Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[C:60]([F:68])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:51]=[CH:52][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:65])[F:66])[CH:61]=[C:60]([F:68])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:69][CH:70]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2cc(F)cc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.3 %

Procedure:
To a solution of 112 mg (0.53 mmol) of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 169 mg of TBTU (0.53 mmol) in 6 ml DMF, were added 0.45 ml (2.63 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 200 mg (0.57 mmol) of (4-tert-butyl-benzyl)-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 21 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; DCM/heptane 9:1) to give 158 mg off-white solid (48%). MS (EI) 548.2 (M)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N+]([O-])=O)[C:10]=1[C:11]#[N:12])([O-:8])=[O:7]>>[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]=1[C:11]#[N:12])([O-:8])=[O:7]
Reactant: C1CCNC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(N2CCCC2)cccc1[N+](=O)[O-]

Procedure:
2-nitro-6-pyrrolidinylbenzonitrile is prepared from pyrrolidine and 2,6-dinitrobenzonitrile as in example 10, m.p. 110°-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=O)=[N:8][C:4]=2[CH:3]=1.[CH3:24][N:25]([CH:27]([N:31]([CH3:33])C)N(C)C)C.[CH3:34][NH:35]N>CCO>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][C:10]3[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)=[N:35][N:25]([CH3:27])[CH:24]=3)=[N:8][C:4]=2[CH:3]=1.[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][C:10]3[CH:34]=[N:35][N:31]([CH3:33])[C:11]=3[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCn1c(CCC(=O)c2cccc(F)c2)nc2cc(Br)ccc21
Reactant: CNN
Reactant: CN(C)C(N(C)C)N(C)C
Solvent: CCO
Product: CCn1c(Cc2cn(C)nc2-c2cccc(F)c2)nc2cc(Br)ccc21
Product: CCn1c(Cc2cnn(C)c2-c2cccc(F)c2)nc2cc(Br)ccc21
Temperature: 60 °C

Procedure:
A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. EtOH (5 mL) and methyl hydrazine (1.1 mmol) are added to the residue. The mixture is heated at 120° C. for 2 hours. The solvent is removed. NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole and 5-bromo-1-ethyl-2-[5-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole. 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole: 1H NMR (CDCl3) δ 7.88 (s, 1H), 7.27-7.42 (m, 4H), 7.00-7.20 (m, 3H), 4.21 (s, 2H), 3.95 (t, 2H), 3.83 (s, 3H), 1.15 (t, 3H). 5-bromo-1-ethyl-2-[5-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole: 1H NMR (CDCl3) δ 7.81 (s, 1H), 7.38-7.45 (m, 2H), 7.32 (dd, 1H), 7.00-7.18 (m, 4H), 4.00 (s, 2H), 3.90 (q, 2H), 3.78 (s, 3H), 1.15 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][NH:10][N:9]=2)[CH:7]=1.[NH:31]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:32]([C:39](O)=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C)N=C=NC(C)C>C1COCC1>[C:45]([O:44][C:42](=[O:43])[NH:31][C@H:32]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:30])=[N:9][NH:10][CH:11]=2)=[CH:20][CH:19]=1)=[O:40])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: O=C(Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1CCCCN1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a mixture of compound 26A (468 mg, 1.11 mmol) and BOC-D-Phg-OH (11A, 280 mg, 1.11 mmol) was added anhydrous THF (10 mL) and the resultant mixture was stirred at rt for 5 min. DIPC (0.258 mL, 1.67 mmol) was added slowly at rt. The reaction mixture was stirred at rt overnight. Solvent was removed. The residua were dissolved in a small amount of ethyl acetate. Solid was removed by filtration. The filtrate was purified by silica column chromatography eluting with hexanes-ethyl acetate (v/v 3/1, 2/1, 1/1) to provide the title compound (27A, 275 mg) as an off-color foam-like powder in 37.8% yield. 1H NMR (CDCl3, 500 MHz) δ 10.74 (br s, 2H), 8.75 (s, 1H), 8.52 (s, 1H), 7.82 (d, 2H, J=8.0 Hz), 7.79 (s, 1H), 7.58 (d, 2H, J=8.5 Hz), 7.43 (m, 5H), 7.21 (dd, 1H, J=8.0, 2.0 Hz), 6.98 (d, 1H, J=9.0 Hz), 5.61 (d, 1H, J=6.5 Hz), 5.56 (s, 2H), 3.90 (d, 1H, J=12.5 Hz), 3.20 (t, 1H, J=12.0 Hz), 2.51 (m, 1H), 1.62 (m, 2H), 1.55-1.30 (m, 11H), 0.91 (m, 1H). LCMS (ESI) m/z 720.27 (MNa+), 676.17 (MNa+), 654.22 (MH+), 554.11, 345.17, 289.12 (100). HPLC: tR=5.55 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1ccc(CN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
Morpholine (0.96 mL) and acetic acid (0.57 mL) are added to a solution of 3-bromo-4-fluorobenzaldehyde (2.03 g) in dichloroethane (40 mL). Sodium triacetoxyborohydride (3.18 g) is added in portions over an hour, and the reaction is stirred at room temperature for 18 hours. The reaction is quenched with a 1 N solution of NaOH (10 mL) and diluted with CH2Cl2 (100 mL). The organic layer is washed with 1 N NaOH (3×35 mL). The aqueous layers are back-extracted with CH2Cl2 (20 mL). The combined organic layers are extracted with 0.1 N HCl (6×25 mL). The combined aqueous layers are basified (pH=12) with 2 N NaOH, and the product is extracted with CH2Cl2 (6×25 mL). The combined organic layers are washed with brine (20 mL) and dried (MgSO4). The solution is concentrated in vacuo to afford 2.23 g (82%) of the title compound as a clear, colorless oil.
Reaction SMILES: C1(S([NH2:10])(=O)=O)C=CC=CC=1.CC(C)=O.[CH3:15][O:16][CH:17]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH:19]([N:24]=[C:25]=[O:26])[CH2:18]1>[OH-].[Na+].O>[CH3:15][O:16][CH:17]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH:19]([NH:24][C:25](=[O:26])[NH2:10])[CH2:18]1
Reactant: COC1CC(N=C=O)CCC1C
Reactant: NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC1CC(NC(N)=O)CCC1C
Reaction time: 2 h

Procedure:
5 g of 4-(β-<3-methoxy-methoxy-thiophen-2-carbonamido>-ethyl)-benzenesulfonamide (melting point 160° - 162°C) were dissolved in 7 ml of 2N sodium hydroxide solution and 50 ml of acetone and 2.4 g of 3-methoxy-4-methylcyclohexyl-isocyanate (boiling at 90°C under a pressure of 10 mm of mercury) were added dropwise at 0° - 5° C. Then stirring was continued for 2 hours, then the whole was diluted with water, and any undissolved matter was filtered off, and the filtrate was acidified with dilute hydrochloric acid. The N-[4-(β-<3-methoxy-methoxy-thiophen-2-carbonamido> -ethyl)-benzenesulfonyl]-N'-(3-methoxy-4-methyl-cyclohexyl)-urea precipitating in crystalline form melted at 125° - 127° C after recrystallization from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([N+:14]#[C-:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Br:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[CH:22]=O>Cl(O)(=O)(=O)=O>[Br:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[C:15]=1[NH:14][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Nc1ccccn1
Reactant: O=Cc1sccc1Br
Reactant: [C-]#[N+]C1CCCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Product: Brc1ccsc1-c1nc2ccccn2c1NC1CCCCC1

Procedure:
Compound (27) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml cyclohexyl isocyanide solution (0.2 M, MC), 0.500 ml 3-bromothiophene-2-carbaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%). Calculated mass 376.3; found mass 376.4/378.3 (ESI-MS)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=3)=[O:26])=[C:20]([C:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=3)[CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[BH-](OC(C)=O)(OC(C)=O)[O:41][C:42]([CH3:44])=O.[Na+].C(C=O)=O>C(Cl)Cl>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:34]1([C:20]2[CH:19]=[C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][NH:8][CH2:44][CH2:42][OH:41])[CH2:13][CH2:14]3)[CH:23]=[CH:22][C:21]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CN)CC3)cc2C2=CCCCC2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=CC=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CNCCO)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A suspension of 4-cyano-1H-imidazole-2-carboxylic acid {4-[1-(2-amino-acetyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl]-amide trifluoroacetic acid salt (as prepared in the previous step, 0.42 g, 0.77 mmol) in CH2Cl2 (20 mL) was treated with Na(OAc)3BH (0.33 g, 1.54 mmol) and solid glyoxal (44.6 mg, 0.77 mmol). The mixture stirred at room temperature for 1 h, and the solvent was evaporated in vacuo. The residue was taken up in MeOH and the solids filtered off, and the filtrate was concentrated in vacuo. Reverse phase HPLC (C-18 column) (20% to 60% acetonitrile in water with 0.1% TFA over 30 min) afforded the title compound (83 mg, 19% over two steps) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.16-8.09 (m, 1H), 8.05-8.01 (m, 1H), 7.22-7.15 (m, 1H), 7.11-7.06 (m, 1H), 5.84-5.79 (m, 1H), 4.72-4.62 (m, 1H), 4.24-3.91 (m, 2H), 3.89-3.80 (m, 2H), 3.28-3.18 (m, 2H), 2.92-2.79 (m, 2H), 2.28 (br s, 4H), 1.98-1.89 (m, 2H), 1.89-1.76 (m, 4H), 1.76-1.57 (m, 2H). LC-MS (ESI, m/z): Calcd. for C26H32N6O3 477.2 (M+H). found 477.2.
Reaction SMILES: [CH:1](=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[C:12]([Cl:25])[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].O>CO.CN(C)C=O.[Pd]>[CH2:1]([CH:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[C:12]([Cl:25])[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2c3cc(Cl)ccc3c(=Cc3ccccc3)c2n2ccnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccccc1)c1ccc(Cl)cc1-2
Yield: 28.4 %

Procedure:
2.1 g of 10-benzylidene-7-chloro-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one dissolved in 20 ml of a mixture of methanol and dimethylformamide (1/1 by volume) are hydrogenated at a temperature in the region of 20° C. and at a pressure of 9.6 bar of hydrogen for 24 hours in the presence of 10% palladium on charcoal. The catalyst is then filtered off under inert atmosphere and the solvents are evaporated off. The brown oil obtained is taken up in 25 ml of methanol and, after addition of 50 ml of distilled water, a pink precipitate forms. The solid thus obtained (1.3 g) is recrystallized in 150 ml of a mixture of methanol and water (1/2 by volume). 0.6 g of 10-benzyl-7-chloro-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained, in the form of a beige solid the melting point of which is greater than 260° C. (Analysis C20H14ClN3 O·0.41 H2O % calculated C: 69.07; H: 4.06; Cl: 10.19; N: 12.08; % found C: 69.0; H: 3.9; Cl: 10.5; N: 12.4).
Reaction SMILES: ClCCl.[OH:4][CH2:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>O>[CH3:32][S:33]([O:4][CH2:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:9]=[CH:8][CH:7]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CCCCc1cccc(CO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCc1cccc(COS(C)(=O)=O)n1
Reaction time: 0.17 h

Procedure:
To a 200 mL round-bottom flask, 50 mL of dichloromethane, 2.78 g of t-butyl 5-(6-hydroxymethylpyridin-2-yl)pentanoate and 2.0 g of diisopropylethylamine were added, and the mixture was stirred at ice temperature for 10 minutes. To the reaction mixture, 0.89 mL of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by chromatography on silica gel (n-hexane-ethyl acetate=3:1) to give 2.28 g of t-butyl 5-(6-methane-sulfonyloxymethylpyridin-2-yl)pentanoate as a yellow oil.
Reaction SMILES: [Cl-].[NH4+:2].[C-:3]#N.[K+].[CH3:6][C:7]1([CH3:14])[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]1.O>CN(C)C=O>[CH3:6][C:7]1([CH3:14])[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH:8]1[C:3]#[N:2]
Reactant: [NH4+]
Reactant: CC1(C)C=CC(=O)CC1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CCC(=O)CC1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Under a nitrogen atmosphere, an aqueous solution (10 ml) of ammonium chloride (2.37 g, 0.0443 mol) and an aqueous solution (20 ml) of potassium cyanide (3.15 g, 0.0483 mol) were added dropwise to a solution of 4,4-dimethyl-2-cyclohexen-1-one (5.0 g, 0.0403 mol) in N,N-dimethylformamide (30 ml) at room temperature, and the resulting mixture was heated to 70° C. After 2 hours, the reaction solution was poured into water and extracted with diethyl ether and then dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2,2-dimethyl-5-oxocyclohexanecarbonitrile (4.033 g, 66%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[N-:33]([C:36]#[N:37])[C:34]#[N:35].[Na+]>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[CH:21]=4)[CH2:16][CH2:15][N:14]3[C:36](=[NH:37])[NH:33][C:34]#[N:35])[CH2:10][CH2:11][CH2:12]2)=[CH:5][CH:4]=1
Reactant: N#C[N-]C#N
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)N(C(=N)NC#N)CC2

Procedure:
Propane-1-sulfonic acid (2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-1,2,3,4-tetrahydro-isoquinolin-7-yloxy}-ethyl)-amide hydrochloride (example 4, 95.0 mg, 0.19 mmol) was dissolved in 1-butanol (10 ml) and sodium dicyanamide (42.3 mg, 0.48 mmol) was added.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7]2.[C:22](O)(=[O:26])[C:23](O)=[O:24]>Cl>[Br:1][C:2]1[C:3]2[CH2:4][CH2:5][N:6]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7][C:8]=2[C:9]2[NH:13][C:22](=[O:26])[C:23](=[O:24])[NH:12][C:10]=2[CH:11]=1
Reactant: Nc1cc(Br)c2c(c1N)CN(CCc1ccccc1)CC2
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2cc(Br)c3c(c2[nH]c1=O)CN(CCc1ccccc1)CC3
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A solution of the product from Example 10 (0.54 g, 1.56 mmol) in 3N HCl (20 mL) was treated with oxalic acid (0.3 b, 2.34 mmol) and refluxed for four hours. When cool to room temperature the precipitate was filtered, suspended in water (70 mL) and basifyed to pH 10. The solids were filtered, and dried to give the title compound (0.37 g, 60%) as a brown solid, mp=290-295° C.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Br)(C)C.[CH3:32][C:33]1[C:38]([CH:39]=[O:40])=[C:37]([CH3:41])[CH:36]=[CH:35][N:34]=1>C1COCC1.[Cl-].[NH4+]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:39]([C:38]3[C:33]([CH3:32])=[N:34][CH:35]=[CH:36][C:37]=3[CH3:41])[OH:40])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccnc(C)c1C=O
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -20 °C
Yield: 60 %

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (0.494 g, 1 mmol) placed in a 10 mL round bottom flask under nitrogen atmosphere was dissolved in anhydrous THF (5 mL). The solution was cooled to −20° C. The magnetically stirring solution was treated with solution of 2.0 M isopropylmagnesium bromide in THF (1.05 mL, 2.1 mmol) drop wise and after the addition was complete the reaction mixture was allowed to warm to 0° C. and maintained at this temperature for 1 h. The resulting deep purple solution was cooled to −20° C. and treated with a solution of 2,4-dimethyl-pyridine-3-carbaldehyde (0.28 g, 2.1 mmol) in THF (2 mL). The mixture was allowed to warm to room temperature and stirred at room temperature over night. After diluting with saturated ammonium chloride solution (10 mL) the product was extracted with ethyl acetate (3×25 mL). The combined organic extract was concentrated and product purified by flash chromatography on silica gel column (10-30% ethyl acetate in hexanes). Product containing fractions were combined and the solvent evaporated to afford 0.33 g of 4-chloro-N-{5-chloro-2-[(2,4-dimethyl-pyridin-3-yl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS: (M+H)/z=550.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (224 mg, 0.65 mmol) and 1-methyl-1H-pyrazol-4-ylamine (0.65 mmol) in THF (6 mL) at 0° C. were added 1-hydroxybenzotriazole hydrate (100.8 mg, 0.65 mmol), N-ethyldiisopropylamine (281.7 μl, 1.613 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (126.2 mg, 0.65 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=3:1 to 1:4) afforded the title compound (201 mg, 73%) which was obtained as a white solid. MS: m/e=424.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([NH:29][CH2:30][CH3:31])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)N(CC)CCN(CC)C3)ncc1Cl

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in an analogous manner to example 712. Product was isolated as a tan solid (0.060 g, 53%); Mp181-186° C.; LCMS (m/e) 494 (M); 1H-NMR (DMSO, 400 MHz) δ 11.56 (s, 1H), 9.30 (s, 1H), 8.81-8.74 (m, 2H), 8.21 (s, 1H), 7.75-7.77 (d, 1H, J=8.09 Hz), 7.44-7.48 (t, 1H, J=7.83 Hz), 7.23-7.25 (d, 1H, J=8.08 Hz), 7.14-7.16 (t, 2H, J=8.09 Hz), 6.99-7.01 (d, 1H, J=8.08 Hz), 3.60 (s, 2H), 3.05-3.07 (q, 2H, J=7.07 Hz), 2.92 (m, 2H), 2.77 (m, 2H), 2.39-2.41 (q, 2H, J=7.33 Hz), 1.18-1.09 (m, 6H), 1.06-1.00 (t, 3H, J=7.08 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:25])=[N:7][N:6]=1)=O.Cl>CN(C=O)C.CO>[Cl:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:24])[C:18]=1[CH2:17][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([CH2:3][OH:2])=[N:6][N:7]=1
Reactant: COC(=O)c1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(CO)c2c1
Yield: 97 %

Procedure:
A suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazin-1-carboxylic acid methyl ester (3.9 g, 10.3 mmoles), prepared as described in example 102, in DMF/CH3OH (30/50 ml) under N2 was portionwise added with NaBH (1.17 g, 30.9 mmoles) in 1.5 hours. The stirring went on for 2.5 hours. The mixture was cooled on ice and added with concentrated HCl up to pH<1, then dried, taken up in water and extracted three times with CH2Cl2, the organic phase was anhydrified and dried to give 3.5 g of the title compound (yield: 97%). m.p.: 190-195° C.