Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36](=[O:61])[C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](=[O:60])[C@H:43]([CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[NH2:44])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>C(O)C.C(N(CC)CC)C>[CH2:28]([O:35][C:36](=[O:61])[C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](=[O:60])[C@H:43]([CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:50]([O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:51])[NH:44][C@@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate [prepared according to Chem. Pharm. Bull, 34, 3747 (1986)] (7.4 g) and Nε -benzyloxycarbonyl-L-lysyl-L-proline benzylester.trifluoroacetic acid salt (4.6 g) in ethanol (40 ml) is adjusted to pH 5 with triethylamine. To this solution is added 2 g of molecular sieves, and the reaction mixture is stirred for 30 minutes. A solution of sodiumcyanoborohydride (1.4 g) in ethanol (40 ml) is dropped therein under stirring for 5 hours, and is kept stirring for further one night. The ethanol is distilled under reduced pressure, thereafter the residue is transferred to ethyl acetate. The ethyl acetate layer is washed with water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue ether is added. The ether layer is washed with water and then ether is distilled under reduced pressure. The residue is applied to silica gel chromatography (ethyl acetate:hexane=2:1) to obtain, from the first effluence, 1.34 g of Nα -[1(R)-ethoxycarbonyl- 5-(1-benzyloxycarbonyl-4-piperidyl)pentyl]-Nε -benzyloxycarbonyl-L-lysyl-L-proline benzylester (Rf=0.62, expansive solvent, F), and from the following effluence, 1.15 g of Nα -[1(S)ethoxycarbonyl-5-(1-benzyloxycarbonyl-4-piperidyl)pentyl]-Nε -benzyloxycarbonyl-L-proline benzylester (Rf=0.52, expansive solvent, F).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][O:12][CH3:13]>CN(C=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[O:9][CH2:11][O:12][CH3:13]
Reactant: Oc1ccc(Br)c(O)c1
Reactant: COCCl
Solvent: CN(C)C=O
Product: COCOc1cc(O)ccc1Br
Reaction time: 0.33 h

Procedure:
To a solution of 4-bromoresorcinol (1.5 g) in DMF (15 mL) at 0° C. was added Nail (0.19 g). After 20 min., chloromethylmethyl ether (0.636 g) was added in and stirred for 2 hrs. Saturated aq. NAHCO3 was added and the product was extracted in EtOAc, dried over Na2SO4, and purified by flash chromatography on silica gel with EtOAc in hexanes (1:6).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]1)(=O)C.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:11]([O:10][CH:6]1[CH2:7][CH2:8][CH2:9][NH:4][CH2:5]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)N1CCCC(OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: c1ccc(COC2CCCNC2)cc1

Procedure:
1-Acetyl-3-benzyloxypiperidine (0.043 mole), sodium hydroxide (0.086 mole) and water (30 ml.) are combined and refluxed for 24 hours. The reaction mixture is saturated with potassium carbonate and extracted three times with ether. The ether is removed by evaporation and the yellow oil is distilled at 92°-94° C. (0.3 mm Hg.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[CH2:12]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCBr
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of thiophene (15 g, 0.178 mole) in 200 mL of dry THF at −78° C., n-BuLi (103 mL, 0.165 mol, 1.6M hexane) was added. The reaction mixture was warmed to RT and stirred for 1 h. After the mixture was cooled to −78° C., 23.15 mL (0.165 mole) of 1-bromohexane was added. The solution was warmed from −78° C. to RT and was stirred overnight. At the end of the reaction, the mixture was poured into ice water, the aqueous layer was extracted with ether, and the organic layer was dried over anhydrous MgSO4. The solvent was removed by rotary evaporation. The residue was redistilled under vacuum to get a colorless liquid (yield=75%). 1H-NMR (300 MHz, CDCl3) δ 7.12 (dd, 1H), 6.92-6.97 (m, 1H), 6.8 (dd, 1H). 2.8 (t, 2H), 1.6-1.9 (q, 2H), 1.30-1.49 (m, 6H), 0.82 (t, 3H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]([NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNC(=O)C=C1c2ccccc2C=Cc2ccccc21

Procedure:
173 mg (0.70 mmol) of 5H-dibenzo[a,d][7]annulen-5-ylidenacetic acid, 130 mg (0.75 mmol) of t-butyl N-(3-aminopropyl)carbamate, 149 mg (0.78 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 0.11 ml (0.79 mmol) of triethylamine were stirred in 5 ml of dichloromethane at room temperature overnight. The reaction mixture was washed with 0.5 N aqueous sodium hydroxide solution and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=7:3) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21]3=[C:22]([CH2:24][CH2:25][N:20]3[CH2:19][C@@H:18]3[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@H:17]23)[CH:23]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[NH:13][C:14]1[CH:15]=[C:16]2[C:21]3=[C:22]([CH2:24][CH2:25][N:20]3[CH2:19][C@@H:18]3[CH2:26][NH:27][CH2:28][C@H:17]23)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(N)cc(c43)[C@H]2C1
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Product: Fc1ccc(C(F)(F)F)cc1Nc1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CC2

Procedure:
Using 3-bromo-4-fluorobenzotrifluoride and following the procedures described in EXAMPLE 17, Parts B and C, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±) -cis-N-[2-fluoro-5-(trifluoromethyl)phenyl]-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 115 as the free base. LRMS (ES)+: 378.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][NH:10][C:9](=[O:19])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[O:19]=[C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][N:10]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: O=c1nc(-c2ccccc2)c(-c2ccccc2)c[nH]1
Reactant: COC(=O)CCCCCCCBr
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)nc1=O

Procedure:
Reaction of 4,5-diphenyl-2(1H)-pyrimidinone and methyl 8-bromooctanoate according to the procedure of Example 1 provided the title compound, m.p. 80°-83° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.C(=O)=O.C[Li].C([Li])CCC.CON(C)[C:41](=[O:43])[CH3:42]>O.C1COCC1>[C:41]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2)(=[O:43])[CH3:42]
Reactant: CON(C)C(C)=O
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Agent: O=C=O
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C

Procedure:
A mixture of N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (1.0 g) and THF (10 ml) was cooled to −78° C. (dry ice bath), and a solution of methyllithium (2.0 ml; 1.6 M in diethyl ether) was added dropwise. One minute after the addition had ended, a solution of butyllithium (1.4 ml; 2.5 M in toluene) was added dropwise. One minute after the addition had ended, N-methoxy-N-methylacetamide (0.24 g) was added. After warming to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: 1:1 heptane/ethyl acetate). The product was thus obtained with the molecular weight of 393.49 (C24H27NO4); MS (ESI): 394 (M+H+).
Reaction SMILES: [Br:1]Br.[CH:3]1([C:6]2[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[N:10]=2)[CH2:5][CH2:4]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:8]1[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]([CH:3]2[CH2:4][CH2:5]2)=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1
Reactant: BrBr
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncn2)nc1C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(-c2ccncn2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Bromine was added to a cooled solution of 4-(2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidine (1.36 g, 4.30 mmol) in DCM at 0° C. followed by saturated aqueous Na2CO3 solution (16 mL, 4.30 mmol). The reaction mixture was stirred for 3 hours at room temperature. After the reaction was judged complete by LCMS analysis, the reaction mixture was allowed to stand and partition. The resulting layers were separated and the aqueous layer was extracted with EtOAc (2×). The combine organic layers were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was by flash chromatography using an EtOAc-hexanes gradient (20-80%) to give 4-(5-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidine (1.07 g, 2.71 mmol, 63%) as a yellow oil: LCMS(m/z): 395.0 (MH+), tR=1.09 minutes; 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H) 0.80-1.50 (m, 4H) 2.06-2.25 (m, 1H) 3.49-3.65 (m, 2H) 6.05 (s, 2H) 7.95-8.07 (m, 1H) 8.82-8.94 (m, 1H) 9.27-9.34 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][NH:7][CH:8]([CH3:12])[CH2:9][O:10][CH3:11].COC1C=C(C=CC=1OC)CN.COCC(=O)C.[OH-].[Na+].[Cl:38][CH:39]([Cl:43])[C:40](Cl)=[O:41]>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CCCCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][N:7]([CH:8]([CH3:12])[CH2:9][O:10][CH3:11])[C:40](=[O:41])[CH:39]([Cl:43])[Cl:38]
Reactant: COCC(C)NCc1ccc(OC)c(OC)c1
Reactant: O=C(Cl)C(Cl)Cl
Agent: COCC(C)=O
Agent: COc1ccc(CN)cc1OC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCC
Product: COCC(C)N(Cc1ccc(OC)c(OC)c1)C(=O)C(Cl)Cl
Temperature: 0 °C
Yield: 61.2 %

Procedure:
A solution consisting of 23.8 g of N-(3,4-dimethoxybenzyl)-N-(2-methoxy-1-methylethyl)amine (prepared by condensing 3,4-dimethoxybenzylamine and methoxy acetone and hydrogenating the condensation product), 80 ml of toluene, and 20 ml of water in which 4 g of solid sodium hydroxide were dissolved is prepared and cooled down to -10° to -15°. Another solution of 14.7 g of dichloroacetylchloride in 10 ml of toluene is then added dropwise thereto while stirring. The mixture is stirred for one hour after all the dichloro-acetylchloride is added and the poured into 1 l of ice-water. The organic layer that formed was then extracted with ether, washed with diluted hydrochloric acid and twice with water, dried and concentrated. The residue crystallises spontaneously and yields 30.9 g of raw product melting at 62°-63°. After recrystalliation from a toluene/pentane mixture one obtained 21.3 g of pure title product melting at 75°-76°.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[N:21]=[C:22]([NH:25][C:26]3[N:31]=[CH:30][C:29]([S:32]CCC(OC)=O)=[CH:28][C:27]=3[O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[S:23][CH:24]=2)[CH2:16][CH2:15]1)(=[O:13])[CH3:12].CC([O-])(C)C.[K+]>CS(C)=O>[O:39]([C:27]1[C:26]([NH:25][C:22]2[S:23][CH:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:11](=[O:13])[CH3:12])[CH2:19][CH2:18]3)[N:21]=2)=[N:31][CH:30]=[C:29]([S:32][C:2]2[C:3]3[CH:10]=[CH:9][S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Reactant: Clc1ncnc2sccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ncnc5sccc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
4-chlorothieno[2,3-d]pyrimidine (0.050 g, 0.29 mmol) and methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (Example 3, Step B, 0.15 g, 0.29 mmol) were dissolved in DMSO (3 mL). The solution was degassed for 15 minutes. KOtBu (0.098 g, 0.88 mmol) was added and the reaction stirred at ambient temperature for two hours. The solution was quenched with water, extracted with dichloromethane, dried, and concentrated. Flash chromatography of the crude material gave the title compound (0.075, 46%). 1H NMR (400 MHz, CDCl3) δ 1.60-1.72 (m, 2H), 2.08-2.15 (m, 2H), 2.11 (m, 3H), 2.65-2.75 (m, 1H), 2.82-2.93 (m, 1H), 3.15-3.24 (m, 1H), 3.91 (d, 1H), 4.72 (d, 1H), 6.49 (s, 1H), 7.15 (d, 2H), 7.19 (t, 1H), 7.27-7.29 (m, 1H), 7.36-7.42 (m, 3H), 7.53 (d, 1H), 8.27 (d, 1H), 8.68 (s, 1H), 8.81 (s, 1H),
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@H:11]([CH2:13][OH:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([CH3:12])[CH2:13][O:14][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 108.7 %

Procedure:
Subsequently, to a solution of [(1S)-1-(hydroxymethyl)ethyl]carbamic acid benzyl ester (4.61 g, 22.0 mmol) in dimethylformamide (140 ml) were added t-butyldiphenylsilyl chloride (6.87 ml, 26.4 mmol) and imidazole (1.80 g, 26.4 mmol) in an ice bath. The resulting mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (8:1→6:1) as the eluant to afford [(1S)-2-(t-butyldiphenylsilyloxy)-1-methylethyl]carbamic acid benzyl ester (10.7 g, yield 100%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1.Cl>CN(C=O)C>[Cl:17][C:16]1[C:11]([O:3][C:4]2[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=2)=[N:12][CH:13]=[C:14]([Cl:18])[CH:15]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ncc(Cl)cc2Cl)n[nH]1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Sodium hydride (60% in oil, 0.2 g, 5.5 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (0.49 g, 5.0 mmol) in DMF (10 ml) at 0° C., and the mixture was stirred for 30 minutes while it was allowed to have room temperature gradually. Then, 2,3,5-trichloropyridine (0.9 g, 5.0 mmol) was added, and the mixture was stirred under heating at 70° C. for 2 days. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (20 ml) and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7→1/2), to give a white solid of 3-(3,5-dichloropyridin-2-yloxy)-5-methylpyrazole (0.7 g, yield: 57.4%). mp: 109-111° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.32 (s, 3H), 5.86 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 9.40-11.50 (br s, 1H).
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1N.[Cl:15]C1C=CC=CC=1/C=C/C(Cl)=O.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1/[CH:42]=[CH:43]/[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[ClH:50]>CO>[ClH:15].[Cl:50][C:49]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1/[CH:43]=[CH:42]/[C:34]1[N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Reactant: O=C(Cl)/C=C/c1ccccc1Cl
Agent: Cl
Agent: Nc1ccccc1Nc1ccccn1
Solvent: CO
Product: Clc1ccccc1/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-2-chlorocinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:21][C@@H:22]([CH3:26])[C:23]([OH:25])=[O:24])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([F:20])[CH:9]=2)[CH:7]=1.B(C1C=C([C:42]([F:45])([F:44])[F:43])C=CC=1O[C@@H](C)C(O)=O)(O)O>>[F:20][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([C:42]([F:45])([F:44])[F:43])[CH:3]=[CH:4][C:5]=2[O:21][C@@H:22]([CH3:26])[C:23]([OH:25])=[O:24])[CH:13]=[CH:12][C:11]=1[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)NC(=O)c1ccc(-c2cc(Cl)ccc2O[C@@H](C)C(=O)O)cc1F
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Product: CC(C)NC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2O[C@@H](C)C(=O)O)cc1F

Procedure:
The title compound was prepared using the product of example 34 step a) and (2S)-2-[2-borono-4-(trifluoromethyl)phenoxy]-propanoic acid [WO2004089885] by the method of example 32 step b).
Reaction SMILES: [C:1]([O:8]C([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.C1COCC1>[C:4]([O:3][C:1]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=1)=[O:8])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCOC(=O)c1csc(N)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
1.39 g of tert-butyl dicarbonate was added to a solution in which 1.00 g of ethyl 2-amino-1,3-thiazole-4-carboxylate, 0.88 g of triethylamine, and 0.07 g of DMAP were dissolved in THF, under ice cooling. Then, after the reaction mixture was stirred at room temperature for 1 hr, it was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous 2N-hydrochloric acid solution and dried over anhydrous magnesium sulfate. After distilling off the solvent, the obtained crude product was washed with a mixed solvent of hexane and t-butyl methyl ether to obtain 1.5 g of the aimed ethyl 2-(tert-butoxycarbonyl)amino-1,3-thiazole-4-carboxylate.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[C:36]([Cl:41])[CH:37]=5)[CH:32]=4)(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11]1)=O)(C)(C)C>Cl.C(O)C>[ClH:41].[NH2:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([S:28]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[C:36]([Cl:41])[CH:37]=5)[CH:32]=4)(=[O:29])=[O:30])[CH2:26][CH2:27]3)=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCc2cc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)ccc2C1
Agent: Cl
Solvent: CCO
Product: NCC1CCc2cc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In saturated aqueous hydrochloric acid in ethanol (5 ml), 1-[[(6RS)-6-(N-tert-butoxycarbonylaminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (0.22 g) was dissolved, followed by stirring at room temperature for 90 minutes. The residue obtained by distilling off the solvent under reduced pressure was recrystallized from a mixed solvent of ethanol and diethyl ether, whereby the title compound (0.14 g, 68%) was obtained.