[O:12][N:1]=[C:2]([C:6]([CH3:10])([CH3:9])[C:7]#[N:8])[CH:3]=1
Reactant: NO
Reactant: CC(C)(C#N)C(N)=CC#N
Agent: Cl
Solvent: CO
Product: CC(C)(C#N)c1cc(N)on1
Temperature: 40 °C
Reaction time: 7 h
Yield: 66.2 %

Procedure:
To 3-Amino-4,4-dimethyl-pent-2-endinitrile (10.0 g, 74 mmol) in MeOH (150 mL) is added NH2OH.HCl (10.0 g, 144 mmol). The mixture is stirred at 40° C. for 7 h, concentrated, suspended in isopropyl acetate (100 mL) and washed with 4 N aq. NaOH (2×100 mL) and brine (50 mL). The extracted org. layer is concentrated to provide 7.40 g of 2-(5-Amino-isoxazol-3-yl)-2-methyl-propionitrile. Yield: 66%; ESI-MS: 152 [M+H]+; 1H-NMR (DMSO-d6): 1.6, 5.1, 6.8 ppm.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[F:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([Cl:43])=[O:42])=[C:39]([C:46]([F:49])([F:48])[F:47])[CH:38]=1>ClCCl>[ClH:43].[C:25]([C:24]1[CH:27]=[CH:28][C:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([N:8]3[CH2:7][CH2:6][CH:5]([N:4]([CH3:3])[C:41](=[O:42])[C:40]4[CH:44]=[CH:45][C:37]([F:36])=[CH:38][C:39]=4[C:46]([F:49])([F:48])[F:47])[CH2:10][CH2:9]3)=[N:12][N:13]=2)=[CH:22][CH:23]=1)#[N:26]
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: CNC1CCN(c2nnc(-c3ccc(C#N)cc3)c3ccccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(F)cc1C(F)(F)F)C1CCN(c2nnc(-c3ccc(C#N)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Charge a 4 mL reaction vial with 4-(4-(4-(methylamino)piperidine -1-yl)phthalazin -1-yl)benzonitrile dihydrochloride (44.7 mg, 0.107 mmol), dichloromethane (1 mL), and triethylamine (0.0598 mL, 0.429 mmol). Flush the reaction vial with nitrogen and add 4-fluoro-2-(trifluoromethyl)benzoyl chloride (033 g. 0.14 mmol). Cap the vial and allow the reaction to stir at room temperature overnight. Evaporate to a residue and purify using silica gel chromatography (40:60, ethyl acetate:hexane, then ethyl acetate). Add 1 N HCl in diethyl ether to a solution of the isolated product in dichloromethane/methanol and remove the solvents by placing under a stream of nitrogen gas. Dry in a vacuum oven at 50° C. to obtain the title compound (36.0 mg. 59%). ES/MS m/z 533.8 (M+1).