Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[CH2:8]2)#[N:2].Br.C(O)(=[O:28])C>>[O:12]=[C:10]1[C:11]2[C:3]([C:1]([NH2:2])=[O:28])=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:8][N:9]1[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3cccc(C#N)c3C2=O)C1
Agent: Br
Product: NC(=O)c1cccc2c1C(=O)N(C1CCNC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 13A (238 mg) in glacial acetic acid (2 mL) was added 33% hydrobromic acid in acetic acid (3 mL), and the mixture was stirred at ambient temperature for 2 hours and concentrated. The concentrate was purified by HPLC (Zorbax C-8, 0.1% trifluoroacetic acid/acetonitrile/water) and treated as described in EXAMPLE 7, Step B. 1H NMR (CD3OD) δ 2.34-2.44 (m, 1H), 2.45-2.56 (m, 1H), 3.37-3.47 (m, 1H), 3.57-3.66 (m, 1H), 3.67-3.78 (m, 2H), 4.66 (d, J=3.4 Hz, 2H), 4.71-4.78 (m, 1H), 7.78 (t, J=7.5 Hz, 1H), 7.87 (d, J=4.0 Hz, 1H), 7.89 (d, J=4.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1>O=P(Cl)(Cl)Cl.O>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
To a solution of 0.64 g (2.75 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 20 mL POCl3 was added 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, followed by stirring for 3 hours in a heat flux condition. The solution was cooled to room temperature and dissolved in distilled water. After the adjustment of pH to 8-10 with ammonia, extraction was conducted using ethyl acetate. The organic layer was dried over magnesium sulfate and vacuum concentrated. The residue thus obtained was separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.61 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 65%).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][N:6]=1)=[O:4].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl.CO>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:3]([C:5]2[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][N:6]=2)=[O:4])[CH2:23][CH2:22]1
Reactant: COC(=O)c1cc(O)c(OCc2ccccc2)cn1
Reactant: CN1CCNCC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCN(C(=O)c2cc(O)c(OCc3ccccc3)cn2)CC1
Temperature: 100 °C
Yield: 17.4 %

Procedure:
To a suspension of 2-methoxycarbonyl-4-hydroxy-5-benzyloxypyridine (18.15 g) in N-methylpiperazine (21.04 g) was heated to 100° C. for 3.5 hours. The resulting viscous solution was cooled to room temperature, diluted with a mixture of chloroform (270 ml) and methanol (30 ml) and subjected to column chromatography on silica gel (800 g) . The eluate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (600 g) . The pure fractions were evaporated in vacuo and the residue was pulverized with diisopropyl ether to give 1-methyl-4-(4-hydroxy-5-benzyloxy-2-pyridylcarbonyl)piperazine (3.99 g) .
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([OH:37])[CH2:32]1.CCN(C(C)C)C(C)C>CCO>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:31]5[CH2:36][CH2:35][CH2:34][C@@H:33]([OH:37])[CH2:32]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: O[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(N3CCC[C@@H](O)C3)n2)c2cc(-c3cccnc3)ncc21
Temperature: 120 °C

Procedure:
To a mixture of 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (200 mg, 0.5 mmol) and (R)-piperidin-3-ol (100 mg, 1.0 mmol) in EtOH 5 mL, was added DIPEA 5 mL. The reaction mixture was heated at 120° C. for 15 h, and the reaction was monitored by LCMS. Upon completion of the reaction, the solvent was distilled off and the crude material was purified via flash chromatography, eluting with 5% to 30% heptane/ethyl acetate to afford (R)-1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ol as a yellow oil, (163 mg, 65%). ESI MS m/z=502.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:13][CH3:14].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][N:31]1[CH2:30][CH2:29][N:28]([C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[Cl:20])[CH2:33][CH2:32]1)[CH2:13][CH3:14]
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)c(Cl)cc21
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3Cl)CC2)C(=O)Nc2cc(F)c(Cl)cc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 5-chloro-3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-(2,4-dichlorophenyl)-piperazine.
Reaction SMILES: [H-].[Na+].C1(S([C:12]2[N:16]=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:14](C)[N:13]=2)(=O)=O)C=CC=CC=1.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]#[N:32])=[CH:25][CH:24]=1.[CH3:33]O>O1CCCC1>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[N:16]=[C:12]2[CH:33]=[C:29]([C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[CH:30]=[C:31]([NH2:32])[N:13]2[N:14]=1
Reactant: CO
Reactant: N#CC=Cc1ccncc1
Reactant: Cn1nc(S(=O)(=O)c2ccccc2)nc1-c1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(-c2ccncc2)cc2nc(-c3ccco3)nn12
Reaction time: 15 h
Yield: 13 %

Procedure:
To a boiling suspension of 5.9 g(0.12 mol) sodiumhydride (55%) in 100 ml tetrahydrofuran was slowly added over a period of 6 hours a mixture of 10.1 g (0.035 mol) 3-benzenesulfonyl-methyl-5-furan-2-yl-1H-[1,2,4]triazole and 4.56 g (0.035 mol) 3-(4-pyridinyl)-2-propenenitrile in 400 ml tetrahydrofuran. Boiling was continued for 15 hours and then 50 ml methanol were added at room temperature. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 95/5 gave 1.3 g (13%) 2-furan-2-yl-7-pyridin-4-yl-[1,2,4]triazolo [1,5-a]pyridin-5-ylamine as yellow crystals with mp. 294-296° C.
Reaction SMILES: [Br:1]C1SC=NN=1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][C:10]=2[S:9][CH2:8]1>C1(C)C(C)=CC=CC=1.CN(C)C=O>[BrH:1].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:15][C:10]=2[S:9][CH2:8]1
Reactant: Brc1nncs1
Agent: c1cc2c(cc1CN1CCNCC1)SCO2
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: Br

Procedure:
A solution of 4 g of 2-bromo-1,3,4 thiadiazole and 13 g of 1-[(2H)-1,3-benzoxathiol-5-yl methyl]piperazine in 200 ml of xylene and 10 ml of anhydrous dimethylformamide was refluxed for 3 hours. Then, the mixture was cooled, the crystals of 1-[(2H)-1,3-benzoxathiol-5-yl methyl]piperazine hydrobromide formed during the reaction were suctioned off, and the xylene filtrate was extracted several times with a 2 N solution of methane sulfonic acid. The acid layer was decanted off then rendered alkaline with an excess of potassium carbonate, and the raw base extracted with chloroform. The organic solution was washed with water, dried over dry potassium carbonate, and the solvent was evaporated off. There were obtained 8 g of an oily residue which was submitted to a high pressure liquid chromatography (Waters apparatus) in the system CH2Cl2 -methanol; 98-2.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5].Br[CH2:13][CH2:14][O:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[C:9]([O:10][CH2:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(I)ccc(O)c1F
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc(I)c(C#N)c1F
Temperature: 25 °C

Procedure:
A mixture of Example 68A (104 mg, 0.39 mmol), 1-bromo-2-methoxyethane (0.088 mL) and K2CO3 (163 mg) in acetone (3 mL) was heated to 60° C. for 18 hours, cooled to room temperature, and partitioned between diethyl ether and water. The extract was dried (MgSO4), filtered, and concentrated to provide 122 mg of the desired product. MS (ESI(+)) m/e 334 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>O>[NH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NCCCN
Reactant: CN(C)c1ccc(-c2cc3ncccc3c(Cl)n2)cc1
Solvent: O
Product: CN(C)c1ccc(-c2cc3ncccc3c(NCCCN)n2)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 5-chloro-7-(4-dimethylaminophenyl)-[1,6]naphthyridine (Example 2) (10 mg, 0.035 mmol) and 1,3-diaminopropane (200 microL, 2.4 mmol) was stirred at 100° C. for 5 hours. After cooling to room temperature, water was added and the resulting mixture was extracted with dichloromethane (2×3 mL). Purification by preparative thin layer chromatography afforded the title compound as a yellow film (8.5 mg). 1H NMR (CDCl3, 400 MHz) δ 8.85 (dd, 1H), 8.10 (d, 2H), 8.07 (d, 1H), 7.50 (s, 1H), 7.21 (dd, 1H), 6.81 (d, 2H), 3.87 (t, 2H), 3.02 (s, 6H), 2.97 (t, 2H), 1.90 (quint, 2H); MS (m/e) calculated for C19H23N5 321.2, found 322.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.[C:10]1(=O)[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=2)=[C:4]([I:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1I
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1C=C(Nc2ccc(Cl)cc2I)CCC1
Yield: 80.7 %

Procedure:
A mixture of 4-chloro-2-iodoaniline (0.5 g, 1.97 mmol), 1,3-cyclohexanedione (0.22 g, 1.96 mmol) and p-toluenesulfonic acid monohydrate (catalytic) in toluene (6 mL) were heated to reflux for 2 h. The reaction was cooled and EtOAc (50 mL) was added and the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent: EtOAc:hexane to give 3-(4-chloro-2-iodophenylamino)cyclohex-2-enone as a yellow solid (0.55 g, 80%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][CH:11]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:12]([NH:14][C:15]1([C:22]#[N:23])[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:13].C(N(CC)C(C)C)(C)C>C(#N)C>[C:22]([C:15]1([NH:14][C:12](=[O:13])[CH:11]([NH:10][C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)#[N:23]
Reactant: N#Cc1ccnc(Cl)n1
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)Nc2nccc(C#N)n2)CC1
Yield: 52 %

Procedure:
2-Chloro-4-pyrimidinecarbonitrile (0.3 mmol, Daves, G. D. Jr., O'Brien, D. E., Cheng, C. C. J. Het. Chem, 1964, 1, 130) and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide (0.7 mmol) were dissolved in acetonitrile (10 mL) containing N,N-diisopropylethylamine (0.6 mmol). The solution was heated to a gentle reflux for 17 h. The volatiles were evaporated and the residue was subjected to chromatography (silica gel, eluant=EtOAc then MeOH). The methanolic fraction was concentrated to a colorless solid which was rechromatographed (10% MeOH/EtOAc) to afford the title compound as a colorless solid (52%). The material was recrystallized from dichloromethane/petroleum ether.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@H:4]([CH3:8])[N:3]1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][CH:17]=2)[N:13]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([N:6]1[CH2:5][C@H:4]([CH3:8])[N:3]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)[C@@H:2]([CH3:1])[CH2:7]1)(=[O:30])[CH3:29]
Reactant: COC(=O)c1cccc2oc(N3[C@@H](C)CNC[C@@H]3C)nc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc2oc(N3[C@@H](C)CN(C(C)=O)C[C@@H]3C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To an ice-cold solution of methyl 2-((2S,6S)-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate (273 mg, 0.943 mmol) in CH2Cl2 (5 mL) was added pyridine (0.114 mL, 1.41 mmol) followed by acetyl chloride (0.100 mL, 1.41 mmol) under an atmosphere of nitrogen. The mixture stirred for 18 h while gradually warming to room temperature. The reaction was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 solution (10 mL), 1 N HCl solution (10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography over silica gel (0% to 50%, 95:15:1.5, CH2Cl2/CH3OH/concentrated NH4OH in CH2Cl2) to give methyl 2-((2S,6S)-4-acetyl-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate as an oil (62.1 mg, 20%). 1H NMR and MS consistent.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[C:19]([NH:27][CH2:28][C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=4)[CH:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.N1C=CC=CC=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O.N>C(Cl)(Cl)Cl>[F:36][C:31]1[CH:30]=[C:29]([CH:34]=[C:33]([F:35])[CH:32]=1)[CH2:28][NH:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][S:44]([CH3:43])(=[O:46])=[O:45])[CH2:5][CH2:6]3)=[CH:11][CH:12]=2)[N:22]=[CH:21][C:20]=1[CH2:23][C:24]([NH2:26])=[O:25]
Reactant: NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Reactant: CS(=O)(=O)Cl
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Reaction time: 0.33 h
Yield: 57.6 %

Procedure:
60 mg of 6-({4-[4-(2-aminoethyl)piperazin-1-yl]phenyl}amino)-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 248) was suspended in 6 mL of chloroform, to which, under ice cooling, 20 mg of pyridine and 17 mg of methanesulfonyl chloride were added, and stirred at the same temperature for 20 minutes. To the reaction mixture, ammonia water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1), recrystallized from chloroform-methanol-ether to obtain 40 mg (57%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: [OH:1][C@:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:6][C:7]([CH3:14])([O:9][Si](C)(C)C)[CH3:8])[CH2:3][CH:4]=O.[NH2:21][C@H:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][N:33]([CH3:36])[C:32](=[O:37])[CH:31]=2)=[CH:26][CH:25]=1)[CH3:23].C([O-])([O-])=O.[K+].[K+].Cl[C:45]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:46]>CO.O>[OH:1][C@:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:6][C:7]([OH:9])([CH3:14])[CH3:8])[CH2:3][CH2:4][N:21]([C@H:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][N:33]([CH3:36])[C:32](=[O:37])[CH:31]=2)=[CH:28][CH:29]=1)[CH3:23])[C:45](=[O:46])[O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C[C@@](O)(CC=O)c1ccccc1)O[Si](C)(C)C
Reactant: C[C@H](N)c1ccc(-c2ccn(C)c(=O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N(CC[C@](O)(CC(C)(C)O)c1ccccc1)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
NaBII4 (0.226 g, 5.97 mmol) is added in portions to a mixture of 9 (1.17 g, 3.98 mmol) and (S)-4-(4-(1-aminoethyl)phenyl)-1-methylpyridin-2(1H)-one (15) (1.00 g, 4.37 g) in MeOH (5 mL). The mixture is stirred at 25° C. for 15 h, then treated with K2CO3 (1.65 g, 11.93 mmol) followed by phenyl chloroformate (0.93, 5.97 mmol). The resultant suspension is then stirred at 25° C. for 1 hour, treated with water (15 mL) over 30 min, and stirred at 25° C. for 2 hours. The solids are collected by filtration, rinsed with MeOH/water (⅓, 20 mL), and dried to provide 14 as off-white solid. Yield: 1.76 g, 79.8%. 1H NMR (DMSO-d6, 500 MHz): δ 7.77 (d, J=7.2 Hz, 1H), 7.66 (m, 2H), 7.46-7.00 (m, 12H), 6.67 (d, J=2.1 Hz, 1H), 6.56 (dd, J=7.0, 2.1 Hz, 1H), 5.82 (s, 1H), 5.28 (br s, 1H), 5.11 (s, 1H), 3.45 (s, 3H), 3.35 (m, 1H), 2.59 (m, 1H), 2.14-1.81 (m, 4H), 1.55-1.29 (m, 3H), 1.01 (s, 3H), 0.61 (s, 3H); 13C NMR (DMSO-d6, 400 MHz): δ 161.97, 154.08, 151.20, 150.09, 147.53, 142.31, 139.85, 135.59, 129.18, 127.59, 127.40, 126.66, 125.87, 125.35, 125.07, 121.77, 114.79, 103.75, 75.53, 71.48, 53.82, 51.19, 44.90, 36.36, 32.80, 29.22, 21.58, 17.00; LC-MS (ES): m/z 555 (M+H), 479 (100).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@:5]1([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C:16]([O:18][CH3:19])=[O:17])[CH:2]=[CH2:3].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH2:1]([C@H:4]1[CH2:8][NH:7][CH2:6][C@@:5]1([NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])[C:16]([O:18][CH3:19])=[O:17])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@@]1(NC(=O)C(F)(F)F)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@H]1CNC[C@@]1(NC(=O)C(F)(F)F)C(=O)OC
Reaction time: 2 h

Procedure:
While under nitrogen, a solution of racemic 1-tert-butyl 3-methyl (3R,4S)-4-allyl-3-[(trifluoroacetyl)amino]pyrrolidine-1,3-dicarboxylate (Step 3, 0.207 g, 0.544 mmol) in methylene chloride (11 mL) was treated with trifluoroacetic acid (838 uL, 10.9 mmol). After stirring for 2 h, the mixture was concentrated and dried under high vacuum overnight to give methyl (3R,4S)-4-allyl-3-[(trifluoroacetyl)amino]pyrrolidine-3-carboxylate trifluoroacetate as a faint yellow foam that was used without further purification. A stirred solution of this intermediate in dry methylene chloride (11 mL) under nitrogen was treated with Et3N (0.341 mL, 2.45 mmol) followed by 4-fluorobenzoyl chloride (0.0979 mL, 0.816 mmol). After stirring at room temperature for 1.5 h, the solution was diluted with methylene chloride (15 mL), washed successively with water (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated aqueous sodium chloride (5 mL). The resulting organic phase was dried over Na2SO4 and concentrated, and purification by radial chromatography (2000 micron silica gel rotor, 40-75% ethyl acetate in hexanes) to give methyl (3R,4S)-4-allyl-1-(4-fluorobenzoyl)-3-[(trifluoroacetyl)amino]-pyrrolidine-3-carboxylate (racemic) (220 mg, 100%) as a faint yellow film. Rf=0.33 (50% Ethyl acetate in hexanes). For intermediate pyrrolidine trifluoroacetate, LC-MS ESI+ MS found for C11H15F3N2O3 m/z 281.1 (M+H). For amide product, LC-MS ESI− MS found for C18H18F4N2O4 m/z 401.1 (M−H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.Cl.[NH2:18][C:19]1[C:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[CH:23][CH:22]=[C:21]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[N:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:18][C:19]1[N:20]=[C:21]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][N:34]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[N:3]=3)[CH2:33]2)[CH:22]=[CH:23][C:24]=1[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27]
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1Cl
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(F)cc2)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Temperature: 120 °C

Procedure:
55 mg (0.24 mmol) of 2-chloro-6-(4-fluorophenyl)pyridine-3-carbonitrile, 83 mg (0.28 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.206 ml (1.18 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 72 mg (54% of theory) of the product were obtained in solid form.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24](O)=[O:25].[CH:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH:33]2[CH2:34][CH2:35][N:36]([C:24]([C:11]3[CH:12]=[N:13][C:14]4[N:15]([N:16]=[CH:17][C:18]=4[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]=3[NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:25])[CH2:37][CH2:38]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)O)cnc12
Reactant: C1CCC(C2CCNCC2)CC1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(C4CCCCC4)CC3)cnc12
Yield: 99 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2,5-dimethylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (150 mg, 0.42 mmol) obtained in Example 88, step 2 and 4-cyclohexylpiperidine (U.S. Pat. No. 4,308,382, 120 mg, 0.72 mmol), the title compound (211 mg, 99%) was obtained.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[C@@H]1(N)CCCC[C@H]1N.[NH:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([C:37]([O:39][CH3:40])=[O:38])=[CH:29]1>CCCCCCCCCCCC.O1CCOCC1.ClCCl>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([N:28]2[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[C:30]([C:37]([O:39][CH3:40])=[O:38])=[CH:29]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: COC(=O)c1c[nH]c2ncccc12
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c2ncccc12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
0.038 g (0.2 mmol) of cuprous iodide, 0.891 g (4.2 mmol) of potassium phosphate, 0.47 g (2 mmol) of 4-bromophenyl methyl sulfone and 0.24 cm3 (2 mmol) of trans-1,2-cyclohexanediamine were added, under an argon atmosphere, to 0.405 g (2.3 mmol) of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate in solution in 0.3 cm3 of dodecane and 6 cm3 of dioxane. After stirring at a temperature in the region of 110° C. for 48 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which was taken up in 20 cm3 of dichloromethane. The resulting organic solution was washed with 20 cm3 of 0.1N hydrochloric acid and filtered, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). Methyl 1-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate, characterized by LC/MS (m/z 331 [MH]+), was thus obtained, which was used directly in the following stage.