Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:27]1[CH:28]=[C:29]([CH2:34][OH:35])[C:30]([Cl:33])=[N:31][CH:32]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:33][C:30]1[C:29]([CH2:34][OH:35])=[CH:28][C:27]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[C:7]3[N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:32][N:31]=1
Reactant: OCc1cc(Br)cnc1Cl
Reactant: OB(O)c1ccc2nccc(N3CCOCC3)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: OCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Temperature: 95 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
(Some starting materials may be obtained from Adesis Inc., New Castle, Del.) A mixture of 4-morpholinoquinolin-6-ylboronic acid (500 mg, 1937 μmol), PdCl2(dppf) (70.9 mg, 96.9 μmol), Na2CO3 (616 mg, 5812 μmol) and (5-bromo-2-chloropyridin-3-yl)methanol (431 mg, 1937 μmol) in DME (8 mL) and water (3 mL) was heated to 95° C. under nitrogen. After 2 h, the mixture was concentrated and the residue was partitioned between water and DCM containing iPrOH (1%). The aqueous layer was extracted several times with DCM containing iPrOH (1%). The combined organic phase was concentrated and suspended in DMSO-MeOH (1:1). This mixture was then filtered, washed with MeOH to give the desired product (230 mg, 94% pure based on LCMS). The filtrate was purified with HPLC and concentrated to an oil. This was partitioned between DCM and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated to a white solid (100 mg). LCMS (ESI, pos. ion): calc'd for C19H18ClN3O2: 355.1; found: 356.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.19-2.39 (m, 1 H) 3.21-3.33 (m, 4 H) 3.95-4.06 (m, 4 H) 4.91 (d, J=5.02 Hz, 2 H) 6.93 (d, J=4.52 Hz, 1 H) 7.88 (d, J=9.03 Hz, 1 H) 8.13-8.27 (m, 3 H) 8.63 (d, J=2.01 Hz, 1 H) 8.79 (d, J=5.02 Hz, 1 H)
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:31][C:23]1[CH:22]=[C:21]([CH2:20][C:19]([NH:18][C:14]2[C:13]([CH3:33])=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[C:9]3=[O:34])=[O:32])[CH:26]=[CH:25][C:24]=1[C:27]([F:30])([F:28])[F:29]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (300.00 mg, 6.2704E-4 mol), potassium carbonate (260 mg, 0.0019 mol), methanol (20 mL, 0.4 mol) and 2 drops of water. The reaction was stirred at room temperature for 20 minutes. The solvent was removed and the reaction mixture was extracted with ethyl acetate and the solvent was removed to obtain the product as a light yellow solid. MS m/z=437.5 (M+H). 1H NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.07 (d, J=8.45 Hz, 1H), 7.79 (t, J=7.85 Hz, 1H), 7.53 (d, J=12.68 Hz, 1H), 7.45 (d, J=7.85 Hz, 2H), 7.37 (d, J=8.45 Hz, 1H), 6.44 (d, J=7.66 Hz, 1H), 5.05-5.00 (m, 1H), 4.93 (t, J=5.66 Hz, 1H), 3.92 (s, 2H), 3.67-3.51 (m, 2H), 2.22 (s, 3H), 1.28 (d, J=7.51 Hz, 3H).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:19]([O:26][C:27](=[O:39])[CH:28]([NH:38][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:34][CH:35]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: COc1ccc(C[C@H](N)C(=O)OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Yield: 77.6 %

Procedure:
A solution of the product from Example Z (2(S)-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.20 g, 0.78 mmol) and 2(S)-amino-3-(4-methoxy-phenyl)-propionic acid benzyl ester (Bachem, 0.459 g, 0.86 mmol) were coupled according to the procedure described in Example 3. The residue was passed through a plug of silica gel eluting with ethyl acetate. The material obtained was purified by crystallization from hot hexane/ethyl acetate to give the title compound as a white solid (0.2 g, 43%), mp=99-101° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1>[CH:1]1([N:7]=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: NC1CCCCC1
Solvent: c1ccccc1
Product: C1CCC(=NC2CCCCC2)CC1
Temperature: 80 °C

Procedure:
Cyclohexylamine Compound 20a (4.64 g, 46.50 mmol) was added to a solution of cyclohexanone Compound 2a (4.0 g, 46.50 mmol) in benzene (100 mL) at ambient temperature under a N2 atmosphere. The mixture was refluxed at 80° C. for 5 hours, using a Dean Stark apparatus for the removal of water, and concentrated to dryness. The crude product was purified by distillation at aspirator pressure to afford cyclohexyl-cyclohexylidene-amine Compound 20b (7.33 g, 88%) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:36][CH:37]=[CH2:38])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[CH:33][S:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27].CO.C1COCC1.[OH-].[Li+].C(OCC)(=O)C.O>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH2:36][CH:37]=[CH2:38])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[CH:33][S:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27]
Reactant: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(-c2cscn2)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)O)CC3)ccc(-c2cscn2)c1OC
Yield: 93.2 %

Procedure:
The compound of Example 16 (22 mg, 40.9 μmol), 1 mL 4:1 methanol/THF, and 100 mL 1N lithium hydroxide were stirred at room temperature for 2.75 hours. The mixture was poured into ethyl acetate/water, and the ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated. Flash chromatography on silica gel using 5:1 hexane/ethyl acetate (1% acetic acid) provided the product (20 mg, 38.1 μmol, 93% yield). High resolution mass spectrum, m/e 479.2114 (calculated for C28H35NO4S (M-CO2), 479.2130).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:8])=[CH:4][CH:3]=1.[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18]>>[Cl:1][C:2]1[S:6][C:5]([C:7]([CH2:9][CH:10]([CH3:14])[C:11]([N:15]2[CH2:22][CH2:21][CH2:20][C@H:16]2[C:17]([OH:19])=[O:18])=[O:13])=[O:8])=[CH:4][CH:3]=1
Reactant: CC(CC(=O)c1ccc(Cl)s1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Product: CC(CC(=O)c1ccc(Cl)s1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
As for Example 1, 3-(5-chloro-2-thenoyl)-2-methylpropionic acid is reacted with L-proline to give 1-[3-(5-chloro-2-thenoyl)-2-methylpropionyl]-L-proline. The mixture of diastereomers is separated. Bromination of [R]-1-[3-(5-chloro-2-thenoyl)-2-methylpropionyl]-L-proline and reaction of the brominated product with sodium thioacetate in acetonitrile gives a mixture of [S-(R*,S*)] and [S-(R*,R*)] isomers of the product of the Example as a glass.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][C:23]3[C:24]4[CH:32]=[C:31](Cl)[N:30]=[CH:29][C:25]=4[N:26]=[CH:27][N:28]=3)=[CH:19][CH:20]=2)[CH:15]=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][C:23]3[C:24]4[CH:32]=[C:31]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[N:30]=[CH:29][C:25]=4[N:26]=[CH:27][N:28]=3)=[CH:19][CH:20]=2)[CH:15]=[N:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cnc(N6CCCC6)cc45)ccc32)cc1
Reaction time: 18 h

Procedure:
Pyrrolidine (2 ml) was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (0.4 g) in a reacti-vial at 100° C. (Procedure C). After 18 hours, the cooled mixture was poured onto water and the precipitate washed with hot ether and crystallised from acetone to give the title compound; δH [2H6]DMSO 10.53(1H,s), 9.75(1H,s), 8.79(1H,s), 8.30(1H,s), 8.23(1H,s), 8.14(1H,s), 7.70(2H,m), 7.28(5H,m), 7.14(1H,s), 5.68(2H,s) 3.50(4H,m), 2.02(4H,m); m/z (M+) 422.
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([NH:14][CH3:15])[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]2[CH:26]=[N:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1.[Br:40]N1C(=O)CCC1=O>CN(C)C=O.O.C(OCC)(=O)C>[Br:40][C:8]1[C:9]([NH:14][CH3:15])=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([O:4][C:3]2[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:2]=2[F:1])=[C:6]([C:16]2[C:17]3[CH:26]=[N:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])[C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1c(Br)cc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of 4-[2-(2,4-difluorophenoxy)-4-(methylamino)-3-nitrophenyl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (0.433 g, 0.776 mmol) in N,N-dimethylformamide (5.0 mL) was cooled to 0° C. Two portions of N-bromosuccinimide (0.159 g, 0.893 mmol) were added with a 5 min interval to the above solution at 0° C., and the resultant reaction mixture was stirred at 0° C. for 30 min, after which time the reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with saturated sodium bicarbonate, dried with sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes [EtOAc contained 5% MeOH]) gave the desired product (444 mg, 90%) as a yellow solid. LCMS calculated for C26H29BrF2N5O5Si (M+H)+: m/z=636.1, 638.1. found: 636.0, 638.1.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([O:8][CH2:9][CH3:10])(=[O:7])[CH:5]=[CH2:6].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.COC1C=CC(O)=CC=1>>[CH3:1][N:2]([CH2:6][CH2:5][C:4]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3]
Reactant: C=CC(=O)OCC
Reactant: CNC
Agent: COc1ccc(O)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: CCOC(=O)CCN(C)C
Temperature: -13 °C

Procedure:
To a chilled (-15° C.) reaction vessel there was added; anhydrous dimethylamine (100 grams); ethyl acrylate (250 grams); phenothiazine (0.5 gram); and p-methoxyphenol (0.5 gram). The mixture was maintained at -13° C. for 2 hours with stirring after which the temperature was allowed to rise to about 25° C. Unreacted dimethylamine and ethyl acrylate were removed by distillation. The product was recovered by distillation at 58° C. and 10 mm. mercury pressure in a yield of 97 per cent. The product, designated herein as Amine Catalyst VIII, has the formula, (CH3)2NCH2CH2C(O)OC2H5, as verified analytically by infrared spectroscopy.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH4+:13].[OH-]>C1COCC1>[NH2:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 4-fluoro-3-nitro-benzaldehyde (570 g, 3.3 mmol) in THF (20 mL) was added NH4OH (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting yellow solid was collected and washed with water, dried under vacuum to give the title compound (300 mg, yield: 53%). 1H-NMR (300 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.57 (d, 1H), 8.18 (br s, 2H), 7.80 (dd, 1H), 7.10 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[NH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[C:30]([F:33])([F:32])[F:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH2:21][NH:20][C:17]([C@H:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:4]3[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=3)[CH2:12]2)=[O:19])=[C:23]([C:30]([F:31])([F:33])[F:32])[CH:24]=1)#[N:27]
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Reactant: N#Cc1ccc(CN)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(C#N)cc3C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (0.100 g, 0.264 mmol) in N,N-Dimethylformamide (DMF) (4 ml) was added 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (0.053 g, 0.264 mmol) followed by diisopropylethylamine (0.101 ml, 0.580 mmol) and 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.128 g, 0.290 mmol). The reaction was stirred at room temperature for 4 hours and then purified by preparative HPLC to provide (cis)-N-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (83 mg, 0.148 mmol, 56%). MS (ES) m/e 448 [M+H]+. 1H NMR (400 MHz, DMSO-D6) 7.8 (bs, 1H), 7.3 (bs, 1H), 7.2 (m, 1H), 6.9 (m, 1H), 3.8 (bs, 2H), 3.3 (bm, 1H), 2.2 (bm, 4H), 1.8-1.5 (bm, 4H), 1.3-1.1 (bm, 4H), 0.8-0.5 (bm, 4H)
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20](O)=[O:21])[C:7]3[C:12](C)=[N:11][N:10]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:20]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:21])[C:7]3[CH:12]=[N:11][N:10]([C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(-c2ccncc2)c2nc(C3CC3)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3-c2ccncc2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 6-cyclopropyl-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (89 mg, 0.302 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (69.0 mg, 0.454 mmol), 1-hydroxy-7-azabenzotriazole (82 mg, 0.605 mmol), DMSO (20 mL), EDC (116 mg, 0.605 mmol), and N-methylmorpholine (0.133 mL, 1.210 mmol). The final product was collected as 0.110 g (80%). LCMS E-S (M+H)=429.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (br. s., 4H), 2.13 (br. s., 3H), 2.25 (br. s., 4H), 3.34 (br. s., 3H), 4.37 (br. s., 2H), 5.89 (br. s., 1H), 7.30 (br. s., 1H), 8.33 (br. s., 2H), 8.67 (br. s., 3H), 11.54 (br. s., 1H).
Reaction SMILES: [OH-:1].[Na+:2].[C:3]1(=[O:9])[O:8][C:6](=[O:7])[CH:5]=[CH:4]1>O>[C:3]([O-:8])(=[O:9])/[CH:4]=[CH:5]\[C:6]([O-:1])=[O:7].[Na+:2].[Na+:2]
Reactant: O=C1C=CC(=O)O1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
Eight parts by weight of sodium hydroxide and 9.8 parts by weight of maleic anhydride are added to 100 parts by weight of water to obtain a homogeneous solution of disodium maleate. On addition of 10.4 parts by weight of sodium bisulfite to the foregoing solution and stirring, the reaction proceeds exothermically. After the evolution of heat has settled down, the stirring is continued for a further 3 hours at 60°C. A rotary evaporator is then used and the water is removed from the reaction mixture to obtain 26.4 parts by weight of a white powder of trisodium sulfosuccinate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11]O)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:13].[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:13]
Reactant: Cc1cc2cc(CO)ccc2n1C
Reactant: CCOC(=O)c1cn[nH]c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)cc(C)n3C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1,2-Dimethyl-1H-indol-5-yl)methanol (crude, 250 mg, 76%, 1.084 mmol), Ethyl 1H-pyrazole-4-carboxylate (266 mg, 1.898 mmol) and Triphenylphosphine (341 mg, 1.3 mmol) in toluene (10.5 ml) Diethyl azodicarboxylate (206 ul, 1.3 mmol) was added at rt. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with brine and extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash-chromatography on silica gel (60 g), gradient of cyclohexane/EA (50 ml/min.) from 100/0 (3 min.) to 70/30 (20 min.) to afford pure ethyl 1-((1,2-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxylate. MS (Method V) [M+H]+=298.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[C:22]=3[Cl:28])=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C(O)=[O:34].O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([OH:34])[C:22]=3[Cl:28])=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:29]([F:30])([F:31])[F:32]
Reactant: O=CO
Reactant: O=C(c1ccnc(Cl)c1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccnc(O)c1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 1 dram vial was charged with 4-chloro-N-[5-chloro-2-(2,3-dichloro-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (15 mg, 0.028 mmol), formic acid (0.39 mL) and water (0.13 mL). The heterogeneous solution was warmed to 100° C. and stirred overnight. The following day, starting material remained; therefore, an additional 0.26 mL of formic acid was added. The reaction was subsequently warmed to 110° C. and stirred overnight. The resultant mixture was neutralized with saturated aqueous sodium bicarbonate, diluted with EtOAc, and the organic layer washed with saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to afford the desired hydroxypyridine: 1H NMR (400 MHz, CD3OD) δ 8.26-8.38 (m, 1H), 8.17-8.20 (m, 2H), 8.02-8.07 (m, 1H), 7.72-7.76 (m, 1H), 7.34-7.37 (m, 1H), 6.17-6.20 (m, 1H); MS (ES) (M+H)+ expected 525.9. found 525.9.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C@@H:17]([NH:19]C(=O)OC(C)(C)C)[CH3:18])=[CH:13][CH:12]=3)[CH2:6][C:5]=12.C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C@@H:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=3)[CH2:6][C:5]=12
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CN2CCn3cnnc3C2)cc1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1ccc(CN2CCn3cnnc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 1-(4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)phenyl)ethylcarbamate (168 mg, 0.47 mmol) in DCM (2 mL) was added TFA (2 mL, 26 mmol) slowly at −78° C. The reaction was stirred at room temperature for 1 h then concentrated and diluted with DCM (10 mL). The solution was stirred with 3 eq. of MP-carbonate resin (3.28 mmol/g, Biotage) for 1 hour at room temperature. The resin was removed by filtration and washed (2×5 mL) with DCM. The filtrate was concentrated and the crude residue was used to next step without further purification.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4]CC1.[CH3:23][N:24]1C(N)=CC=[N:25]1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[N:24]([CH3:23])[N:25]=[CH:4][CH:5]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Cn1nccc1N
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccnn2C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1-methyl-1H-pyrazol-5-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 2.09 (s, 3H), 2.27 (s, 3H), 3.38 (s, 3H), 4.42 (s, 2H), 5.98 (s, 1H), 7.14 (d, J=7.5 Hz, 1H), 7.24 (t, J=6.7 Hz, 1H), 7.38 (s, 1H), 7.70 (t, J=7.0 Hz, 1H), 8.43 (d, J=5.2 Hz, 1H); MS (ESI) m/z 310.2 (M+1)+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[N+:7]([CH:9](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:10])#[C-:8].[H-].[Na+].[Cl-].[Na+]>C(OCC)C.CS(C)=O>[CH3:10][C:9]1[NH:7][CH:8]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[CH:3]=1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: C=CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(=O)c1c[nH]c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A solution of methyl acrylate (0.523 mL, 5.81 mmol) and 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.215 g, 5.81 mmol) in diethyl ether (16.5 mL) and DMSO (8.5 mL) were added dropwise to a stirred suspension of sodium hydride (60% dispersion) (0.372 g, 9.29 mmol) in diethyl ether (25 mL) under nitrogen. The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was poured into 2% sodium chloride solution (200 mL), layers separated and the aqueous extracted with Et2O (4×50 mL), the organic layers were combined washed with water (50 mL), dried over Na2SO4, filtered and evaporated to afford beige solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired compound as a white solid (0.527 g, 65.2% yield); 1H NMR (400.132 MHz, CDCl3) δ 2.19 (3H, s), 3.72 (3H, s), 6.23 (1H, m), 7.21 (1H, m), 8.09 (1H, s); m/z (LC-MS, ESI+), RT=1.30 min (no mass ion detected).