Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:10])[NH:5][N:6]=[CH:7][C:8]=1[CH3:9])#[N:2].[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:1]([C:3]1[C:4](=[O:10])[N:5]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:6]=[CH:7][C:8]=1[CH3:9])#[N:2]
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cn[nH]c(=O)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cn2ncc(C)c(C#N)c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A mixture of 4-cyano-5-methyl-3-pyridazinone (P. Schmidt and J. Druey, Helvetica Chemica Acta, 37, 1467 (1954)) (0.93 g, 6.9 mmol) and NaH (50% in oil, 0.344 g, 8.6 mmol) in DMF (15 mL) was stirred at rt for 1 hour. 4-Methoxybenzyl chloride (1.34 g, 8.6 mmol) was added, and the mixture was stirred for 16 hours. The mixture was diluted with water, and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered and evaporated. Trituration of the residue with ethyl acetate gave 4-cyano-2-(4-methoxybenzyl)-5-methyl-3-pyridazinone (0.83 g, 3.2 mmol, 46%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=[C:4]([N+:26]([O-:28])=[O:27])[CH:3]=1.C(O)(C(F)(F)F)=O.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[C:48]([C:49](O)=[O:50])=[C:47]([CH3:52])[NH:46][N:45]=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>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:49]([C:48]3[C:44]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[O:37][CH3:36])=[N:45][NH:46][C:47]=3[CH3:52])=[O:50])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:14][C:15](=[O:25])[C:16]2[CH:17]=[CH:18][C:19]([N:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=2)=[C:4]([N+:26]([O-:28])=[O:27])[CH:3]=1
Reactant: COc1ccccc1-c1n[nH]c(C)c1C(=O)O
Reactant: CN(C)c1ccc(C(=O)Nc2cc(N3CCNCC3)c(Cl)cc2[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1n[nH]c(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of N-(4-chloro-2-nitro-5-(piperazin-1-yl)phenyl)-4-(dimethylamino)benzamide, 2 TFA (Preparation D, 35 mg, 0.055 mmol) in DMF (2 ml) was added 3-(2-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (Preparation O, 15.44 mg, 0.066 mmol), HATU (25.3 mg, 0.066 mmol), followed by DIEA (0.048 ml, 0.277 mmol). The reaction was stirred at r.t. for 10 mins. Purified by prep-HPLC to afford 14 mg (33%) of the title compound. HPLC/MS (Method SZ6): (ES+) m/z (M+H)+=618; Rt=2.98 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH:12]=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.S(=O)(=O)([OH:16])N.Cl([O-])=O.[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[C:11]([C:12]([OH:16])=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: COc1c(C=O)ccc2c1CCC2
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: COc1c(C(=O)O)ccc2c1CCC2
Temperature: 26.5 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a clear solution of 4-Methoxy-indan-5-carbaldehyde (11.5 gm, 0.065 mole) in Dichloromethane (100 ml), Sulphamic acid (19.0 gm, 0.196 mole) was added at 25-28°. A solution of Sodium chlorite (15.28 gm, 0.169 mole) in water (50 ml) was added at 5-10° C. The reaction mixture was stirred for 5 hours at 25-28° C. Finally the reaction mixture was poured into water (200 ml) and extracted with Dichloromethane (2×200 ml). The organic layer was dried over Sodium sulphate, distilled under vacuum to give 12.0 gm of desired product as a viscous oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)[C:19](=[O:35])[C:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=2)=[C:21]([CH:23]2[CH2:25][CH2:24]2)[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]3[NH:3][C:4](=[O:7])[O:5][N:50]=3)=[CH:41][CH:42]=2)[C:19](=[O:35])[C:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=2)=[C:21]([CH:23]2[CH2:24][CH2:25]2)[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C2CC2)c(-c2ccc(OCC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C2CC2)c(-c2ccc(OCC)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogen carbonate (0.76 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-4-cyclopropyl-5-(4-ethoxyphenyl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.38 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.38 g, 90%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CS(C)=O.[CH3:15][N:16]([CH3:23])[CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>O>[CH3:15][N:16]([CH3:23])[CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: CN(C)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A 100 ml flask was charged with 1-fluoro-4-nitrobenzene (2.122 ml, 20 mmol), dimethylsulfoxide (30 ml), N,N-dimethylpiperidin-4-amine (2.82 g, 22.00 mmol) and triethylamine (5.58 ml, 40.0 mmol). The resulting solution was stirred at 100° C. under nitrogen for 24 hours. The reaction mixture was allowed to cool, and was poured in stirring cold water (1000 ml) and the solid collected by filtration and washed with water. The precipitate was vacuum dried to provide the title compound. MS (ESI(+)) m/e 249.9 (M+H)+.
Reaction SMILES: C[Si:2]([CH3:11])([O:7][CH2:8][CH2:9][SH:10])[O:3][CH2:4][CH2:5][SH:6].C(N(CC)CC)C.ClC([SiH3])(Cl)Cl.[SH:24][CH2:25][CH2:26][OH:27]>CCOCC>[CH3:11][Si:2]([O:3][CH2:4][CH2:5][SH:6])([O:7][CH2:8][CH2:9][SH:10])[O:27][CH2:26][CH2:25][SH:24]
Reactant: C[Si](C)(OCCS)OCCS
Reactant: OCCS
Agent: [SiH3]C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](OCCS)(OCCS)OCCS

Procedure:
The 2-[methyl-bis(2-sulfanylethoxy) silyl]oxyethanethiol (2) was synthesized according to the same procedure as 2-[dimethyl(2-sulfanylethoxy)silyl]oxyethanethiol (1), using triethylamine (8.08 g, 0.080 mol), trichloromethylsilane (3.98 g, 0.027 mol), and 2-mercaptoethanol (6.24 g, 0.080 mol) in ether (400 mL). 2-[methyl-bis(2-sulfanylethoxy) silyl]oxyethanethiol (2) was obtained as a clear, colorless, foul-smelling liquid (6.81 g, 93.2%). The product was purified by distillation under reduced pressure and obtained as a clear, colorless, foul-smelling liquid (4.53 g, 62.0%), Bp=128-129° C. at 0.25 mmHg.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCC(=O)CC(=O)OC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCCCC(=O)C(=Cc1ccc(Br)cc1)C(=O)OC

Procedure:
A mixture of 1.58 g (10 mmol) of methyl 3-oxoheptanoate, 1.85 g (10 mmol) of 4-bromobenzaldehyde, 0.04 ml of piperidine, 0.12 ml of acetic acid and 10 ml of toluene is heated to the refluxing temperature in a 25-ml round-bottomed flask equipped with a Dean and Stark apparatus. After two hours of heating, the theoretical amount of water is recovered and the toluene is evaporated off under vacuum.
Reaction SMILES: [C:1]([O-])([O-])(OCC)[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([NH2:17])[C:12]([NH2:16])=[CH:13][C:14]=1[F:15]>C(O)C>[Cl:8][C:9]1[C:14]([F:15])=[CH:13][C:12]2[NH:16][C:1]([CH3:2])=[N:17][C:11]=2[CH:10]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: Nc1cc(F)c(Cl)cc1N
Solvent: CCO
Product: Cc1nc2cc(Cl)c(F)cc2[nH]1
Yield: 39 %

Procedure:
A 4.96 g portion of ethyl orthoacetate dissolved in 10 ml of ethanol was added to 50 ml of ethanol solution containing 4.68 g of 4-chloro-5-fluorobenzene-1,2-diamine and heated under reflux for 4 hours. After concentration of the reaction liquid, the thus formed residue was purified by a silica gel column chromatography to obtain 2.10 g (39%) of 5-chloro-6-fluoro-2-methyl-1H-benzimidazole from a chloroform-methanol (10:1) eluate. ES+: 185
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[F:48])[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[F:48])[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccccc4F)cc3OCC)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccccc4F)cc3OCC)CC1)CC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-5-ethoxy-2′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (250 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with 2 M hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (153 mg).
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:13]1[O:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][CH2:14][CH:13]([OH:15])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:16][CH:17]([CH3:18])[CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CO1
Reactant: OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(O)COCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 100 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane, 2 g of dry silica gel and 2 ml of benzyl alcohol was heated at 100° C. for 16 hours. After filtration of the silica gel, the filtrate was evaporated under reduced pressure to obtain 105 mg of (2RS, 3S)-3-carbobenzoxyamino-2-hydroxy-5-methylhexyl benzyl ether as a colorless oil. To a solution of 86 mg of the ether obtained in 10 ml of methanol was added 0.14 ml of a 2N-hydrochloric acid, and the mixture was hydrogenated over 17 mg of palladium charcoal under hydrogen atmosphere. After filtration of the catalyst, the filtrate was evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 17 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexyl benzyl ether hydrochloride as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[O:3]1.[Cl:16][S:17](O)(=[O:19])=[O:18]>ClC(Cl)Cl>[S:17]([Cl:16])([C:7]1[C:6]([CH3:13])=[C:5]([CH3:14])[C:4]2[O:3][C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]=2[C:8]=1[CH3:12])(=[O:19])=[O:18]
Reactant: Cc1cc(C)c2c(c1C)OC(C)(C)CC2
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1c(C)c(S(=O)(=O)Cl)c(C)c2c1OC(C)(C)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.7 %

Procedure:
The starting material for this synthesis was 2,2,5,7,8-pentamethylchroman and 77.55 g, 0.38 mol was dissolved in trichloromethane (1 liter) and cooled to 0° C. Chlorosulphonic acid (176.85 g, 1.52 mol) in a further 800 ml of solvent was added and the mixture stirred for 15 minutes at 0° C. and then for a further hour without cooling. The reaction mixture was poured onto ice and the organic layer separated off. This organic layer was then washed with 5% sodium carbonate solution, with saturated sodium bicarbonate solution and with brine. The aqueous washings were combined and extracted with more solvent. The original organic layer and the organic extract were combined, dried over anhydrous magnesium sulphate, stirred with activated charcoal and filtered through kieselguhr. Most of the trichloromethane was removed in vacuuo and then petroleum ether (40/60° C.) was added and the remainder of the trichloromethane was removed in vacuo. This crude product was dissolved in more petroleum ether and the solution cooled to 0° C. and filtered to give 45.96 g of Pmc-Cl (yield 39.7%, melting point 77-82° C.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].[C:25](OCC)(=O)C.C(OCC)C>CN(C)C=O>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:25])[S:11]([CH2:14][CH2:15][CH3:16])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCCS(=O)(=O)Nc1cccc(C(C)=O)c1
Reactant: CCOC(C)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCS(=O)(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1
Temperature: 150 °C
Yield: 96 %

Procedure:
1 g (4.14 mmol) of N-(3-acetylphenyl)-1-propane-sulfonamide were dissolved in 10 ml of N,N-dimethylformamide. To the resultant solution 2.77 ml (20.74 mmol) of N,N-dimethylformamide dimethyl acetal were added and heated at 150° C. for 2 h. The solvent was removed by reduced pressure distillation to yield an oil, which was treated with a mixture of ethyl acetate-ethyl ether. A small quantity of a solid precipitated which was discarded. The filtrate was evaporated to dryness, dissolved in dichloromethane, and the organic layer was washed with 4×50 ml of water and evaporated to dryness. 1.23 g (yield=96%) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl-1-propane-sulfonamide were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([OH:24])[CH:13]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)[CH:10]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.O1CCOCC1>O=[Mn]=O.C1COCC1>[C:20]([O:19][C:17]([N:15]1[CH2:14][CH:13]([C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[C:2]3[Cl:1])=[O:24])[CH2:16]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1nc2ccc(C(O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 85 °C

Procedure:
To a flask containing tert-butyl 3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)methyl)azetidine-1-carboxylate (4.75 g, 8.85 mmol, Intermediate 13: step a) was added 1,4-dioxane (200 mL) and THF (100 mL) to give a homogeneous solution. Activated MnO2 (5.0 g, 57.5 mmol) was then introduced and the mixture was heated to 85° C. After 3 hours the reaction mixture was filtered through Celite® while still warm and rinsed with additional THF and concentrated. Chromatography on silica gel (10% acetone-hexane increasing to 25% acetone) provided the title compound as an off white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O.[H][H]>C(O)C.[Ni]>[F:1][C:2]([F:14])([F:15])[CH:3]([OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1C(O)C(F)(F)F
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1C(O)C(F)(F)F

Procedure:
A solution of 1,1,1-trifluoro-2-hydroxy-2-(2-nitrophenyl)ethane from Step 1 (5.45 g, 24.64 mmol) in 90 mL of ethanol was hydrogenated over 200 mg of Raney Nickel at 5 psi hydrogen over a 8 h period at 23° C. After removing the catalyst by filtration, concentration in vacuo afforded a quantitative yield of 1,1,1-trifluoro-2-hydroxy-2-(2-aminophenyl)ethane as a orange-yellow solid: 1H NMR (CDCl3) δ4.32 (br s), 5.03 (q, J=6 Hz), 6.28 (br s), 6.67-6.78 (m), 7.08-7.23 (m); 13C NMR (CDCl3) 66.6 (q, J=33 Hz), 121.9, 124.9, 127.2 (q, J=280 Hz,), 129.3, 130.1, 133.6; MS (EI) 191 (M+), 173, 122. IR (neat) 3395, 3325, 3400-3100. Anal. Calc'd. for C8H8NOF3: C, 50.26; H, 4.22; N, 7.33. Found: C, 50.47; H, 4.57; N, 7.05.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=3)=[CH:4][CH:3]=1.[I-].[N:23]1([C:33](N2C=C[N+](C)=C2)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[C:12]([O:18][C:33]([N:23]2[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]2)=[O:34])[CH:11]=3)=[CH:20][CH:21]=1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: Cc1c(Cc2ccc(F)cc2)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(Cc2ccc(F)cc2)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-(4-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=444 (M+1), Rt: 5.36 min.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH2:25][CH2:26][CH2:27][CH3:28].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(S(O)(=O)=O)C>ClCCl.C(O)(C)C>[NH2:24][C:17]1[C:16]2[N:15]=[C:14]([CH2:25][CH2:26][CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCN
Reactant: O=C(Cl)c1ccccc1
Agent: CCS(=O)(=O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)c1ccccc1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
Triethylamine (0.07 mL, 0.5 mmol) was added to a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 mL). The reaction mixture was cooled in an ice bath. Benzoyl chloride (0.07 mL, 0.5 mmol) was added and the reaction mixture was removed from the ice bath. The reaction mixture was washed twice with water and then concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 10% methanol in dichloromethane to provide an oily brown material. This material was dissolved in a minimum amount of isopropanol and then ethanesulfonic acid (55 mg, 0.5 mmol) was added with stirring. The reaction mixture was stirred at ambient temperature for ˜1 hour and then heated briefly in a sand bath until it became homogeneous. The solution was allowed to cool to ambient temperature and then was chilled in an ice bath. The resulting precipitate was isolated by filtration to provide 111 mg of N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]benzamide as a crystalline solid, m.p. 127.8–128.8° C.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].N[C:9]1[CH:13]=[CH:12][NH:11][C:10]=1[C:14](OCC)=[O:15]>C(O)C>[N:6]1[C:9]2[CH:13]=[CH:12][NH:11][C:10]=2[C:14](=[O:15])[NH:7][CH:5]=1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: N=CN
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc[nH]c12
Yield: 85.2 %

Procedure:
Formamidine acetate (20 g, 0.19 mol.) was added to a solution of crude 2-ethoxycarbonyl-3-aminopyrrole (14) (15.3 g, 0.1 mol.) in ethanol (150 ml) and the solution was heated under reflux for 16 h and then cooled. The solid formed was filtered, washed with ethanol and dried to give 3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (1) (11.5 g, 85.2 mmol.). Recrystallized from water it had mp >300° C. 1H NMR (d6-DMSO) was as reported3. 13C NMR δ 154.0, 145.0, 141.8, 127.7, 118.2, 103.3.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].[CH2:6]([NH:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C=O.[C:17](=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:5][CH2:14][N:13]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:17])[CH:2]([CH3:4])[CH3:3]
Reactant: CNCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)CO
Agent: C=O
Agent: [K+]
Product: CC(C)COCN(C)Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of isobutanol (19.2 g., 0.26 mole) and N-benzyl-N-methylamine (30 g., 0.25 mole) is added excess 40 percent formaldehyde (25 g.). The mixture reacts exothermically, and two layers form. Potassium carbonate is added to form a saturated aqueous layer. The mixture is stirred overnight, then extracted thoroughly with diethyl ether. The ether layer is dried, then evaporated under vacuum to provide a residual oil. The residue is distilled under vacuum to provide N-benzyl-N-methylaminomethyl isobutyl ether, b.p. 72°-77° C. at 1.5 mm. Hg as a clear liquid. The structure is established by nuclear magnetic resonance analysis.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Br:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:20])(=[O:3])[CH3:2].O1CCCC1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[S:27]>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([Br:19])=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[NH:20][C:26]1=[S:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCNc1c(N)cnc2cc(Br)ccc12
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)OCCCn1c(=S)[nH]c2cnc3cc(Br)ccc3c21
Temperature: 71 °C
Reaction time: 1.5 h
Yield: 47.2 %

Procedure:
To a round-bottomed flask containing 3-[(3-amino-7-bromoquinolin-4-yl)amino]propyl acetate (54.5 g, 161.1 mmol) was added anhydrous tetrahydrofuran (THF, 1.4 L), followed by 1,1′-thiocarbonyldiimidazole (31.6 g, 177.3 mmol) and the reaction mixture was stirred at 71° C. for 1.5 h. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure to afford an oil. The oil was dissolved in dichloromethane (1.3 L) and the solution was washed with water (3×600 mL). During each wash a significant amount of precipitate was observed which was isolated to afford 3-(7-bromo-2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propyl acetate (28.9 g) as a light brown solid.