Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H](CC(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.B.O1CCCC1.[CH:27]1(/[CH:33]=[C:34](/[N:41]2[CH:45]=[N:44][CH:43]=[N:42]2)\[C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl>ClCCCl>[CH:27]1(/[CH:33]=[C:34](/[N:41]2[CH:45]=[N:44][CH:43]=[N:42]2)\[CH:35]([OH:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)(C)C(=O)/C(=C\C1CCCCC1)n1cncn1
Agent: B
Agent: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Reaction time: 24 h

Procedure:
In a nitrogen atmosphere, a solution of 0.485 g (1.8 mmoles) of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol in 5 ml of 1,2-dichloroethane was added dropwise at -78° C. to a solution comprising 1.8 ml (1.8 mmoles) of 1.00M borane-tetrahydrofuran solution and 2 ml of 1,2-dichloroethane, and the temperature of the mixture was raised from -78° C. to room temperature over about 2 hours. Thereafter, a solution of 0.31 g (1.2 mmoles, E/Z=99.9/0.1) of (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one in 3 ml of 1,2-dichloroethane was added dropwise to this solution, and stirring was carried out for 24 hours. The reaction product was decomposed with addition of 6 ml of 2N hydrochloric acid to the solution, and after removing (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol hydrochloride by filtration, the organic layer was washed with water and concentrated under reduced pressure The residue was purified on a column packed with 2 g of silica gel with chloroform as a developing solvent to obtain (-)-(E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol. The conversion was 100%, and the composition of the product was: E-form alcohol, 99.1% and Z-form alcohol, 0.9%. The enantiomer ratio of the E-form alcohol was: (+)-isomer, 16.3% and (-)-isomer, 83.7%.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH2:28]>>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2ccccc2OC)n(C)c(=O)c1O
Reactant: Cc1ccc(CN)cc1C
Product: COc1ccccc1-c1nc(C(=O)NCc2ccc(C)c(C)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3,4-dimethylbenzylamine (102 mg, 0.75 mmol). The title product was obtained as a brown solid (53.5 mg, 91% yield). 1HNMR (500 MHz, CDCl3) δ: 12.50–11.95 (1H, br s), 7.85 (1H, t, J=4.58 Hz), 7.47 (1H, td, J=8.24, 1.83 Hz), 7.27 (1H, dd, J=17.63, 0.83 Hz), 7.09–7.02 (4H, m), 6.97 (1H, d, J=8.24 Hz), 4.49 (2H, d, J=5.79 Hz), 3.81 (3H, s), 3.34 (3H, s) 2.23 (3H, s), 2.22 (3H, s). HRMS (ESI) calcd for C22H24N3O4 (M+H): 394.1767; found: 394.1781.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[C:8]2[N:7]([CH3:12])[C:6]3[CH2:13][CH:14]4[NH:18][CH:17]([C:5]=3[C:4]=2[C:3]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]4.[C:26]1([S:32](C2C=CC=CC=2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([S:32]([C:2]2[CH:10]=[C:9]([F:11])[C:8]3[N:7]([CH3:12])[C:6]4[CH2:13][CH:14]5[NH:18][CH:17]([C:5]=4[C:4]=3[C:3]=2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]5)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)cc(F)c31)C1CCC(C2)N1
Reactant: O=S(=O)(c1ccccc1)c1ccccc1
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)cc(F)c31)C1CCC(C2)N1
Yield: 26 %

Procedure:
The product of step C was converted to the phenylsulfone derivative following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, 75:25 hexane/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-4-fluoro-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (61 mg, 26%) as an off-white solid: 1H NMR (CDCl3, 300 MHz): δ 7.91-7.99 (m, 3H), 7.43-7.55 (m, 3H), 7.28-7.36 (m, 1H), 5.13-5.31 (m, 1H), 4.58-4.70 (m, 1H), 3.78 (s, 3H), 3.14-3.50 (m, 1H), 2.41 (d, J=19.2 Hz, 1H), 2.12-2.40 (m, 2H), 1.86-1.97 (m, 1H), 1.58-1.68 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [Cl-].[CH2:2]([O:6][C:7](=[O:10])[CH2:8][NH3+:9])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH2:18]([O:20][C:21](=[O:27])[C:22](OCC)=[O:23])[CH3:19]>C(O)C>[CH2:18]([O:20][C:21](=[O:27])[C:22]([NH:9][CH2:8][C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[O:10])=[O:23])[CH3:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCOC(=O)C[NH3+]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCOC(=O)CNC(=O)C(=O)OCC
Temperature: 50 °C
Yield: 151.7 %

Procedure:
2-Butoxy-2-oxoethanaminium chloride (573.5 g, 3.42 mol) was suspended in 7 L of ethanol and triethylamine (415 g, 4.1 mol) was added. Diethyloxalate (1.0 Kg, 6.8 mol) was added and the reaction warmed to 50° C. for 3 hours. The reaction was cooled, the volatiles were removed under vacuum and the residue was dissolved in methylene chloride and washed with two 4 L portions of water and dried over MgSO4. The next day the reaction was filtered, evaporated to give ˜1.2 Kg of an oil that was chromatographed on silica eluting with Heptane/EtOAc to give product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1>C(O)(=O)C>[N+:1]([C:16]1[CH:17]=[C:12]([CH2:11][CH:8]2[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]2)[CH:13]=[CH:14][C:15]=1[OH:18])([O-:4])=[O:2]
Reactant: Oc1ccc(CC2CCNCC2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CC2CCNCC2)ccc1O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Concentrated nitric acid in acetic acid (8 mL 70% HNO3 aq in 16 mL acetic acid) was added slowly to a stirred solution of 4-(piperidin-4-ylmethyl)phenol (Guzikowski et al, J. Med Chem., 2000, 43, 984–994) (100 mmol) in acetic acid (300 mL) and the resultant slurry stirred at 80° C. for 1 h. The reaction mixture was then filtered and evaporated in vacuo to give the title compound as a brown solid.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C([O:12][C:13](=O)[C:14]1[CH:19]=[C:18]([CH:20]=[CH2:21])[C:17]([N:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:16][CH:15]=1)C.[NH4+].[Cl-].O>C1COCC1>[C:26]([O:25][C:23](=[O:24])[NH:22][C:17]1[C:18]([CH:20]=[CH2:21])=[CH:19][C:14]([CH2:13][OH:12])=[CH:15][N:16]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: C=Cc1cc(C(=O)OCC)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(CO)cnc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
DIBAL (25 ml, 1M in hexane) was added dropwise to a solution of 6-bis(tert-butoxycarbonyl)amino-5-vinyl-nicotinic acid ethyl ester (2.00 g, 5.1 mmol) in THF (40 ml) at 0° C. The mixture was stirred at room temperature for 1 h. NH4Cl (sat.) was added carefully followed by water, and the mixture was concentrated under reduced pressure. The residue was suspended in 5% MeOH in dichloromethane and filtered through silicagel. The filtrate was dried and concentrated under reduced pressure to give (5-hydroxymethyl-3-vinyl-pyridin-2-yl)carbamic acid tert-butyl ester (1.00 g, 78%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:41])=[C:19]([C:21]4[NH:25][C:24]([C:26]5([CH3:39])[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35](C)(C)C)=[O:33])[CH2:28][CH2:27]5)=[N:23][C:22]=4[CH3:40])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(C2CN(C(C3C=CC(C)=C(C4N=C(C5CCN(C(OC(C)(C)C)=O)CC5)NC=4C)C=3)=O)C2)=CC=1)#N.Cl.[F:83]C1(C2C=CC(C#N)=CC=2)CNC1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:83])[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:41])=[C:19]([C:21]4[NH:25][C:24]([C:26]5([CH3:39])[CH2:31][CH2:30][N:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]5)=[N:23][C:22]=4[CH3:40])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(C)CCN(C(=O)OC(C)(C)C)CC2)nc1C
Agent: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: COC(=O)N1CCC(C)(c2nc(C)c(-c3cc(C(=O)N4CC(F)(c5ccc(C#N)cc5)C4)ccc3C)[nH]2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 184, except tert-butyl 4-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate (compound 185.3) was used in place of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 530 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.[Cl:16][C:17]1[C:24]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=[C:21]([Cl:31])[C:18]=1[CH:19]=[O:20].[OH-].[K+].O>CO>[Cl:16][C:17]1[C:24]([O:25][CH2:26][C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=[C:21]([Cl:31])[C:18]=1[CH:19]([C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)[NH:13][CH:14]=1)[OH:20]
Reactant: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1Cl
Reactant: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cc(-c2cnc3[nH]cc(C(O)c4c(Cl)ccc(OCC(F)(F)F)c4Cl)c3c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (109, 100.0 mg, 0.51 mmol, prepared as described in Example 35) in methanol (30 mL) were added 2,6-dichloro-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde (115, 154 mg, 0.56 mmol) and potassium hydroxide (596.0 mg, 10.62 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 25% methanol in dichloromethane to give the desired compound (116, 0.18 g, 75.7%).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C[N+](C)=C[Cl:20].[Cl-]>>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][Cl:20])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Product: N#Cc1ccc(Cn2cncc2CCl)cc1

Procedure:
combining 1-(4-Cyanobenzyl)-5-Hydroxymethyl-imidazole of formula IA ##STR37## with Vilsmeier reagent to obtain 1-(4-Cyanobenzyl)-5-Chloromethylimidazole of formula IF: ##STR38##
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1([OH:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:43]1([CH2:49][N:50]2[CH2:55][CH2:54][N:53]3[N:56]=[C:57]([CH2:59]O)[CH:58]=[C:52]3[CH2:51]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[O:42]([CH2:59][C:57]1[CH:58]=[C:52]2[CH2:51][N:50]([CH2:49][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:55][CH2:54][N:53]2[N:56]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Oc1ccccc1
Reactant: OCc1cc2n(n1)CCN(Cc1ccccc1)C2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CN2CCn3nc(COc4ccccc4)cc3C2)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
Di-tert-butyl azodicarboxylate (0.76 g, 3.3 mmol) was added to a stirred solution of triphenylphosphine (0.87 g, 3.3 mmol), phenol (0.31 g, 3.3 mmol) and 4,5,6,7-tetrahydro-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-methanol (1.2 mL, 2.75 mmol) in THF (0.6 mL) in a sealed tube and under N2. The mixture was stirred at 120° C. for 20 minutes under microwave irradiation and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents were evaporated in vacuo to yield 4,5,6,7-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine (0.65 g, 74% yield) as a colorless oil that precipitated upon standing. C20H21N3O LCMS: Rt 3.03, m/z 320 [M+H]+ (see LCMS Method 1).
Reaction SMILES: Cl[Si](Cl)(Cl)Cl.[N-:6]=[N+:7]=[N-:8].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31](=O)[NH:32][CH:33]3[CH2:35][CH2:34]3)[CH:26]=1)[CH2:19][C:18]2([CH3:38])[CH3:37])=[O:14])[CH3:11]>C(#N)C>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]3[N:32]([CH:33]4[CH2:34][CH2:35]4)[N:8]=[N:7][N:6]=3)[CH:26]=1)[CH2:19][C:18]2([CH3:37])[CH3:38])=[O:14])[CH3:11]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)NC3CC3)c1)N2
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(-c3nnnn3C3CC3)c1)N2
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a stirred solution of tetrachlorosilane (5.3 mL, 46.3 mmol), sodium azide (5.6 g, 87 mmol) in dry acetonitrile (20 mL) was added 2-(3-cyclopropylcarbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.3 g, 3.3 mmol) at room temperature. Then the mixture solution was stirred at room temperature for over night. LC/MS showed that reaction finished completely. The reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (150 mL×2), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) afforded 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (908.2 mg, 66%) as a white solid: MS (ESI) M+1=418.1.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH:4]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:20]([O:26][CH2:27][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:4]([C:5]2([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:3][N:2]([CH3:1])[CH3:19])=[CH:17][CH:16]=1)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CC(c1ccc(OCOC(=O)C(C)(C)C)cc1)C1(O)CCCCC1

Procedure:
4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol (1 g, 3.79 mmol), chloromethyl pivalate (0.75 g, 5 mmol), anhydrous K2CO3 (0.7 g, 5 mmol) and KI (75 mg, 0.5 mmol) were stirred in acetonitrile (50 mL) and refluxed overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate was dried (MgSO4) and evaporated to give the title compound as a minor component.
Reaction SMILES: C[Zn]C.Cl[C:5]1[N:14]=[C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].Cl[C:22]1C=CC(C(OC)=O)=C(OCC(F)(F)F)N=1>>[CH3:22][C:5]1[N:14]=[C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(OCC(F)(F)F)nc1Cl
Reactant: COC(=O)c1ccc(Cl)nc1OCC(F)(F)F
Agent: C[Zn]C
Product: COC(=O)c1ccc(OCC(F)(F)F)nc1C
Temperature: 75 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Dimethylzinc (40.0 mL, 40.0 mmol) is added dropwise a solution of methyl 2-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (2.70 g, 10.0 mmol, Step-2) including methyl 6-chloro-2-(2,2,2-trifluoroethoxy)nicotinate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.816 g, 1.00 mmol) and stirred at 75° C. for 1 hour. After cooling room temperature, the resulting mixture is quenched by carefully added water. The reaction mixture is extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-Hexane/ethyl acetate (20:1) to give 0.89 g (36% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1([C:12]([OH:14])=[O:13])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH2:27]([O:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]([NH:1][C:2]1([C:12]([OH:14])=[O:13])[CH:9]2[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]1[CH2:11]3)[CH2:10]2)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(NC1(C(=O)O)C2CC3CC(C2)CC1C3)OCc1ccccc1
Temperature: 50 °C

Procedure:
1.015 g of 2-amino-2-adamantanecarboxylic acid and 6 ml of bis(trimethylsilyl)acetamide in 10 ml of DCM is heated to reflux for one and a half hours. 0.75 ml of benzyloxycarbonyl chloride is added and the mixture is heated at 50° C. for 15 minutes. The reaction medium is cooled to -70° C., decomposition is then effected by adding ice and the mixture is extracted with AcOEt. The organic phase is washed with water (twice) and with brine, dried over MgSO4 and evaporated under vacuum. The product crystallizes in hexane; 1.164 g are obtained.
Reaction SMILES: Cl.[SH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:15][CH2:16][N:17]=[C:18]=[S:19].[CH3:20][S:21]([OH:24])(=[O:23])=[O:22]>O1CCCC1>[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].[SH:2][CH:3]1[CH2:6][N:5]([C:18]2[S:19][CH2:15][CH2:16][N:17]=2)[CH2:4]1
Reactant: S=C=NCCCl
Reactant: SC1CNC1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: SC1CN(C2=NCCS2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of 63.3 mg of 3-mercaptoazetidine hydrochloride (12) obtained in the above Example 10 dissolved in 1.0 ml of dried tetrahydrofuran, there was added 0.07 ml of triethylamine in the stream of nitrogen at a room temperature, and the resulting solution was stirred for 30 minutes. To this solution, there was added dropwise a solution of 70.3 mg of 2-chloroethylisothiocyanate dissolved in dried tetrahydrofuran, and the resulting solution was further stirred for one hour. After the reaction liquid was cooled to 0° C., 0.04 ml of methanesulfonic acid was added dropwise, and the resulting solution was stirred for 30 minutes, and, then, the solvent was evaporated in a vacuum. To the obtained residue, there was added 1.0 ml of dried methanol, and the resulting solution was subjected to heating and reflux for one hour, and, then, the solvent was evaporated in a vacuum. The obtained residue was separated and purified by thin-layer chromatography, and, thus, there was obtained 53.4 mg (yield: 39.2%) of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine methanesulfonate (13) in the form of colorless oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=3[F:32])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)cc2)o1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 24 h

Procedure:
2-(4-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(4-chlorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.OS(O)(=O)=O.[CH3:20][CH2:21]O>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([O:14][CH2:20][CH3:21])=[O:13])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCO
Reactant: Cc1ccc2c(C(=O)O)cccc2n1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1cccc2nc(C)ccc12

Procedure:
To a slurry of compound 73a (3.1 g, 16 mmol) in EtOH (50 mL) was added concentrated H2SO4 (1.0 mL) and the resultant slurry was refluxed overnight. The homogeneous solution was cooled, diluted with DCM (300 mL), washed with 1N NaOH (1×100 mL), dried (Na2SO4), and concentrated in vacuo to give compound 73b as an off-white solid. Mass spectrum (LCMS, ESI pos.) Calcd. For C13H13NO2: 216.2 (M+H). found 216.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH3:20])C(=O)C)[CH3:2].[OH-].[K+].O>CCO>[CH2:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:20]
Reactant: CCc1ccccc1N(C(C)=O)c1ccccc1CC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1ccccc1Nc1ccccc1CC
Reaction time: 6 h
Yield: 85 %

Procedure:
The N,N-bis(2-ethylphenyl)acetamide (8.1 g, 30.30 mmol) and KOH (5 g), in EtOH (50 mL), was stirred and heated to reflux overnight. 20 hrs later additional KOH (10 g) was added, wth stirring to reflux continued for an additional 6 hrs. It was cooled, poured into H2O (125 mL) and extracted with ethyl acetate (2×350 mL). The combined organics were washed with brine, dried (MgSO4), filtered and concentrated to dryness, affording a dark red oil (5.8 g, 85%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH3:32]>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][O:17][CH3:32])[CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CI
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (800 mg, 2.02 mmol) prepared in Step B of Example A8 in THF was added NaH (73 mg, 3.03 mmol) and iodomethane (430 mg, 3.03 mmol) at 0° C., and the solution was stirred at rt for 2 h. After the reaction finished, the solution was concentrated in vacuo, extracted with 1N-HCl and EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex=1/2) to give the title compound (784 mg, 94.6%).