Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)=[O:1]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CO)cc23)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(C=O)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.8 %

Procedure:
A mixture of tert-butyl [6-(hydroxymethyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (0.46 g, 1.1 mmol), manganese dioxide (chemically treated product, 1.4 g, 16 mmol) and tetrahydrofuran (20 ml) was stirred at room temperature for 12 hrs. The reaction mixture was filtered, and the filtrate was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-formyl-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (0.28 g, yield 62%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[CH2:24]([S:31][CH:32]([CH:35]([O:38][CH3:39])[O:36][CH3:37])[CH2:33][NH2:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([S:31][CH:32]([CH:35]([O:36][CH3:37])[O:38][CH3:39])[CH2:33][NH:34][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1)(=[O:17])=[O:16])=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1nccn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(OC)C(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3nccn3C)c2[nH]1)SCc1ccccc1
Yield: 102.2 %

Procedure:
A solution of 7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxylic acid (2.64 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (2.10 g), N-ethyldiisopropylamine (3.2 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.6 g) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 16 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=35:65-50:50) to give the title compound (4.5 g, yield: 100%) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B(O)O)[CH:3]=[N:2]1.Br[C:10]1[CH:11]=[C:12]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][N:16](C3CCCCO3)[C:13]2=[CH:14][N:15]=1>>[C:19]1([C:18]2[C:12]3[C:13](=[CH:14][N:15]=[C:10]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[CH:11]=3)[NH:16][N:17]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Product: c1ccc(-c2n[nH]c3cnc(-c4cn[nH]c4)cc23)cc1
Yield: 23 %

Procedure:
Following the procedures as described in Example 136, 1H-pyrazol-4-ylboronic acid and 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and the product was deprotected to give 137 as a yellow solid (26 mg, 23%) over two steps. 1H NMR (400 MHz, DMSO) δ 12.9 (s, 1H), 9.05 (s, 1H), 8.37-8.09 (m, 5H), 7.56 (m, 1H), 7.44 (m, 1H)
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[CH:25]([CH:27]2[CH2:29][CH2:28]2)[OH:26])[C:5]1=[O:32])C=C.I([O-])(=O)(=O)=O.[Na+].CC[O:42][C:43]([CH3:45])=[O:44]>C(#N)C.O.O.[Ru](Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:6]([C@@H:24]([CH2:30][CH3:31])[C:25]([CH:27]3[CH2:28][CH2:29]3)=[O:26])[C:5](=[O:32])[C@:4]([CH2:45][C:43]([OH:42])=[O:44])([CH3:1])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(C)=O
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)C2CC2)C1=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC[C@@H](C(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-cyclopropyl-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 417, Step A; 60 mg, 0.123 mmol) in EtOAc (1 mL), acetonitrile (1 mL) and water (1.5 mL) was added ruthenium chloride hydrate (2.8 mg, 0.012 mmol) and sodium meta-periodate (6.83 μl, 0.123 mmol) (portionwise over 5 minutes). The reaction was stirred at rt for 20 minutes and then partitioned between EtOAc (60 mL) and water (20 mL). The separated aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. Purification by column chromatography (12 g, SiO2, hexanes/IPA, 1:0 to 9:1) gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)=[O:14])[CH:3]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:28][CH:29]=2)=[O:14])[CH:3]=1
Reactant: CCOC(=O)COc1ccc(CNC(=O)c2cc(N)c(C#N)c(OCC)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1nc(C(=O)NCc2ccc(OCC(=O)O)cc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of Example 188A (102 mg, 0.26 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL) was added 2N NaOH (300 μL, 0.6 mmol). The reaction mixture was stirred at ambient temperature for 2 hr, and then acidified with 600 μL 1N HCl. It was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to provide the titled compound as white solid (95 mg, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20](I)[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].N1C=CC=CC=1C1C=CC=CN=1.[CH2:36]([S:38]SCC)[CH3:37]>CN(C)C=O.[Zn].[Ni](Br)Br>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([S:38][CH2:36][CH3:37])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(I)c1O
Reactant: CCSSCC
Agent: Br[Ni]Br
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Product: CCSc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C#N)c1O
Temperature: 110 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
3-(3-cyano-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (500 mg) was dissolved in N,N-dimethylformamide (5 mL), and 2,2′-bipyridine (18 mg), zinc powder (149 mg), nickel bromide (25 mg) and diethyl disulfide (70 mg) were added to the solution, and then the mixture was stirred at 110° C. for 1 hour. After the reaction solution was filtered, 1N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) and then crystallized from diethylether-ethyl acetate to obtain the title compound (63 mg) as a colorless crystal.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:37])[CH2:35][CH3:36])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.25 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, propionyl chloride (0.2 g, 2.13 mmol) was added. The mixture was stirred at room temperature for 17 hours. Solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (60 ml) and washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed and the resulting solid was slurried in hot C2H5OH (10 ml) to give after filtration N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide (0.41 g, 64%) as a white solid: mp 219–221° C.; 1H NMR (DMSO-d6) δd 11.15 (s, 1H), 8.42 (t, J=5.8 Hz, 1H), 7.87–7.67 (m, 3H), 5.19–5.12 (dd, J=5.3 and 12.5 Hz, 1H), 4.72 (d, J=5.8 Hz, 2H), 2.98–2.84 (m, 1H), 2.65–2.48 (m, 2H), 2.26–2.17 (m, 2H), 2.09–2.04 (m, 1H), 1.05 (t, J=7.8 Hz, 3H); 13C NMR (DMSO-d6) δ d 173.52, 172.81, 169.79, 167.53, 167.01, 139.52, 134.79, 133.20, 131.55, 127.10, 121.86, 48.89, 37.69, 30.95, 28.43, 22.03, 9.90; Anal. Calcd. For C17H17N3O5+0.19 H2O: C, 58.88; H, 5.05; N, 12.12. Found: C, 58.77; H, 4.97; N, 12.12.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26](Br)=[CH:27][CH:28]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:11]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)#[CH:32]>CN(C=O)C>[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]([C:32]#[C:31][C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)=[CH:27][CH:28]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:11]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Br)o3)cc2)C1
Reactant: C#Cc1ccc(C)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1ccc(C#Cc2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.042 ml of diisopropylamine was added under argon to 3.8 mg of Pd(tBu)2Cl2 and 0.95 mg of Cul in 0.2 ml of DMF. A solution of 94.6 mg of 5-bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide in 0.3 ml of DMF and a solution of 4-ethynyltoluene in 0.3 ml of DMF were then added dropwise. The solution was stirred at room temperature overnight. The precipitate which had separated out was filtered off with suction and the filtrate purified by preparative HPLC. The desired product with the molecular weight of 413.52; MS (ESI): 414 was obtained as hydrotrifluoroacetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[C:27]([C:28]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH2:6]2)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC1(C)CCC(Nc2ncnc3c(N)cccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(Nc2ncnc3c(NC(=O)c4c(Cl)ccc(CNC(=O)C(C)(C)C)c4F)cccc23)CC1
Yield: 5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-dimethylcyclohexyl)quinazoline-4,8-diamine (Intermediate-15, 100 mg, 0.37 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 212 mg, 0.99 mmol), oxalyl chloride (188 mg, 1.49 mmol), DMF (1 drop) and DIPEA (143 mg, 1.11 mmol) in CH2Cl2 (5 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, CDCl3): δ 9.91 (s, 1H), 8.96 (d, 1H), 8.55 (s, 1H), 7.51-7.44 (m, 3H), 6.11 (br s, 1H), 5.67 (br s, 1H), 4.50 (d, 1H), 4.19 (m, 1H), 1.69-1.60 (m, 4H), 1.38-1.28 (m, 4H), 1.12 (s, 9H), 0.95 (s, 3H), 0.92 (s, 3H); MS (m/z): 540.36 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](O)=[O:15])[CH:8]=2)[N:3]=1.[F:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([N:25]3[CH2:26][CH2:27][CH:22]([F:21])[CH2:23][CH2:24]3)=[O:15])[CH:8]=2)[N:3]=1
Reactant: Nc1ccc2cc(-c3ccccc3C(=O)O)ccc2n1
Reactant: FC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccc2cc(-c3ccccc3C(=O)N3CCC(F)CC3)ccc2n1

Procedure:
To a microwave reaction vessel was added ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.7 g, 13 mmol), 6-bromoquinolin-2-amine (2.0 g, 9.0 mmol), PdCl2(PPh(t-Bu)2)2 (0.084 g, 0.13 mmol), potassium acetate (1.8 g, 18 mmol), EtOH (9.9 ml, 170 mmol) and water (2.4 ml, 134 mmol). The reaction mixture was heated at 85° C. for 8 h, and was then partitioned between EtOAc and water. The organic layer was washed with water and brine and allowed to stand for 72 h. The supernatant was decanted from the resulting precipitate and the precipitate was dried in vacuo to give ethyl 2-(2-aminoquinolin-6-yl)benzoate. Step 2 6-(2-Ethoxyphenyl)quinolin-2-amine (1.0 g, 3.8 mmol) was taken up in THF and then 5N NaOH was added and the solution was stirred for 72 h. DCM was added and the solid was filtered to give ethyl 2-(2-aminoquinolin-6-yl)benzoate. Step 3 A solution of 2-(2-aminoquinolin-6-yl)benzoic acid (50 mg, 0.19 mmol), 4-fluoropiperidine (25 mg, 0.24 mmol), HATU (91 mg, 0.24 mmol), DIEA (100 uL, 0.57 mmol), and DMF (1 mL) was heated in a shaker oven at 60° C. for 1 h. The resulting solution was purified by HPLC (CH3CN/water modified with 0.1% TFA) to give (2-(2-aminoquinolin-6-yl)phenyl)(4-fluoropiperidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 350 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:1].[ClH:1].[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=2)[CH2:25][CH2:24]1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3ccccc3c(N3CCN(CCO)CC3)n2)cc1
Product: Cl

Procedure:
A mixture of 1-chloro-3-(4-methoxyphenyl)isoquinoline (0.79 g) obtained in Example 10-2, 1-(2-hydroxyethyl)piperazine (0.6 g), and potassium carbonate (0.83 g) was reacted in dimethylformamide (10 ml) at 100° C. for 6 hr. The reaction mixture solution was evaporated. Ethyl acetate and water were added to the resulting residue. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[OH-].[K+].[NH4+:12].[OH-].[CH2:14](O)[CH3:15]>>[N:12]1[CH:8]=[CH:7][CH:6]=[CH:2][C:1]=1[C:4]1[C:9]([C:15]2[CH:14]=[CH:2][CH:1]=[CH:4][N:5]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(=O)c1ccccn1
Reactant: [NH4+]
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: c1ccc(-c2cccnc2-c2ccccn2)nc1

Procedure:
6-(2-(4-Iodophenyl)ethynyl)pyridine-3-ter-pyridine (Compound 94, Scheme 24) was prepared by stirring a mixture of Compound 93 (500 mg, 1.5 mmol), 2-Acetylpyridine (550 mg, 4.5 mmol), KOH 85% (360 mg, 4.5 mmol, and NH4OH 29% (7.5 ml, 6 mmol) in anhydrous ethyl alcohol (25 ml) and reflux for 14 hours. Thereafter the crude solid was collected by filtration, and washed with cold EtOH to produce the ter-pyridine Compound 94 as a brownish solid (65% yield).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[N:6][CH:7]=[CH:8][CH:9]=1.Cl.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30]Cl>CN(C)C=O>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][N:10]([C:5]1[C:4]([NH2:3])=[CH:9][CH:8]=[CH:7][N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: Nc1cccnc1Nc1ccccc1C(=O)c1ccccc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1N

Procedure:
To a stirred suspension of sodium hydride (in mineral oil) in anhydrous dimethylformamide, under nitrogen atmosphere was added, portionwise, [2-[(3-amino-2-pyridinyl)amino]phenyl]phenylmethanone. To the mixture was added 3-dimethylaminopropyl chloride hydrochloride to give a solution containing some of the title compound as indicated by chemical ionization mass spectrascopy analysis. With time, this cyclized spontaneously to the corresponding pyrido[2,3-b][1,4]benzodiazepine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][C:3]([CH2:9][C:10]([NH2:12])=[O:11])=[C:2]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: NC(=O)Cc1cnc(Cl)cc1Cl
Reactant: NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=O)Cc1cnc(Cl)cc1NC1CCCCC1
Yield: 93 %

Procedure:
200 mg of 4,6-dichloropyridine-3-carboxyamide synthesized according to the method described in US2006/0217417 was dissolved in 2 mL of ethanol, to which 156 mg of cyclohexylamine and 203 mg of N,N-diisopropylethylamine were added, and heated at reflux for 8 hours. After cooling, the solvent was evaporated, and 10 mL of water was added to the residue, neutralized by adding 2 mol/L hydrochloric acid in water under ice cooling, extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was recrystallized from chloroform-hexane to obtain 243 mg (92%) of the title compound as colorless needle crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][CH:22]=[CH:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].ClC1C=C(C=CC=1)C(OO)=[O:31]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[CH2:24][CH2:23][CH:22]2[O:31][CH:21]23)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC=C3)cc1
Solvent: ClCCl
Product: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC2OC32)cc1

Procedure:
A solution of a 3:1 mixture of N-(4-cyanophenyl)-N-(7,8-dihydro-1-naphthyl)-2,2,2-trifluoro acetamide and the corresponding 5,6-dihydro isomer (4.3 g, 13 mmol) and m-chloroperoxybenzoic acid (80-85%, 4.0 g, 19 mmol) (Aldrich) in methylene chloride (60 ml) was stirred for 50 minutes at room temperature. The solution was diluted with methylene chloride (100 ml), washed with saturated NaHCO3 solution (2×30 ml), dried (K2CO3), and concentrated in vacuo. The epoxide isomers were separated by chromatography on silica gel eluting with diethyl ether:hexane (7:13 to 9:11) and recrystallization of the enriched isomer from diethyl ether:hexane. The mother liquor was combined with some mixed fractions from the chromatography and purified by repeating the procedure. The combined solid was dried under high vacuum to give N-(4-cyanophenyl)-2,2,2-trifluoro-N-(1a,2,3,7b -tetrahydronaphth[1,2-b]oxiren-4-yl)acetamide (2.8 g). 1H NMR (CDCl3, 200 MHz) δ: 1.69 (dt, J=14,5 Hz, 1H, CH2), 2.03-2.25 (m, 1H, CH2), 2.31-2.69 (m, 2H, CH2), 3.70-3.78 (m, 1H, OCH), 3.90 (d, J=4 Hz, 1H, OCH), 7.29-7.42 (m, 4H, Ar), 7.50-7.60 (m, 1H, Ar), 7.63 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C19H13F3N2O2 : C, 63.69; H, 7.82. Found: C, 63.70; H, 3.66; N, 7.76.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>C(N(CC)CC)C.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: Nc1ccccc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccccc2)c1
Yield: 94.6 %

Procedure:
A solution of 13.4 mL (147 mmol) of aniline in 30.7 mL of triethylamine was slowly added to a solution containing 25.1 g (147 mmol) of 3-methoxybenzoyl chloride in methylene chloride. The resulting reaction mixture was reacted for approximately thirty minutes and then diluted with 1N sodium bicarbonate. The resultant layers were separated and the organic layer was washed sequentially with water, 1M sodium hydroxide and then brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 31.6 g of an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[CH:13]1([N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[NH:22][CH:19]1[CH2:20][CH2:21][N:16]([CH:13]2[CH2:15][CH2:14]2)[CH2:17][CH2:18]1
Reactant: NC1CCN(C2CC2)CC1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cnc(NC2CCN(C3CC3)CC2)c(Cl)c1

Procedure:
A mixture of EXAMPLE 387A (0.4 g), 1-cyclopropylpiperidin-4-amine (0.3 g) and N,N-diisopropylethylamine (0.37 mL) in dioxane (3 mL) was heated at 100° C. for 18 hours. The crude product was isolated by concentration and was purified on silica gel, which was eluted with ethyl acetate to give the title compound.