Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]([F:30])([F:29])[C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:23][NH2:24])=[S:22])[CH2:17][CH2:16]1)=[O:14].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2](=[O:8])[NH:24][NH:23][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=2[C:10]([F:29])([F:9])[F:30])[CH2:16][CH2:17]1)=[S:22])[CH3:7]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NNC(=S)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)NNC(=S)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
Ethyl chlorooxoacetate (0.84 mL, 7.54 mmol) was added dropwise to a stirred solution of 4-(2-trifluoromethylbenzoyl)piperazine-1-carbothioic acid hydrazide (2.18 g, 6.56 mmol) and triethylamine in 8 mL of DMF at 0° C. over 15 minutes. The mixture was stirred for 1 hour, then 100 mL of ethyl acetate was added. The mixture was washed with water and brine, dried over anhydrous Na2SO4, and evaporated below 30° C. to dryness to yield oxo-{N′-[4-(2-trifluoromethylbenzoyl)piperazine-1-carbothioyl]hydrazino}acetic acid ethyl ester in quantitative yield (2.88 g).
Reaction SMILES: [C:1]([O:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([O-:24])=[O:23].[NH2:33]/[C:34](/[CH3:40])=[CH:35]\[C:36]([O:38][CH3:39])=[O:37]>C(O)(C)C>[C:16]1([CH:8]([O:7][C:1]([C:2]2[CH:28]([C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=3)[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([CH3:40])[NH:33][C:3]=2[CH3:5])=[O:6])[CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)CC(=O)OC(CN1CCCCC1)c1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(CN2CCCCC2)c2ccccc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
In 300 ml of isopropanol are dissolved 28.9 g of 1-phenyl-2-piperidinoethyl acetoacetate, 15.1 g of m-nitrobenzaldehyde and 11.5 g of methyl β-aminocrotonate, and the mixture is refluxed under heating for 17 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (eluent:chloroform:methanol=10:1 (by volume)). The eluate containing the object compound is concentrated and recrystallized from isopropanol to give 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-(1-phenyl-2-piperidinoethyl)ester as crystals melting at 183°-185° C. (decomposition). This is α-diastereoisomer. The hydrochloride thereof melts at 238°-240° C. (decomposition). The β-diastereoisomer which can be obtained in similar manner melts at 127°-130° C. (from isopropanol), and the hydrochloride thereof melts at 222°-223° C. (decomposition) (from ethanol).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:31])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]4=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:44])[O:42][CH3:43]>CO.C1COCC1>[Cl:31][C:9]1[C:10]([NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]3=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]3[N:18]=2)=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:41](=[O:44])[O:42][CH3:43])[CH2:3][CH2:4]1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CCC(N)CC3)c2Cl)nn2c(C#N)cnc12
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(Nc2cc(C#N)cc(N3CCC(NC(=O)OC)CC3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
2-((3-(4-aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 329) (40 mg, 0.092 mmol) was mixed with N,N-diisopropylethylamine (0.2 ml, 1.145 mmol) in MeOH (1 ml) and THF (1 ml). methyl carbonochloridate (0.05 ml, 0.646 mmol) was added. The mixture was stirred at r.t. for 1 hr. LC/MS showed product formation. The white precipitate was formed and collected by filtration, washed with cold MeOH (15 ml), then water (5 ml) and dried with air-suction to give 31.7 mg of desired product.
Reaction SMILES: BrC1C=C2C(C([C:13]3[C:14](F)=[C:15](NS(CCC)(=O)=O)[CH:16]=[CH:17][C:18]=3F)=O)=CNC2=NC=1.N1C=C([C:33]([OH:35])=[O:34])C=N1.[F:36][C:37]1[C:42]([C:43]([C:45]2[C:53]3[C:48](=[N:49][CH:50]=[C:51]([C:54]4[CH:55]=[N:56][NH:57][CH:58]=4)[CH:52]=3)[NH:47][CH:46]=2)=[O:44])=[C:41]([F:59])[CH:40]=[CH:39][C:38]=1[NH:60][S:61]([CH2:64][CH2:65][CH3:66])(=[O:63])=[O:62]>>[F:36][C:37]1[C:42]([C:43]([C:45]2[C:53]3[C:48](=[N:49][CH:50]=[C:51]([C:54]4[CH:55]=[N:56][NH:57][CH:58]=4)[CH:52]=3)[NH:47][CH:46]=2)=[O:44])=[C:41]([F:59])[CH:40]=[CH:39][C:38]=1[NH:60][S:61]([CH2:64][CH2:65][CH3:66])(=[O:62])=[O:63].[C:18]1([O:35][C:33]([N:56]2[CH:55]=[C:54]([C:51]3[CH:52]=[C:53]4[C:45]([C:43](=[O:44])[C:42]5[C:41]([F:59])=[CH:40][CH:39]=[C:38]([NH:60][S:61]([CH2:64][CH2:65][CH3:66])(=[O:62])=[O:63])[C:37]=5[F:36])=[CH:46][NH:47][C:48]4=[N:49][CH:50]=3)[CH:58]=[N:57]2)=[O:34])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cn[nH]c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cn[nH]c4)cc23)c1F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C(=O)Oc5ccccc5)c4)cc23)c1F

Procedure:
Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide 23 is prepared according to Scheme 1a, replacing N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fluoro-benzenesulfonamide 21 with propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide and replacing 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine 22 with 1H-pyrazole-4-carboxylic acid. Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide 23 is further reacted according to Scheme 1b to provide 4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazole-1-carboxylic acid phenyl ester P-1016.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.[CH3:13][C:14]1[CH:18]=[C:17]([CH2:19][OH:20])[S:16][N:15]=1.C(N(CC)CC)C.O>C(#N)C>[CH3:13][C:14]1[CH:18]=[C:17]([CH2:19][O:20][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[S:16][N:15]=1
Reactant: Cc1cc(CO)sn1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1cc(COC2=NS(=O)(=O)c3ccccc32)sn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.3 %

Procedure:
In 8 ml of acetonitrile were dissolved 0.78 g (3.88 mmol) of 3-chloro-1,2-benzoisothiazole 1,1-dioxide and 0.50 g (3.88 mmol) of (3-methylisothiazol-5-yl)methanol. To the resulting solution was dropwise added 0.51 g (5.0 mmol) of triethylamine, followed by stirring at room temperature for 5 hours to give rise to a reaction. After the completion of the reaction, 16 ml of water was added. The resulting crystals were obtained by filtration and washed with water and isopropyl alcohol to obtain 0.30 g (yield: 26%) of 3-(3-methylisothiazol-5-ylmethoxy)-1,2-benzoisothiazole 1,1-dioxide as a light brown powder (melting point: 202 to 204° C.)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=O)([O-:3])=[O:2].[CH3:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:18]([C:17](=[O:22])[CH3:16])[C:19](=[O:21])[CH3:20])[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])([O-:3])=[O:2]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Product: CC(=O)C(=Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1)C(C)=O

Procedure:
The procedure described in Example 1 was repeated by using 2.12 g of 3,5-dinitro-4-hydroxybenzaldehyde and 1.5 g of 2,4-pentanedione. Yield 1.9 g, mp 158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38](Br)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1)=[O:31])[CH3:28].CN(C=O)C>C(OCC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[CH:33]=1)=[O:31])[CH3:28]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Temperature: 90 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
6-Chloro-3-tributylstannyl-1H-indazole (1.04 g, 2.35 mmol), copper(I) iodide (17 mg, 0.09 mmol,) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (400 mg, 0.90 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed with bubbling nitrogen for 10 min, then tetrakis(triphenylphosphine)palladium (0) (52 mg, 0.045 mmol) was added and the reaction was stirred under nitrogen at 90° C. for 15 h. The reaction mixture was cooled, diluted with diethyl ether (60 mL) and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane with 0.5% ammonium hydroxide) to afford 300 mg (65%) of 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a foaming solid. MS: (M+H)+=516.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][OH:15])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].O[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][O:15][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g of (E)-3-(trans-4-pentylcyclohexyl)allyl alcohol, 2.9 g of 4-hydroxybenzaldehyde, 4.1 g of diethyl azodicarboxylate, 6.2 g of triphenylphosphine and 100 ml of tetrahydrofuran was stirred at room temperature overnight and then concentrated. The residue was suspended in 300 ml of hexane, filtered and again concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from hexane gave 4.5 g of pure 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]benzaldehyde with m.p. 55° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(OCC)(=O)C>C1COCC1>[CH2:27]([O:26][C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
tert-Butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (3.0 g, 13.0 mmol) was dissolved in THF (60 mL), followed by cooling to 0° C. Thereafter, aqueous sodium carbonate solution (30 mL) and benzyl chloroformate (2.8 mL, 19.6 mmol) were added, and the mixture was stirred for one hour. Ethyl acetate was added to the reaction solution, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=90/10, 50/50) to obtain 4.29 g of the title compound as a pale yellow solid (90%).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4]O.N1C(C)=CC(C)=CC=1C.[Cl-:21].[Li+]>CN(C=O)C.CS(Cl)(=O)=O>[Cl:21][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: [Cl-]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)=CCC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a stirred solution of 30.0 g (0.194 mol) of (E)-3,7-dimethyl-2,6-octadien-1-ol and 28.27 mL (0.213 mol) of 2,4,6-collidine under argon at room temperature was added dropwise 8.23 g (0.194 mol) of lithium chloride in 100 mL of DMF. The mixture was cooled to 0° C and treated with 16.56 mL (0.213 mmol) of methanesulfonyl chloride dropwise over 10 minutes. The reaction was stirred at 0° C. for 1.5 hours (solid present), then was poured into 500 mL of ice/water. The aqueous solution was washed three times with 200 mL portions of hexane, the organic layers were combined and washed with 5% KHSO4, water, NaHCO3, brine, dried (MgSO4) and evaporated to provide 29.95 g of a pale yellow oil. Rapid flash chromatography was performed on 400 g of silica gel, eluting with 3:9 EtOAc/hexane. Pure product fractions were combined and evaporated to provide 25.20 g (75%) of title compound as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]2[N:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:2]1.[C:24]1([N:34]=[C:35]=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([NH:34][C:35]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]3[N:13]=[C:12]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)[CH:11]=[CH:10][N:9]=3)[CH2:2]2)=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Solvent: C1CCOC1
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)Nc2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.7 %

Procedure:
To a suspension of 15 mg of 2-[(piperidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (from EXAMPLE 6) in 2 mL of THF was added 11 mg of naphthyl isocyanate. The mixture was stirred at room temperature for 2 days, then concentrated. The residue was purified by flash chromatography, eluting with a gradient system of 2:1 CH2Cl2-acetone to 1:1 CH2Cl2-acetone, to yield 12 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.56 (s, 1H), 8.25 (br s, 1H) 8.14 (d, J=8.0 Hz, 6.69 (d, J=5.3 Hz, 1H), 4.04 (br s, 1H), 3.85 (br d, J=1.7 Hz, 1H), 3.40-3.55 (m, 2H), 3.12 (br s, 1H), 3.05 (br t, J=9.6 Hz, 1H), 2.36 (br s, 1H), 1.90-2.10 (m, 2H), 1.74-1.85 (m, 1H), 1.56-1.68 (m, 1H), 1.42 (ddt, J=3.9, 10.1, 10.1 Hz, 1H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](=[O:37])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:22]([C:34](=[O:36])[CH3:35])[CH:21]=1)[NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH3:4]>CO>[CH2:3]([O:5][C:6](=[O:37])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:22]([CH:34]([OH:36])[CH3:35])[CH:21]=1)[NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)=O)c1)NC(=O)c1c(Cl)cccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)O)c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
NaBH4 (12 mg) was added to a solution of 3-acetyl-N-(2,6-dichlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester (0.1 g) in MeOH (3 mL) and the mixture was stirred at room temperature for 2 h. The mixture was quenched with 1 N HCl and extracted with CH2Cl2. The extract was washed successively with 1 N HCl and brine, dried and evaporated. The residue was purified by a flash column chromatography (silica gel; eluent: hexanes/EtOAc 3:1) to yield 45 mg of N-(2,6-dichlorobenzoyl)-3-(1-hydroxyethyl)-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester. ESMS: m/z 516 (MH+).
Reaction SMILES: [Mg].[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:20](=[S:22])=[S:21].Cl>C1COCC1>[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([C:20]([SH:22])=[S:21])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: S=C=S
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(C(=S)S)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension prepared by suspending 0.95 g (39 mmol) of magnesium in 200 ml of THF was added dropwise a solution prepared by dissolving 9.28 g (30 mmol) of 4-(trans-4-n-pentylcyclohexyl) bromobenzene in 80 ml of THF, at room temperature while being stirred in 1 hour, and then heated to reflux for 2 hours to prepare a Grignard reagent. To this solution was added dropwise 5.7 g (75 mmol) of carbon disulfide at room temperature in 30 min and stirred as it was overnight. To this reaction solution was added 150 ml of 1M hydrochloric acid to terminate the reaction and extracted with 350 ml of toluene. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under a reduced pressure, and the residue was recrystallized from heptane to obtain 4.74 g of 4-(trans-4-n-pentylcyclohexyl)phenyldithiocarboxylic acid (yield 51.5%).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]2[CH:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]([CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:11]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:10]2[CH:47]([CH2:49][CH:50]=[CH2:51])[OH:48])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:59](Cl)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[C:59]([O:48][CH:47]([CH2:49][CH:50]=[CH2:51])[CH:10]1[CH:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:11]1[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCC(O)C1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(COCc2ccccc2)N1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCC(OC(=O)c1ccccc1)C1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(COCc2ccccc2)N1Cc1ccccc1
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of Compound (XIII) (3.00 g; 4.40 mmoles) and triethyl amine (2.4 mL; 17.6 mmoles) in methylene chloride (25 mL), cooled at 0° C., was added benzoyl chloride (1.6 mL; 13.2 mmoles). The reaction was kept at room temperature for 16 hours, then water (5 mL) and saturated aqueous sodium bicarbonate solution (40 mL) were added. The phases were separated, and the aqueous phase was extracted with methylene chloride (30 mL). The combined organic solution was dried over sodium sulfate and the solvent evaporated under reduced pressure. The crude oil was purified via flash chromatography (silica gel; 1:4 ethyl acetate:hexane) to yield 3,4,5-tris(phenylmethoxy)-6-[(phenylmethoxy) methyl]-1-(phenylmethyl)-α-(2-propenyl)-2-piperidinemethanol benzoate (ester) (XIV) (1.92 g; 56%) as a clear, colorless oil and recovered Compound (XIII) (0.60 g; 0.88 mmoles). IR (neat) 1719 cm-1 (C=0); MS (FAB-MNBA) 788 (MH+), 680 (MH + --PhCH2OH); 1H nmr (CDCl3) δ 2.4 (m, 1H), 2.9 (dt, 1H), 3.5-4.0 (m, 8H), 4.1 (d, 1H), 4.4 (s, 2H), 4.5-4.9 (m, 9H), 5.4-5.6 (m, 1H), 7.1-7.4 (m, 27H), 7.5 (m, 1H), 8.1 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1)=[O:22]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc3c(c2)CCCC3=O)c1
Yield: 92 %

Procedure:
Reaction of 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in THF (6 mL) with m-anisoyl chloride (90 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 3-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide (135 mg, 0.46 mmol, 92% yield) as a white powder after purification by flash chromatography on silica gel (eluent:EtOAc/DCM 0/10 to 2/8).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:27]=[C:26](/[CH:28]=[CH:29]/[CH:30]([C:35]2[CH:40]=[C:39]([Cl:41])[C:38]([Cl:42])=[C:37]([Cl:43])[CH:36]=2)[C:31]([F:34])([F:33])[F:32])[CH:25]=[CH:24][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)=[O:12]>C(Cl)Cl>[NH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:10]1[CH:24]=[CH:25][C:26](/[CH:28]=[CH:29]/[CH:30]([C:35]2[CH:40]=[C:39]([Cl:41])[C:38]([Cl:42])=[C:37]([Cl:43])[CH:36]=2)[C:31]([F:34])([F:32])[F:33])=[CH:27][C:9]=1[Br:8]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.4 %

Procedure:
TFA (0.5 mL) was added to a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)ethylcarbamate (200 mg, 0.31 mmol) in CH2Cl2 (10 mL) at 0° C. and the reaction mixture was then stirred at ambient temperature for 18 h. The volatiles were evaporated under reduced pressure; water was added to the residue and the mixture extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 1-5% MeOH in CH2Cl2 to afford the title compound as a brown solid (50 mg, 31%): 1H NMR (400 MHz, DMSO-d6) δ 8.56 (bs, 1H), 7.70 (bs, 2H), 7.94-7.91 (m, 3H), 7.62-7.59 (m, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.00 (dd, J=15.6, 9.2 Hz, 1H), 6.77 (d, J=15.6 Hz, 1H), 4.84-4.81 (m, 1H), 3.46-3.41 (m, 2H), 2.95-2.92 (m, 2H); ESIMS m/z 528.72 ([M+H]+); IR (thin film) 3435, 1671, 1113, 722, 555 cm−1.