Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:13]=[C:14]([N:18]([CH3:30])[C:19](=[O:29])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH:25]4[CH2:28][CH2:27][CH2:26]4)[CH3:24])[CH:15]=[CH:16][CH:17]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:31][O:32][C:33]1[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:37][C:38]=1[CH3:39]>CN(C=O)C.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]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:13]=[C:14]([N:18]([CH3:30])[C:19](=[O:29])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH:25]4[CH2:28][CH2:27][CH2:26]4)[CH3:24])[CH:15]=[CH:16][CH:17]=3)[N:9]=[C:10]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[C:33]([O:32][CH3:31])[CH:34]=3)[C:3]=12
Reactant: CN(C(=O)/C=C/CN(C)C1CCC1)c1cccc(-n2nc(I)c3c(N)ncnc32)c1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nn(-c3cccc(N(C)C(=O)/C=C/CN(C)C4CCC4)c3)c3ncnc(N)c23)ccc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
To a stirred solution of (E)-N-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide (52) (222 mg, 0.4 mmol) and 2-(3-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (119 mg, 0.48 mmol) in DMF/H2O (4 mL/1 mL) were added Pd(dppf)Cl2 (16 mg, 0.02 mmol) and K3PO4.3H2O (320 mg, 1.2 mmol). The resulting mixture was purged with N2 (3×) and stirred at 80° C. overnight. Solvents were removed in vacuo. The residue was pre-purified by flash chromatography (silica gel, 0 to 10% MeOH in DCM with 0.3% TEA) followed by a prep HPLC to provide (E)-N-(3-(4-amino-3-(3-methoxy-4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide (53) (29 mg, 14%) as a white solid. LC-MS (ESI): m/z (M+1) 512.3. 1H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 8.29 (d, J=9.4 Hz, 1H), 8.19 (t, J=2.0 Hz, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.32-7.22 (m, 3H), 6.72-6.61 (m, 1H), 5.99 (d, J=13.0 Hz, 1H), 3.89 (s, 3H), 2.98-2.78 (m, 2H), 2.77-2.62 (m, 1H), 2.25 (s, 3H), 1.87 (s, 3H), 1.83-1.71 (m, 2H), 1.71-1.54 (m, 2H), 1.50-1.32 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:22]([CH2:23][N:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][CH3:26])=[CH:21][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]2)=[O:7])=[CH:4][C:3]=1[Br:33].[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][C:50](O)=[O:51].C1(N=C=NC2CCCCC2)CCCCC1>>[NH2:1][C:2]1[C:22]([CH2:23][N:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][CH3:26])=[CH:21][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][C:50](=[O:51])[CH2:49][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[NH:42][C:36]3[C:35]([Cl:34])=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:41])[CH2:14][CH2:13]2)=[O:7])=[CH:4][C:3]=1[Br:33]
Reactant: CCN(Cc1cc(C(=O)OCCCN2CCN(CCO)CC2)cc(Br)c1N)C1CCCCC1
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCN(Cc1cc(C(=O)OCCCN2CCN(CCOC(=O)Cc3ccccc3Nc3c(Cl)cccc3Cl)CC2)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from N-{3-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzoyloxy]-propyl}-N'-(2-hydroxyethyl)-piperazine and 2-[(2,6-dichlorophenyl)amino]-phenyl-acetic acid with dicyclohexyl-carbodiimide, analogous to Example 4.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:31])[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[O:29][N:28]=[C:27]([CH3:30])[CH:26]=3)[CH:20]=2)=O)=[CH:12][C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[C:10]([O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:11]1[C:10]([O:39][CH2:40][C:41]([F:42])([F:44])[F:43])=[CH:9][C:8]2[N:7]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[O:29][N:28]=[C:27]([CH3:30])[CH:26]=4)[CH:20]=3)[CH2:16][C:15](=[O:31])[NH:14][C:13]=2[CH:12]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(-c5ccccc5F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from [2′-fluoro-5-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example M23) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (21 mg).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH-].[Na+].[N+:16]([CH3:19])([O-:18])=[O:17]>>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[CH2:19][N+:16]([O-:18])=[O:17])=[CH:6][CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])CC(O)c1ccc(C(F)(F)F)nc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a stirred solution of 2-chloro-6-(trifluoromethyl)nicotinaldehyde (Int-17) (70 g, 1.0 eq.) in nitro methane (700 mL) was added sodium hydroxide (6.7 g, 0.5 eq.) at room temperature. The resulting reaction mixture was heated to 100° C. and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to remove nitro methane quenched with ice water (500 mL) and extracted with ethyl acetate (2×1.0 L). The combined organic layer was washed with water (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get pure 1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-nitroethanol (Int-18) (65.0 g, 72.0%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].C(OO)(=[O:12])C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N+:5]([O-:12])=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: CC(=O)OO
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)c[n+]([O-])cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-amino-3,5-dichloro pyridine (5.0 gm, 0.0306 moles) in chloroform (100 mL) was added 20% peracetic acid solution (200 ml, 0.597 moles) (20% peracetic acid was prepared as per Vogel's Practical Organic Chemistry, Vol. V, page no. 458). Reaction mixture was then stirred at room temperature for 48 hrs, cooled to 5-10° C. and quenched with sodium sulphite till iodide test disappeared. Chloroform as well as acetic acid was removed under reduced pressure. The residue obtained was purified on silica gel column using 5% methanol in chloroform as an eluent to give product as light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH2:22]1>>[ClH:19].[ClH:19].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][NH:30][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:23][CH2:22]1
Reactant: CN1CCN(CCCN)CC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCN3CCN(C)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 80 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 3-(4-methylpiperazin-1-yl)propylamine as described in Steps 5 and 6, Example 24 to give the title compound as a white solid (80% yield). LC/MS: RT 1.82 min; m/e 439; 1H NMR (δ, ppm): 8.01 (1H, s), 7.56 (1H, d), 7.35 (1H, s), 7.18 (1H, d), 2.70-3.60 (m), 2.40 (2H, q), 2.33 (3H, s), 2.50-2.10 (6H, m), 1.89 (2H, m), 1.09 (3H, t).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:7]1[CH:8]=[C:9]([S:17]([NH2:20])(=[O:19])=[O:18])[S:10][C:11]=1[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH3:6])(=O)[CH3:2].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([NH:4][CH:5]([C:7]1[CH:8]=[C:9]([S:17]([NH2:20])(=[O:19])=[O:18])[S:10][C:11]=1[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH3:6])[CH3:2]
Reactant: CCS(=O)(=O)c1sc(S(N)(=O)=O)cc1C(C)NC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(C)c1cc(S(N)(=O)=O)sc1S(=O)(=O)CC

Procedure:
To a stirred, refluxing suspension of 4-(1-acetamidoethyl)-5-ethylsulfonylthiophene-2-sulfonamide (2.61 g, 0.0077 mol) in dry tetrahydrofuran under nitrogen atmosphere was added dropwise over 1/2 hour a solution of dimethylsulfide borane complex (2.3 ml of a 10 M solution, 0.023 mol) in dry THF (10 ml). The cloudy solution which formed was stirred at reflux for 11/2 hours. The mixture was cooled in ice and acidified by the dropwise addition of 6N HCl (10 ml), and concentrated in vacuo at room temperature. The moist solid residue was basified with saturated NaHCO3 and was extracted with ethyl acetate (4×50 ml). The amino product was extracted into 3N HCl (4×25 ml). The combined HCl extracts were neutralized with NaHCO3 and extracted with ethyl acetate (4×50 ml). The ethyl acetate extract was dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature. A colorless oil was obtained which solidified to a white solid upon trituration in ethyl acetate. The crude yield was 1.99 g or 80%. The solid after recrystallization from ethyl acetate had m.p. 135-137.5° C. NMR supported the structure and HPLC confirmed the purity.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[N:5]([N:9]=[C:10]([CH3:24])[C:11]=2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])[C:6](=[O:8])[CH:7]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)C.C(OCC)(=O)C.Cl>[CH3:24][C:10]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])=[C:4]2[N:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:7]=[C:6]([OH:8])[N:5]2[N:9]=1
Reactant: Cc1nn2c(=O)cc(Cl)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Reactant: C1COCCN1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nn2c(O)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C

Procedure:
To a solution of 5-chloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidin-7(4H)-one (55 mg, 0.155 mmol) in ethanol (1.5 mL) was added morpholine (40.4 mg, 0.464 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 145° C. for 3 hour. The reaction mixture was then diluted with ethyl acetate (15 mL) and 5% HCl solution (3 mL). Two layers were separated. Organic layer was dried, concentrated and purified with silica gel column (methanol/DCM, 0-10%). The titled compound was obtained. (37 mg, 59%); LC/MS: MS (ES+) m/e 407 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 3H) 2.45 (s, 3H) 3.31 (d, J=4.80 Hz, 3H) 3.29 (br. s., 1H) 3.69 (br. s., 1H) 3.67 (d, J=5.05 Hz, 3H) 3.96 (s, 2H) 5.07 (s, 1H) 7.15 (br. s., 1H) 7.25-7.32 (m, 1H) 7.54 (d, J=7.83 Hz, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][N:26]1[C:34]2[CH2:33][CH2:32][C:31]([CH3:36])([CH3:35])[CH2:30][C:29]=2[C:28]([Sn](CCCC)(CCCC)CCCC)=[N:27]1>CN(C=O)C.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.[Cu]I>[CH:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:29]4[CH2:30][C:31]([CH3:35])([CH3:36])[CH2:32][CH2:33][C:34]=4[N:26]([CH3:25])[N:27]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CC(C)(C)CC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CC(C)(C)CC4)nc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 75.4 %

Procedure:
2-Bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (124 mg, 301 μmol) and 1,5,5-trimethyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole (see Example 13, 219 mg, 483 μmol.61) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (17.4 mg, 15.0 μmol) and CuI (5.39 mg, 60.2 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (115 g column, 50 μm from Analogix, 0-70% EtOAc/hexanes, 30 min gradient) to give N-isopropyl-2-(1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (113 mg, 227 μmol, 76%) as a light yellow solid. MS (M+Na)+=497; 1H NMR (CDCl3) δ: 9.08 (s, 1H), 8.28 (s, 1H), 5.68 (s, 2H), 4.38-4.56 (m, 1H), 3.86 (s, 3H), 3.50-3.59 (m, 2H), 2.80 (s, 2H), 2.65 (t, J=6.4 Hz, 2H), 1.69 (t, J=6.6 Hz, 2H), 1.36 (d, J=6.8 Hz, 6H), 1.07 (s, 6H), 0.88-0.96 (m, 2H), −0.06 (s, 9H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[C:7]=2[CH:6]=[N:5]1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:28]1[CH2:32]CC[CH2:29]1>C(#N)C>[CH:1]1([N:4]2[C:12]3[CH:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[C:7]=3[CH:6]=[N:5]2)[CH2:32][CH2:28][CH2:29][CH2:2]1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1cc(C(F)(F)F)cc2c1cnn2C(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc(C(F)(F)F)cc2c1cnn2C1CCCC1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 30 %

Procedure:
To a stirred solution of methyl 1-acetyl-6-(trifluoromethyl)-1H-indazole-4-carboxylate (1 equiv.) in acetonitrile (3 mL per 1 mmol), cesium carbonate (1.5 equiv.) was added followed by bromocyclopentane (2 equiv.). The reaction mixture was stirred at 90° C. for 3-4 h. On completion of reaction, acetonitrile was removed under reduced pressure and water was added. Extraction was carried out using ethyl acetate and the combined organic layers washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain methyl 1-cyclopentyl-6-(trifluoromethyl)-1H-indazole-4-carboxylate (yield 30-35%). The structure was confirmed as the desired regioisomer by NOE.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH2:23])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:24](Cl)(=[O:32])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23][C:24](=[O:32])[O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(Cl)Oc1ccccc1
Product: O=C(N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1)Oc1ccccc1

Procedure:
Phenyl (1R,2R)-2-((S)-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using (1R,2R)—N1-(1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (from intermediate C, Example 2) (30 mg, 0.094 mmol) and phenyl carbonochloridate (14.75 mg, 0.094 mmol) according to General Procedure G to give 5 mg (10% yield) of the product as a yellow solid. Anal. Calcd. for C24H30N4O4 m/z 438.5, found: 439.4 (M+H)+; 1H NMR (500 MHz, MeOH-d3) δ ppm 8.09 (d, J=9.3 Hz, 2H), 7.26 (t, J=8.0 Hz, 2H), 7.17 (d, J=7.7 Hz, 1H), 7.11-7.05 (m, 2H), 6.90 (d, J=7.7 Hz, 1H), 3.86 (d, J=13.2 Hz, 1H), 3.68-3.55 (m, 3H), 3.47-3.36 (m, 2H), 3.26-3.19 (m, 1H), 2.29 (br. s., 1H), 2.21-2.15 (m, 1H), 2.10 (br. s., 1H), 1.99-1.74 (m, 5H), 1.62-1.36 (m, 4H); 13C NMR (126 MHz, MeOH-d3) δ ppm 156.21, 140.60, 129.95, 126.33, 126.25, 122.30, 121.96, 115.57, 115.10, 61.27, 54.06, 52.88, 50.25, 49.28, 32.42, 29.24, 28.01, 24.92, 24.37, 22.67.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].O>C(O)(C)C>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4]([NH:15][CH2:12][CH2:13][CH3:14])[N:3]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Reactant: CCCN
Solvent: CC(C)O
Solvent: O
Product: CCCNc1nc(N)c(C=O)nc1Cl
Temperature: 25 °C
Reaction time: 20.5 h

Procedure:
In 1.2 ml of isopropyl alcohol there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine (0.095 g) 0.0005 M) prepared in Step B, after which n-propylamine (32 g; 0.042 ml; 0.00055 M) was added, and the reaction mixture was stirred at room temperature for 20.5 hours. When water was added to the reaction mixture, product precipitated, was filtered, and dried (23 mg). Additional product precipitated, was filtered, and dried (46 mg). The product was recrystallized from ethyl acetate/hexane. Elemental Analysis for C8H11N4OCl.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 64 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:34])[CH:40]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCC(N2CCCCC2)CC1
Yield: 77 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light red solid (77%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH3:15][NH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>>[CH3:15][N:16]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)[C:12]1[S:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[N:13]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: N#C[S-]
Reactant: CCOC(=O)c1ccc(NC)cc1
Agent: [NH4+]
Product: CCOC(=O)c1ccc(N(C)c2nc(=O)c3cccnc3s2)cc1
Yield: 88.8 %

Procedure:
The reaction procedure of Example 57 was followed except that 162 mg of 2-chloronicotinoyl chloride, 72 mg of ammonium thiocyanate and 169 mg of ethyl 4-(methylamino)benzoate were used. As a result, 279 mg of ethyl 4-[N-methyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]benzoate was obtained.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[N:13]([CH3:16])C=O.[Br:17]N1C(=O)CCC1=O>O>[NH2:13][C:16]1[C:8]([CH3:7])=[CH:9][C:10]([Br:17])=[CH:2][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: O
Product: Cc1cc(Br)cc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 1.5 g of 2-amino-5-chlorobenzoic acid and 100 ml of N,N-dimethylformamide was added 1.8 g of N-bromosuccinimide at room temperature, and the mixture was stirred at room temperature for 10 hours. After 30 ml of water was poured into the reaction mixture, the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.2 g of 2-amino-5-bromo-3-methylbenzoic acid of the formula:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]>>[C:1]1([C:7]2[O:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1I
Reactant: C#Cc1ccccc1
Product: c1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert phenylacetylene and 2-iodophenol to the title product. Purification by flash chromatography (hexanes as the eluent) gave the analytically pure product as a white solid (358 mg, 93% yield). 1H NMR (300 MHz, CDCl3) δ 7.86-7.83 (dd, J=6.97, 2H) 7.56-7.49 (m, 2H), 7.41-7.39 (m, 2H), 7.34-7.18 (m, 3H), 6.97 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 155.88, 154.86, 130.44, 129.20, 128.75, 128.51, 124.89, 124.24, 122.91, 120.89, 111.16, 101.28. Anal. Calcd. for C14H10O: C, 86.57; H, 5.19. Found C, 86.41; H, 5.34. m.p.: 120° C. (lit., 3118-120° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[NH2:10])=[O:4].[CH3:12][C:13]1([CH3:20])[O:18][CH2:17][C:16](=O)[CH2:15][O:14]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[NH:10][CH:16]1[CH2:17][O:18][C:13]([CH3:20])([CH3:12])[O:14][CH2:15]1)=[O:4]
Reactant: CC1(C)OCC(=O)CO1
Reactant: COC(=O)c1sc(Br)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(Br)cc1NC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.6 %

Procedure:
A suspension of 3-amino-5-bromo-thiophene-2-carboxylic acid methyl ester (0.5 g, 2.12 mmol) in dry THF (0.6 mL) was treated with 2,2-dimethyl-[1,3]dioxan-5-one (253 μl, 2.12 mmol), followed by dibutyltin dichloride (32 mg, 0.11 mmol). After 5 min phenyl silane (280 μl, 2.27 mmol) was added and the reaction was stirred at room temperature for 3 days. It was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution and brine. The organic layer was separated, dried over MgSO4, evaporated and left on vacuum pump overnight. The residue was triturated with hexane-ether (4:1) mixture (2×100 mL). The soluble portion was evaporated and purified by chromatography over silica gel (hexane:ethyl acetate—95:5) yielding pure 5-bromo-3-(2,2-dimethyl-[1,3]dioxan-5-ylamino)-thiophene-2-carboxylic acid methyl ester (220 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9](C(C)(C3C=CC=CC=3)C)[CH:10](O)[C:6]=2[CH:5]=[C:4]([CH3:22])[N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[NH:9][CH2:10][C:6]=2[CH:5]=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)N(C(C)(C)c1ccccc1)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: Cc1cc2c(c(Cl)n1)C(=O)NC2
Yield: 63.5 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-chloro-1-hydroxy-6-methyl-2-(1-methyl-1-phenylethyl)-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (70.0 mg, 0.220 mmol) was dissolved in nitromethane (3.5 mL), and the solution was treated with trifluoroacetic acid (0.509 mL, 6.60 mmol) and triethylsilane (0.141 mL, 0.880 mmol), followed by purification by slurry using isopropylether/hexane to obtain 4-chloro-6-methyl-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (25.5 mg, yield 63%).