Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16](=[O:19])[NH:17][CH:18]=1>CN(C)C=O.O>[CH:1]1([CH2:4][N:17]2[CH:18]=[C:13]([I:12])[CH:14]=[C:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:16]2=[O:19])[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: O=C(Nc1cc(I)c[nH]c1=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cc(I)cn(CC2CC2)c1=O)OCc1ccccc1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Cyclopropylmethyl bromide (0.100 mL, 0.99 mmol) and cesium carbonate (0.323 mg, 0.99 mmol) were added to a solution of benzyl 5-iodo-2-oxo-1,2-dihydropyridin-3-ylcarbamate (0.245 g, 0.66 mmol) in dimethylformamide (3 mL) and stirred overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 10% to 50% ethyl acetate in hexanes gradient elution) gave the title compound (0.190 g). MS 425 (M+1)
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[C:32]([CH:33]=O)=[CH:31][CH:30]=[C:29]1[C:35]([O:37][CH3:38])=[O:36])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:38][O:37][C:35]([C:29]1[N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:32]([CH2:33][N:18]2[CH2:19][CH2:20][CH:15]([O:14][CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:16][CH2:17]2)=[CH:31][CH:30]=1)=[O:36]
Reactant: COC(=O)c1ccc(C=O)n1C(=O)OC(C)(C)C
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Into a 100-mL three-neck flask, 1.1 g (4.0 mmol) of 4-benzhydryloxypiperidine synthesized in Production Example 1, 1.0 g (4.0 mmol) of methyl N-tert-butoxycarbonyl-5-formylpyrrole-2-carboxylate, and 20 mL of dichloromethane were fed under an argon atmosphere, and the internal temperature was cooled to 0° C. Thereinto, 1.3 g (6.1 mmol, 1.5 eq.) of sodium triacetoxyborohydride was added at an internal temperature of not higher than −5° C., and the mixture was stirred for 5 minutes at the same temperature. Then, the mixture was heated to a room temperature and stirred overnight.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>CC(C)=O.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:4]=1
Reactant: C1CSCCN1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(NC2CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CSc1nc(NC2CCCCC2)c([N+](=O)[O-])c(N2CCSCC2)n1
Temperature: 25 °C

Procedure:
3.0 gm of 2-methylmercapto-4-chloro-5-nitro-6-cyclohexylamino-pyrimidine were dissolved in 30 ml of acetone, a solution of 1.38 gm of potassium carbonate in 1.5 ml of water was added, and the mixture was admixed with a solution of 1.2 gm of thiomorpholine in 10 ml of acetone. The resulting mixture was stirred at room temperature, whereby after a short time a voluminous, crystalline precipitate was formed which was further increased by addition of water. The mixture was suction-filtered and the filter cake, 2-methylmercapto-4-thiomorpholino-5-nitro-6-cyclohexylamino-pyrimidine, was recrystallized from isopropanol. Yield: 2.3 gm (62% of theory), m.p. 145°-146°C.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[S:15][CH:16]=[CH:17][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[O:29]>O1CCCC1>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[S:15][CH:16]=[CH:17][C:9]2=3)=[O:7])=[CH:18][CH:19]=1)=[O:29]
Reactant: Cc1ccccc1N=C=O
Reactant: Nc1ccc(C(=O)N2CCCCc3sccc32)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(C(=O)N2CCCCc3sccc32)cc1
Temperature: 110 °C
Yield: 54.2 %

Procedure:
A mixture of 0.409 g of 4-(4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno [3,2-b]azepine and 0.60 g of 2-methylphenylisocyanate in 2 ml of tetrahydrofuran is heated in an oil bath at 110° C. for 16 hours. The mixture is concentrated under vacuum and the residue chromatographed on preparative silica gel plates with ethyl acetate-hexane (1:1) as solvent to give a solid. Crystallization from ethyl acetate-hexane gives 0.33 g of white crystals, m.p. 179°-182° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:14]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]([OH:21])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22](I)[CH3:23].O>CN(C)C=O>[CH2:3]([N:10]1[CH:14]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]([O:21][CH2:22][CH3:23])=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Sodium hydride (60%, oily, 1.20 g) was added to a solution of ethyl 1-benzyl-3-hydroxy-1H-pyrazol-4-ylacetate (7.81 g) in N,N-dimethylformamide (100 ml) at 0° C., which was stirred at room temperature for 15 minutes. Ethyl iodide (2.40 ml) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-benzyl-3-ethoxy-1H-pyrazol-4-ylacetate (7.52 g, yield 87%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1([CH3:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>>[CH3:6][C:7]1([CH3:13])[CH2:12][CH2:11][N:10]([CH2:1][C@H:3]2[CH2:4][O:5]2)[CH2:9][CH2:8]1
Reactant: CC1(C)CCNCC1
Reactant: ClC[C@@H]1CO1
Product: CC1(C)CCN(C[C@H]2CO2)CC1

Procedure:
The compound is prepared analogously to J. Amer. Chem. Soc. 80; 1958, 1257 by reacting (S)-epichlorohydrin with 4,4-dimethylpiperidine, while the reaction temperature should not exceed 35° C.: Boiling point: 101-104° C./15 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[N:27]=[CH:28][S:29][CH:30]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1cscn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(thiazol-4-yl)propionate hydrochloride (General Procedure H with methanol and HCl on methyl (S)-2-amino-3-(thiazol-4-yl)propyl acid (Synthetech)), the title compound was prepared as a solid (mp=136-139° C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/DCM) and the product was purified by recrystallization from DCM.
Reaction SMILES: [O:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C(Cl)Cl>[C:31]([O:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:11]2[CH:22]=[CH:23][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)=[CH:14][CH:15]=1)(=[O:34])[CH:32]=[CH2:33]
Reactant: C=CC(=O)Cl
Reactant: OCCc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 0 °C
Yield: 86 %

Procedure:
To a 1 L three-neck round bottom flask equipped with mechanical stirrer were charged 2-[4-(4-phenoxyphenoxy)phenyl]ethanol (61.2 g, 0.2 mol), anhydrous triethylamine (60 mL, 0.42 mol), and anhydrous methylene chloride (300 mL). The solution was cooled in an ice/salt bath under dry air blanket for 15 mins. Acryloyl chloride (22 mL, 0.27 mol) was added into the vigorously stirred cold solution through an addition funnel over 60 min and the addition rate was adjusted to keep the temperature of the reaction mixture below 10° C. After the addition, the reaction mixture was stirred in the ice/salt bath for additional two hours followed by quenching with the addition of 2M HCl (300 mL). The mixture was extracted with ethyl acetate (300 mL×3) and the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2), and dried over MgSO4. Filtration and removal of solvents under reduced pressure gave the crude product as light brown oil which was purified on silica gel using Hexanes/Ethyl acetate (9/1, v/v) as eluent to give P3E2EA as a white powder (62 g, 86%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=O.N1C=CC=CC=1C1C=CC=CN=1.[Li]CCCC.[CH3:27][C:28](C)([CH:32]=[CH2:33])[C:29](Cl)=O>C1COCC1.CCOCC>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C:28]([CH3:29])([CH3:27])[CH:32]=[CH2:33])[CH3:9]
Reactant: C=CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)CC(=O)O
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(C)(C)C(=O)CC(=O)OCC
Reaction time: 3 h
Yield: 101.3 %

Procedure:
Monoethyl hydrogen malonate (7.2 g, 0.05 mol) and bipyridyl (few milligrams) were dissolved in THF (90 ml) and the system was flushed with nitrogen. The solution was cooled to −70°, then BuLi (2.5 M in hexanes, 37 ml, 0.09 mol) was added. After the addition of only ˜10 ml of BuLi the solution turned pink and additional THF (15 ml) was required to enable magnetic stirring. The cooling bath was removed and the remaining BuLi was added, the temperature was allowed to reach −10°, upon which the solution turned colorless. The mixture was again cooled to −60° and a solution of 2,2-dimethyl-but-3-enoyl chloride (4.1 g, 0.03 mol) in THF (12 ml) was added dropwise. After addition was complete the mixture was allowed to warm to 0° and stir for 3 h, then it was added to a 1:1 mixture of ether/1M HCl (260 ml) at 0° and stirred for a further 1.5 h. The organic layer was removed, washed with HCl (1 M), sodium bicarbonate solution, brine then dried and evaporated to give 4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (5.6 g, 98%). (Hayashi et al., J. Org. Chem., 65:8402-8405 (2000). Distillation with a Kugelrohr oven (160°/1 mmHg) afforded pure material.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:17][C:18]([F:50])([F:49])[C:19]1[CH:20]=[C:21]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:22][N:23]1[C:27]([CH3:28])=[C:26]([Sn](CCCC)(CCCC)CCCC)[N:25]=[N:24]1>CN(C=O)C>[F:50][C:18]([F:17])([F:49])[C:19]1[CH:20]=[C:21]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:22][N:23]1[C:27]([CH3:28])=[C:26]([C:2]2[C:7]([C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[N:25]=[N:24]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1C
Reactant: O=C(c1ccccc1Cl)c1cccnc1Br
Solvent: CN(C)C=O
Product: Cc1c(-c2ncccc2C(=O)c2ccccc2Cl)nnn1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 54.1 %

Procedure:
Dissolve (2-bromo-pyridin-3-yl)-(2-chloro-phenyl)-methanone (148 mg, 0.50 mmol) and 1-(3,5-bis-trifluoromethyl-benzyl)-5-methyl-4-tributylstannanyl-1H-[1,2,3]triazole (449 mg, 0.75 mmol) in DMF (5 mL) and degass, then add dichlorobis(triphenylphosphine) palladium (70 mg, 0.10 mmol). Seal the mixture under N2 and heat at 80° C. for 24 hours. Concentrate, dissolve in CHCl3, wash with saturated potassium fluoride solution (2×), saturated potassium bicarbonate solution, brine, dry over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-40% EtOAc/hexane followed by recrystallization from EtOAc/hexane to afford the title compound (142 mg, 54%). MS(IS) 525 (M+1); TLC (60% EtOAc/hexane) Rf=0.30.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)([OH:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: CCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCC(O)(c1ccc(Br)cc1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a solution of 4-(4-Bromo-benzoyl)-benzoic acid ethyl ester (2.0 g, 6 mmol) in THF (20 mL) at 0° C. is added hexylmagnesium bromide (2M, 3.3 mL). After stirring at room temperature for 2 hours, it is quenched with saturated ammonium chloride, extracted with EtOAc. The organic is concentrated and purified by column chromatography to give 4-[1-(4-Bromo-phenyl)-1-hydroxy-heptyl]-benzoic acid ethyl ester (0.48 g, 19%), which is taken into methanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving to afford the titled compound (0.47 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20].N1CCCCC1>C(O)C>[NH2:22][C:21]1[O:1][C:2]2=[C:3]3[C:8](=[CH:9][CH:10]=[C:11]2[CH:17]([C:16]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:18]=1[C:19]#[N:20])[CH:7]=[N:6][CH:5]=[CH:4]3
Reactant: Oc1cccc2cnccc12
Reactant: COc1ccc(C=C(C#N)C#N)cc1OC
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C2C(C#N)=C(N)Oc3c2ccc2cnccc32)cc1OC
Temperature: 25 °C

Procedure:
To a stirred suspension of 5-hydroxyisoquinoline (2.90 g) and 3,4-dimethoxy benzylidenemalononitrile (4.28 g) in ethanol (11 ml) was added dropwise piperidine (1.70 g). The suspension was then heated at reflux temperature for one hour forming a red solution. This was then allowed to cool to room temperature, depositing a brown solid. This was filtered off and washed with ethanol and ether and dried in vacuo at 60° C., yielding 2-amino-4-(3,4-dimethoxyphenyl)- 4H-pyrano[2,3-f] isoquinoline-3-carbonitrile as a yellow-brown solid, m.p. 225°-228° C.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[K].[SH:18][CH2:19][CH2:20][OH:21].CN(C)C(=O)C.Cl>>[OH:21][CH2:20][CH2:19][S:18][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1
Reactant: OCCS
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Agent: Cl
Agent: [K]
Solvent: CC(=O)N(C)C
Product: O=c1c2ccccc2sc2ccc(SCCO)cc12

Procedure:
5.6 g. (0.0225 mol) of 2-chlorothioxanthone and 2.6 g. (0.0225 mol) of the potassium salt of 2-mercaptoethanol are stirred for 18 hours in 20 mol of N,N-dimethylacetamide at 100° C. The reaction mixture is then poured into 2N hydrochloric acid and extracted with ethyl acetate. After conventional work-up and chromatographic purification, 3.5 g. of the analytically pure compound IIIaof melting point 94° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][OH:18])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].N1C(C)=CC=CC=1C.O([Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])S(C(F)(F)F)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][O:18][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CO
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](OCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-1,2,5-oxadiazole-3-carboxamide (3.2 g, 0.012 mol) in dichloromethane (DCM) (23 mL) at 0° C. was added 2,6-lutidine (3.4 mL, 0.029 mol) followed by triisopropylsilyl triflate (4.1 mL). The solution was stirred at 0° C. for 30 min and then the reaction was warmed to rt overnight. The reaction was concentrated and chromatographed on a silica column eluting with 15% ethyl acetate/hexane to yield a colorless oil (4.59 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ: 11.03 (s, 1H), 8.01 (dd, J=6.7, 2.6 Hz, 1H), 7.67 (ddd, J=9.1, 4.3, 2.6 Hz, 1H), 7.44 (dd, J=9.1, 9.1 Hz, 1H), 5.2 (s, 2H), 1.09 (m, 3H), 0.99 (d, J=7.1 Hz, 18H); MF=C19H27ClFN3O3Si; LCMS calculated for C19H28ClFN3O3Si(M+H)+: m/z=428.157.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:34])[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[N:6][CH:5]=1.[OH-].[Na+]>CO.O>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][N:6]=2)=[O:34])=[CH:21][C:22]=1[C:30]([F:31])([F:33])[F:32])(=[O:28])=[O:27]
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCCO2)c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)Nc2ccc(C(=O)O)cn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A solution of 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 15, 21 mg, 0.04 mmol) in methanol (0.40 mL) was treated with a 1N aqueous sodium hydroxide solution (0.20 mL, 0.20 mmol). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was then diluted with water and concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid (15 mg, 75%) as a colorless gum: EI-HRMS m/e calcd for C22H23F3O6S (M+H)+ 501.1302, found 501.1305.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F:7][C:8]([F:15])([F:14])[C:9]([F:13])=[C:10]([F:12])[F:11].CC(C)C>>[F:11][C:10]([CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([F:12])[CH:9]([F:13])[C:8]([F:15])([F:14])[F:7]
Reactant: C1=CCCCC1
Reactant: FC(F)=C(F)C(F)(F)F
Agent: CC(C)C
Product: FC(C(F)(F)F)C(F)(F)C1C=CCCC1
Yield: 60.5 %

Procedure:
Cyclohexene (2.8 g., 34.2 mmole) and hexafluoropropene (1.71 g., 11.4 mmole), heated at 320° for 4 days in a Pyrex ampoule gave: (i) hexafluoropropene (0.06 g., 0.40 mmole; 4% recovery), (ii) cyclohexene (1.9 g., 23.2 mmole; 67% recovery), b.p. 83°, (iii) a liquid mixture (2.5 g.), b.r. 50°-110°/13 mm. Hg., from which was isolated (preparative g. l. c.) 3-(1,1,2,3,3,3-hexafluoropropyl)-cyclohexene (1.6 g., 6.9 mmole; 63% based on C3F6 consumed). Found: C, 47.0; H, 4.3; F, 48.5%; M (mass spectrometry), 232. C9H10F6 requires C, 46.6; H, 4.3; F, 49.1%; M, 232, b.p. 160°-161° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].CN(C(ON1N=N[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH2:37][CH:42]3[CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: NC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Nc1nc(-n2cc(C(=O)NCC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The trisilyl derivative acid 20 (0.14 g, 0.2 mmol) was then dissolved in 5 mL dichloromethane. To the solution was added HBTU (0.19 g, 0.4 mmol), HOBt (0.076 g, 4 mmol), N-methylmorpholine (0.04 g, 0.4 mmol) and cat. DMAP. The mixture was allowed to stir at RT for 24 h. The mixture was then washed with 10% citric acid, saturated NaHCO3, brine and dried over MgSO4. The solvent was removed and the residue was treated with 5 mL 0.5N NH4F/MeOH. The solution was heated at reflux for 24 h. The solvent was evaporated and the residue was purified by preparative TLC to afford compound 21, MS 445.26 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1>C(=O)(O)[O-].[Na+]>[CH:1]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)Cc1ccc(NC=O)cc1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of acetic anhydride (14.3 mL, 151 mmol) and formic acid (22.8 mL, 605 mmol) was stirred at room temperature for 1 h. Methyl (4-aminophenyl)acetate (5.00 g, 30.3 mmol) was added and the resulting mixture was stirred overnight. Saturated aqueous sodium bicarbonate (10 mL) was added and the resulting mixture was extracted with DCM (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.31 g) as a yellow oil, which was used in the next reaction without further purification.