Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:8][C:9]([F:25])([F:24])[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[N:11]=1>>[F:24][C:9]([F:8])([F:25])[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:19])[N:11]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: COC(=O)CCN
Product: COC(=O)CCNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 75 %

Procedure:
This compound was synthesized from methyl 3-aminopropanoate and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (120 mgs, yield 75%). MS (ESI) m/z: Calculated for C14H12F3N3O4: 343.08. found: 344.1 (M+H)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([C:17](C)([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])[CH2:14][CH2:15][CH3:16].C(O)C>O>[CH3:23][CH:17]([CH2:13][CH2:14][CH2:15][CH3:16])[C:18]([OH:20])=[O:19]
Reactant: CCCCC(C)(C(=O)OCC)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCCCC(C)C(=O)O
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A mixture of 40 g of p-toluenesulfonic acid monohydrate and 313 g of diethyl butylmethylmalonate was heated to 125°-135° C. in a flask equipped with a distillation column packed with Raschig rings. After 15 minutes, ethanol began to reflux in the distillation head. Ethanol was distilled as it formed and the pot temperature was maintained at 120°-126° C. by periodic addition of water to the pot. After 22 hours, the distillation of ethanol had ceased. The mixture then was cooled and treated with 70 ml of water. The layers were separated to afford 159.2 g (90.6% yield) of 2-methylhexanoic acid (99.8% pure by VPC).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[O:21]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:34][C:31]2[CH:30]=[CH:29][C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:33][CH:32]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)Nc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 4-phenoxy-phenylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H23NO6 [M+H]+: 421.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:1](=[O:12])[CH2:2][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:16][CH:15]=1
Reactant: Clc1ccccc1
Reactant: O=C1Cc2ccccc2C(=O)O1
Product: O=C(Cc1ccccc1C(=O)O)c1ccc(Cl)cc1

Procedure:
2-[2-(4-Chlorophenyl)-2-oxoethyl]-benzoic acid (above) was prepared by method I using homophthalic anhydride and chlorobenzene. In this case, it was found to be advantageous to heat the reaction to 85° C. for 4 hours. The product was isolated by flash chromatography.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:16].S([O-])([O-])=O.[Na+].[Na+]>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+:16]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])c1ccc(I)cc1
Temperature: 40 °C

Procedure:
4-Iodobenzenesulphonyl chloride (30.2 g, 100 mmol) was added in portions to a vigorously stirred solution of sodium bicarbonate (16.8 g, 200 mmol) and anhydrous sodium sulphite (24 g, 190 mmol) in water (100 ml) at 70°-80° C. The temperature was kept at 70°-80° C. by intermittent heating. When the addition was complete, the mixture was heated and stirred at 70°-80° C. for a further hour. The mixture was then filtered and the filtrate allowed to cool to approximately 40° C. The resulting solid which crystallised from the solution was separated by filtration, washed with ice-cold water and dried in vacuo for 48 hours over sodium hydroxide and calcium chloride, to give sodium 4-iodobenzenesulphinate m.p. >350° C., which was used without further purification or characterisation.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
Triethylamine (0.94 mL, 6.71 mmol) was added to a stirred reaction mixture of N-tert-butoxycarbonyl piperazine (0.50 g, 2.68 mmol) in tetrahydrofuran (6 mL) at 0° C., then the reaction mixture was stirred at room temperature for 15 minutes. A solution of 4-bromo-benzenesulfonyl chloride (0.686 g, 2.68 mmol) in tetrahydrofuran (4 mL) was added to the reaction mixture and stirring continued for another 2 hours. Tetrahydrofuran was evaporated off under reduced pressure, then the reaction mixture was diluted with ethyl acetate (20 mL). The inorganic materials were filtered off through a celite bed. The filtrate was washed with 2 N aqueous HCl (5 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to yield 1.00 g (92%) of 4-(4-bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid, which was used in the next step without further purification. MS cald. for C15H21BrN2O4S [(M+NH4)+] 422, obsd. 422.1.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][O:6][CH3:7])=[O:4].[OH:8]/[N:9]=[C:10](/[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)\[C:11]([OH:13])=[O:12]>CS(C)=O>[CH3:7][O:6][NH:5][C:3]([CH2:2][O:8]/[N:9]=[C:10](/[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)\[C:11]([OH:13])=[O:12])=[O:4]
Reactant: CONC(=O)CCl
Reactant: O=C(O)/C(=N\O)c1cccs1
Solvent: CS(C)=O
Product: CONC(=O)CO/N=C(\C(=O)O)c1cccs1
Yield: 34 %

Procedure:
This compound was prepared by the method of Preparation 4 from methyl chloroacetohydroxamate and E-2-hydroxyimino-2-(thien-2-yl)acetic acid, νmax (Nujol) 3380 (--NH--), 1750, 1729 (--CO2H), 3700-2400 (bonded OH), 1690 cm-1 (--CONH--), τ(DMSO d6) 2.2-3.0 (thienyl), 5.49 (--OCH2CO--), 6.38 (--OCH3). Yield 34%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([OH:40])[CH2:38][CH2:39]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(O)CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(O)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)piperidin-4-ol. MS (ESI): mass calcd. for C21H21FN4O3S, 428.13; m/z found, 429.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36-8.31 (m, 2H), 8.10-8.06 (m, 1H), 7.99 (m, 1H), 7.73-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.40 (m, 1H), 7.34-7.28 (m, 2H), 3.66-3.55 (m, 1H), 3.20-3.08 (m, 2H), 2.71-2.61 (m, 2H), 1.72-1.63 (m, 2H), 1.39-1.26 (m, 2H).
Reaction SMILES: [Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH2:3][CH2:4][CH3:5].[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: OCc1ccccc1
Reactant: CCCC(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(Cl)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution of crude (133) (6.0 g) and benzyl alcohol (4.1 mL, 39.2 mmol) in dichloromethane at 0° C. was added dicyclohexylcarbodiimide (6.07 g, 29.4 mmol) and DMAP (120 mg, 0.98 mmol), and the resulting reaction mixture was stirred at room temperature for 2 h, then filtered through a pad of Celite. The filtrate was washed with brine and dried over Na2SO4. After filtration and evaporation, the crude product was purified by flash chromatography on silica gel, eluting with 10% ethyl acetate in hexane, to afford 5.8 g of the desired ester (134). (CDCl3, 400 MHz): δ 0.95 (t, J=7.4 Hz, 3H), 1.72-1.20 (m, 14H), 2.34 (s, 2H), 3.19 (m, 2H), 5.10 (s, 2H), 5.47 (t, J=6.2 Hz, 1H), 6.42 (t, J=5.8 Hz, 1H), 7.33 (m, 5H).
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](O)=[O:11])(=[O:4])[CH3:3].[CH2:13]([C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:2]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([N:23]1[CH2:24][C@H:20]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21][C@H:22]1[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[CH:30][CH:29]=1)=[O:26])=[O:11])(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: CC(=O)N1CCC[C@H]1C(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 36.2 %

Procedure:
Proceeding as in Example 1, but substituting (S)-1-acetylpyrrolidine-2-carboxylic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 93, (2S,4R)-1-((S)-1-acetylpyrrolidine-2-carbonyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (11.5 mg, 36.2%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.96 (s, 1H), 7.54 (m, 2H), 7.29-7.24 (m, 4H), 7.20-7.14 (m, 5H), 6.93 (m, 2H), 4.46 (m, 2H), 3.47-3.37 (m, 4H), 2.66 (m, 2H), 1.95-1.83 (m, 8H), 1.76-1.69 (m, 2H). MS (EI) for C31H32FN3O4. found 530.6 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[NH:13][N:12]=[N:11]1.[CH3:16]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1
Reactant: CN(C)C=O
Reactant: COc1cccc(-n2nn[nH]c2=O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cccc(-n2nnn(C)c2=O)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the above-mentioned 1-(2-methyl-3-methoxyphenyl)-1,4-dihydrotetrazole-5-one 10.00 g and N,N-dimethylformamide 100 mL was added 55% sodium hydride 2.47 g under ice-cooling. The mixtures were raised to room temperature and were stirred for one hour. To the reaction mixtures was added methyl iodide 3.5 mL under ice-cooling. The mixtures were raised to room temperature and were stirred for fourteen hours. To the reaction mixtures was added water and the mixtures were extracted with ethyl acetate. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methyl-3-methoxyphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 2.19 g.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:28].O.CCCCCC.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH2:28])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C(ON1C(=O)CCC1=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
60 mg of (2S,5R)-2,5-dioxopyrrolidin-1-yl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate was dissolved in dehydrated dichloromethane (0.8 mL), followed by cooling to 0° C. 0.12 mL of concentrated aqueous ammonia was added to the reaction solution, followed by stirring at room temperature for 1 hour. Subsequently, water (10 mL) was added and the organic layer was fractionated, followed by sequential washing with water and saturated brine and drying over anhydrous magnesium sulfate. The residue resulting from concentration of the solvent under reduced pressure was applied to silica gel column chromatography (hexane/ethyl acetate=1/3), and subsequently crystallized with chloroform/hexane=1:3 to afford 30.4 mg of the title compound as a colorless crystalline powder.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2C=C[CH:12]=[CH:11][CH:10]=2)=[C:5]([O:15][CH3:16])[CH:4]=1.C(C1C=CC(CO)=CC=1OC)CCC>>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Cl:1])=[CH:4][C:5]=1[O:15][CH3:16])[CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(CCl)ccc1-c1ccccc1
Agent: CCCCc1ccc(CO)cc1OC
Product: CCCCc1ccc(CCl)cc1OC

Procedure:
Following the same procedure for the preparation of 4-Chloromethyl-2-methoxy-biphenyl, the title compound is prepared from (4-Butyl-3-methoxy-phenyl)-methanol (crude material from the previous step). The crude material is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14]>>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]2[C:13](=[O:14])[CH:12]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)CC(=O)CCl
Product: O=c1cc(CCl)nc2ccc(F)cn12
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 2-amino-5-fluoropyridine (5.1673 g, 46.09 mmol), ethyl 4-chloro-acetoacetate (8.097 mL, 59.92 mmol), and polyphosphoric acid (80.00 g) was stirred at 110° C. After 4 h, the mixture was removed from the heat. The cooled mixture was suspended in water (100 mL) and the mixture was neutralized with 2 N NaOH (550 mL) until the pH 7. The resulting precipitate was collected by filtration, washed with water (1 L), and air-dried overnight to give 2-(chloro-methyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (1 H, dd, J=4.9, 2.9 Hz), 8.14 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.79-7.86 (1 H, m), 6.59 (1 H, s), 4.68 (2 H, s); Mass Spectrum (ESI) m/e=212.9 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[CH:4]=[C:3]1[C:15]([O:17]CC)=[O:16].[OH-].[Na+].Cl>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[CH:4]=[C:3]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(=O)O)cc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A mixture of ethyl 1-methyl-6-(trifluoromethyl)-1H-indole-2-carboxylate (90 mg, 0.33 mmol) and 2 mol/L aqueous sodium hydroxide solution (0.42 mL, 0.83 mmol) in methanol (2 mL) was stirred at room temperature for 2 hours. Then, 2 mol/L hydrochloric acid was added, and the formed precipitate was collected by filtration to give 75.6 mg (94% yield) of the title compound as a white solid:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([F:23])[CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])=[C:16]([F:23])[CH:15]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
Combine 4-bromo-2-fluoro-benzoic acid (5.0 g, 22.83 mmol), thionyl chloride (10 mL, 0.137 mol) in toluene (10 mL) and reflux for 2 h. Evaporate the reaction mixture to obtain 4-bromo-2-fluoro-benzoyl chloride (5.0 g, 93%) and use for the next step without further purification. Dissolve tert-butylamine (0.8 mL, 5.12 mmol) and triethylamine (0.8 mL, 6.32 mmol) in anhydrous DCM (20 mL), cool to 0° C. and add a solution of 4-bromo-2-fluoro-benzoyl chloride (1.0 g, 4.22 mmol) in anhydrous DCM (10 mL). Stir the reaction mixture at 0° C. for 10 min, warm to ambient temperature and continue to stir for 30 min. Wash the reaction mixture with brine (2×10 mL), dry the organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (1.0 g, 87%). MS (ES+) m/z: 275 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].ClC(OC)=O.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccncc1Br
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccncc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a mixture of 3-bromoisonicotinic acid (2.5 g, 12.37 mmol, 1 eq.) and TEA (3.44 mL, 24.75 mmol, 2.0 eq.) in THF (100 mL) was added methyl chloroformate (1.2 mL, 14.85 mmol, 1.2 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min and filtered. To this filtrate was added a suspension of NaBH4 (0.95 g, 24.75 mmol, 2 eq.) in water (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, quenched with NH4Cl(aq) solution, extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-bromopyridin-4-yl)methanol (1.2 g, 52%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.37 (d, J=4.9 Hz, 1H), 7.37 (d, J=4.9 Hz, 1H), 4.61 (d, J=5.5 Hz, 2H), 2.3 (t, J=5.5 Hz, 1H). LRMS (M+H+) m/z 188.0.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]2[CH:44]=[CH:45][CH:46]=[CH:47][C:2]1=2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C(OCC)(=O)C>[S:1]1[C:5]([C@H:6]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[O:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]2[CH:44]=[CH:45][CH:46]=[CH:47][C:2]1=2
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2cc3ccccc3s2)[C@H](O)C[C@@H]1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CCC/C=C\C[C@H]1[C@@H](O)CC(=O)[C@@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Temperature: -25 °C

Procedure:
(Z)-Methyl 7-((1R,2R,3R,5S)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3,5-dihydroxycyclopentyl)hept-5-enoate, 10a, is dissolved in acetone (0.1 M) and cooled to −25° C. Jones reagent (1 molar equivalent) is added dropwise with stirring. Upon completion, as judged by TLC, the reaction is quenched with isopropyl alcohol and the crude reaction mixture is diluted with ethyl acetate, washed three times with brine, and dried over magnesium sulfate. After filtration and solvent evaporation, the product is purified by flash chromatography using hexanes-ethyl acetate as eluent to afford both (Z)-methyl 7-((1R,2R,5S)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-5-hydroxy-3-oxocyclopentyl)hept-5-enoate (11a, first to elute) and (Z)-methyl 7-((1R,2R,3R)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoate (12a).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=1>>[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][O:28][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:21][CH:20]=1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: OCCCc1ccncc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCCCc1ccncc1

Procedure:
The title compound, brown solid, m.p. 147-50° C. and MS: m/e=374.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 3-pyridin-4-yl-propan-1-ol.
Reaction SMILES: [OH:1][C:2]([CH3:37])([CH2:34][O:35][CH3:36])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.I[C:39]1[CH:44]=[CH:43][N:42]([CH3:45])[C:41](=[O:46])[CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:37])([CH2:34][O:35][CH3:36])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:39]3[CH:44]=[CH:43][N:42]([CH3:45])[C:41](=[O:46])[CH:40]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COCC(C)(O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: Cn1ccc(I)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COCC(C)(O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)O1

Procedure:
A mixture of (S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 196.29 mmol), 4-iodo-1-methylpyridin-2(1H)-one (60.49 mg, 255.2 mmol), Pd(PPh3)2Cl2 (20 mg), and aq Cs2CO3 solution (2 mol/L, 3 mL) in 1,4-dioxane (4 mL) was stirred at reflux for 2 hours. After the reaction was finished, the mixture was washed with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to afford two isomers of (6S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one.
Reaction SMILES: [N:1]([C:3]1[C:4]([C:14]([F:17])([F:16])[F:15])=[N:5][NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O>C(O)C.[Pd]>[NH2:1][C:3]1[C:4]([C:14]([F:17])([F:16])[F:15])=[N:5][NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Nc1c(C(F)(F)F)n[nH]c1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1c(C(F)(F)F)n[nH]c1-c1ccccc1
Reaction time: 7.5 h

Procedure:
A solution of 6.6 g of 4-nitroso-5-phenyl-3-trifluoromethyl-1H-pyrazole (prepared as in Saloutin et al, J. Flourine Chem, vol 84, pp 107–111) in 200 mL ethanol was treated with 2.0 g 10% palladium/carbon catalyst and hydrogenated at RT and 50 psi for 7.5 hours. The reaction mixture was filtered through celite and washed well with ethanol. The filtrate was concentrated to give the title compound as a yellow solid.