Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[CH:18]=C(OCC2C=CC=CC=2)[C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:15][C:14]=1[C:33]1[O:37]N=[C:35]([CH3:38])[C:34]=1[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)C1C=CC=CC=1.C(OCC)(=O)C.[CH3:53][OH:54]>[Pd]>[OH:54][C:53]1[CH:18]=[C:13]2[C:14]([C:33](=[O:37])[C:34]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[C:35]([CH3:38])[O:12]2)=[CH:15][C:16]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CO
Reactant: COc1ccc(-c2c(C)noc2-c2cc(-c3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C)oc3cc(O)c(-c4ccccc4)cc3c2=O)cc1
Temperature: 60 °C

Procedure:
Ammonium formate (3.2 g, 50 mmol) was added to a solution of 5-(4,6-bis-benzyloxy-biphenyl-3-yl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (1.4 g, 2.5 mmol) in methanol (20 ml)/ethyl acetate (10 ml) under a nitrogen atmosphere. Palladium on carbon (10%) (cat.) was added and the suspension heated, at 60° C. for ˜18 hrs. The suspension was allowed to cool and ethyl acetate (150 ml) added, and the suspension filtered. The filtrate was washed with water (3×100 ml) and saturated aqueous sodium chloride solution (50 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale brown gum. Trituration with methanol gave 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-6-phenyl-chromen-4-one as an off-white solid, dried in vacuo.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([CH3:13])[CH:11]([OH:14])[CH:10]([CH3:15])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:27](Cl)(=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[C:27]([O:14][CH:11]1[CH:12]([CH3:13])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][CH:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:10]1[CH3:15])(=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CC1C(c2ccccc2)NC(c2ccccc2)C(C)C1O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Li]CCCC
Product: CCCCCCCCCCCC(=O)OC1C(C)C(c2ccccc2)NC(c2ccccc2)C1C
Yield: 74.4 %

Procedure:
The general procedure of Example 1 is repeated using 28.1 g (0.10 mol) of 2,6-diphenyl-3,5-dimethyl-4-hydroxypiperidine, 40 mL (0.10 mol) of n-butyllithium (2.5M in hexanes) and 21.8 g (0.10 mol) of lauroyl chloride. 34.5 g (74% yield) of the title compound is isolated after purification by LC (silica gel, ethyl acetate/hexane): mp 74°-76° C.
Reaction SMILES: [CH:1]([C:4]([CH3:6])=[O:5])([CH3:3])[CH3:2].[F:7][C:8]([F:12])([F:11])[S:9]Cl>C(Cl)Cl>[CH3:2][C:1]([S:9][C:8]([F:12])([F:11])[F:7])([CH3:3])[C:4](=[O:5])[CH3:6]
Reactant: FC(F)(F)SCl
Reactant: CC(=O)C(C)C
Solvent: ClCCl
Product: CC(=O)C(C)(C)SC(F)(F)F
Reaction time: 8 h
Yield: 80.7 %

Procedure:
334 g of methyl isopropyl ketone in 1.2 liters of methylene chloride were initially introduced into a narrow stirred vessel equipped with a condenser. 220 g of trifluoromethane-sulphenyl chloride were introduced, at room temperature in the course of 4 hours, through an inlet tube extending to the bottom of the vessel. The reaction mixture was allowed to stand overnight. It was then distilled. 242 g (80.7% of theory) of crude 3-methyl-3-trifluoromethylthio-butan-2-one were obtained and purified by fractional distillation: boiling point: 60° C./50 mbar and refractive index nD20 =1.4030. ##STR12##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16]O>S(=O)(=O)(O)O>[CH3:16][O:14][C:13](=[O:15])[CH:12]=[CH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2 (Step 1); 1.0 g, 4.8 mmol) was dissolved in methanol (10 mL) in the presence of catalytic amount of sulfuric acid. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was cooled at 5° C. and quenched with saturated sodium carbonate solution (2 mL). The solid obtained was filtered and dried.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=[S:20])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][NH2:43])[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>C1C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][NH:43][C:19]([NH:18][C:14]3[CH:13]=[C:12]([N:6]4[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]([CH3:25])=[C:5]4[C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:16][CH:15]=3)=[S:20])[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cccc(C2CCN(CCCN)CC2)c1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N=C=S)c1
Solvent: c1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(NC(=S)NCCCN2CCC(c3cccc(OC)c3)CC2)c1
Yield: 94.8 %

Procedure:
1,4-Dihydro-2,6-dimethyl-4-(3-isothiocyanatophenyl)-3,5-pyrazinedicarboxylic acid, dimethyl ester (500 mg, 1.4 mmol) was refluxed with 4-(3-methoxyphenyl)-piperidine-1-propanamine (380 mg, 1.5 mmol) in 8 mL of benzene for 2 hours. Chromatographic purification (on silica gel, 100% methylene chloride first, followed by 10% (v/v) methanol in methylene chloride) of the residue after concentration in vacuo gave the title compound as a yellow foam (807 mg, 95%); 1H-NMR (CDCl3) δ 7.61 (br, 1H), 7.20 (t, 1H, J=7.9 Hz), 7.12 (t, 1H, J=8.1 Hz), 6.88 (br, 1H), 6.60 (m, 3H), 6.57 (dd, 1H, J=8.3, 2.1 Hz), 6.47 (br, 1H), 3.78 (s, 3H), 3.73 (s, 6H), 3.60-3.80 (m, 2H), 2.94 (m, 2H), 2.37 (s, 6H), 2.25-2.50 (m, 3H), 2.03 (m, 2H), 1.60-1.85 (m, 4H), 1.40-1.60 (m, 2H); 13C-NMR (CDCl3) δ 166.0, 159.6, 152.5, 149.2, 147.7, 130.2, 129.5, 119.5, 115.8, 113.1, 112.2, 111.1, 109.7, 108.8, 63.6, 55.2, 54.2, 51.8, 42.5, 32.8, 25.4, and 18.0.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([OH:16])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]([F:40])([F:39])[C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=1[CH2:29]Br.C(Br)C1C=CC=CC=1>O.C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([O:16][CH2:29][C:28]1[CH:31]=[C:32]([C:35]([F:37])([F:38])[F:36])[CH:33]=[CH:34][C:27]=1[C:26]([F:25])([F:39])[F:40])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(CBr)c1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C(F)(F)F)c(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
(1R*,2R*,5R*)-8-Benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 151 mg, 0.52 mmol) was treated with sodium hydride (41 mg, 60% in oil, 1.03 mmol) at 0° C. in a solution of THF (2 ml) and allowed to warm to room temperature. The mixture was recooled to 0° C. and 2,5-bis(trifluoromethyl)benzyl bromide (0.24 ml, 1.30 mmol) added and the mixture heated to 50° C. for 2 days. A further 1.30 mmol of the benzyl bromide was added and the mixture further heated for 50° C. for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a yellow solid. This was purified by flash column chromatography [25% ethyl acetate in iso-hexane] to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([NH:11][S:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: Nc1cc(Br)cc2[nH]ccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc(Br)cc3[nH]ccc23)cc1
Yield: 118.5 %

Procedure:
6-Bromo-1H-indol-4-amine (500 mg, 1.97 mmol) was treated with 4-methoxybenzene-1-sulfonyl chloride (446 mg, 2.16 mmol) according to the method described in Preparation 15b to give 890 mg (100% yield) of the title compound. Purity 87%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.C(O)C>[CH2:12]([O:19][C:20]([N:3]1[C:2]([NH2:1])=[CH:7][C:6]([NH2:8])=[N:5][CH2:4]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc(N)ncn1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC1=CC(N)=NCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
To a mixture of 4,6-diaminopyrimidine (4.7 g), ethanol (500 ml) and water (200 ml) was added 1N sodium hydroxide (13.25 ml) while cooling with ice water. After the dropwise addition of 1N hydrochloric acid (26.5 ml) thereto, benzyloxycarbonyl chloride (4.5 g) was dropwise added thereto. After being stirred at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give crystals. The crystals were collected by filtration and recrystallized from chloroform:methanol=5:1 to give 2.4 g of N-benzyloxycarbonyl-4,6-diaminopyrimidine, melting point 194° C.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[C:1]1([NH:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CNc1cccc2ccccc12

Procedure:
In 5 ml of THF, 500 mg of 1-naphthylamine was added, then 168 mg of sodium hydride (60% in oil) was added and the resultant mixture was stirred for 30 min under ice cooling. To the reaction mixture, 0.46 ml of ethyl bromoacetate was added and the mixture was refluxed for 5 hr. The reaction mixture was evaporated under reduced pressure and the resultant residue was re-dissolved in ethyl acetate. The obtained solution was washed with 5% sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and subjected to a silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give 720 mg of ethyl 1-naphthylaminoacetate. In 10 ml of ethanol, 460 mg of the ester was dissolved, 3.78 ml of 1N—NaOH aqueous solution was added and the resultant mixture was stirred for 1 hr. The reaction mixture was evaporated under reduced pressure, neutralized by the addition of 1N—HCl and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and crystallized by the treatment with ether to give 188 mg of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[S:12].C(N(CC)CC)C>C(O)C>[NH2:15][C:14]1[CH:16]=[CH:17][N:10]=[C:11]([S:12][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:13]=1
Reactant: Nc1cc[nH]c(=S)n1
Reactant: CCOC(=O)CCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCSc1nccc(N)n1

Procedure:
In a nitrogen atmosphere, 28.6 ml (200 mmol) of ethyl 4-bromobutyrate was added to a solution of 25.44 g (200 mmol) of 2-thiocytosine and 30.7 ml (220 mmol) of triethylamine in 400 ml of ethanol at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→1/9) to yield 46.31 g (96.0%, white crystal) of the desired product.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:22])([CH3:21])[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[O:26][CH2:27][CH:28]1[O:30][CH2:29]1>C(O)(C)C>[CH2:1]([N:8]([CH2:29][CH:28]([OH:30])[CH2:27][O:26][C:25]1[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=1[CH3:23])[C:9]([CH3:22])([CH3:21])[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](=[O:17])[NH2:18])=[CH:14][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(COc1ccc(C(N)=O)cn1)NCc1ccccc1
Reactant: Cc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: Cc1ccccc1OCC(O)CN(Cc1ccccc1)C(C)(C)COc1ccc(C(N)=O)cn1

Procedure:
A solution of 12 g of 6-(2-benzylamino-2,2-dimethylethoxy)-nicotinic acid amide and 12 g of 1-(2-methylphenoxy)2,3-epoxy-propane in 150 ml of isopropanol is boiled for 28 hours under reflux. After working up analogously to Example 1(c), crude 1-[N-benzyl-N-[2-(5-carbamoyl-2-pyridyloxy)-1,1-dimethyl-ethyl]-amino]-3-(2-methyl-phenoxy)-2-propanol is obtained, which is used further without additional purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:10])[S:5][C:6]=1[CH2:7][CH2:8][CH3:9].[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18]([NH:10][C:4]2[S:5][C:6]([CH2:7][CH2:8][CH3:9])=[C:2]([CH3:1])[N:3]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCCc1sc(N)nc1C
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCCc1sc(NS(=O)(=O)c2cccc(Cl)c2C)nc1C
Yield: 46 %

Procedure:
The title compound was prepared from 4-methyl-5-propyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 110 mg (46% yield): HRMS Calcd (found) for C14H17ClN2O2S2 m/z 344.0420 (344.0403).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[O:15](S(C(F)(F)F)(=O)=O)[S:16]([C:19]([F:22])([F:21])[F:20])(=O)=[O:17]>ClCCl.N1C=CC=CC=1>[F:20][C:19]([F:22])([F:21])[S:16]([O:12][C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:13])[N:7]=[C:6]([CH3:14])[CH:5]=[CH:4]2)(=[O:17])=[O:15]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc2c(Br)c(O)c(C)cc2n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(Br)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-2,7-dimethylquinolin-6-ol (1.04 g, 3.1 mmol) in dichloromethane (50 mL) and pyridine (10 mL) was added Tf2O (1.1 mL, 6.2 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, quenched with slowly addition of NaHCO3 solution at 0° C. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give the desired product. Column purification gave pure product. LCMS-ESI+: calc'd for C12H9BrF3NO3S: 383.9 (M+H+); Found: 383.9 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:41][C:39]([CH3:42])([CH3:40])[CH2:38][N:35]1[CH:36]=[CH:37][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:30])=[N:34]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)O)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (62 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 114.06 mg, 0.3 mmol) and iPr2NEt (0.1 mL, 0.6 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (23.1 mg, 20.8%) as an off-white powder. HRMS (ES+) m/z Calcd for C30H33Cl2F2N5O2S+H [(M+H)+]: 604.2052. found: 604.2052.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([O:16]CC)=[O:15])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)nn1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Ethyl 1-(4-fluorophenyl)-5-methylpyrazole-3-carboxylate (3 g) was dissolved in a mixed solvent of ethanol (15 ml) and water (15 ml) and sodium hydroxide (0.6 g) was added. The mixture was stirred at a refluxing temperature for 30 min. Ethanol was evaporated and to the residue was added dilute hydrochloric acid. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (2.1 g), melting point: 177° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:12])[O:4][C:5]([CH2:10][CH3:11])([CH3:9])[CH2:6][C:7]=1[OH:8].[Cl:13][C:14]1[CH:26]=[CH:25][C:17]2[N:18]([CH:22]([CH3:24])[CH3:23])[C:19]([SH:21])=[N:20][C:16]=2[CH:15]=1>>[Cl:13][C:14]1[CH:26]=[CH:25][C:17]2[N:18]([CH:22]([CH3:24])[CH3:23])[C:19]([S:21][C:2]3[C:3](=[O:12])[O:4][C:5]([CH2:10][CH3:11])([CH3:9])[CH2:6][C:7]=3[OH:8])=[N:20][C:16]=2[CH:15]=1
Reactant: CCC1(C)CC(O)=C(Cl)C(=O)O1
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Product: CCC1(C)CC(O)=C(Sc2nc3cc(Cl)ccc3n2C(C)C)C(=O)O1

Procedure:
The title compound was prepared from 3-Chloro-6-ethyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one (from Step 1) and 5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol using the coupling method described in Example C(4).
Reaction SMILES: [CH2:1]([C:6]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][NH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:16]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([NH:25][C@H:26]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:27](O)=[O:28])=[O:24])[N:18]=[CH:17]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>CN(C=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C@@H:26]([NH:25][C:23](=[O:24])[CH2:22][CH2:21][C:19]2[N:18]=[CH:17][NH:16][CH:20]=2)[C:27](=[O:28])[N:8]2[CH2:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:9]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(C[C@@H](NC(=O)CCc2c[nH]cn2)C(=O)O)cc1
Reactant: CCCCCC1(c2ccccc2)CNC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCC1(c2ccccc2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]cn2)C1
Reaction time: 4 h
Yield: 53.7 %

Procedure:
70 mg (0.345 mmol) of 3-pentyl-3-phenylazetidine and 100 mg (0.315 mmol) of (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoic acid are solubilized in 1 ml of DMF. 67 mg (0.345 mmol) of EDC and 47 mg (0.345 mmol) of HOBT are added to this solution. The whole is left to stir for 4 hours and is then treated with 1N sodium hydroxide and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. The crude product obtained is purified by silica gel chromatography (eluent 9/1 dichloromethane/methanol). 85 mg of N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 49%.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:8]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:7]=[CH:6][C:5]=1[C:15]([O:17]CC)=[O:16].O>CCO>[Cl:3][C:4]1[N:8]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:7]=[CH:6][C:5]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnn(-c2ncccn2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(-c2ncccn2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 N aqueous sodium hydroxide solution (2.0 mL) is added to a suspension of ethyl 5-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylate (250 mg, 1.11 mmol) in 5.0 mL of EtOH. The reaction mixture is stirred at RT for 1 h. Water is added, and the solution is washed with EtOAc. The aqueous layer is cooled to 0° C. and acidified to pH=2-3 with conc. HCl. The precipitated solid is collected by vacuum filtration and dried in vacuo to give the title compound as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:17]([CH:16]([CH2:19][CH3:20])[CH2:15][N:11]1[C:12]2[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]1=[O:21])[CH3:18]
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)ncc21
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A mixture of 1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.12 mmol), 4-aminobutyric acid (732 mg, 7.1 mmol) and NaOMe solution (10.7 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 19 mg of the title compound as a yellow solid. MS: (+) m/z 452.32 (M+1).