Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C=O)C>[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CCOC(=O)c1cc2cc[nH]c2cn1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
To a stirred solution of ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.50 g, 2.63 mmol) in DMF (10 mL) under a nitrogen atmosphere was added sodium hydride (0.087 g, 80% in mineral oil, 2.89 mmol) and 2,4-difluorobenzyl bromide (0.60 g, 2.89 mmol). The resulting mixture was stirred for 16 hours at ambient temperature. It was quenched with water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (2×30 mL), dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography. Elution with hexane/ethyl acetate (1:1) provided the title compound as a light yellow solid (0.40 g, 48% yield). 1H NMR (CD3OD) δ ppm. 8.86 (s, 1H), 8.47 (s, 1H), 7.71 (d, 1H, J=3.2 Hz), 7.31 (dd, 1H, J=6.3 Hz), 6.94-7.05 (m, 2H), 6.79 (d, 1H, J=3.2 Hz), 5.63 (s, 2H), 4.46 (q, 2H, J=7.3 Hz), 1.45 (t, 3H, J=7.3 Hz). LCMS (API-ES, M+H+): 317.0
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:13]=[O:14].CC(=CC)C.[O-:20]Cl=O.[Na+]>CN(C)C=O.O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([OH:20])=[O:14]
Reactant: [O-][Cl+][O-]
Reactant: Cc1cc(-c2ccccc2)sc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccccc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a stirred solution of 3-methyl-5-phenyl-thiophene-2-carbaldehyde (0.200 g, 0.99 mmol) and 2-methyl-2-butene (2.77 g, 0.040 mol) in dimethylformamide (4 ml) at 0° C. was added NaClO2 (0.894 g, 9.89 mmol) and NaH2PO4 (1.09 g, 7.91 mmol) in water (5 ml). The solution was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed at reduced pressure and the residue partitioned between dichloromethane (10 ml) and 1N HCl solution (10 ml). The organic was separated, the aqueous layer extracted with dichloromethane (2×5 ml). The combined organic layers were dried (MgSO4) and the solvent removed at reduced pressure to give a yellow oil. Purification by flash column chromatography 50% ethyl acetate/petrol 40-60° C.) gave the sub-title compound as a white solid (0.14 g, 69% yield): 1H NMR (400 MHz, CDCl3) δH 2.65 (3H, s), 7.25 (1H, s) 7.35-7.80 (5H, s).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][S:16]([C:12]1[CH:11]=[C:10]([S:7]([N:6]2[C:2]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[CH:3][C:4]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:5]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:17]
Reactant: OB(O)c1cccnc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cccnc2)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1)C(=O)OC(C)(C)C
Yield: 66.7 %

Procedure:
Using tert-butyl [(5-bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (459 mg), 3-pyridineboronic acid (222 mg), sodium carbonate (287 mg) and tetrakis(triphenylphosphine)palladium (53.1 mg), a procedure as in Reference Example 267 was performed to give the title compound as a white solid (yield 305 mg, 67%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH:18]2[CH2:20][CH:10]([CH2:11][C:12]3[CH:13]=[C:14]([OH:21])[CH:15]=[CH:16][C:17]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH:23](Cl)([F:25])[F:24].[OH-].[K+]>O1CCOCC1>[CH2:1]([N:8]1[CH2:19][CH:18]2[CH2:20][CH:10]([CH2:11][C:12]3[CH:13]=[C:14]([O:21][CH:23]([F:25])[F:24])[CH:15]=[CH:16][C:17]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)CC1CC2CN(Cc2ccccc2)C1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Oc1ccc2c(c1)CC1CC2CN(Cc2ccccc2)C1

Procedure:
11-Benzyl-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-5-ol (572 mg, 2.05 mmol) was stirred in dioxane (5 mL) and H2O (1 mL) at reflux under a balloon of freon (HCF2Cl). To this was added 3N KOH dropwise so as to maintain a pH˜12. The consumption of starting material was monitored by TLC for over 2 hours. The reaction was cooled, diluted with H2O (40 mL) and extracted with EtOAc. The organic layer was washed with a sat. aq. Na2CO3 soln. (25 mL) and brine (25 mL), dried (MgSO2), filtered and concentrated to an oil (620 mg, 92%). GCMS m/e 329 (M+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][NH:13][C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:25]1([C:31]([O:33][CH3:34])=[O:32])[CH:29]=[CH:28][C:27](=[O:30])[O:26]1>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][N:13]([C:25]3([C:31]([O:33][CH3:34])=[O:32])[CH:29]=[CH:28][C:27](=[O:30])[O:26]3)[C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1(Cl)C=CC(=O)O1
Reactant: O=C(Cc1ccccc1)N[C@@H]1CONC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(N2OC[C@@H](NC(=O)Cc3ccccc3)C2=O)C=CC(=O)O1
Yield: 43.3 %

Procedure:
In 8 ml of dichloromethane was suspended 110 mg of (4R)-4-phenylacetamido-3-isoxazolidinone. To the suspension were added, under ice-cooling and stirring, 0.14 ml of triethylamine and 2 ml of dichloromethane solution dissolving 106 mg of the Compound (27) obtained in Example (27). The reaction solution was stirred at room temperature for 40 minutes, washed with water and dried (Na2SO4). The solvent was then evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:3) to give 78 mg of the subject Compound (30) as colorless oil.
Reaction SMILES: CS([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:6]=1)(=O)=O.[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:38]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:6]=1)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: CS(=O)(=O)c1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
4'-Methanesulfonyl-2,2':6',2"-terpyridine (4.67 g, 0.015 mol) and hexadecyl alcohol (2.42 g, 0.010 mol) were added to N,N-dimethylformamide (0.1 liter). At 15°C., sodium hydride (60% content, oil dispersion, 0.8 g) was added thereto over a period of about 10 minutes. The entire solution was stirred for 30 minutes and then the reaction mixture was reacted under reflux for 4 hours. After cooling to room temperature, the reaction mixture was poured into an aqueous 4 M sodium chloride solution (0.3 liter). The crystal that precipitated was taken out by filtration under suction and then washed with water and hexane. The crystal was again dissolved in chloroform and washed with 1 M hydrochloric acid and water. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The resulting crystal was recrystallized from hexane to obtain 4.36 g of the above-entitled product (T-6). Yield: 92%. m.p. 97.5° to 99.0° C.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[C:17]([O:16][CH3:15])=[O:23])=[O:6]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCN1C(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A mixture of 18.51 g (0.10 mol; 1.0 eq) of 2-fluoro-3-nitrobenzoic acid and 100 ml of thionyl chloride was refluxed for 3 hours. The excess thionyl chloride was then concentrated and the residue was co-evaporated twice with toluene. The resulting acid chloride was taken up in 250 ml of dichloromethane. To this mixture, cooled to 0° C., were added 16.56 g (0.10 mol; 1.0 eq) of L-proline methyl ester hydrochloride and then 30.50 ml (0.22 mol; 2.2 eq) of triethylamine. After 30 minutes at 0° C. and one hour at ambient temperature, the reaction medium was diluted and washed with 250 ml of a 1 M aqueous hydrochloric acid solution and then with 250 ml of a saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated. 25.64 g of methyl (S)-1-(2-fluoro-3-nitrobenzoyl)pyrrolidine-2-carboxylate were obtained. Yield=87%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]#[N:19]>C(#N)C>[C:18]([CH2:17][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)#[N:19]
Reactant: N#CCCl
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 1-(2-hydroxyethyl)piperazine (2.60 g, 20 mmol) in acetonitrile (35 ml) was added potassium carbonate (3.04 g, 22 mmol) and chloroacetonitrile (1.51 g, 20 mmol) was dropped thereinto with ice cooling. The mixture was stirred at room temperature for 30 minutes and then stirred at 45° C. for 30 minutes. This reaction mixture was filtered off, the filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (100 g of silica gel; developing solvent, chloroform:ammonia-saturated methanol=20:1→10:1) to provide 3.20 g (yield 95%) of 4-(cyanomethyl)piperazine-1-ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([OH:14])[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]([OH:14])[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=1
Reactant: Cc1nc2c(O)cc([N+](=O)[O-])cc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(O)cc(N)cc2o1

Procedure:
To a solution of 6-nitro-4-hydroxy-2-methylbenzoxazole (5.1 g, 0.026 mole) in THF (100 ml) and methanol (50 ml) were added about 0.5 g of 10 percent palladium on carbon. The mixture was placed on the Parr-shaker apparatus and hydrogenated two hours. At this time hydrogen uptake was complete (6.3 psi, 0.079 mole). The catalyst was removed and the solvents were removed under reduced pressure. The resulting off-white solid (4.1 g, 97.0 percent) was collected and dried. TLC showed the product to be pure. A ninhydrin test for amines was positive. A silver test for hydroxylamine was negative.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:21][N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=1)=[O:19]
Reactant: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Reactant: CNc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CN(C(=O)c1cc(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Phenylquinoline-4-carboxylic acid chloride hydrochloride (10.7 g) is added in portions over a period of 15 minutes, with stirring, to a solution of N-methylaniline (12.8 g) in methylene chloride (75 ml), cooled to 0° C. The mixture is stirred for 2 hours 30 minutes at 10° C. The solution obtained is washed with a 20% strength solution of acetic acid in water (120 ml). The acetic acid solution is extracted with methylene chloride (100 ml). The organic phases are combined, washed with water (3×100 ml), dried over magnesium sulphate and evaporated under reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[CH:5]=1)([O-])=O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[CH:5]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)cc1F
Yield: 96 %

Procedure:
A mixture of 4-nitro-2-fluorobenzonitrile (1.83 g, 5 mmol) and iron (1.68 g, 6 mmol) in a mixture of acetic acid (40 ml) and ethyl acetate (40 ml) was refluxed for 2 hours. The solid was filtered off and the filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield 4-amino-2-fluorobenzonitrile (54a) (0.653 g, 4.8 mmol, 96%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([NH2:19])[N:3]=1.[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([NH2:19])[N:3]=1)[CH3:21]
Reactant: CCO
Reactant: Nc1nc(Cl)c(-c2ccncc2)c(-c2ccco2)n1
Product: CCOc1nc(N)nc(-c2ccco2)c1-c1ccncc1

Procedure:
The title compound was synthesized in a similar manner to Example 3 using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].C1COCC1.[OH-].[Li+].Cl>CO>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cnc(OCC2CC2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
A mixture of methyl 5-chloro-6-(cyclopropylmethoxy)nicotinate (2.00 g), THF (15 mL), methanol (1.7 mL) and 2 M aqueous lithium hydroxide solution (8.3 mL) was stirred at room temperature for 20 min. The reaction mixture was neutralized with 1 M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, and the obtained solid was washed with diethyl ether/hexane to give the title compound (1.68 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].CCCCCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([O:14][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Yield: 100.5 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl-4-piperidone (14.9 g, 74.8 mmol) in DMF (35 mL) was added TMSCl (11.4 mL, 89.7 mmol) and then Et3 N (25.0 mL, 179 mmol) dropwise at room temperature, and the reaction mixture was heated at 80° C. for 18 hr. Hexane was added to the reaction mixture, and the resulting mixture was washed with sat. NaHCO3 and brine, dried over Na2SO4, and concentrated to dryness. Chromatography of the residue with hexane-EtOAc (5:1, v/v) as eluent gave 1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine (20.4 g, 99%) as a yellow oil. 1H-NMR (CDCl3) δ 0.19 (s, 9H), 1.46 (s, 9H), 2.05–2.15 (m, 2H), 3.48–3.56 (m, 2H), 3.83–3.91 (m, 2H), 4.79 (broad s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]1=[O:19].Cl[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.C(N(CC)CC)C.CN(C)C=O>>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][N:15]([C:21]3[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:14]2)[C:10]1=[O:19]
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: O=C1N(c2ccccc2Cl)CC[C@]12CCCNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1N(c2ccccc2Cl)CC[C@]12CCCN(c1ncc(Cl)cc1Cl)C2
Temperature: 180 °C

Procedure:
A mixture of (5S)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (18.2 mg, 0.0000604 mol), 2,3,5-trichloropyridine (16 mg, 0.000091 mol) and triethylamine (0.025 mL, 0.00018 mol) in N,N-dimethylformamide (0.4 mL, 0.005 mol) was irradiated with microwaves to heat the mixture to 180° C. for 20 min. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 410.1/412.1/414.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([C@@H:14]([NH:18][C:19]([C@H:21]([CH2:30][CH:31]=[CH2:32])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.I[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:36]([CH3:46])[CH:35]=1>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([C@@H:14]([NH:18][C:19]([C@H:21]([CH2:30]/[CH:31]=[CH:32]/[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:36]([CH3:46])[CH:35]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cc(I)ccc1-c1ccccc1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](COC)c1ccccc1)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C/C=C/c1ccc(-c2ccccc2)c(C)c1)CC(=O)OC(C)(C)C)C(C)C)c1ccccc1
Yield: 66 %

Procedure:
According to the method of Preparation 15 a), tert-butyl (3R)-3-({[({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-(1S)-2-methyl-1-propyl]amino}carbonyl)hex-5-enoate (from c) above) (1.08 g, 2.42 mmol) was reacted with 4-iodo-2-methyl-1-phenylbenzene (Preparation 29)(1.07 g, 3.63 mmol) under palladium catalysis at reflux in acetonitrile for 18 h. After being cooled, the mixture was diluted with ethyl acetate (200 mL) and washed sequentially with 5% aqueous citric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate=30:1 to 3:1) to give tert-butyl (3R, 5E)-3-({[({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-(1S)-2-methyl-1-propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate as a pale brown foam (980 mg, 66%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(O[C@H]2CCCC[C@@H]2c2ccccc2)cc1F
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (270 mg, 0.449 mmol) prepared in Example 1a and triethylsilane (0.30 mL) in dichloromethane (3.0 mL), trifluoroacetic acid (3.0 mL) was added at room temperature, and the reaction solution was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (dichloromethane/methanol=95:5) to yield the title compound (186 mg, 92%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28]1>C(Cl)Cl>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[C:7]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:28]1
Reactant: NC1CCN(c2ccccn2)C1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1NC1CCN(c2ccccn2)C1
Temperature: 130 °C

Procedure:
A mixture of (2-chloro(3-pyridyl))-N-(3-trifluoromethylphenyl)carboxamide and 1-(2-pyridyl) pyrrolidine-3-ylamine (Step A) was heated at 130° C. neat for 3 h. The reaction was cooled and diluted with CH2Cl2 and washed with H2O twice followed by brine. The organic layer was dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography with EtOAc and further mixed with MeOH and 1 N HCl/Et2O (2 ml). The solution was evaporated to furnish the titled compound. MS (ES+): 428 (M+H); (ES−): 426 (M−H). Calc'd. for C22H20F3N5O−427.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH:11]12[CH2:17][CH2:16][CH:15]1[C:14](=[O:18])[O:13][C:12]2=[O:19]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][C:14]([CH:15]2[CH2:16][CH2:17][CH:11]2[C:12]([OH:19])=[O:13])=[O:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: O=C1OC(=O)C2CCC12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NC(=O)C2CCC2C(=O)O)cc1Cl
Yield: 35.4 %

Procedure:
A solution of 4-amino-2-chlorobenzonitrile (1229 mg, 8.06 mmol), 3-oxabicyclo[3.2.0]heptane-2,4-dione (1016 mg, 8.06 mmol) and TEA (1.123 mL, 8.06 mmol) in toluene (10 mL) was stirred at 80° C. for 14 hr. To the reaction mixture was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by COOH-silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane), and crystallized from ethyl acetate to give 2-((3-chloro-4-cyanophenyl)carbamoyl)cyclobutanecarboxylic acid (795 mg, 2.85 mmol, 35.4%) as colorless crystals.