Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.F[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[N:30][N:29]=[N:28]4)=[CH:23][N:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Fc1ccc(-n2cnnn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCNc3ccc(-n4cnnn4)cn3)CC2)nc1
Temperature: 70 °C

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (50 mg, 0.18 mmol) from Example 5 step 3 and 2-fluoro-5-(1H-tetrazol-1-yl)pyridine (35.6 mg, 0.20 mmol) from step 1 were added in NMP (0.89 mL), then potassium carbonate (73.8 mg, 0.53 mmol) was added and the reaction was heated to 70° C. 6.5 hours. The reaction was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (20 mL), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filtered and concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 40% ethyl acetate/hexane to give the title compound as a white-solid.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(OP([CH2:21][C:22]([O:24][CH3:25])=[O:23])(OCC)=O)C.C[O-].[Na+]>C1C=CC=CC=1.CO>[CH3:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CCCCCCCCCC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CCCCCCCCCC(C)=CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Undecanone (methyl nonyl ketone) (1′) (73.9 g, 434 mmols) and methyl (diethylphosphono)acetate (99.4 g, 433 mmols) were dissolved in dry benzene (300 ml). The solution was stirred at room temperature, and a 28% sodium methoxide solution (83.7 g) in methanol was slowly added. Stirring was continued overnight at room temperature. The reaction mixture was poured into ice water, and extracted with diethyl ether. The organic layer was washed (water and a saturated aqueous solution of sodium chloride), and dried (sodium sulfate), followed by removing the solvent in a vacuum to obtain methyl 3-methyl-2-dodecenoate (2′) as a geometric isomer mixture.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:58](Br)[CH3:59]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH2:58][CH3:59])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
48.0 mg of compound (6) was dissolved in 0.4 ml of dry dimethylformamide, and about 5 mg of sodium hydride was added under cooling with ice. After 15 minutes, 19 μl of ethyl bromide was added, and the reaction solution was stirred under cooling with ice. After 50 minutes, the reaction solution was brought back to room temperature and allowed to react for another 90 minutes under stirring. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×25 cm) and eluted with n-hexane-ethyl acetate (4:1) to give 36.8 mg of compound (27) as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:3]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(-n2cnc(Br)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-n2cnc(Br)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-1-(4-nitrophenyl)-1H-1,2,4-triazole (0.51 g, 1.9 mmol), SnCl2-2H2O (2.14 g, 9.5 mmol) and EtOH (4 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature and basified with NaOH (2M aq.) until pH 7˜9. The resulting precipitate was filtered through Celite and washed with EtOH. The EtOH filtrate was concentrated in vacuo and the crude residue was dissolved in water and extracted with EtOAc (3×). The combined organics were dried (MgSO4) and concentrated in vacuo to provide the desired product as a white solid. 1H NMR (CDCl3, 400 MHz) δ8.28 (s, 1H), 7.40 (d, 2H), 6.79 (d, 2H), 3.90 (br s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([C:10](OC)=O)=[CH:5][CH2:6]2.C1(C#[N:22])C=CC=CC=C1.CN.[OH-].[Na+]>CO>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([C:10]#[N:22])=[CH:5][CH2:6]2
Reactant: COC(=O)C1=CCC2CCC1N2C
Reactant: N#CC1C=CC=CC=C1
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C2CC=C(C#N)C1CC2

Procedure:
The reaction scheme C shown below is an example of reaction scheme for synthesizing an anhydroecgonine derivative (the formula 3) and a phenyltropane derivative (the formula 6) without producing cocaine as an intermediate. In detail, the reaction scheme C is a scheme in which methyl (1RS)-8-methyl-8-azabicyclo-[3.2.1]oct-2-ene-2-carboxylate (7:(1RS)-AECG ; such an abbreviation of a compound name is hereinafter described in a parenthesis and properly used) is synthesized, and then a fluoropropyl group is introduced thereinto at the N-8 position to synthesize methyl [1RS-(2-exo,3-exo)]-8-(3-fluoropropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (12:(1RS)-β-CIT-FP). Specifically, 2,4,6-cycloheptatriene-1-carbonitrile (4:CHT-CN) is allowed to react with methylamine in methanol solvent in the presence of sodium hydroxide to obtain (1RS)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carbonitrile (6:(1RS)-AECG-CN). The cyano group of this compound is hydrolyzed and then converted to a methyl ester group to obtain methyl (1RS)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate (7:(1RS)-AECG), which is allowed to react with phenylmagnesium bromide (PhMgBr) by a well-known method to obtain methyl [1RS-(2-exo,3-exo)]-3-phenyl-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (8:(1RS)-β-CPT). The tropane portion of this compound is converted to nortropane at the N-8 position, followed by substitution by a fluoropropane group at the N-8 position, whereby (1RS)-β-CIT-FP 12 can be obtained. optically active (1R)-β-CIT-FP can be obtained by optical resolution of (1RS)-β-CIT-FP 12 or by subjecting (1RS)-nor-β-CIT 11 to optical resolution to obtain an optically active substance in the course of the synthesis and continuing reactions shown in Reaction scheme C.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+]([O-])=O)[C:19]=1[C:20]#[N:21])([O-:17])=[O:16]>>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:22]1[CH:23]=[CH:24][CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[C:19]=1[C:20]#[N:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)[Si](C)(C)OCCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 46 %

Procedure:
Prepared as in Example 215c from 5-(tert-butyldimethyl-silyloxy)pentan-1-ol and 2,6-dinitrobenzonitrile as a pale yellow solid in 46% yield. MS 365 (MH+).
Reaction SMILES: [CH3:1][P:2]([C:5]1[N:6]=[C:7]([O:12][CH3:13])[C:8](N)=[N:9][CH:10]=1)([CH3:4])=[O:3].Cl[C:15]1[N:20]=[C:19]([Cl:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:21][C:19]1[C:18]([C:22]([F:24])([F:23])[F:25])=[CH:17][N:16]=[C:15]([C:8]2[C:7]([O:12][CH3:13])=[N:6][C:5]([P:2]([CH3:4])([CH3:1])=[O:3])=[CH:10][N:9]=2)[N:20]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1nc(P(C)(C)=O)cnc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1nc(P(C)(C)=O)cnc1-c1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared in Example 33: 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, is allowed to stirred at room temperature for 15 minutes until a clear solution is obtained. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at 60 degrees for 1 hour. The reaction mixture is cooled to room temperature and filtered to obtain a white solid. The white solid is washed with 50 mL of water three times and followed by 50 mL of Ethyl ether three times. The white solid is dried under vacuum to yield 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:15]([Cl:21])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][Mg]Br>C1COCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])([CH3:22])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[C:15]([Cl:21])=[N:16][CH:17]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide (123.5 mg, 0.317 mmol) was dissolved in THF (2.6 ml) and cooled in an ice water bath under nitrogen. Then, methylmagnesium bromide (0.65 ml, 1.4 M solution in toluene/tetrahydrofuran (75:25), 0.91 mmol) was added via syringe, and the reaction was allowed to slowly warm to room temperature. After 2 hours and 45 minutes, more methylmagnesium bromide (0.50 ml) was added, and stirring was continued at room temperature. After 75 minutes, more methylmagnesium bromide (0.93 ml) was added, and stirring was continued. After another hour, the reaction quenched with saturated ammonium chloride. The layers were separated, and the aqueous phase was extracted with 10:1 DCM/MeOH. Organic extracts combined, concentrated, and taken on to the next step. MS (ESI pos. ion) m/z: 405 (MH+, 79Br), 407 (MH+, 81Br). Calculated exact mass for C14H14BrClN2O3S 404 (79Br), 406 (81Br).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([NH:29][CH3:30])=[O:28]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:23][CH2:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CNC(=O)c1ccccc1CN
Product: CNC(=O)c1ccccc1CNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
2′-Methyl-N-{2[(methylamino)carbonyl]benzyl}-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-(aminomethyl)-N-methylbenzamide using method M. NMR; δH [2H6]—DMSO 9.03,(1H, t), 8.41,(1H, q), 7.98,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.52,(3H, m), 7.43-7.37,(3H, m), 7.30,(1H, m), 4.62,(2H, d), 2.79,(3H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.02 min, MH+ 441.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([C:12]2[S:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:20]([C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([CH3:32])[C:24]=1[NH2:25])(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([C:23]1[C:24]([NH:25][C:17]([C:15]2[N:16]=[C:12]([CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)[S:13][CH:14]=2)=[O:19])=[C:26]([CH3:32])[C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1csc(C2CCCCC2)n1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(C)=O)c(NC(=O)c2csc(C3CCCCC3)n2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
POCl3 (1.4 mL, 14.9 mmol) was added drop wise at −35° C. over 5 min, to a stirred solution of 2-cyclohexylthiazole-4-carboxylic acid (117, 1.5 g, 7.1 mmol) and 2-acetyl-5-methoxy-6-methylaniline (1.27 g, 7.1 mmol) in dry pyridine (40 mL). After 1 h, the reaction mixture was successively warmed up to room temperature for 2.5 h, evaporated and neutralized with an aqueous solution of sodium bicarbonate. The precipitate was filtered, washed with water and dried to give 2.6 g (95%) of the title compound 118: m/z=373 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:4][N:3]=[C:2]2[NH:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1ccc2c(-c3ccc(C)cc3)nnc(Cl)c2c1
Product: COc1ccc2c(-c3ccc(C)cc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(4-methylphenyl)phthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH-].[K+].[CH:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[CH:14]=[O:15]>C1(C)C=CC=CC=1>[C:1]([CH2:2][CH2:3][C:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[CH:14]=[O:15])#[N:4]
Reactant: O=CC1CC2C=CC1C2
Reactant: C=CC#N
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CCCC12C=CC(CC1C=O)C2
Reaction time: 6 h

Procedure:
To a solution of acrylonitrile in 50 mL of toluene was added at room temperature 2 mL of 10% aqueous solution of KOH. To this was added 5-norbornene-2-carboxaldehyde (6.1 g, 50 mmol) at ambient temperature within a period of 2 h. The resulting mixture was stirred for 6 h, quenched with 3 N aqueous HCl, extracted with toluene, dried over MgSO4. Solvent and residual starting materials were removed to give the title compound.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]=[CH2:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:19][CH:18]([C:20](=[O:25])N(OC)C)[CH2:17]2)=[CH:12][CH:11]=1>C1COCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([NH:26][C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:17][CH:18]([C:20](=[O:25])[CH2:8][CH2:7][CH:6]=[CH2:5])[CH2:19]2)=[CH:14][CH:15]=1
Reactant: CON(C)C(=O)C1CC(NC(=O)c2ccccc2)(c2ccc(Cl)cc2)C1
Reactant: C=CCCBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CC(NC(=O)c2ccccc2)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.2 h

Procedure:
Magnesium powder (1.05 g, 42.0 mmol) was placed into a round-bottomed flask with a small piece of iodine. Dry THF was added to cover the magnesium and the solution was heated to a gentle reflux for 30 minutes. While refluxing, a second solution of 4-bromo-1-buten (4.72 mL, 42.0 mmol) in dry THF (5 mL) was added. After 12 min, the mixture was cooled to room temperature and added to a solution of N-(1-(4-chlorophenyl)-3-(methoxy(methyl)carbamoyl)cyclobutyl)benzamide (1.12 g, 3.0 mmol) in dry THF (30 mL). After 2 h, the reaction was quenched with saturated aqueous NH4Cl. 1M HCl was added to pH-3 and the solution was extracted with diethyl ether (×2). The combined organic layers were washed successively with 1M HCl, water and saturated aqueous sodium chloride, dried over MgSO4, filtered and concentrated to give the crude product that was used to the next step without further purification. 1H NMR (CDCl3, 600 MHz) δ 7.76 (d, J=7.2 Hz, 2H), 7.47-7.50 (m, 1H), 7.46 (d, J=8.7 Hz, 2H), 7.40-7.43 (m, 2H), 7.33 (d, J=8.7 Hz, 2H), 6.77 (s, 1H), 5.72-5.80 (m, 1H), 4.92-5.01 (m, 2H), 3.16-3.22 (m, 1H), 2.90-2.94 (m, 2H), 2.82-2.86 (m, 2H), 2.54 (t, J=7.3 Hz, 2H), 2.30-2.35 (m, 2H). ESI MS found for C22H22ClNO2 m/z [368.4/370.4 (M+1)].
Reaction SMILES: [F:1][C:2]1([F:16])[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:17]([NH:24][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1([F:16])[F:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)(F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)(F)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (0.250 g, 1.06 mmol) in CH2Cl2 (4.5 mL) was added benzylamine (0.13 mL, 1.17 mmol) and sodium triacetoxyborohydride (0.356 g, 1.59 mmol) and the solution was stirred at rt for 22 h. The reaction mixture was treated with sat. aq. Na2CO3 and extracted with EA (3×50 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Heptane/EA, 1:1) to give tert-butyl 4-(benzylamino)-3,3-difluoropiperidine-1-carboxylate. LC-MS-conditions 08: tR=0.65 min; [M+H]+=327.32.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:13]([C:16]([F:20])=[C:17]([F:19])[F:18])[CH2:14]Br>C(#N)C>[F:20][C:16](=[C:17]([F:19])[F:18])[CH2:13][CH2:14][S:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: FC(F)=C(F)CCBr
Reactant: Sc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)=C(F)CCSc1nccs1
Yield: 86.4 %

Procedure:
2-Mercaptothiazole (5.18 g), potassium carbonate (6.72 g) and 4-bromo-1,1,2-trifluorobutene-1 (9.21 g) are refluxed in acetonitrile (60 ml) in the presence of argon gas for 6 hours by heating. After the reaction mixture has reached room temperature, it is filtered and the solvent is distilled off. The residue is dissolved in dichloromethane and washed with 5% aqueous solution of sodium hydroxide and water in this order. It is dried over unhydrous sodium sulfate and purified by column chromatography (eluent: dichloromethane) to obtain 2-(3,4,4-trifluoro-3-butenyl-thio)thiazole (8.6 g) as pale yellow liquid (n20D 1.5200).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[Br:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[F:21]>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[F:21])[O:22][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: Oc1ccc(F)c(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
Add TBSCl (3.37 g, 22.37 mmol) and imidazole (1.9 g, 27.96 mmol) to a solution of 3-bromo-4-fluoro-phenol (3.56 g 18.64 mmol) in CH2Cl2 (60 ml). Stir the solution at ambient temperature for 3 hours. Quench the reaction with water (30 mL). Extract the aqueous layer with CH2Cl2 (30 mL×3). The combined organic layers are washed with brine, dried over Na2SO4, concentrated under vacuum. The residue is purified by silica gel chromatography (petroleum ether) to give (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane as colorless oil (5.81 g, 99%), MS (m/z): 303 (M−1).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]([C:22]1[CH:23]=[C:24]([CH:30]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:32]=1[OH:33])[CH:25]=[CH:26][C:27](O)=[O:28])([CH3:21])([CH3:20])[CH3:19].P(Cl)(Cl)Cl.Cl>N1C=CC=CC=1>[C:34]([C:31]1[CH:30]=[C:24]([CH:23]=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:32]=1[OH:33])[CH:25]=[CH:26][C:27]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)=[O:28])([CH3:36])([CH3:37])[CH3:35]
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(N2CCN(C(=O)C=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1
Yield: 74 %

Procedure:
To a solution of 18.75 g. (80 mmole) ethyl 4-(piperazin-1-yl)-benzoate and 22.1 g. (80 mmole) 3,5-di-tert.-butyl-4-hydroxycinnamic acid in 160 ml. anhydrous pyridine is added dropwise, with ice cooling, a solution of 5.5 g. (40 mmole) phosphorus trichloride and 25 ml. anhydrous pyridine and the reaction mixture is further stirred for 1 hour with ice cooling, then poured on to ice and acidified with concentrated hydrochloric acid. The aqueous phase is extracted with ethyl acetate and the extracts are washed three times with 0.5N hydrochloric acid, dried and evaporated. The residue is recrystallised twice from a mixture of 240 ml. ethanol and 80 ml. water to give 29.2 g. (74%) of the desired product; m.p. 147°-150° C.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[OH:26][C:27]1([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([F:25])([F:23])[F:24])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:30]2[CH2:31][CH2:32][C:27]([C:34]3[O:35][CH:36]=[CH:37][N:38]=3)([OH:26])[CH2:28][CH2:29]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C1CCC(O)(c2ncco2)CC1
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3ncco3)CC2)C1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine (113.0 mg, 0.3188 mmol) of Step C-2 of Example 1 in THF (1 mL) was added 4-hydroxy-4-(1,3-oxazol-2-yl)cyclohexanone (80.3 mg, 0.443 mmol) followed by triethylamine (0.5 mL, 3.6 mmol) and finally sodium triacetoxyborohydride (135 mg, 0.638 mmol). After being stirred overnight, the reaction was quenched by addition of NaOH solution. The resulting solution was extracted with methylene chloride. The extract was dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography eluting with EtOAc/1% NH4OH to give two isomers. Isomer 1: 73 mg. MS calculated for C28H36F3N3O3: (M+H)+520; found 520.1. Isomer 2: 56 mg. MS found 520.1.\