Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C@H:15]1[CH2:22][N:21]2[C:23]3[CH:24]=[C:25]([C:36]([O:38][CH3:39])=[O:37])[CH:26]=[CH:27][C:28]=3[C:29]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:20]2[C:19]2[CH:40]=[CH:41][CH:42]=[CH:43][C:18]=2[O:17][CH2:16]1)C1C=CC=CC=1.CC(O)=O>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH:30]1([C:29]2[C:28]3[CH:27]=[CH:26][C:25]([C:36]([O:38][CH3:39])=[O:37])=[CH:24][C:23]=3[N:21]3[C:20]=2[C:19]2[CH:40]=[CH:41][CH:42]=[CH:43][C:18]=2[O:17][CH2:16][C@@H:15]([O:14][CH2:13][CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH2:22]3)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1Cc1ccccc1)COc1ccccc1-3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a solution of methyl (7S)-7-[(1-benzylpyrrolidin-2-yl)methoxy]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.07 M) in EtOAc, was added an excess of AcOH (>50 eq) and Pd(OH)2/C. The atmosphere in the reaction flask was charged with H2 and the reaction stirred vigorously under a H2 atmosphere (balloon) at RT for 2 d. The mixture was filtered and the filtrate concentrated in vacuo. The crude was purified by FC (gradient from EtOAc/PE 6:4+1% NEt3 to EtOAc/PE 8:2+1% NEt3+5% MeOH) to afford the product (50%). (ES+) m/z 489 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11](O)=[O:12])C)=O)(C)(C)C.[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:26][O:27][CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1>>[CH3:6][NH:8][CH2:10][C:11]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:26][O:27][CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)=[O:12]
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: CCOC(=O)C(=NOC)c1csc(NC(=O)CNC)n1

Procedure:
The subtitle compound was prepared from N-[tert-butoxycarbonyl]sarcosine (2.00 g) and ethyl 2-amino-alpha-[methoxyimino]-4-thiazoleacetate (2.66 g) by the method of example 10 step (i).Yield 2.77 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccccc1O[C@@H]1CCCNC1
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a solution of tert-butyl (R)-3-(2-ethoxyphenoxy)piperidine-1-carboxylate (73 g, 227 mmol) in CH2Cl2 (300 mL) at 20-25° C. was added trifluoroacetic acid (150 mL). The reaction mixture was allowed to stir at 20-25° C. for 4 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in H2O (200 mL) and basified with saturated NaHCO3 solution (200 mL). The mixture was extracted with EtOAc (3 times with 200 mL). The organic extracts were dried over Na2SO4 and concentrated to afford (R)-3-(2-ethoxyphenoxy)piperidine (45 g, 89%). MS (ES+) 222.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4](O)[CH:5]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)=[O:11])[CH2:6][CH2:7][CH2:8][CH3:9].CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH:4]([F:30])[CH:5]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)=[O:11])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCC(C(=O)N1CCC[C@H]1c1ncco1)[C@H](O)C(=O)OC
Solvent: ClCCl
Product: CCCCC(C(=O)N1CCC[C@H]1c1ncco1)C(F)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2(S)-hydroxy-3-(2(S)-oxazol-2-yl-pyrrolidin-1-carbonyl)-heptanoic acid methyl ester C-1 (5 mmol) in DCM (5 mL) is added DAST (15 mmol) at −20° C. The solution is stirred for 16 hours at rt. The reaction mixture is washed with aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated then purified on silica gel (EtOAc/hexanes) to afford 2-(R/S)-fluoro-3-(2(S)-oxazol-2-yl-pyrrolidin-1-carbonyl)-heptanoic acid methyl ester C-2.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:8]=2)[CH2:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(OCC)C>C(Cl)(Cl)Cl>[C:27]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:8]=2)[CH2:3]1)(=[O:29])[CH3:28]
Reactant: COC(=O)c1cc(F)c(N2CCC(N)C2)nc1Nc1ccc(F)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Yield: 99.4 %

Procedure:
In 6.5 ml of chloroform was dissolved 650 mg of methyl 6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate, and 190 mg of acetic anhydride was added to the resulting solution, after which the resulting mixture was subjected to reaction at room temperature for 10 minutes. The solvent was then removed by distillation under reduced pressure. To the crystalline material thus obtained was added 2 ml of diethyl ether, after which crystals were collected by filtration to obtain 720 mg (yield 99.4%) of methyl 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate having a melting point of 199°-200° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[CH3:24])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:42].C(OCC)C>CC(O)(C)C>[CH2:10]([O:9][CH2:8][C@@H:7]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[CH3:24])[CH2:6][F:42])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [F-]
Reactant: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: Cc1cc(Br)ccc1[C@@H](CF)COCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To 24A (0.74 g, 1.790 mmol) in tBuOH (10 mL) was added TBAF (1.0 M in THF, 5.37 mL, 5.37 mmol). The mixture was stirred at 80° C. for 2 h. Ethyl ether was added and the mixture was filtered. The filtrate was evaporated and the crude product was purified by flash chromatography (0-30% EtOAc/hexanes) to give 24B (0.46 g, 1.364 mmol, 76% yield) as colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.27-7.43 (m, 7H) 7.13 (d, J=8.34 Hz, 1H) 4.74 (d, J=5.56 Hz, 1H) 4.62 (d, J=5.56 Hz, 1H) 4.47-4.59 (m, 2H) 3.71-3.81 (m, 1H) 3.60-3.70 (m, 1H) 3.37-3.57 (m, 1H) 2.33 (s, 3H); 19F NMR (376 MHz, chloroform-d) δ ppm −224.19 (s, 1F).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[N:7][CH:6]=[N:5][C:4]=2[N:3]([CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[N:2]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[CH2:10][N:3]1[C:4]2[N:5]=[CH:6][N:7]=[CH:8][C:9]=2[N:1]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1nnc2cncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ncc2nnn(C[C@@H]3CCCN3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
1,1-Dimethylethyl (2S)-2-(3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-1-pyrrolidinecarboxylate (1.98 g, 6.54 mmol) was dissolved in a mixture of CH2Cl2 (10 mL) and TFA (2.5 mL) and allowed to stir at room temperature overnight. When the reaction was complete as determined by LCMS, the solution was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (5 mL) and washed with 1 N aq. NaOH (30 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to provide 3-[(2S)-2-pyrrolidinylmethyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine (758 mg, 57%). LCMS: (M+H)+: 205.1.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[CH:23]=[CH:24][C:25]2[N:26]([N:28]=[CH:29][N:30]=2)[N:27]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:22]3[CH:23]=[CH:24][C:25]4[N:26]([N:28]=[CH:29][N:30]=4)[N:27]=3)[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: Clc1ccc2ncnn2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C(OC2CCN(c3ccc4ncnn4n3)CC2)c2ccccc2)cc1
Yield: 54.4 %

Procedure:
4-(Diphenylmethoxy)piperidine (1.12 g) and 6-chloro[1,2,4]triazolo[1,5-b]pyridazine (558 mg) were dissolved in 1-butanol (25 ml), followed by addition of N-ethyldiisopropylamine (700 mg). The mixture was refluxed under heating for 17 hours. After being cooled, the mixture was concentrated under reduced pressure. Ice-water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of hexane and ethyl acetate (1:3). Fractions containing the objective compound were collected and recrystallized from ethanol to yield the title compound (757 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:11][CH:12]=1)[CH3:2]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCN(Cc1ccccc1F)C(=O)COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
N-Ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenoxy)acetamide (0.177 g, 0.586 mmol) was dissolved in acetonitrile (10 ml), methyl 2-(bromomethyl)benzoate (0.147 g, 0.642 mmol) and dipotassium carbonate (0.161 g, 1.167 mmol) were added. The solution was stirred for 2 hours at 60° C. EtOAc (20 ml) was added and the organic phase was washed with two portions of brine (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.242 g of methyl 2-[(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenoxy)methyl]benzoate (yield 91.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([CH3:21])[CH:12]=[C:13]([F:20])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[F:20][C:13]1[CH:14]=[C:15]2[C:10](=[C:11]([CH3:21])[CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: CC(C)(N)C(=O)O
Reactant: Cc1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)cc2c1NC(c1cccc(NC(C)(C)C(=O)O)c1)CC2(C)C
Temperature: 25 °C
Yield: 28.3 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-fluoro-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline (348.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-fluoro-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (104.8 mg, 30.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 371.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30](=[O:34])[CH2:31][C:32]#[N:33])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)([CH3:39])[CH:37]=O.N1CCCC1.[Si](Cl)(C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30]([C:31](=[CH:35][C:36]([CH3:39])([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH3:37])[C:32]#[N:33])=[O:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCOCC1
Reactant: N#CCC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To the mixture of 3-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidin-1-yl]-3-oxo-propanenitrile (90.6 mg, 0.200 mmol), 2-methyl-2-morpholino-propanal (98.3 mg, 0.590 mmol) in DCM (2 mL) in an ice bath was added pyrrolidine (0.1 mL, 1.19 mmol) and TMS-Cl (0.1 mL, 0.79 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour and the reaction mixture directly loaded on silca gel plate, purified by EtOH:CH2Cl2 5% to get pure product 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-4-morpholino-pent-2-enenitrile (23 mg) as a white powder. LC-MS (ES, m/z): 597 [M+H]
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[Cl:61]C1C=C(N=C=S)C=CC=1>>[Cl:61][C:7]1[CH:2]=[C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: S=C=Nc1cccc(Cl)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(Cl)c4)cc3)ccc2C1=O

Procedure:
The compound of example 266 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 3-chlorophenyl isothiocyanate. The compound of example 266 was used directly without isolation for the preparation of compound of example 267.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:15]([O:16][CH2:17][O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=[C:12]([O:22][CH2:23][O:24][CH3:25])[C:11]=1[O:26][CH3:27])(=O)=O.[I-:28].[Na+]>CC(C)=O.CN(C)P(=O)(N(C)C)N(C)C>[I:28][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:15]([O:16][CH2:17][O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=[C:12]([O:22][CH2:23][O:24][CH3:25])[C:11]=1[O:26][CH3:27]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCOS(C)(=O)=O)c1OC
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOc1cc(OC)c(OCOC)c(CCCCI)c1OC
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1.5 Grams of 4-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]butyl methanesulfonate was dissolved in a mixed solvent of 40 ml of acetone with 4 ml of hexamethylphosphoric triamide, then 2 g of sodium iodide was added to thereto and the whole mixture was heated at 70° C. in an oil bath and stirred for 1.5 hours. After the completion of the reaction, the reaction mixture was concentrated under a reduced pressure, then 200 ml of diethyl ether was added thereto, and washed twice with 100 ml of water, further washed twice with 100 ml of a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure to yield 1.3 g of 1-(4-iodobutyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene. Colorless oily substance.
Reaction SMILES: C(OC([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]1OCC)=O)C.Cl.Cl.N[C@@H](CC(C)C)[C@H:23](C1C=CC=CN=1)[OH:24].C(N(CC)CC)C>ClCCl>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:15]=1[CH:14]([CH2:13][CH2:12][CH3:11])[CH2:23][OH:24]
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: CC(C)C[C@H](N)[C@@H](O)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CO)c1ccccn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 3.32 g sample of (S) 2-tert-butoxycarbonyl-amino-4-methyl-(R)1-(2-pyridinyl)pentan-1-ol, 0-acetate was dissolved in a mixture of 3 ml of methanol and 8 ml of 5N sodium hydroxide. The solution was stirred at 10° C. for 2 hours and then extracted with dichloromethane. The extract was dried (Na2SO4) and the solvent removed under vacuum to give 2.69 g of (S) 2-tert-butoxycarbonylamino-4-methyl-(R)1-(2-pyridinyl)-pentan-1-ol as an oil. To the preceding compound (2.69 g) was added 15 ml of 2N anhydrous hydrochloric acid in ethyl acetate. After stirring at room temperature, the solvent was removed under vacuum to give 2.46 g of (S) 2-amino-4-methyl-(R)1-(2-pyridinyl)-pentan-1-ol, dihydrochloride as tan crystals, mp 152°-154° C. To a solution of N-[(phenylmethoxy)carbonyl]-L-phenylalanyl-D,L-2-ethoxyglycine (2.0 g; 5 mmol) (Reference Example 12) and 5 mmol of 2-ethoxy- 1(2H)-quinolinecarboxylic acid ethyl ester in 50 ml of dichloromethane is added 5 mmol of (S)-2-amino-4-methyl-(R)1-(2-pyridinyl)pentan-1-ol, dihydrochlorde and 4 ml of triethylamine in 25 ml of dichloromethane. The mixture is stirred at room temperature for 20 hours and worked-up as described for Reference Example 8 to give N-[N-[(phenylmethoxy)carbonyl)-L-phenylalanyl-D,L-2-ethoxyglycyl]-(S)2-amino-4-methyl-(R)1-(2-pyridinyl pentan-1-ol as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:44]3[CH2:45][CH2:46][N:41]([C:38](=[O:40])[CH3:39])[CH2:42][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)N1CCNCC1
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H34N4O3F3Cl2 [(M+H)+] 661.1955, observed 661.1947.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13]([O:18][CH3:19])(=[O:17])[C:14]([CH3:16])=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:15][C:14]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)([CH3:16])[C:13]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)=O
Reactant: COc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(O)c1ccc2cc(OC)ccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
A mixture of 2-methoxynaphthalene (20,0 g, 126 mmol) and methyl pyruvate (19,3 g, 190 mmol) in dichloromethane (100 mL) was added to a suspension of aluminium chloride (25,3 g, 190 mmol) in dichloromethane (100 mL) at 6° C. over 140 minutes. The solution was stirred for a further 15 minutes at this temperature and added to ice/water. Methyl 2-hydroxy-2-(6-methoxynaphth-2-yl)propionate (52% yield) and 2-methoxynaphthalene (34% recovery) were the primary components of the reaction mixture.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:6]#[CH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[C:1]([O:4][C@@H:5]([CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][O:12][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C:6]#[CH:7])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#C[C@H](CC[C@H](O)CO)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#C[C@H](CC[C@H](O)COS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
A solution of(3S,6S)-3-acetoxy-6,7-dihydroxy-hept-1-yne 14 (4.3 g, 23.1 mmol) in CH2Cl2 (50 mL) containing pyridine (3.7 mL, 46.2 mmol) was cooled to 0° C. and treated with p-toluene sulfonyl chloride (4.4 g, 23.1 mmol) and stirred at room temperature for 5 h. The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with aqueous CuSO4 solution (2×25 mL) followed by water (2×25 n mL). Organic layer was dried (Na2SO4), evaporated and purified by chromatography (Si-gel, 15% EtOAc-hexane); first eluted was (3S,6S)-3-acetoxy-6,7-di-p-toluene sulfonyloxy-hept-1-yne 15a (1.14 g) in 10% yield as a yellow syrup. 1HNMR (CDCl3, 200 MHz): δ1.48-1.8 (m, 4H, H-3,4), 2.0 (s, 3H, OAc), 2.31 (d, 1H, J 2.5 Hz, H-7) 2.4 (s, 3H, Ar—CH3), 3.94 (d, 2H, J 4.5 Hz, H-1), 4.5-4.64 (m, 1H, H-2), 5.06-5.18 (m, 1H, H-5), 7.20-7.3, 7.56-7.7 (m, 4H each, Ar—H).
Reaction SMILES: [CH2:1](S(C1N(C2C=CC=CC=2)N=NN=1)(=O)=O)[CH2:2][CH2:3][CH3:4].[K].C[Si](C)(C)N[Si](C)(C)C.[CH:29]([C@@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:32]1)=O.O>COCCOC>[CH:29](/[C@@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:32]1)=[CH:1]\[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)c1nnnn1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C=O)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: COCCOC
Solvent: O
Product: CCC/C=C/[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To a mixture of 5-butylsulfonyl-1-phenyl-1H-tetrazole (3.54 g) and anhydrous ethylene glycol dimethyl ether (60 ml) at −60° C. was added 0.5 M hexamethyldisilazane potassium solution (in toluene, 26.6 ml), and the mixture was stirred for 20 minutes. Under the same condition, a solution of t-butyl cis-4-formylcyclohexylcarbamate (3.02 g) in anhydrous ethylene glycol dimethyl ether (15 ml) was added to the mixture. And the reaction mixture was gradually warmed to 25° C. and stirred overnight. To the reaction mixture was added water, and the mixture was stirred for 1 hour, then extracted with diethyl ether, and the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 2.38 g of t-butyl cis-{4-[(E)-1-pentenyl]cyclohexyl}carbamate.