Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].B(F)(F)F.CCOCC.Cl>O1CCCC1>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1
Reaction time: 0.17 h

Procedure:
In 50 ml of tetrahydrofuran was dissolved 1.0 g of N-(cyclohexylmethoxycarbonyl)-tyrosine. To the solution, 380 mg of sodium borohydride was added with stirring. After 10 minutes, to the mixture was added dropwise 15 ml of tetrahydrofuran solution containing 1.45 ml of boron trifluoride etherate. The mixture was stirred for 20 hours. After addition of 3% hydrochloric acid, the mixture was concentrated and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was dissolved in chloroform and subjected to column chromatography with 10 g of silicagel to give N-(cyclohexylmethoxycarbonyl)tyrosinol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[CH3:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:37][C:31]1[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(Cl)cc1C(=O)NC(C)(C)C
Product: CC(C)(C)NC(=O)c1cc(Cl)ccc1CC(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.56 g, 4.8 mmol) and N-tert-butyl-5-chloro-2-methyl-benzamide (3.25 g, 14 mmol), followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[CH3:28])=[C:10]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-:29].[Na+].OO>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:29])[NH2:27])=[CH:22][C:21]=3[CH3:28])=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1scc(-c2ccc(Br)cc2)c1-c1ccc(C#N)cc1C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C(N)=O)ccc1-c1c(-c2ccc(Br)cc2)csc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
Lastly, Step 5 of Scheme II was followed: A mixture of crude ethyl 3-(4-(4-bromophenyl)-3-(4-cyano-2-methylphenyl)thiophen-2-yl)propanoate (210 mg, 0.46 mmol) in DMSO (3 mL) was added aqueous solution of NaOH (2M, 1 mL), followed by the addition of H2O2 (0.2 mL). The mixture was stirred at room temperature for 10 minutes. The mixture was quenched with saturated aqueous Na2SO3 and extracted with a mixture of DCM/iPrOH (3/1). The combined organic layer was dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC (48-78% acetonitrile+0.15% trifluoroacetic acid in water, over 15 min.) to afford 3-(4-(4-bromophenyl)-3-(4-carbamoyl-2-methylphenyl)thiophen-2-yl)propanoic acid (17.0 mg, yield 8.3%). 1H NMR (CD3OD 400 MHz): δ 7.66 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.20-7.19 (m, 3H), 7.11-7.08 (m, 2H), 2.62-2.81 (m, 2H), 2.50 (t, J=7.6 Hz, 2H), 1.98 (s, 3H). MS (ESI): m/z 446.0 [M+3]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([CH:25]4[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]([OH:14])CO)[C:3]=12.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([CH:25]4[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:26]4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]=[O:14])[C:3]=12
Reactant: COc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a solution of tert-butyl 3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (0.93 g, 1.7 mmol) in tetrahydrofuran (13 mL) and water (8 mL) was added acetic acid (26 μL, 0.45 mmol) and sodium periodate (1.12 g, 5.23 mmol) at 0° C. After stirring for 3 h with only slight warming, the reaction was not yet complete so it was placed in the refrigerator overnight. Water was added to the reaction and extracted with dichloromethane (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (eluted with 40-85% ethyl acetate in hexanes) to give 0.47 g (54%) of the desired product. LCMS calculated for C24H30ClN6O4 (M+H)+: m/z=501.2; Found: 501.3. 1H NMR (300 MHz, CDCl3) δ 10.05 (s, 1H), 8.37 (s, 1H), 7.39 (s, 1H), 6.55 (q, J=7.1 Hz, 1H), 5.89 (s, 1H), 4.42-3.95 (m, 6H), 3.67 (s, 3H), 2.25 (s, 3H), 1.90 (d, J=7.1 Hz, 3H), 1.44 (s, 9H) ppm.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:31]([C@H:36]1[CH2:41][CH2:40][C@H:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:48]=O)[CH2:44][CH2:43]2)[CH2:38][CH2:37]1)[CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1>[F:2][CH2:3][CH2:4][CH:5]=[CH:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([C@H:39]2[CH2:40][CH2:41][C@H:36]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38]2)[CH2:43][CH2:44]1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=CCCF)CC2)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (6.9 g, 17.1 millimols) with THF (40 ml) was cooled down to -20° C., followed by adding t-BuOK (1.9 g, 17.1 millimols) to the mixture, stirring the mixture for 30 minutes, dropwise adding to the mixture, a THF (30 ml) solution of trans-4-(trans-4-pentylcyclohexyl)cyclohexanecarbaldehyde (4.1 g, 15.5 millimols) so as to keep the temperature at -20° C., stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 1, except that the quantity of ethyl acetate used for extraction was made 150 ml, to obtain raw trans-(trans-4-(4-fluorobutenyl)cyclohexyl)-4-pentylcyclohexane (4.2 g).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:14]3[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:26](O)=[O:27])[CH:20]=4)[NH:15]3)[CH:10]=[C:11]([F:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29]1([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:31][CH2:30]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:14]3[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:26]([NH:35][S:32]([CH:29]5[CH2:31][CH2:30]5)(=[O:34])=[O:33])=[O:27])[CH:20]=4)[NH:15]3)[CH:10]=[C:11]([F:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(C2CCCCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cc(F)cc(C2CCCCC2)c1
Temperature: 65 °C
Yield: 20.6 %

Procedure:
A mixture of 2-(3-cyclohexyl-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (60 mg, 0.16 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (45 mg, 0.24 mmol), 4-dimethylaminopyridine (29 mg, 0.24 mmol), cyclopropane sulfonamide (58 mg, 0.48 mmol) in dichloromethane (10 mL) was heated at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(3-cyclohexyl-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (16 mg, 20%) as a light yellow solid: LC/MS m/e calcd for C27H33FN2O3S (M+H)+: 485.6, observed: 485.3.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:18]=[CH:17][C:16]([CH3:20])([CH3:19])[C:15]2[C:8]=1[CH:9]=[C:10]1[C:14]=2[CH:13]=[N:12][N:11]1[CH2:21][CH:22](O)[CH3:23].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([CH:22]([CH3:23])[CH2:21][N:11]1[C:10]2=[CH:9][C:8]3[C:15]([C:16]([CH3:20])([CH3:19])[CH:17]=[CH:18][C:7]=3[F:6])=[C:14]2[CH:13]=[N:12]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)Cn1ncc2c1=CC1=C(F)C=CC(C)(C)C=21
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cn1ncc2c1=CC1=C(F)C=CC(C)(C)C=21)N=[N+]=[N-]
Yield: 89.5 %

Procedure:
1 ml (13 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.7 g (6.5 mmol) of (RS)-1-(7-fluoro-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 3.6 ml (26 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction S mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.85 g (13 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.66 g (90%) of (RS)-1-(2-azido-propyl)-7-fluoro-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a pink solid (358 mg).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9](S(C(F)(F)F)(=O)=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([C:4]1[C:12]2[NH:11][C:10]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2S(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 100 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfonylbenzimidazole (1.00 g, 2.32 mmol) and anhydrous methanol (18 ml). This solution was cooled to 0° C. and potassium carbonate (641 mg, 4.64 mmol) was added. The resulting mixture was stirred for two hours at 0° C., permitted to warm to room temperature, and stirred at this temperature for about three days. The progress of the reaction was monitored by thin layer chromatography. The desired title product was further purified by radial chromatography.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]12[CH2:19][CH2:18][CH2:17][N:16]=[C:15]1[CH2:14][CH2:13]CC[CH2:10]2.N12CCCC1=NCCC2.N=C=N>C(N(CC)CC)C.C(Cl)(Cl)Cl.C(#N)C.CS(C)=O.CN(C)C=O>[CH:17]12[CH2:10][NH:9][CH2:19][C:18]1=[CH:13][CH2:14][CH2:15][NH:16]2
Reactant: C1CCC2=NCCCN2CC1
Agent: C1CN=C2CCCN2C1
Agent: N=C=N
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C1=C2CNCC2NCC1

Procedure:
Compound (II) is reacted with N-tosyl-L-prolyl chloride in an organic solvent such as methylene chloride or chloroform or in a mixture of water and the said organic solvents in the presence of an organic base such as triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or an inorganic base such as sodium bicarbonate or sodium carbonate at -20° C. to 30° C. to give Compound (a). Compound (a) may also be prepared by reacting Compound (II) with N-protected L-proline in a solvent such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile or chloroform in the presence of an organic or inorganic base such as triethylamine, DBU or DBN and dicyclokexyl carbodiimide. Compound (a) is subjected to column chromatography and acid-catalized hydrolysis to obtain Compound (IIa) and Compound (IIa').
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Br)(Br)([Br:19])=O>C1(C)C=CC=CC=1>[Br:19][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]=1
Reactant: CCC(CC)c1cccc2[nH]c(=O)n(C)c12
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Product: CCC(CC)c1cccc2nc(Br)n(C)c12
Yield: 11.1 %

Procedure:
A mixture of 7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (2.10 g, 10.0 mmol), phosphoric tribromide (5.73 g, 20.0 mmol) and toluene (10 mL) was heated under reflux for 16 hr. The reaction mixture was concentrated in vacuo. The residue was dissolved in saturated sodium hydrogen carbonate solution and ethyl acetate, and extracted. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (312 mg, 1.11 mmol, 11%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=O)[O:16]CC)=[C:4]([F:20])[CH:3]=1.[OH:21][CH:22]([C:27](OC)([CH3:29])[CH3:28])[C:23]([O:25]C)=O>CCCCCC>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:23](=[O:25])[C:22](=[C:27]([CH3:28])[CH3:29])[O:21][C:15]2=[O:16])=[C:4]([F:20])[CH:3]=1
Reactant: COC(=O)C(O)C(C)(C)OC
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCCCCC
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 195 °C
Yield: 21.3 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (2.00 g, 6.63 mmol), methyl 2-hydroxy-3-methoxy-3-methylbutanoate (2.69 g, 16.6 mmol) and stannous acetate (0.20 g) were introduced into a two-necked eggplant type flask (50 cc) equipped with a Dean Stark and heated at 195° C. for 3 hours with stirring. After completion of the reaction, hexane (10 mL) was added, and the insolubles were filtered off. The filtrate was concentrated under reduced pressure, and the resulting oily substance was purified through a silica gel column (benzene/hexane=1/3) to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione as white crystals (0.50 g, yield 21.3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](F)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.CN(C)C=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: c1c[nH]cn1
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2nc(-c3ccccn3)no2)cc(-n2ccnc2)c1

Procedure:
In a screw cap vial equipped with stir bar added 3-(2-Pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (20 mg, 0.08 mmol), potassium carbonate (20.8 mg, 0.15 mmol), imidazole (7.7 mg, 0.11 mmol) and dimethylformamide (1 ml). Stirred the resulting mixture at 120° C. for 2 h. The reaction mixture was diluted with chloroform (30 ml) and washed with water (30 ml). The aqueous phase was re-extracted with chloroform (30 ml) and the combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 2% methanol in dichloromethane to isolate the free base of the desired compound as a white solid. The free base was converted to it's hydrochloride salt (10.0 mg), white solid. 1H-NMR (DMSO), δ (ppm): 9.85 (s, 1H), 8.86 (m, 4H), 8.49 (s, 1H), 8.23 (d, 1H), 8.13 (t, 1H), 7.95 (s, 1H), 7.73 (dd, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C@H:4]([CH3:23])[CH2:3]1.[OH:24][C:25]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)C>[OH:24][C:25]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:30][CH2:29][CH:28]([NH:1][C@@H:2]2[CH2:6][N:5]([C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)[C@H:4]([CH3:23])[CH2:3]2)[CH2:27][CH2:26]1
Reactant: O=C1CCC(O)(c2ccccn2)CC1
Reactant: C[C@@H]1C[C@H](N)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)O
Product: C[C@@H]1C[C@H](NC2CCC(O)(c3ccccn3)CC2)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
N-{2-[(2R,4S)-4-Amino-2-methylpyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide (200 mg, 0.607 mmol) and 4-hydroxy-4-pyridin-2-yl-cyclohexanone (116 mg, 0.607 mmol) were dissolved in 2-propanol (10 mL). After stirring for 30 minutes, sodium triacetoxyborohydride (257 mg, 1.21 mmol) was added and the mixture was stirred at room temperature overnight. TLC indicated complete conversion to desired products in about a 1:1 ratio of two isomers. The reaction mixture was chromatographed on silica gel eluting with dichloromethane to 10% methanol/dichloromethane/0.5% ammonium hydroxide to give 229 mg (75%) as a mixture of isomers. 1H NMR (CDCl3, mixture of isomers) δ 8.53 (m, 1H), 8.13 (bs, 1H), 8.02 (d, 1H), 7.75 (m, 2H), 7.58 (t, 1H), 7.40 (m, 2H), 7.22 (m, 1H), 4.05-4.38 (m, 3H), 3.80 (m, 1H), 3.56 (m, 1H), 3.42 (m, 1H), 3.19 (m, 1H), 3.04 (m, 1H), 2.65 (m, 1H), 2.47 (m, 1H), 2.16 (m, 2H), 1.40-2.00 (m, 7H), 1.43 (d, 3H). LCMS (M+H)+: Higher Rf isomer m/z=505.2; Lower Rf isomer m/z=505.2.
Reaction SMILES: [C@@H]1(C2C=CC=C(CC3SC(CC)=CC=3)C=2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[F:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Br:43])[CH:38]=3)=O)[S:32][C:31]=2[CH:44]=1>>[Br:43][C:39]1[CH:38]=[C:37]([CH2:35][C:33]2[S:32][C:31]3[CH:44]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=3[CH:34]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: O=C(c1cccc(Br)c1)c1cc2ccc(F)cc2s1
Agent: CCc1ccc(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)s1
Product: Fc1ccc2cc(Cc3cccc(Br)c3)sc2c1

Procedure:
To a solution of 2,4-difluorobenzaldehyde (5.0 g) in dimethylsulfoxide (100 ml) were added methyl thioglycolate (3.45 ml) and triethylamine (10 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was poured into ice-cold water. The mixture was extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give 6-fluoro-2-methoxycarbonylbenzo[b]thiophene (1.32 g) as colorless powder. GC-EI-Mass m/Z 210 (M). (2) The above 6-fluoro-2-methoxycarbonylbenzo[b]thiophene was treated in a manner similar to Reference Example 4-(1) to give 6-fluorobenzo[b]thiophen-2-ylcarboxylic acid as colorless powder. ESI-Mass m/Z 195 (M−H). (3) The above 6-fluorobenzo[b]thiophen-2-ylcarboxylic acid was treated in a manner similar to Reference Example 4-(2) to give 6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene as colorless powder. APCI-Mass m/Z 240 (M+H). (4) A solution of 1,3-dibromobenzene (493 mg) in tetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 0.86 ml). The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of the above 6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene (500 mg) in tetrahydrofuran (3 ml). The mixture was warmed to room temperature, and added thereto was a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-85:15) to give 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone (479 mg) as a pale yellow solid. APCI-Mass m/Z 335/337 (M+NH4). (5) The above 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone was treated in a manner similar to Reference Example 5-(2) to give 3-bromo-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene as a colorless solid.
Reaction SMILES: [Br:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[Br:1][C:2]([F:7])([F:6])[C:3]([O:5][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: O=C(O)C(F)(F)Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: O=C(OCc1ccccc1)C(F)(F)Br

Procedure:
This compound was prepared according to Example 2a from bromodifluoroacetic acid (9.82 g; 68.7 mmol), benzyl alcohol (7.0 g; 65 mmol), and p-toluenesulphonic acid monohydrate (50 mg) in cyclohexane (120 mL). The crude product obtained after evaporation was used as is without any further workup in 3b.