Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:32])[NH:41][CH2:40][CH2:39][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCCc1ccccc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 61.4 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 2-phenylethylamine (available from Aldrich Chemical Company, Inc.; 75 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-phenethylcarbamoyl-biphenyl-2-carboxylic acid (74 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 8.62 (t, J=5.4 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.18-7.35 (m, 5H), 3.52 (q, J=6.7 Hz, 2H), 2.88 (t, J=7.4 Hz, 8H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25]CCO)=[CH:21][CH:20]=1.C(O)C>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:25][C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCCCc1ccncc1
Reactant: CCOC(=O)CC(=O)COCCN1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccncc1
Reaction time: 18 h
Yield: 165.4 %

Procedure:
A solution of ethyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (6.46 g, 25.20 mmol) and 3-(4-pyridyl)propanol (1.9 ml, 14.49 mmol) was heated in toluene (500 ml), with azeotropic removal of ethanol, for 4 h. The solution was allowed to cool with stirring for 18 h and was then concentrated to give the title compound (8.35 g). Electrospray MS m/z 349 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:13]([N:15]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=2[N:38]([CH2:41][C@H:42]2[CH2:47][CH2:46][C@H:45]([CH2:48][C:49]([OH:51])=[O:50])[CH2:44][CH2:43]2)[CH2:39][CH3:40])[C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25][CH3:26])=[CH:18][N:17]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:54](O)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.CCN=C=NCCCN(C)C.Cl.O>ClC(Cl)C.CN(C1C=CN=CC=1)C>[CH2:54]([O:50][C:49](=[O:51])[CH2:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([CH2:41][N:38]([C:29]2[CH:30]=[CH:31][C:32]([C:34]([F:36])([F:37])[F:35])=[CH:33][C:28]=2[CH2:27][N:15]([CH:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:53])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH3:14])[C:16]2[N:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][S:25][CH3:26])=[CH:20][N:21]=2)[CH2:39][CH3:40])[CH2:43][CH2:44]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CCN(C[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere, a solution of the (S)-isomer-dominant semi-chiral compound (4) of trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (744.1 g, 0.95 mol) obtained in Step 2 in anhydrous dichloroethane (11.6 L) was added with benzyl alcohol (113.1 g, 1.05 mol), WSC.HCl (200.5 g, 1.05 mol) and DMAP (11.9 g, 98 mmol) under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was added with water (10 L), and the mixture was extracted with chloroform (19 L, 14 L). The organic layer was washed with saturated brine (12 L), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 28 g, developing solvent: heptane/ethyl acetate=6/1) to obtain a semi-chiral compound (5) of trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid benzyl ester (yellow oil, 745.8 g, yield: 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccnc(OCc3nc(-c4ccco4)oc3C)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccnc(OCc3nc(-c4ccco4)oc3C)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (639 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (569 mg, yield: 94%). This was recrystallized from ethanol-hexane. Melting point: 138–139° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:9]
Reactant: CCNCC
Reactant: O=C(O)c1cc(Br)ccc1Oc1cccnc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1cccnc1F
Reaction time: 8 h

Procedure:
A mixture of crude 5-bromo-2-(2-fluoropyridin-3-yloxy)benzoic acid (8.00 g, 25.6 mmol), diethylamine (6.63 mL, 64.1 mmol) and TBTU (8.23 g, 25.6 mmol) in 8 mL of DMF was stirred overnight. The reaction was quenched with Sat. NaHCO3, extracted with EA/H=2:1, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA 100:5 to 100:10 to 100:20 to 3:1) gave 5-bromo-N,N-diethyl-2-(2-fluoropyridin-3-yloxy)benzamide as a yellow solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH2:19])(=[O:9])=[O:8])[CH:2]=1
Reactant: Nc1ccccc1N
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: Cc1cccc(S(=O)(=O)Nc2ccccc2N)c1

Procedure:
The sulfonamide was synthesized from 3-tolyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.73 g, 28%).EI-MS m/z 263 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl:19][C:20]1[CH:25]=[C:24](/[C:26](/[C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:42][CH2:41]3)=[C:36]([O:43][CH3:44])[N:35]=2)=[CH:27]\[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=[CH:22][C:21]=1[OH:45].O>CN(C)C=O>[Si:12]([O:11][CH2:10][CH2:9][CH2:8][O:45][C:21]1[CH:22]=[CH:23][C:24](/[C:26](/[C:34]2[N:35]=[C:36]([O:43][CH3:44])[C:37]([CH:40]3[CH2:41][CH2:42]3)=[CH:38][CH:39]=2)=[CH:27]\[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:25][C:20]=1[Cl:19])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: COc1nc(/C(=C/C2CCOCC2)c2ccc(O)c(Cl)c2)ccc1C1CC1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(/C(=C/C2CCOCC2)c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c2)ccc1C1CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Potassium carbonate (214 mg) and (3-bromopropoxy)(tert-butyl)dimethylsilane (240 μL) were added to a solution of 2-chloro-4-[(E)-1-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethenyl]phenol obtained in Example 1-53(2) (200 mg) in N,N-dimethylformamide (4 mL), and the mixture was stirred at 65° C. for 1.5 hours and at room temperature overnight. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 6-{(E)-1-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-3-chlorophenyl]-2-(tetrahydro-2H-pyran-4-yl)ethenyl}-3-cyclopropyl-2-methoxypyridine as a colorless oil (245 mg, 80%).
Reaction SMILES: N1N=C(C2C=CC=CC=2C([N:14]2[CH2:18][CH:17]3[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:16]3[CH2:15]2)=O)NC=1.[CH3:29][C:30]1[N:34]=[C:33]([C:35]2[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=2[C:37]([OH:39])=O)[O:32][N:31]=1.N1N=C(C2C=CC=CC=2C(O)=O)NC=1>>[CH3:29][C:30]1[N:34]=[C:33]([C:35]2[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=2[C:37]([N:14]2[CH2:18][CH:17]3[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:16]3[CH2:15]2)=[O:39])[O:32][N:31]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Agent: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1noc(-c2ccccc2C(=O)N2CC3CN(C(=O)OC(C)(C)C)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 59 substituting 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated for C21H26N4O4, 398.20; m/z found, 399.2. 1H NMR (500 MHz, CDCl3): 8.12 (d, J=7.8 Hz, 1H), 7.63 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.55 (td, J=7.7 Hz, 1.3 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 3.97-3.86 (m, 1H), 3.76-3.61 (m, 2H), 3.56-3.33 (m, 3H), 3.29-3.15 (m, 1H), 3.08-2.93 (m, 2H), 2.90-2.82 (m, 1H), 2.45 (s, 3H), 1.51-1.41 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:7]([S:8]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1nc(C)cnc1N
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
4-Dimethylaminopyridine (0.1 g) was added to a solution of 2-chloropyridine-3-sulphonyl chloride (1.06 g), 2-amino-3-methoxy-5-methylpyrazine (0.695 g) and pyridine (0.424 ml) in dichloromethane (5 ml) and the mixture was stirred at ambient temperature for 18 hours. The solution was then transferred to a silica gel Mega Bond Elut column. Elution with 0-40% ethyl acetate/hexane gave 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.47 g) as an oil; 1H NMR (d6-DMSO): 2.3 (s, 3H), 3.9 (s, 3H), 7.5 (s, 1H), 7.65 (dd, 1H), 8.45 (dd, 1H), 8.7 (dd, 1H); mass spectrum (+ve CI): 315 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][N:25]([CH2:3][C:4]2[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=2)[CH2:24][CH2:23]3)=[CH:18][CH:19]=1
Reactant: Clc1ccc(-c2ccc3c(c2)CCNC3)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3cc(-c4ccc(Cl)cc4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 75.5 %

Procedure:
A suspension of 1.69 g (0.0087 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 95 ml of dimethylformamide was treated with 2.035 g (0.00726 mol) of 6-(4-chlorophenyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride and 3.35 ml (0.0;24 mol) of triethylamine and stirred at room temperature under argon for 66 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water. 16 ml of a 1N aqueous sodium hydroxide solution were added dropwise thereto, the mixture was extracted and chromatographed over silica gel with ethyl acetate/isopropyl alcohol 9:1 as the eluent and digested in diethyl ether. 2.0 g (63%) of 5-[6-(4-chlorophenyl)-3,4-dihydro-1H-isoquinolin-2-ylmethyl]-2-methyl-pyrimidin-4-ylamine were obtained as a white solid. An analytical sample was recrystallized from ethyl acetate and gave white crystals; m.p. 205°-208°.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[C:14](Cl)(=[O:17])[CH2:15][CH3:16]>N1C=CC=CC=1.C(Cl)Cl>[CH3:12][C:8]1[CH2:7][CH2:6][CH:5]2[C:9]=1[CH2:10][CH2:11][CH:2]([O:1][C:14](=[O:17])[CH2:15][CH3:16])[CH2:3][C:4]2=[CH2:13]
Reactant: CCC(=O)Cl
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C1CC(OC(=O)CC)CCC2=C(C)CCC12
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of 2.5 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene in 5 ml of pyridine and 50 ml of methylene chloride was treated at -10° with 1.73 ml of propionyl chloride. After 3 hours stirring, the solution was poured on to ice and worked up in a conventional manner. After distillation of the crude product under high vacuum, there were obtained 3.15 g (96%) of pure 1-methyl-4-methylene-6-propionyloxy-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.05 65°-70°; IR(film): νmax = 1380, 1730, 1640, 1460, 1440, 1375, 1340, 1270, 1190, 1158, 1080, 1018, 895 cm-1. The compound has a woody, spicy, balsamic, slightly earthy odour.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[F:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:14]([O:12][C:9]1[C:10]2[C:5](=[CH:4][C:3]([F:13])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]ccc2cc(F)c(Cl)cc12
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
14.7 g of 7-chloro-6-fluoro-2H-isoquinolin-1-one (7) were dissolved in 150 ml of toluene. After addition of 30.9 g of silver carbonate and 15.3 g of benzyl bromide, the mixture was stirred at 80° C. for 3 h. After cooling down to room temperature, the reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane and washed with water, dried with magnesium sulfate and evaporated. Final purification by preparative HPLC gave 11.6 g of the title compound. Rt=2.51 min (Method B). Detected mass: 288.1/290.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)=[O:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CC1(C)OB(c2cccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2)OC1(C)C
Yield: 98.7 %

Procedure:
To a solution of 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (100 mg, 0.46 mmol) in dichloromethane (4 mL), 1-chloro-4-isocyanato-2-trifluoromethyl-benzene (100 mg, 0.46 mmol) was added. The mixture was stirred until disappearance of the starting material. The solvent was evaporated to dryness to give 200 mg of 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]urea in quantitative yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14](SC)=[N:15][CH2:16][Si](C)(C)C)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:2].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[N:25]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:23][C:24]1[CH:29]=[C:28]([C:30]2([C:32]([F:33])([F:34])[F:35])[CH2:31][C:14]([C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[N:12][CH:11]=[N:10]4)=[C:3]([CH:4]=3)[C:1]#[N:2])=[N:15][CH2:16]2)[CH:27]=[C:26]([Cl:36])[N:25]=1
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(-n2cncn2)c(C#N)c1
Reactant: C=C(c1cc(Cl)nc(Cl)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C2=NCC(c3cc(Cl)nc(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To the crude solution of methyl 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbimidothioate (Japanese patent application JP2008-143120) was added 2,6-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (0.15 g) and the resultant mixture was cooled to −10° C. Additionally, a solution of tetrabutylammonium fluoride (0.70 mL of 1.0 M in THF) in THF was added over 10 minutes under argon atmosphere. The reaction mixture was stirred for 30 minutes at the same temperature and returned to room temperature gradually, and then stirred 3 hours. Water was added to the reaction liquor, and aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous brine, and subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 5-[3-(2,6-dichloropyridin-4-yl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.14 g) at a yield of 46%.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C@@H:20]([OH:35])[CH2:21][C@@H:22]([C:31]([OH:34])([CH3:33])[CH3:32])[C:23]([NH:25][CH2:26][C@@H:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.Cl.[O:44]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]([NH:53][C@H:54](C(O)=O)[CH2:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]=[CH:58][CH:57]=2)=[O:52])[CH2:46][CH2:45]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[O:44]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]([NH:53][C@H:54]([C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:36][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[C@@H:20]([OH:35])[CH2:21][C@@H:22]([C:31]([OH:34])([CH3:33])[CH3:32])[C:23]([NH:25][CH2:26][C@@H:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[CH2:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]=[CH:58][CH:57]=2)=[O:52])[CH2:46][CH2:45]1
Reactant: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: O=C(CN1CCOCC1)N[C@@H](Cc1cccc2ccccc12)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)CN1CCOCC1)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of 150 mg (0.25 mmoles) of (2S, 4S, 5S)-5-{N-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino}-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-[2(S)-methylbutyl]hexanamide (prepared as described in Example 1) in 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and diethyl ether was added to the residue. The solvent was then again removed by distillation under reduced pressure. This operation was repeated in total three times, and then the final residue was dried under vacuum for 8 hours. The dried material was suspended in 10 ml of anhydrous tetrahydrofuran, and then 100 mg (0.29 mmoles) of N-morpholinoacetyl-3-(1-naphthyl)-L-alanine were added to the resulting suspension, followed by 0.04 ml (0.26 mmoles) of 95% diethyl cyanophosphate and 0.11 ml (0.79 mmoles) of triethylamine, all whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 8 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel thin layer chromatography (using a 10:1 by volume mixture of methylene chloride and methanol as eluent), to give 150 mg (yield 73%) of the title compound as white crystals, melting at 141°-143° C.
Reaction SMILES: Cl.O.N[CH:4]([CH2:8]C1C=CC=CC=1)[C:5](O)=O.[CH2:15]([O:18][C:19]1[CH:30]=[CH:29][C:22]([CH2:23][C@@H:24]([C:26]([OH:28])=[O:27])[NH2:25])=[CH:21][CH:20]=1)[C:16]#[CH:17]>[OH-].[Na+].CO>[CH2:8]([O:27][C:26](=[O:28])[CH:24]([NH2:25])[CH2:23][C:22]1[CH:29]=[CH:30][C:19]([O:18][CH2:15][C:16]#[CH:17])=[CH:20][CH:21]=1)[C:4]#[CH:5]
Reactant: C#CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCOC(=O)C(N)Cc1ccc(OCC#C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The propargyl ester (1.6 g, 5.5 mmol) from the previous step was dissolved in a mixture of aqueous 2 N NaOH (14 mL) and MeOH (10 mL). After stirring for 1.5 h at room temperature, the pH was adjusted to 7 by adding conc. HCl. Water (20 mL) was added and the mixture was kept at 4° C. overnight. The precipitate was filtered, washed with ice-cold H2O, and dried under vacuum yielding, 1.23 g (90%) of 1 in FIG. 11 (2-Amino-3-phenylpropionic acid (1) (also known as p-propargyloxyphenylalanine) as a white solid. 1H NMR (400 MHz, D2O) (as the potassium salt in D2O) δ 7.20 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 4.75 (s, 2H), 3.50 (dd, J=5.6, 7.2 Hz, 1H), 2.95 (dd, J=5.6, 13.6 Hz, 1H), 2.82 (dd, J=7.2, 13.6 Hz, 1H); 13C NMR (100 MHz, D2O) δ 181.3, 164.9, 155.6, 131.4, 130.7, 115.3, 57.3, 56.1, 39.3; HRMS (CI) m/z 220.0969 [C12H13NO3 (M+1) requires 220.0968].