Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:6]([CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)[Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 111.2 %

Procedure:
A stirred solution of 3-bromobenzyl alcohol (21) (10.0 g, 53.5 mmol), 4-dimethylaminopyridine (0.33 g, 2.7 mmol), and t-butylchlorodiphenylsilane (17.6 g, 64.2 mmol) in anhydrous CH2Cl2 (240 mL) was cooled to 0° C. under argon. Triethylamine (8.1 g, 80.2 mmol) was added dropwise via syringe and the reaction mixture was allowed to warm to room temperature over 3.5 h. The reaction solution was washed with water, and the aqueous portion was extracted again with CH2Cl2. The organic layers were combined, washed sequentially with 1N HCI solution, water, and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 25.3 g of 22 as a clear, pale yellow oil. Purification by column chromatography (20:1 ratio silica gel/crude product; elution with 5% to 7.5% ethyl acetate/hexanes) yielded 21.2 g (93%) of 22 as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ7.63-7.65 (m, 4H, ArH), 7.35-7.48 (m, 8 H, ArH), 7.18-7.28 (m, 2H, ArH), 4.72 (s, 2H, CH2OSi), and 1.05 (s, 9H, SiC(CH3)3).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[F:9][C:10]([F:42])([F:41])[C:11]1[CH:12]=[C:13]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:14][O:15][CH2:16][C:17]([OH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23]>CC(C)=O>[F:9][C:10]([F:41])([F:42])[C:11]1[CH:12]=[C:13]([CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=1)[CH2:14][O:15][CH2:16][C:17]([OH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][N:20]([CH3:1])[C:21](=[O:26])[C:22]([F:24])([F:25])[F:23]
Reactant: O=C([O-])[O-]
Reactant: O=C(NCCC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(CCC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)C(=O)C(F)(F)F
Temperature: 60 °C

Procedure:
Excess amount of potassium carbonate (150 mg, 1.1 mmol) and excess amount of methyl iodide (0.040 ml, 0.064 mmol) were mixed with N-(4-(3,5-bis(trifluoromethyl)benzyloxy)-3-hydroxy-3-phenylbutyl)-2,2,2-trifluoroacetamide (15 mg, 0.030 mmol) in acetone (2 ml). The reaction mixture was heated in microwave at 60° C. for 10 minutes. The salt precipitate was filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC to give the desired N-methylacetamide. 1H NMR (300 MHz, MeOH) δ ppm 7.84 (s, 3 H) 7.46–7.54 (m, 2 H) 7.35 (ddd, J=8.14, 6.50, 4.76 Hz, 2 H) 7.22–7.30 (m, 1 H) 4.61–4.73 (m, 2 H) 3.62–3.75 (m, 2 H) 3.40–3.55 (m, 1 H) 3.11–3.37 (m, 1 H) 3.01 (s, 2 H) 2.93 (s, 1 H) 2.15–2.31 (m, 2 H); LRMS [ESI, (MH+−H2O)] m/z calcd for C22H19NO2F9 500.13, found 499.97.
Reaction SMILES: [OH-].[Na+].C1(C[O:10][C:11]([C:13]2([NH:19][C:20]([C:22]3[S:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[CH:26]=3)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])C=CC=CC=1.CCOCC>O1CCCC1>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH:26]=[C:22]1[C:20]([NH:19][C:13]1([C:11]([OH:12])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:21]
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1cc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NC1(C(=O)O)CCCCC1)c1cc2ccccc2s1
Yield: 83.8 %

Procedure:
42 ml of 2N aqueous sodium hydroxide solution was added to a solution of 10 g (24 mmol) of 1-[(2-benzothienylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethyl ester in 20 ml of tetrahydrofuran, and the mixture was heated under reflux for 3 days. After ether was added to the reaction solution to wash it, the aqueous layer was neutralized by concentrated hydrochloric acid, and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain 6.1 g (80%) of the title compound.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([C:20]#[N:21])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C>C1COCC1>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([CH2:20][NH2:21])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
7-Benzenesulfonyl-chroman-4-carbonitrile (300 mg, 1 mmol) was dissolved in 10 mL THF, and 237 ul (2.5 mmol) of BH3.DMF was added. The reaction mixture was stirred for one hour at room temperature, and then heated to 80° C. for twenty minutes. The reaction mixture was then cooled, quenched by addition of methanol, and diluted with water. The aqueous mixture was extrated with EtOAc. The organic phase was dried over MgSO4, and solvent was removed under reduced pressure to yield 95 mg (31%) of C-(7-benzenesulfonyl-chroman-4-yl)-methylamine. MS: 304 (M+H)+. This product was dissolved in 2N HCl/EtOH and recrystallized by addition of Et2O to afford 52 mg of the corresponding hydrochloride salt. Mp: 246.8-249.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][NH:18][CH3:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][N:18]([CH3:19])[CH2:17][C:11]1([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: ClCCCBr
Reactant: CNCC1(c2ccc(OC)c(OC)c2)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(CN(C)CCCCl)CCCCC2)cc1OC
Reaction time: 16 h

Procedure:
A solution of 3.40 g (0.0129 mol) of 1-(3,4-dimethoxyphenyl)-N-methyl-1-cyclohexanemethanamine in 50 ml of abs. dimethylformamide was treated with 3.57 g (0.0258 mol) of anhydrous potassium carbonate. The mixture was stirred at 5° and treated with 1.4 ml (0.0129 mol) of 1-bromo-3-chloropropane and subsequently stirred initially at 30° for 4 hours and thereafter at room temperature for 16 hours. The solvent was then evaporated at room temperature under reduced pressure and the residue was treated with water. The mixture was extracted three times with ether and the organic extracts were dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oily residue was distilled under a pressure of 300 Pa at 195°, whereby there was obtained N-(3-chloropropyl)-1-(3,4-dimethoxyphenyl)-N-methylcyclohexanemethanamine as a colourless viscous oil which was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12](Cl)=[CH:11][C:10]=2[CH3:16])[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[NH:18][NH2:19]>C(O)CCC>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([NH:19][NH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]=2[CH3:16])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)NN
Reactant: Cc1cc(Cl)nnc1-c1cccc(C#N)c1
Solvent: CCCCO
Product: CCOC(=O)NNc1cc(C)c(-c2cccc(C#N)c2)nn1

Procedure:
A 3.15 g. portion of 6-(m-cyanophenyl)-5-methyl-3-chloropyridazine and 2.85 g. of ethyl carbazate in 50 ml. of butanol is stirred at reflux temperature for 4 hours. The mixture is concentrated free of solvent and the oily concentrate is triturated with water and a little ether. The resulting solid is recovered by filtration, air dried and recrystallized several times from ethanol giving a white solid, m.p. 189°-190° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][C:13]2=[O:22])[CH:5]=[CH:6][C:7]=1[Sn](C)(C)C.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2>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.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][C:13]2=[O:22])[CH:5]=[CH:6][C:7]=1[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2
Reactant: Brc1ccc2ncccc2c1
Reactant: CC(=O)NCC1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NCC1CN(c2ccc(-c3ccc4ncccc4c3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(±)-N-[[3-[3-fluoro-4-(trimethylstannyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (PREPARATION 19, 0.367 g, 0.88 mmol), 6-bromoquinoline (0.239 g, 1.15 mmol) and bis(triphenyl-phosphine)palladium(II) chloride (0.062 g, 0.088 mmol) are combined with DMF (10 ml). The reaction mixture is thoroughly purged with nitrogen and then heated to 80° under nitrogen. After 2 hr, little progress is noted by TLC and so the reaction mixture is heated to 95° for a further 2 hr. At this point, TLC revealed the reaction is complete. The mixture is cooled to 20°-25° and concentrated under reduced pressure to give a crude material which is purified by chromatography over silica gel (10 g of silica gel; eluted with methanol/chloroform, 1→4%) to give the racemic title compound, mp 216°-219° (dec); IR (internal reflectance) 3411, 3281, 1743, 1657, 1630, 1566, 1521, 1499, 1416, 1226, 1194 cm-1 ; NMR (CDCl3, 300 MHz) 8.95, 8.26-8.20, 8.00, 7.92, 7.61, 7.57, 7.47, 7.35, 6.08, 4.84, 4.13, 3.86, 3.80-3.62, 2.05 δ; MS (m/z) 379 (100.0, M+), 335, 307, 276, 264, 251.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:12]1[N+:17]([O-:18])=[C:16]2[CH2:19][CH2:20][CH2:21][C:15]2=[C:14]([Cl:22])[CH:13]=1>O1CCOCC1.C(Cl)Cl>[Cl:22][C:14]1[CH:13]=[C:12]([O:4][CH:1]([CH3:3])[CH3:2])[N+:17]([O-:18])=[C:16]2[CH2:19][CH2:20][CH2:21][C:15]=12
Reactant: CC(C)O
Reactant: [O-][n+]1c(Cl)cc(Cl)c2c1CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)Oc1cc(Cl)c2c([n+]1[O-])CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of iso-propanol (0.047 g, 0.79 mmol) in dioxane (3 mL) at rt was added potassium tert-butoxide (0.053 g, 0.47 mmol). The mixture was stirred at rt for 30 min. Then, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.100 g, 0.39 mmol) in dioxane (1 mL) was added and the mixture was heated under microwave irradiation to 100° C. for 30 min. After this time, the mixture was diluted with methylene chloride and washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.079 g, 88%) as a white solid. MW=227.69. 1H NMR (CDCl3, 300 MHz) δ 6.73 (s, 1H), 4.90-4.85 (m, 1H), 3.23 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H), 1.44 (d, J=6.0 Hz, 6H); APCI MS m/z 228 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5](C2CCCCO2)[C:6]=1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:13]=[CH:14]2)=[CH:9][CH:8]=1.CO.[ClH:31]>O1CCOCC1>[ClH:31].[CH3:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:13]=[CH:14]2)=[CH:9][CH:8]=1
Reactant: Cc1cnn(C2CCCCO2)c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cn[nH]c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of N-(7-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide (43 mg, 0.11 mmol) in methanol (3 mL, 70 mmol) was added 4.0 M of hydrogen chloride in 1,4-dioxane (0.30 mL). The reaction mixture was stirred at 40° C. for 1 hour and then evaporated in vacuo. The residue was triturated with 0.5 mL N,N-dimethylformamide, and the resulting light yellow precipitate was collected, rinsed with ethyl acetate, and dried under vacuum to yield 17.3 mg (46%) of N-(7-(4-methyl-1H-pyrazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide hydrochloride. LCMS (ESI): RT (Min)=3.816, M+H=293.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.22 (s, 1H), 8.44 (s, 1H), 8.27 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.63 (s, 1H), 2.31 (s, 3H), 2.14-2.01 (m, 1H), 0.93-0.76 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2>CN(C=O)C>[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:25]2
Reactant: Nc1ccc2c(c1)CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4ccc(N)cc4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 56.2 %

Procedure:
157 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 242 mg of 5-aminoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 124 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH:11]([C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][O:22][C:16]1[CH:15]=[CH:14][C:13]([CH:11]=[O:12])=[CH:21][C:17]=1[C:18]([O:20][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])=[O:19]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCc2ccc(F)cc2F)c(C(=O)OCc2ccc(F)cc2F)c1
Yield: 95.6 %

Procedure:
2,4-Difluorobenzyl bromide (0.77 mL, 6 mmol, 1 eq) was added dropwise to a stirred solution of 5-formylsalicylic acid (1 g, 6 mmol, 1 eq) and cesium carbonate (5.87 g, 18 mmol, 3 eq) in N,N-dimethylformamide (30 mL). The reaction mixture was diluted with ethyl acetate (50 mL) and the organic solution washed with water (50 mL), saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL), then dried over sodium sulfate and evaporated in vacuo to give the product as a white powder (1.2 g, 50%). 1H NMR (CDCl3) δ9.91 (s, 1H, O═C—H), 5.37 (s, 2H, CH2Ar), 5.25 (s, 2H, CH2Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([CH2:12][N:13]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH:23](OCC)[O:24]CC)[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([CH2:12][N:13]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH:23]=[O:24])[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C(OCC)OCC)ncn1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C=O)ncn1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
In 20% aqeuous acetic acid (10 ml) was dissolved ethyl 1-[4-(4-chlorobenzoyl)benzyl]-4-(diethoxymethyl)-imidazole-5-carboxylate (1.20 g) and the mixture was stirred at room temperature for 8 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed serially with water, saturated aqueous NaHCO3 solution, and water, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (671 mg; yield 67%). 1H-NMR (CDCl3) δ: 1.38(3H,t,J=7.OHz), 4.41(2H,q,J=7.OHz), 5.66(2H,s), 7.26(2H,d,J=8.8Hz), 7.46(2H,d,J=8.8Hz), 7.70-7.79(5H,m), 10.42(1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=2)[C:32]([NH:31][C:23]2[C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:28]([CH3:30])[CH3:29])=[O:33])=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccc(N(Cc2ccc(Cl)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 50.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-chlorophenyl)methyl](4-isopropylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.9 g) as starting materials, N-[(4-chlorophenyl)methyl]-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (0.9 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27]([OH:29])=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27]([O:29][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)OCOC(=O)C(C)(C)C)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 4-(((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.12 g, 0.23 mmol) and TEA (0.06 g, 0.6 mmol) in DMF (6 mL) was added chloromethyl pivalate (0.12 g, 0.8 mmol). And the mixture was stirred at 60° C. for 3 hours, and cooled to 25° C. To the reaction mixture was added DCM (100 mL). The organic layer was washed with brine (80 mL×6) and dried over unhydrous Na2SO4. The crude product was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=8/1) to give the title compound as yellow oil (0.09 g, 62%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:26](=[O:29])[NH:27][CH3:28])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:10][CH:9]1[CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:26](=[O:29])[NH:27][CH3:28])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:10][CH:9]1[CH2:30][CH2:31][OH:32])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)OC(C)(C)C)C(CCO[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1

Procedure:
A solution of 2-[2-(tert-butyldimethylsilanyloxy)ethyl]-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)-piperazine-1-carboxylic acid tert-butyl ester, 59, (15.9 g, 23.5 mmol) and 1 M tetrabutylammonium fluoride (40 mL) is stirred for 24 hours. The reaction solution is filtered through a pad of silica gel, the filtrate is concentrated in vacuo, and the resulting crude product purified over silica gel (EtOAc/hexane 1:2, 1:1, then 5% methanol in EtOAc) to afford the desired product.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:26]=1[CH2:27]Br>>[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:26]=1[CH2:27][O:2][C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)=[O:3]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Clc1cccc(Cl)c1CBr
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3c(Cl)cccc3Cl)(CC1)CC2
Yield: 89.4 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 2,6-dichlorobenzyl bromide (24.5 mg) were used to obtain (2S,4S)-1-[[N-[4-(2,6-dichlorobenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (40.0 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=2[CH3:32])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[S:43])[C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=2[CH3:32])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=S)NCc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
To the stirred solution of (E)-N-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson's reagent (0.14 g, 0.351 mmol) and the reaction was irradiated at 100° C. for 1 h, then cooled to ambient temperature and concentrated under reduced pressure to provide crude compound. The crude product was purified by preparative HPLC to afford the product as yellow color solid (0.03 g, 49%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:44])[C@@H:27]([C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=2)[CH2:28][CH2:29][CH3:30])=[CH:22][CH:21]=1>C1COCC1>[F:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:26]([OH:44])([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=2)[C@@H:27]([C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])=[CH:33][CH:32]=2)[CH2:28][CH2:29][CH3:30])=[CH:3][CH:4]=1
Reactant: CCC[C@@H](C(=O)c1ccc(OC)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Fc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)C(O)(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-4-fluoronaphthalene (229 mg, 1.02 mmol) in THF (6 mL) at −78° C. was added BuLi (2.5 M in hexanes, 0.434 mL, 1.086 mmol), then the solution was stirred for one hour. A solution of t-butyl (R)-4-[2-(4-methoxyphenyl)-1-propylethan-2-one-1-yl]benzoate (prepared using the procedure for INTERMEDIATE 4, 250 mg, 0.678 mmol) in THF (2 mL) was added and the solution was stirred for an additional hour. The solution was quenched with saturated NH4Cl (aq), then diluted with EtOAc (50 mL). The organic layer was separated, washed with water then brine, dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to afford the title compound. LC1 1.30 min. [M+H−H2O]+ 497.