Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.ClCCl.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C>[C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH2:21][CH2:22][CH:23]=[O:24])[CH:15]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ncc1Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of N-(1-adamantylmethyl)-5-chloro-2-(3-hydroxypropyl)isonicotinamide (0.12 g, 0.33 mmol) (Example 14(ii)) in dry dichloromethane (10 mL) Dess-Martin periodinane (0.14 g, 0.33 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. The reaction was treated with diethyl ether (20 mL) and a saturated sodium bicarbonate solution containing sodium thiosulfate (0.37 g, in 4 mL). The mixture was stirred for 10 minutes and the organics separated; washed with brine (10 mL); dried over anhydrous magnesium sulfate; filtered; treated with acetic acid (0.30 mL) and concentrated. MS: APCI(+ve) 361, 363 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10]1.CN(C)[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc[nH]n1
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccn(-c2ccc(F)cc2)n1
Temperature: 110 °C
Yield: 76.5 %

Procedure:
To a solution of 1-fluoro-4-iodo-benzene (1.47 g, 6.6 mmol, 1.3 eq) and ethyl 1H-pyrazole-3-carboxylate (0.71 g, 5.1 mmol, 1 eq) in 15 mL of toluene was added CuI (0.19 g, 1.0 mmol, 0.2 eq), trans-N,—N-dimethylcyclohexane 1,2-diamine (0.4 mL, 2.5 mmol, 0.2 eq), and potassium carbonate (1.4 g, 10 mmol, 2 eq). The reaction mixture was heated at 110° C. for 2 d then filtered and concentrated. The residue was purified by silica gel column chromatography (hex:EtoAc 4:1) to afford ethyl 1-(4-fluorophenyl)pyrazole-3-carboxylate (0.92 g, 3.9 mmol, 77%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[C:6]#[N:7])(=[O:3])[CH3:2].[CH2:20](N(CC)CC)C>>[C:1]([O:4][C:5](=[C:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:20])[C:6]#[N:7])(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)OC(C#N)C(Cl)c1ccc(CC(C)C)cc1
Product: CC(=O)OC(C#N)=C(C)c1ccc(CC(C)C)cc1

Procedure:
Following generally the procedure of Example 1, 3-methyl-3-pentyl-glycidonitrile (II) is treated with propionoyl bromide (III) in the presence of a catalytic amount of triethylamine hydrobromide to form 2-propionoyloxy-3-bromo-3-methyl-3-pentylpropionitrile (IV). The propionitrile (IV) is treated with triethylamine to form the 2-propionoyloxy-3-methyl-3-pentylacrylonitrile (V) enolacylate. The enol-acylate (V) is treated with aqueous potassium hydroxide to form the potssium 2-methylheptanoate salt (VI). The reaction mixture is treated with potassium hypochlorite to destroy cyanide ion in the mixture. The potassium salt (VI) is removed from the reaction mixture and diluted with a Skellysolve B-water mixture and then treated with 12N sulfuric acid to form the 2-methylheptanoic acid. Such acid is useful for modifying starches. (U.S.S.R Patent 348,576; C.A., 78 31775 w.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([N:11]([CH3:19])[CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:8][C:6]=2[N:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1.C([O-])(=O)C.[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH2:26][C:27]1[N:28]=[CH:29][C:30]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]3[S:10][C:9]([N:11]([CH3:19])[CH:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[N:8][C:6]=3[N:7]=2)=[CH:31][CH:32]=1
Reactant: CN1CCC(N(C)c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCC(N(C)c2nc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
5-Chloro-N-methyl-N-(1-methylpiperidin-4-yl)-7-morpholinothiazolo[4,5-d]pyrimidin-2-amine, 2-aminopyridine-5-boronic acid pinacol ester (2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M potassium acetate (3 eq) and acetonitrile. The solution was microwaved at 140° C. for 10 minutes. The solvent was removed in vacuo and the resulting precipitate was purified by reverse phase silica gel chromatography to give the product 144.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][NH2:19].[C:20]([OH:24])(=[O:23])[CH:21]=O>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][N:19]=[CH:21][C:20]([OH:24])=[O:23]
Reactant: O=CC(=O)O
Reactant: Cc1ccc(Cl)c(Nc2ccccc2CON)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Nc2ccccc2CON=CC(=O)O)c1Cl
Reaction time: 16 h
Yield: 34.8 %

Procedure:
A solution in THF of O-[2-[(2,6-dichloro-3-methylphenyl)amino]phenylmethyl]hydroxylamine (0.50 g, 1.71 mmol), prepared as in step 3, and glyoxylic acid (0.18 g, 1.99 mmol) in THF was stirred for 16 hours. The solution was then diluted with aqueous citric acid and extracted with ethyl acetate (100 mL). The extract was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to yield an off white solid which was purified by chromatography on silica gel (10% methanol-chloroform). The resulting residue was crystallized from EtOAc/hexanes to provide glyoxylic acid-O-[2-[(2,6-dichloro-3-methylphenyl)amino]phenylmethyl] oxime (0.21 g, 33%) as a white solid. mp 185°-187° C. 1H NMR (300 MHz, DMSO-d6) δ2.38 (s, 3 H), 5.17 (s, 2 H), 6.19 (d, J=7.5 Hz, 1 H), 6.82 (t, J=7.5 Hz, 1 H), 6.97 (s, 1 H), 7.09 (t, J=7.5 Hz, 1 H), 7.25 (m, 2 H), 7.44 (m, 2 H). MS (DCI/NH3) m/z 353 (M+H)+. Anal. Calcd for C16H14N2O3Cl2 ×1.0 H2O: C, 51.76; H, 4.34; N, 7.54. Found: C, 51.78; H, 3.69; N, 7.15.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:25][C:26]1([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:29][NH:28][CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:28]3[CH2:29][C:26]([CH2:30][N:31]([CH3:33])[CH3:32])([F:25])[CH2:27]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CN(C)CC1(F)CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 1.8 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.50 g, 1.0 eq.) was dissolved in DCM (10 mL). The reaction mixture was cooled to −60° C., at which temperature 1-(3-fluoroazetidin-3-yl)-N,N-dimethylmethanamine (0.22 g, 1.2 eq) and T3P (50% in EtOAc) (1.08 g, 1.2 eq.) were added, followed by DIPEA (0.36 g, 2 eq.). The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography to give 12 mg of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3-((dimethylamino)methyl)-3-fluoroazetidin-1-yl)prop-2-en-1-one (3% yield). 1H NMR (400 MHz, CDCl3) δ=9.75 (s, 1H), 8.62 (s, 2H), 7.94 (s, 1H), 7.24-7.21 (d, J=10.8 Hz, 1H), 5.69-5.66 (d, J=10.8 Hz, 1H), 4.37-4.25 (m, 2H), 4.22-4.15 (m, 2H), 2.82-2.76 (d, 2H), 2.35 (s, 2.35, 1H); LCMS for C19H19F7N5O [M+H]+ 466.4 found 466.3 at retention time 2.263 min
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[NH:16][N:17]=[C:18]([C:19]([F:22])([F:21])[F:20])[C:5]=12.Cl[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26].O>CN(C=O)C.C(Cl)Cl>[Cl:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[C:6]2[N:16]([CH2:24][C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[N:17]=[C:18]([C:19]([F:22])([F:20])[F:21])[C:5]=12
Reactant: O=C(CCl)N1CCCC1
Reactant: FC(F)(F)c1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1nc(C(F)(F)F)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Reaction time: 21 h
Yield: 14.8 %

Procedure:
Sodium hydride (18 mg, 0.45 mmol) was added to a solution of 4-chloro-5-phenyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridazine (115 mg, 0.38 mmol) and 2-chloro-1-pyrrolidin-1-yl-ethanone (81 mg, 0.55 mmol) in dry DMF (1.5 ml) and the reaction stirred for 21 h. Water and CH2Cl2 where added and the aqueous phase was extracted with CH2Cl2. The organic phases where combined, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate/isohexane 2:8 to 1:0) followed by preparative HPLC yielding Compound Iaa as a white solid (23 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][N:20]([CH3:46])[CH:21]1[C:30]2[CH2:29][O:28][C:27]([CH:31]=[O:32])=[CH:26][C:25]3=[CH:33][N:34]([Si](C(C)C)(C(C)C)C(C)C)[CH:35]=[C:23]([C:24]=23)[CH2:22]1>O1CCCC1.O.C(OCC)(=O)C>[CH3:19][N:20]([CH3:46])[CH:21]1[C:30]2[CH2:29][O:28][C:27]([CH:31]=[O:32])=[CH:26][C:25]3=[CH:33][NH:34][CH:35]=[C:23]([C:24]=23)[CH2:22]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(C=O)OCC3=C2C(=C1)CC3N(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C1CC2=CNC=C3C=C(C=O)OCC1=C32
Reaction time: 3 h
Yield: 88 %

Procedure:
Tetra-n-butylammoniumfluoride (1 mol/l tetrahydrofuran solution) 2.2 ml was added to compound (45) 496 mg in tetrahydrofuran 10 ml with cooling in ice. The mixture was stirred for 3 h, diluted with water and ethyl acetate and, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (2:1) to give colorless crystals, 273.2 mg. This was recrystallized from acetone-isopropyl ether to give the titled compound as colorless crystals, m.p.175-176° C., 2654 mg. Yield 88%.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.C[O:25][C:26]1[CH:27]=[CH:28][C:29]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:36][CH2:35]2)=[C:30]([CH:33]=1)[C:31]#[N:32]>>[OH:25][C:26]1[CH:27]=[CH:28][C:29]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:36][CH2:35]2)=[C:30]([CH:33]=1)[C:31]#[N:32]
Reactant: COc1ccc(N2CCC(c3ccccc3)CC2)c(C#N)c1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: N#Cc1cc(O)ccc1N1CCC(c2ccccc2)CC1
Yield: 44.6 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 5-methoxy-2-(4-phenylpiperidino)benzonitrile (99 mg), and the resulting crude product was purified on TLC (developer, hexane: ethyl acetate=2:1) to provide 5-hydroxy-2-(4-phenylpiperidino)benzonitrile (42 mg).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5]1)#[N:2].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[C:1]([CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([Cl:14])=[O:10])[CH2:5]1)#[N:2]
Reactant: N#CCC1CC(C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC1CC(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-cyanomethylcyclobutane carboxylic acid (4.0 g, 28.8 mmol) in dichloromethane (50 ml) was added two drops of dimethylformamide followed by oxalyl chloride (12 ml). The mixture was stirred overnight at room temperature followed by removal of the solvent and excess reagent in vacuo. The resulting oil was dissolved in dry dichloromethane and the solvent evaporated to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH3:9])[C:4](=[O:10])[C:3]=1[N+:11]([O-])=O>[Pd].CCO.C1COCC1>[NH2:11][C:3]1[C:4](=[O:10])[N:5]([CH2:8][CH3:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CCn1ccc(N)c([N+](=O)[O-])c1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCn1ccc(N)c(N)c1=O
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A solution of 4-amino-1-ethyl-3-nitro-1H-pyridin-2-one (0.94 g, 5.13 mmol) in 1:3 EtOH/THF (20 mL) was hydrogenated over 10% Pd/C (0.55 g, 0.51 mmol) at room temperature. After 1 h, the catalyst was removed by filtration, rinsing with MeOH. The filtrate was concentrated to provide 3,4-diamino-1-ethyl-1H-pyridin-2-one (0.75 g, 95% yield). 1H-NMR (DMSO): δ 6.87 (d, 1H, J=7.2 Hz), 5.76 (d, 1H, J=7.6 Hz), 5.10 (m, 2H), 3.87 (m, 2H), 3.79 (q, 2H, J=7.2 Hz), 1.14 (t, 3H, J=7.2 Hz). MS: calculated for C7H11N3O+H 154.1; found: 154.2.
Reaction SMILES: Cl.[CH3:2][CH:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)N)[CH3:4].CC[O:16][C:17]([CH2:19][CH:20]1[C:25](=O)[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18]>>[F:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[N:5]([CH:3]([CH3:4])[CH3:2])[C:25]1[CH:20]([CH2:19][C:17]([OH:16])=[O:18])[CH2:21][CH2:22][CH2:23][C:24]2=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: CC(C)N(N)c1ccc(F)cc1
Agent: Cl
Product: CC(C)n1c2c(c3cc(F)ccc31)CCCC2CC(=O)O

Procedure:
Following the procedure of Example 1, but using 1-(2-propyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([CH:42]=[O:43])[CH:41]=1)[C:37]#[N:38].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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.[Pd]>[C:37]([C:36]1[CH:35]=[C:34]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:41]=[C:40]([CH:42]=[O:43])[CH:39]=1)#[N:38]
Reactant: N#Cc1cc(Br)cc(C=O)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C#N)cc(C=O)c4)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2.0 mL, 0.7 mL) was added 3-bromo-5-formylbenzonitrile (68 mg, 0.3 mmol) and K2CO3 (83 mg, 0.6 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis (triphenylphosphosphine) palladium (0) (11 mg, 0.01 mmol). The reaction was heated in a microwave for 20 min at 160° C. It was then purified by Gilson Preparatory HPLC to give 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([C@H:27]4[CH2:32][CH2:31][C@H:30]([C:33]([O:35]CC5C=CC=CC=5)=[O:34])[CH2:29][CH2:28]4)=[N:25][CH:26]=[C:18]1[C:17](=[O:43])[NH:16]3)=[O:12])[CH2:6][CH2:5]2.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([C@H:27]4[CH2:28][CH2:29][C@H:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]4)=[N:25][CH:26]=[C:18]1[C:17](=[O:43])[NH:16]3)=[O:12])[CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1cnc([C@H]3CC[C@H](C(=O)OCc4ccccc4)CC3)n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1cnc([C@H]3CC[C@H](C(=O)O)CC3)n12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 676 mg of benzyl trans-4-{7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-8-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxalin-1-yl}cyclohexane carboxylate were added 6.7 mL of methanol and 1.5 mL of a 3 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 16 hours. 1 M hydrochloric acid was added thereto, and the precipitate was collected by filtration and washed with water. The obtained solid was air-dried, suspended in chloroform, collected by filtration, and dried under reduced pressure to obtain 485 mg of trans-4-{7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-8-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxalin-1-yl}cyclohexanecarboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:33]C1C=CC2C3N(CC(C)C)C(C)=NC=3C=NC=2C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-:33])=[CH:14][C:13]3[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cn1cnc2cnc3ccc(OCc4ccccc4)cc3c21
Reactant: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Product: CC(C)Cn1cnc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c21

Procedure:
The general method described in Part B of Example 3 was followed using 8-benzyloxy-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (2.1 g, 6.3 mmol) in lieu of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline. After the work-up, 2.16 g of 8-benzyloxy-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinoline were obtained as a white solid and used without purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5[CH2:41][CH2:40]CO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CCC[C@H]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:37]1([CH2:36][NH:35][CH2:34][C:32]2[CH:33]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]3)[CH:29]=[C:30]([F:42])[CH:31]=2)[CH2:41][CH2:40]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Agent: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCC5CC5)c4)cc23)CC1
Yield: 38.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-cyclopropylmethanamine (37 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 21.1 mg of the title compound (38.7%).
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][C:7]([N:9]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:14]3[C:13](=[O:19])[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.[H-].[Na+].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Br.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][N:12]1[C:13](=[O:19])[CH:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[N:9]([C:7](=[O:8])[CH2:6][N:5]2[C:4](=[O:24])[C:3]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]3[C:1]2=[O:29])[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]1=2
Reactant: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)C2CCCC12
Reactant: COc1ccccc1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CN1C(=O)C2CCCC2N(C(=O)CN2C(=O)c3ccccc3C2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
To a suspension of 4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (389 mg, 1.0 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% liquid paraffin dispersion, 44 mg, 1.1 mmol). The mixture was stirred for 10 minutes at room temperature. To this mixture was added 2-methoxybenzyl bromide (241 mg, 1.2 mmol), which was stirred for 90 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride (3 mL), which was diluted with water. The resulting solid was collected by filtration, which dissolved in chloroform. The solution was dried over magnesium sulfate, which was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was recrystallized from chloroform-ethanol to give 234 mg (yield 46%) of a mixture of cis-compound and trans-compound. m.p. 261°-272° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]([NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)=[S:17])[CH:12]([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:16]([NH:15][CH2:11][CH:12]([CH3:14])[CH3:13])=[S:17])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)CNC(=S)Nc1cccc(N)c1
Solvent: ClC(Cl)Cl
Product: CC(C)CNC(=S)Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1

Procedure:
A solution of freshly distilled p-chlorophenyl isocyanate (1.38 g.) in 10 ml. chloroform is added at room temperature in one portion to a solution of 1-isobutyl-3-(m-aminophenyl)thiourea (2.0 g.) in chloroform (30 ml.). The product precipitates rapidly and is filtered off after several hours. The filter cake is washed with chloroform and dried to give 1-(3-p-chlorophenylureido)-3-(3-isobutylthioureido)-benzene, m.p. 195°-196° C.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[OH:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:11]=1[CH:12]=O>O.CO>[OH:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:11]=1[CH:12]=[N:7][OH:8]
Reactant: NO
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(O)c(C=NO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A solution of 68.0 g (0.83 mol) of sodium acetate and 68.0 g (0.98 mol) of hydroxylamine hydrochloride in 300 ml of water is added dropwise to a solution of 80.5 g (0.45 mol) of 2-hydroxy-5-methoxycarbonylbenzaldehyde in 300 ml of methanol and the mixture is stirred at 25° C. for 2 hours. The product which has precipitated is filtered off with suction, washed with water and dried in vacuo over phosphorus pentoxide to give 70.4 g of the title compound.