Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:12]([N:14]1[CH2:18][CH2:17][C@@H:16]([OH:19])[C:15]1=[O:20])=[O:13])C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:12]([N:14]1[CH2:18][CH2:17][C@@H:16]([OH:19])[C:15]1=[O:20])=[O:13]
Reactant: COc1ccc(C(=O)N2CC[C@@H](O)C2=O)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CC[C@@H](O)C2=O)cc1O

Procedure:
2.20 g of (R)-1-(3-benzyloxy-4-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone are hydrogenated in 60 ml of tetrahydrofuran over 1.80 g of 5% palladium/carbon with hydrogen at atmospheric pressure. After removal of the catalyst by filtration, concentration of the filtrate and recrystallization of the residue from ethyl acetate/n-hexane, there is obtained (R)-1-(3-hydroxy-4-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone of melting point 129°-131°; [α]D20 =+175°; [α]54620 =+216°; [α]43620 =+451° (chloroform, c=1.0).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Cl:9][C:10]1[C:11]([C:18]#[N:19])=[N:12][CH:13]=[C:14]([Cl:17])[C:15]=1Cl.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[C:11]([C:18]#[N:19])=[N:12][CH:13]=[C:14]([Cl:17])[C:15]=1[O:6][CH2:5][C:4]([F:8])([F:7])[F:3]
Reactant: OCC(F)(F)F
Reactant: N#Cc1ncc(Cl)c(Cl)c1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ncc(Cl)c(OCC(F)(F)F)c1Cl
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
Into 5 ml of tetrahydrofuran was suspended 0.12 g of sodium hydride (60% oily), and 0.27 g of trifluoroethyl alcohol was added at 10° C. After stirring for 10 minutes, 0.5 g of 3,4,5-trichloropyridine-2-carbonitrile was added at 0° C., the mixture was stirred for 20 hours, and the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.6 g of 3,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile. 3,5-Dichloro-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.CO.[CH2:18]([NH2:20])[CH3:19]>C(Cl)Cl>[CH2:9]([O:8][CH2:7][CH2:6][NH:20][CH2:18][CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCNCCOCc1ccccc1
Temperature: 110 °C
Yield: 72 %

Procedure:
To 7.0 g (30 mmol) of 2-(benzyloxy)ethyl methanesulfonate, a 75 ml methanol solution of 2M ethylamine was added, and the mixture was heated at 110° C. in a sealed tube for 2 hours. Then, the reaction mixture was returned to room temperature, and then diluted with methylene chloride. The dilution was washed with a saturated aqueous solution of sodium hydride. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 3.85 g (72%) of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][NH:24][O:25][CH3:26])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][N:24]([O:25][CH3:26])[C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CONCCCc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(CCCc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 95 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[3-(3,4-dichlorophenyl)-propyl]-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (95% yield): mp 105-106° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.91 (6H, s, CH3), 2.13 (2H, m, CH2), 2.77 (2H, t, J=7.9 Hz, CH2), 3.86 (2H, t, J=7.0 Hz, NCH2), 3.88 (3H, s, OCH3), 6.54 (1H, broad s, CH), 7.2 (H, broad dd, aromatic), 7.44 (1H, broad d, J=2 Hz, aromatic), 7.50 (1H, d, J=8.1 Hz, aromatic). Anal. calcd for C17H19Cl2NO5: C, 52.59; H, 4.93; N, 3.61. Found: C, 52.68; H, 5.08; N, 3.50.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1.[CH2:14]([O:19][C:20]1[C:25]([C:26]2[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=[C:28]([C:38]#[N:39])[CH:27]=2)=[CH:24][C:23]([C:40]#[N:41])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH3:18].O>CS(C)=O>[C:40]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:25]([C:26]2[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=[C:28]([C:38](=[NH:39])[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=3)[CH:27]=2)[CH:24]=1)#[N:41]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCCCCOc1ccc(C#N)cc1-c1cc(C#N)ccc1OCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCOc1ccc(C#N)cc1-c1cc(C(=N)Nc2cccc(C(F)(F)F)c2)ccc1OCCCCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A slurry of sodium hydride (50% in oil, 1.76 g), m-aminobenzotrifluoride (5.91 g) and 6,6'-dipentyloxy[1,1'-biphenyl]-3,3'-dicarbonitrile (6.9 g; additional material is added to the batch of part (A) in 50 ml of anhydrous dimethylsulfoxide is stirred at room temperature for 3 days. The reaction mixture is poured into water and the resultant precipitate collected by filtration. The dried material is chromatographed on 1 liter of silica gel eluting with (1) dichloromethane and (2) 1% methanol/dichloromethane to yield 5'-cyano-2',6-bis(pentyloxy)-N-[3-(trifluoromethyl)phenyl][1,1'-biphenyl]-3-carboximidamide (melting point 74°-75° C after 2 recrystallizations from cyclohexane). The column is next eluted with 2% methanol/dichloromethane to yield 1.3 g of the desired product. Two recrystallizations of this material from 1% hydrochloric acid/methanol yields 900 mg of the title compound, melting point 207°-210° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[F:25][C:26]([F:31])([F:30])[S:27][CH2:28]Cl.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:28][S:27][C:26]([F:31])([F:30])[F:25])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)SCCl
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(CSC(F)(F)F)CC3)c(F)cc2c1=O
Yield: 33.7 %

Procedure:
3.3 g (10 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are heated at 90° in 50 ml of dimethylformamide with 4 g (27 mmol) of trifluoromethylthiomethyl chloride, 2.1 g of triethylamine, 1.7 g of potassium iodide and 0.2 g of tetrabutylammonium iodide for 16 hours. The solution is poured into 50 ml of water and the precipitate is filtered off with suction and boiled up with methanol. 1.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-trifluoromethylthiomethyl-1-piperazinyl)-3-quinolinecarboxylic acid of melting point 247°-250° (with decomposition) are obtained.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1.[CH2:19]([C:21]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.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>[CH2:19]([C:21]1[C:22]([CH:23]=[O:24])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1)[CH3:20]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Cc1ccc(-c2nc(Br)ns2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1c(C=O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Temperature: 120 °C
Yield: 89.2 %

Procedure:
To a solution of 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-(2-methylpropyl)benzonitrile (D60) (500 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (424 mg) and tripotassium phosphate (988 mg) in N,N-dimethylformamide (DMF) (4 mL) and water (1 mL) stirred under nitrogen was added Pd(Ph3P)4 (179 mg). The mixture was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulphate, concentrated and purified by column chromatography to give 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-(2-methylpropyl)benzonitrile (D63) (520 mg). δH (CDCl3, 400 MHz): 1.00 (6H, d), 1.37 (3H, t), 2.81 (2H, d), 3.38 (2H, q), 4.11 (1H, m), 7.48 (2H, m), 8.02 (1H, d), 8.14 (2H, m), 8.30 (1H, d), 10.48 (1H, s). MS (ES): C22H21N3OS requires 375. found 376.1 (M+H+).
Reaction SMILES: CC(C1C=CC=CC=1N)CC(C)C.CC(C)CC(C1C=CC=CC=1N)=C.CC(C1C=CC=CC=1N)=CC(C)C.[CH3:40][CH:41]([CH3:64])[CH2:42][C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52]([C:54]1[C:55]([C:60]([F:63])([F:62])[F:61])=[N:56][N:57]([CH3:59])[CH:58]=1)=[O:53])=[CH2:44]>>[CH3:44][C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52]([C:54]1[C:55]([C:60]([F:62])([F:63])[F:61])=[N:56][N:57]([CH3:59])[CH:58]=1)=[O:53])=[CH:42][CH:41]([CH3:64])[CH3:40]
Reactant: C=C(CC(C)C)c1ccccc1NC(=O)c1cn(C)nc1C(F)(F)F
Agent: C=C(CC(C)C)c1ccccc1N
Agent: CC(=CC(C)C)c1ccccc1N
Agent: CC(C)CC(C)c1ccccc1N
Product: CC(=CC(C)C)c1ccccc1NC(=O)c1cn(C)nc1C(F)(F)F
Yield: 68 %

Procedure:
The same procedures as described in Example 2(1) were carried out except that 2-(1,3-dimethylbutyl)aniline was replaced by a 1:1 mixture of 2-(4-methyl-1-pentene-2-yl)aniline and 2-(1,3-dimethyl-1-butenyl) aniline. A mixture of N-[2-(4-methyl-1-pentene-2-yl)phenyl]-3-trifluoromethyl-1-methylpyrazole-4-carboxamide and N-[2-(1,3-dimethyl-1-butenyl)phenyl]-3-trifluoromethyl-1-methylpyrazole-4-carboxamide was obtained as a yellow crystal. Yield was 68%. Melting point was 66-74 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][F:14])=[C:11]([C:15]([OH:17])=O)[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:46]2[CH:47]=[CH:48][CH:49]=C[C:45]=2[N:44]=[N:43]1.NN1CCCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][F:14])=[C:11]([C:15]([NH:43][N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:17])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CF
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCCCC1)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CF
Yield: 64 %

Procedure:
Part D: 1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-fluoromethyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide. 1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-fluoromethyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide was obtained by reacting 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-fluoromethyl-1H-imidazole-4-carboxylic acid (0.87 g, 2.18 mmol), diisopropylethylamine (DIPEA) (0.84 mL, 4.80 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (0.99 g, 2.62 mmol) and 1-aminopiperidine (0.28 mL, 2.62 mmol) for 16 hours at room temperature. The resulting mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, successively washed with aqueous NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated to give a crude solid. This solid was further purified by flash chromatography. 1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-fluoromethyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide was obtained in 64% yield, mp 162–163° C.; 1H-NMR (600 MHz, DMSO-d6) δ 1.35–1.41 (m, 2H), 1.61–1.66 (m, 4H), 2.80–2.84 (m, 4H), 5.63 (d, J=48 Hz, 2H), 7.36 (d, J=8 Hz, 2H), 7.44 (dd, J=8 and 2 Hz, 1H), 7.48 (d, J=8 Hz, 2H), 7.55 (d, J=2 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 9.10 (s, 1H); HRMS (C22H21Cl3FN4O) [M+H]+: found m/z 481.0760, calcd 481.0765.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc(F)c1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Product: COc1ccc(NC(=O)Nc2cccc(F)c2)cc1-c1c(F)cnn1C
Yield: 55 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-fluorophenylisocyanate, in a similar manner as described in Example 1.68, providing 15 mg (55% yield) of Compound 33: LCMS m/z (%)=359 (M+H, 100). 1H NMR (400 MHz, J acetone-d6) δ: 8.38 (s, 1H), 8.21 (s, 1H), 7.64 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.59 (d, J=12.0 Hz, 1H), 7.48 (d, J=2.8 Hz, 1H), 7.39 (d, JH,F=4.8 Hz, 1H), 7.27 (dd, J1=14.8 Hz, J2=8.0 Hz, 1H), 7.15 (d, J=9.6 Hz, 1H), 7.12 (s, 1H), 6.72 (dd, J1=9.6 Hz, J2=7.2 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −114.00 (m, 1F), −177.35 (d, JH,F=3.8 Hz, 1F).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.C([Li])CCC.CCCCCC.[Br-].[Mg+2].[Br-].C1(S([CH:37]2[CH2:41][CH2:40][CH:39]([O:42][CH3:43])[O:38]2)(=O)=O)C=CC=CC=1>C1COCC1.[Br-].[Zn+2].[Br-]>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([CH:37]2[CH2:41][CH2:40][CH:39]([O:42][CH3:43])[O:38]2)[CH:7]=[C:6]([O:8][CH3:9])[C:5]=1[O:10][CH3:11]
Reactant: COC1CCC(S(=O)(=O)c2ccccc2)O1
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C2CCC(OC)O2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To stirred solution of 1-bromo-3,4,5-trimethoxybenzene (2.47 g, 10 mmol) in THF (20 ml) at -78° C. was added 2.5M n-butyllithium in hexane (4.4 ml, 11 mmol). After 0.75 h the solution was cannulated into a mixture of 1M zinc(II) bromide in THF (11 ml, 11 mmol) and magnesium(II) bromide etherate (2.86 g, 15 mmol) in THF (10 ml) at -78° C. The resulting mixture was allowed to warm to room temperature over 1 h and then sonicated for 0.4 h. A solution of 2-benzenesulphonyl-5-methoxytetrahydrofuran (1.85 g, 7.5 mmol) in THF (10 ml)was added and the mixture stirred at room temperature for 1 h, sonicated for 1 h and stirred overnight. The reaction was quenched by the addition of aqueous ammonium chloride (20 ml). Work up and purification as described for Example 1(b) gave 2-(3,4,5-trimethoxyphenyl)-5 -methoxytetrahydrofuran (0.55 g, 27%) as a colourless oil.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([CH:29]2[C:33](=[O:34])[CH:32]=[CH:31][CH:30]2[OH:35])=[C:24]([CH3:36])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(O)C>CC(C)=O.[Cl-].[Na+].O>[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([CH:29]2[C:30](=[O:35])[CH:31]=[CH:32][C:33]2=[O:34])=[C:24]([CH3:36])[CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C=CC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C=CC1=O
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of Jones reagent (1.67 M, 60 ml, 100 mmol) is added, dropwise, to a solution of 5-(4-benzyloxy-2,6-dimethylphenyl)-4-hydroxycyclopent-2-enone (30.9 g) in acetone (500 ml) at 0° C., and the resulting solution is stirred at 0° C. for 2 hours. Propan-2-ol (50 ml) is added and the mixture is stirred for a further 2 hours, then brine (200 ml) is added and the reaction mixture is extracted with ethyl acetate (2×250 ml). The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 2-(4-benzyloxy-2,6-dimethylphenyl)cyclopent-4-ene-1,3-dione (18.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][N:33]2C(OC(C)(C)C)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NCC2CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NCC2CC2)CC1)[C@@H]1Cc2ccccc2CN1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-(2-[(cyclopropylmethyl)-amino]phenyl}piperidyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (431 mg, 0.64 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (207 mg). MS (ESI, pos. ion) m/z: 571 (M+1); (ESI, neg. ion) m/z: 569 (M−1). Calc'd for C34H39ClN4O2: 570.28. Anal. Calcd for C34H39ClN4O2-2.4C2HF3O2: C, 55.16; H, 4.94; N, 6.63. Found: C, 55.18; H, 5.13; N, 6.61.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[CH2:32][OH:33])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:27][CH3:28])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH2:24][CH2:25][CH3:26])[CH:13]=1.[CH2:34]([Mg]Br)[CH3:35]>>[CH2:27]([C:11]1[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:34][CH3:35])([OH:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH2:24][CH2:25][CH3:26])=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:29]=[CH:30][C:31]([CH2:32][OH:33])=[C:3]([CH2:2][OH:1])[CH:4]=2)=[CH:9][CH:10]=1)[CH3:28]
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(OCc2ccc(CO)c(CO)c2)ccc1CC
Reactant: CC[Mg]Br
Product: CCCc1cc(C(O)(CC)CC)ccc1-c1cc(OCc2ccc(CO)c(CO)c2)ccc1CC

Procedure:
In a manner similar to that of Example 1(q), by reacting 830 mg (1.9 mmol) of 1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2′-ethyl-2-propylbiphenyl-4-yl}-1-propanone with 5.1 ml (15.2 mmol) of ethylmagnesium bromide (3M/ether), and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (40/60), 700 mg (77%) of {4-[6-ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol are obtained in the form of white crystals with a melting point of 101° C.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:10])=[C:7]([OH:22])[CH:6]=1.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[O:10])=[C:7]([O:22][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:6]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
To a stirred suspension of sodium hydride (420 mg of 60%, 10.5 mmoles) in DMF (10 ml) was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.612 g, 5 mmoles) and the mixture stirred for 20 minutes, followed by cooling (ice water) and addition of methyl bromoacetate (832 mg, 5.44 mmoles). The mixture was stirred for 20 minutes in the cold and another 10 minutes at ambient temperature followed by pouring into 70 ml of ice-cold water. A separated solid was filtered and dried to give 1.58 g of crude product mp 92°-94°. This was recrystallized from methylene chloride-ether to give 1.21 g of the title compound as a white crystalline solid, mp 94°-95° (67.6% yield). The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ 8.2 (s, 1H); 6.16 (s, 1H); 4.7 (s, 2H); 4.40 (bs, 2H); 3.86 (s, 3H); 3.54 (m, 2H); 2.6 (m, 6H); 1.04 (t, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[C:8]([O:11][CH2:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])(=[O:10])[CH3:9].C(OC(=O)C[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])C.Cl>C(O)C.O>[F:26][C:25]([F:28])([F:27])[C:24]([NH:15][C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][CH2:12][O:11][C:8](=[O:10])[CH3:9])=[O:29]
Reactant: CC(=O)OCC[C@H](N)C(=O)O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)OCC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reaction time: 14 h
Yield: 45.1 %

Procedure:
7.6 g (55 mol) of potassium carbonate are added to a suspension of 9.9 g (50 mmol) of O-acetyl-L-homoserine hydrochloride and 7.8 g (55 mmol) of trifluoroacetylacetic acid ethyl ester in 200 ml of ethanol, and stirring is carried out for 14 hours. 10.8 g (110 mmol) of 37% hydrochloric acid and 200 ml of water are then added. The product obtained after removal of the ethanol by distillation is filtered off with suction, washed with water and dried. 5.8 g (45%) of N-trifluoroacetyl—O—acetyl-L-homoserine are obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Sc1ncccn1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ncccn3)s2)c(C(=O)C2CCCC2)c1
Yield: 32.3 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(pyrimidin-2-ylsulfanyl)-thiazol-2-yl]-urea (142 mg, 32%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-mercaptopyrimidine (222 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [N:1]1([C:5]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C1COCC1.CO>[N:1]1([C:5]2([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH2:11])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: [Li]c1ccccc1
Reactant: N#CC1(N2CCC2)CCCC1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NC(c1ccccc1)C1(N2CCC2)CCCC1
Yield: 47 %

Procedure:
The title compound (0.45 g, 47%) was prepared from 1-(1-azetidinyl)cyclopentanecarbonitrile D13 (0.60 g, 4.0 mmol), and phenyllithium in ethers (2.6 ml of a 1.7M solution; 4.4 mmol) in THF (5 ml), followed by reaction with sodium borohydride (0.456 g, 12 mmol) in methanol (5 ml) in a similar manner to that described in D2. 1H NMR (CDCl3) δ: 0.67 (1H, m), 1.06 (1H, m), 1.32 (4H, m), 1.48 (2H, m), 1.91-2.03 (4H, m), 3.24 (4H, m), 3.83 (1H, s), 7.20-7.32 (3H, m), 7.44 (2H, m).