Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH2:28][O:29][Si](C(C)(C)C)(C)C)[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[N:12]2[C:23](=[O:27])[N:24]([CH3:26])[N:25]=[C:11]12)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C:10]1([CH2:28][OH:29])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[N:12]2[C:23](=[O:27])[N:24]([CH3:26])[N:25]=[C:11]12
Reactant: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OC2(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OC2(CO)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
4,4-Bis(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one (3 g) was dissolved in THF (15 mL). 1.0 M TBAF in THF solution was added (14 mL, 2.5 eq.). The reaction solution was stirred at room temperature for one hour and then evaporated. The residue was purified by Combiflash chromatography (methanol in dichloromethane=0-20%) to give 4,4-bis(hydroxymethyl)-2-methyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one (1.6 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH3:21][C:22]1[CH:23]=[C:24]([C:29]2[NH:30][C:31]3[C:36]([CH:37]=2)=[CH:35][C:34]([NH2:38])=[CH:33][CH:32]=3)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH2:5]([O:4][C:2](=[O:3])[NH:38][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:24]1[CH:23]=[C:22]([CH3:21])[CH:27]=[C:26]([CH3:28])[CH:25]=1)=[CH:37]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(C)cc(-c2cc3cc(N)ccc3[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(-c2cc3cc(NC(=O)OCc4ccccc4)ccc3[nH]2)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(3,5-dimethylphenyl)-5-amino-1H-indole (1.16 g in 60 mL dry methylene chloride) at −60 ° C. was added 0.86 mL benzyl chloroformate followed by 1 mL diisopropylethylamine and the mixture warmed slowly to 0° C. After 45 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride and the mixture extracted with methylene chloride. The organic portion was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (hexane:methylene chloride:ethyl acetate, 8:8:1; then 7:7:1) gave the title compound (1.68 g).
Reaction SMILES: [C:1]([C:5]1(O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[C:8]([CH3:17])([CH3:16])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[C:8]([CH3:17])([CH3:16])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)CCC(O)(C(C)(C)C)c2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(Br)cc21
Temperature: 70 °C

Procedure:
A mixture of the crude 1-t-butyl-1-hydroxy 4,4-dimethyl-7-bromo-1,2,3,4-tetrahydronaphthalene , MeOH (30 mL) and p-TSA (150 mg) were heated for 17 h at 70° C. Reaction mixture was cooled to ambient temperature and solid K2CO3 was added and the MeOH was removed by evaporation. The residue was diluted with ether. The ether layer was washed with water and brine and the ether was dried (MgSO4) and removed by evaporation. Purification by silica gel chromatography yielded 1.65 g (28%, in two steps) the title compound as a clear oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH2:22][CH3:23])=[CH:16][N:15]=2)[C:12]=1[CH3:13])=[O:7])C>C(O)C>[CH2:22]([O:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]2)=[N:15][CH:16]=1)[CH3:23]
Reactant: CCOCc1ccc(-n2ncc(C(=O)OCC)c2C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOCc1ccc(-n2ncc(C(=O)O)c2C)nc1
Temperature: 70 °C
Yield: 83.4 %

Procedure:
1N Aqueous solution of sodium hydroxide (2.3 ml) was added at room temperature to a solution of 1-[5-(ethoxymethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (223 mg) in ethanol (16 ml), and stirred at 70° C. for an hour. Then, 1N aqueous solution of sodium hydroxide (4.6 ml) was added and stirred at 70° C. for an hour. After the reaction, ethanol was evaporated, 1N hydrochloric acid aqueous solution was added to adjust the solution to pH 1 to 2 and the precipitated solid was collected by filtration to give 1-[5-(ethoxymethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxylic acid (168 mg) as a white solid.
Reaction SMILES: Cl.C1(C[N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[OH:16])[CH2:11][CH2:10]2)C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[F:37][C:35]([F:36])([F:38])[O:34][C:31]1[CH:30]=[CH:29][C:28]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)([OH:16])[CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[CH:33][CH:32]=1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 0.8 gram of 10% palladium on charcoal (catalyst) was placed in the reaction vessel. To this were cautiously added 25 mL of nitrogen-purged methanol, a solution of 0.8 gram (0.001 mole) of N-phenylmethyl-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine hydrochloride in 10 mL of methanol, and then 0.9 gram (0.010 mole) of ammonium formate. Upon completion of addition, the reaction mixture was heated at reflux for about 45 minutes. The reaction mixture was then cooled to ambient temperature and diluted with 1:1-methylene chloride/methanol. The mixture was filtered through a pad of diatomaceous earth/fiberglass, and the filtrate was concentrated at about 30° C. under reduced pressure to a residue. The residue was taken up in about 70 mL of ice/water and made basic with aqueous 5% sodium hydroxide solution. The mixture was extracted with methylene chloride, and the extract was washed with an aqueous solution saturated with sodium chloride. The organic layer was then dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was stirred with petroleum ether, and 0.5 gram of solid 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine was collected by filtration. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([O:24][C:25]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[CH:44][C:26]=1[C:27]([NH:29][C:30]1[CH:42]=[C:41](Br)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>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(OCC)(=O)C.O.COCCOC>[CH2:17]([O:24][C:25]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[CH:44][C:26]=1[C:27]([NH:29][C:30]1[CH:42]=[C:41]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Water (0.60 mL), 2-methylphenylboronic acid (0.029 g), sodium carbonate (0.047 g), and bis(triphenylphosphine)palladium(II) dichloride (2.5 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-bromobenzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-91% hexane/ethyl acetate] to obtain 0.10 g of tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-(2-methylphenyl)benzoate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]=O>>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]1[NH:10][CH2:9][CH2:8][N:3]2[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]12
Reactant: Cc1ccc(CCC=O)c(C)c1
Reactant: Cc1cn(CCN)c(C)n1
Product: Cc1ccc(CCC2NCCn3c(C)nc(C)c32)c(C)c1

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(2,4-dimethyl-phenyl)-propionaldehyde. LC-MS: tR=0.62 min.; [M+H]+=284 g/mol.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([Cl:20])[C:6]([Cl:19])=[C:7]([O:17]C)[CH:8]=2)[C:3]1=[O:21].Cl.N1C=CC=CC=1>O>[CH3:1][C:2]1([CH3:22])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([Cl:20])[C:6]([Cl:19])=[C:7]([OH:17])[CH:8]=2)[C:3]1=[O:21]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)C(=O)c2c(cc(O)c(Cl)c2Cl)C1c1ccccc1
Temperature: 180 °C

Procedure:
A stirred mixture of 2,2-dimethyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone (6.5 g., 0.02 mole) and pyridine hydrochloride (60 g.) is heated at 180° C. for 2 hours, then poured into water (800 ml.). The 2,2-dimethyl-3-phenyl-5-hydroxy-6,7-dichloro-1-indanone which separate (5.10 g.) melts at 259°-262° C. after recrystallization from ethanol water, 2:1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:19]=[C:18](C(F)(F)F)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[CH:16]=3)[N:11]=2)[CH2:6]1)=[O:4].[Br:35]C1C2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)N=C(C=O)C=1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:19]=[C:18]([Br:35])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[CH:16]=3)[N:11]=2)[CH2:6]1)=[O:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)cc(Br)c3c2)CC1
Reactant: COC(=O)C1CN(Cc2cc(C(F)(F)F)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Product: COC(=O)C1CN(Cc2cc(Br)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid methyl ester using 4-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-quinoline-2-carbaldehyde as starting material. ESI-MS (M+H+): 489.20/491.20.
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:7]([NH:14][CH2:15][C:16](O)=[O:17])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl.C1CCCCC1.CCOC(C)=O>[CH3:3][C:2]([CH3:5])([CH3:4])[CH2:1][NH:6][C:16](=[O:17])[CH2:15][NH:14][C:7](=[O:8])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)CN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)CNC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 193.6 %

Procedure:
To a mixture of neopentylamine (174.3 mg; 2 mmol; 1 eq) and boc-glycine (385.4 mg; 2.20 mmol; 1.10 eq) in DCM (30 ml), are added triethylamine (832 μl; 6 mmol; 3 eq) and 2-chloro-1-methylpyridinium iodide (1533 mg; 6 mmol; 3 eq). The mixture is stirred overnight at RT. The reaction is followed by TLC (cyclohexane/EtOAc 1:1). The reaction mixture is then washed twice with NH4Cl sat. solution and twice with NaHCO3 sat. solution. The organic layer is dried over Na2SO4, filtered and concentrated to give 946 mg of an orange oil, which is purified by flash chromatography (cyclohexane/EtOAc gradient, from 9/1 to 1/1 over 30 min). The title product is isolated as a slightly yellow solid (96.7 mg; 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:13][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(CO)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a mixture of dichloromethane (5 mL) and the (6-methoxy-pyridin-2-yl)-methanol (105 mg, 0.75 mmol) described in Manufacturing Example 99-1-1 was added thionyl chloride (82.4 μL, 1.13 mmol), which was stirred for 30 minutes at room temperature. A saturated sodium hydrogencarbonate aqueous solution was added to this reaction mixture, which was then extracted with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (105.8 mg, 89%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:37])([C:33]([F:36])([F:35])[F:34])[C:30](O)=[O:31]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30](=[O:31])[C:29]([F:37])([F:28])[C:33]([F:36])([F:35])[F:34])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)C(F)(F)F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C(F)(F)C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 2,2,3,3,3-pentafluoro-propionic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=425.2 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[C:8](=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:19]=[C:17]([CH3:18])[CH2:16][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:8](=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5]1
Reactant: O=c1cccccc1N1CCNCC1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)CN1CCN(c2cccccc2=O)CC1
Yield: 42 %

Procedure:
A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatrien-1-one (12.4 g, described in Example 3), 1-chloro-2-propanone (5.55 g), potassium carbonate (11.04 g) and acetonitrile (120 ml) was refluxed for 4 hr and filtered. Chloroform and water were added to the filtrate. The organic phase was separated, washed with water, dried and evaporated. The residue was chromatographed on silica gel using methanol-ethyl acetate and the eluates were evaporated to give an oil (6.21 g) of 2-[4-(2-oxopropyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one: ir(CHCl3) 3660, 3360, 1720, 1710, 1660 nd 1560 cm-1 ; uv max(MeOH) 351 (ε=9210), 255 (ε=13915) and 221 nm(ε=11750); nmr(CDCl3) δ2.12 (s, 3H), 2.62 (t, 4H), 3.21 (s, 2H), 3.35 (s, 4H) and 6.40-7.10 (m, 5H); and Anal. Calcd for C14H18N2O2 : C, 68.26% H, 7.37% N, 11.37% and Found: C, 67.83% H, 7.59% N, 11.44%.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[N:18]=[N:19][C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:21][CH:22]=1.[Si:28]([O:35][C:36]1([CH2:40]/[CH:41]=[N:42]/[S:43]([C:45]([CH3:48])([CH3:47])[CH3:46])=[O:44])[CH2:39][CH2:38][CH2:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1COCC1.O>[Si:28]([O:35][C:36]1([CH2:40][CH:41]([NH:42][S:43]([C:45]([CH3:48])([CH3:47])[CH3:46])=[O:44])[C:22]2[CH:21]=[C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:19]=[N:18][C:17]=2[Cl:16])[CH2:39][CH2:38][CH2:37]1)([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)Cc1ccc(Cl)nn1
Reactant: CC(C)(C)S(=O)/N=C/CC1(O[Si](C)(C)C(C)(C)C)CCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Cc1cc(C(CC2(O[Si](C)(C)C(C)(C)C)CCC2)NS(=O)C(C)(C)C)c(Cl)nn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2,2,6,6-Tetramethylpiperidine (0.68 ml, 4.0 mmol) was dissolved in 120 ml THF and 1-butyllithium (1.5 ml, 3.8 mmol) was added at −78° C. drop wise. The mixture was allowed to warm to 0° C. (over a period of 5 min) and kept there for 5 min. The mixture was cooled back to −78° C. and a solution of 3-chloro-6-neopentylpyridazine (0.45 g, 2.4 mmol) in 10 ml of THF was added drop wise. Stirring was continued for 20 min and a solution of (E)-N-(2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide (1.450 g, 4.4 mmol) in 5 ml THF was added drop wise. Stirring was continued for 10 min and the mixture was hydrolyzed with H2O. The mixture was extracted with EtOAc (3×300 ml) dried over MgSO4 and evaporated. The crude product was used in the next step without further purification.
Reaction SMILES: S(O)(O)(=O)=O.N[C:7]1[CH:8]=[C:9]([B:13]([OH:15])[OH:14])[CH:10]=[CH:11][CH:12]=1.NC1C=C(B(O)[OH:24])C=CC=1.OS(O)(=O)=O.N([O-])=O.[Na+].C>O>[OH:24][C:7]1[CH:8]=[C:9]([B:13]([OH:15])[OH:14])[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: OB(O)c1cccc(O)c1
Yield: 93.6 %

Procedure:
A stirred solution of 3-aminophenylboronic acid hemisulfate (6.2 g; 33.3 mmol) and 50% H2SO4 (3.7 ml; 33.3 mmol) in H2O (100 ml) at −2° C. was added a solution of NaNO2 (2.5 g; 36.3 mmol) in H2O (20 ml) over 1 h. The reaction mixture was slowly added to a stirred solution of conc. H2SO4 (25 ml) in H2O (20 ml) at reflux. After complete addition, the reaction mixture was refluxed for 30 min., cooled, added activated charcoal, heated to reflux, cooled and filtered through celite. The filtrate was saturated with NaCl (s), filtered and extracted with Et2O (5×100 ml). The combined organic fractions were dried (Na2SO4) and evaporated to dryness to give 4.3 g (94%) product.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1>O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][N:17]=[C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]2)=[CH:12][CH:11]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C1CCCC(=O)C1
Solvent: O
Product: O=C1CCCC(=NNc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,3-cyclohexanedione (5.05 g, 45 mmol) in water is treated over a 10 min period with an aqueous suspension of p-chlorophenylhydrazine (8.06 g, 45 mmol), stirred at room temperature for 16 h and filtered. The filtercake is washed with water and dried in vacuo to give the title product which is used as in Example 132.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[CH:9]3[CH2:18][CH:6]([CH2:7][CH2:8]3)[C:5]1=2)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][N:4]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[CH:9]3[CH2:18][CH:6]([CH2:7][CH2:8]3)[C:5]1=2
Reactant: CCOC(=O)c1cc2c(n1CC#N)C1CCC2C1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)c1cc2c(n1CCN)C1CCC2C1
Yield: 50.3 %

Procedure:
A suspension of 167d (4.0 g, 16 mmol) and Raney Ni (400 mg) in methanol (60 mL) was hydrogenated in a Parr apparatus at 50 psi overnight. The mixture was filtered through a pad of CELITE® and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 methylene chloride/methanol to afford 167e as a yellow solid (2.0 g, 50%). MS: [M+H]+ 249.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)[C:5](=[O:18])[N:4]=[CH:3]1.[CH2:19](N)C>CO>[CH2:1]([N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:11]=[CH:12][CH:13]=2)[C:5](=[O:18])[N:4]=[CH:3]1)[CH3:19]
Reactant: Cn1cnc(=O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CCN
Solvent: CO
Product: CCn1cnc(=O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
Two g. of the intermediate atropamide of Example 2 was reacted with 1 cc. of 20 percent aqueous ethylamine in 20 ml. of methanol. The reaction mixture was stirred at reflux temperature for 6 hours and evaporated to dryness, and the residue was recrystallized from ethyl acetatehexane. The product was 1.3 g. of 1-ethyl-5-(α,α,α-trifluoro-m-tolyl)-4(1H)-pyrimidinone, m.p. 172°-173° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH2:25]1[CH2:39][O:38][C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH2:28][CH2:29][CH2:30]Br)[O:26]1.O>COCCOC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:30][CH2:29][CH2:28][C:27]1([O:26][CH2:25][CH2:39][O:38]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: BrCCCC1(c2ccccc2)OCCO1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(CCCC1(c2ccccc2)OCCO1)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of 1.1 g of 2-(1-naphthylmethyl)malonic acid diethyl ester in 20 ml of dry 1,2-dimethoxyethane was added 0.22 g of a 50% sodium hydride (suspension in oil) under cooling, the mixture was stirred for 1 hour. To the reaction mixture was added 1.0 g of 4,4-ethylenedioxy-4-phenylbutyl bromide obtained, the mixture was heated under reflux for 17 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 1.2 g of 2-(4,4-ethylenedioxy-4-phenylbutyl)-2-(1-naphthylmethyl)malonic acid diethyl ester.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(O)C>CCCCCC>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCCC1O
Solvent: CCO
Solvent: CCCCCC
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCC[C@@H]1O

Procedure:
Racemic (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone of Example 5 was subjected to chiral HPLC (Chiralpak AD, 21.1×250 mm, 50% ethanol in hexane). The second peak which eluted displayed a negative optical rotation and was arbitrarily assigned the (S)-configuration. The title compound was isolated as a white solid, [α]D=−36.69 (c=1.0, chloroform).