Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][NH:16]C(OCC2C=CC=CC=2)=O)[C@@H:10]([CH2:28][CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[C:9]1=[O:39])(C)(C)C>FC(F)(F)C(O)=O.CO.[C].[Pd]>[NH2:16][CH2:15][C:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9](=[O:39])[C@@H:10]1[CH2:28][CH2:29][CH2:30][NH2:31])=[O:27]
Reactant: CC(C)(C)OC(=O)CN1CCN(C(=O)CNC(=O)OCc2ccccc2)[C@@H](CCCNC(=O)OC(C)(C)C)C1=O
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NCCC[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 ml of trifluoroacetic acid was dissolved 500 mg of (S)-4-benzyloxycarbonylaminoacetyl-3-(3-t-butoxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid t-butyl ester. The solution was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure to leave an oily product, which was dissolved in 10 ml of methanol. To the solution was added 10 mg of 10% palladium-carbon. The mixture was stirred for one hour at room temperature under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to leave a crude product of (S)-4-aminoacetyl-3-aminopropyl-2-oxopiperazine-1-acetic acid. This product was dissolved in a mixture of 10 ml of water and 10 ml of dioxane. To the solution was added 400 mg of sodium hydrogencarbonate. Subsequently, 420 mg of 3-(4-carboxyphenylamino)-1,2,4-oxadiazolin-4H-5-one produced in Reference Example 25 and 250 mg of N-hydroxysuccinimide were dissolved in 5 ml of dimethylformamide. To the solution was added 450 mg of dicyclohexyl carbodiimide. The mixture was stirred for 3 hours at room temperature, followed by concentration under reduced pressure to leave an oily substance. This substance was dissolved in 5 ml of dioxane, which was added to the solution of (S)-4-aminoacety]-3-aminopropyl-2-oxopiperazine-1-acetic acid prepared as above. The mixture was stirred for 6 hours at room temperature. The reaction mixture was neutralized with 1N HCl, which was then concentrated under reduced pressure to give a crude product, followed by purification by means of a sephadex LH-20 column to afford 230 mg of the title compound as a colorless amorphous powdery product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH:8][C:9](C2CCOC2)=O)=[CH:2]1.[O:16]=P(Cl)(Cl)Cl.[C:21]1(C)C=C[CH:24]=[CH:23][CH:22]=1>>[O:16]1[CH2:24][CH2:23][CH:22]([CH:6]2[CH2:7][N:8]=[CH:9][C:2]3[S:1][CH:5]=[CH:4][C:3]2=3)[CH2:21]1
Reactant: O=C(NCCc1ccsc1)C1CCOC1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1
Product: C1=NCC(C2CCOC2)c2ccsc21

Procedure:
Tetrahydro-3-furoic acid (2-thiophen-3-yl-ethyl)-amide(3.35 g), POCl3 (4.06 ml) were reacted in toluene (150 ml) exactly as described in example 4. 2.77 g of 4-tetrahydrofuran-3-yl-4,5,-dihydrothieno[2,3-c]pyridine was isolated identified by NMR and MS: M+=207.
Reaction SMILES: C[C:2]1[C:3]([S:12][C:13]2[CH:18]=[C:17](C)[CH:16]=[C:15](C)[CH:14]=2)=[C:4]([N+]([O-])=O)[C:5](=[O:8])[NH:6][CH:7]=1.C(C1C(SC2C=C(C)C=C(C)C=2)=C(C(OCC)=O)C(=O)NC=1C)C.CC1C=C(S)C=C(C)C=1>C(O)C.C(N(CC)CC)C>[C:13]1([S:12][C:3]2[CH:2]=[CH:7][NH:6][C:5](=[O:8])[CH:4]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(C)cc(Sc2c(C)c[nH]c(=O)c2[N+](=O)[O-])c1
Agent: CCOC(=O)c1c(Sc2cc(C)cc(C)c2)c(CC)c(C)[nH]c1=O
Agent: Cc1cc(C)cc(S)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1cc(Sc2ccccc2)cc[nH]1

Procedure:
As for the method described for obtaining compound 7a in example 10, a mixture of compound 15 (1.00 g, 4.1 mmoles) in 10 ml of ethanol and 1 ml of triethylamine was agitated until homogeneous. 3,5-dimethylthiophenol (0.61 ml, 4.5 mmoles) was added. After 12 hours under reflux, the white precipitate was isolated by filtration and crystallised in ethyl acetate. Product 15 was obtained (1.05 g, 82%) in the form of white crystals: melting point 202° C.; NMR-1H (DMSO-d6) δ 12.17 (1H, s, NH-1), 7.22 (1H, s, H-4'), 6.92 (1H, s, H-2' and 6'), 4.09 (2H, q, J=7 Hz, COOCH2CH3), 2.45 (2H, q, J=7 Hz, CH2CH3), 2.27 (3H, s, CH3 -6), 2.25 (6H, s, CH3 -3' and 5'), 1.15 (3H, t, j=7 Hz, COOCH2CH3), 0.85 (3H, t, J=7 Hz, CH2CH3). Anal. C19H23NO3S (C, H, N, S).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45](O)=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C2(O)CCCC2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Pyridine (0.83 mL, 12 mmol) and trifluoromethanesulfonic anhydride (1.2 mL, 7.1 mmol) were added to a solution of 4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (Example 33-(1); 2.6 g, 6.9 mmol) in dichloromethane (26 mL) at −10° C., and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=4/1) to give the title compound (1.8 g, 51%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH:18]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CCOC(C)=O.CO>[CH3:2][CH2:1][O:3][C:4]1[CH:5]=[C:6]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: CCCN1CC=C(c2ccc([N+](=O)[O-])c(OCC)c2)CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN1CCC(c2ccc(N)c(OCC)c2)CC1
Reaction time: 8 h
Yield: 101.1 %

Procedure:
4-[3-(ethyloxy)-4-nitrophenyl]-1-propyl-1,2,3,6-tetrahydropyridine (0.536 g, 1.85 mmol) was place in a 40 mL high vial and dissolved in 10 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.196 g, 0.092 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step E (0.491 g, 1.87 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.61 (d, J=1.10 Hz, 1H), 6.47-6.53 (m, 2H), 4.41 (bs, 2H), 3.95 (q, J=6.96 Hz, 2H), 2.91 (d, J=10.07 Hz, 2H), 2.19-2.31 (m, 3H), 1.86-1.97 (m, 2H), 1.61-1.68 (m, 2H), 1.56 (td, J=12.18, 3.11 Hz, 2H), 1.37-1.47 (m, 2H), 1.29 (t, J=6.96 Hz, 3H), 0.83 (t, J=7.33 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH:22]=[N:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2.C(OCC)C>C1COCC1.CCCCCC>[F:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH:22]([NH:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2)[C:3]1([C:2]([F:7])([F:6])[F:1])[CH2:4][O:5]1
Reactant: FC(F)(F)C1CO1
Reactant: COc1ccc(C=Nc2cccc3[nH]c(=O)ccc23)c(F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(Nc2cccc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(F)c1
Temperature: -10 °C
Yield: 8.7 %

Procedure:
To 600 mg (3.9 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 624 mg (3.9 mmol) 2-fluoro-4-methoxybenzaldehyde in 12 ml toluene are added 18 μl acetic acid and 2 g molecular sieve. The mixture is heated over 25 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeotrophed with small portions of toluene to obtain 5-{[1-(2-fluoro-4-methoxyphenyl)-methylidene]amino}-1H-quinolin-2-one are quantitatively. 0.81 ml (11.6 mmol) 1,1,1-trifluoroepoxypropane in 12 ml THF and 3.5 ml hexane are cooled to −100° C. and 3.75 ml of a 2.5 M n-butyl lithium solution (9.4 mmol) in hexane are added over 10 minutes while the temperature does not exceed −95° C. 10 Minutes after complete addition 1.11 g (12 mmol) 5-{[1-(2-fluoro-4-methoxyphenyl)-methylidene]amino}-1H-quinolin-2-one in 10 ml THF are added over 15 minutes while the temperature does not exceed −95° C. After tree hours at −100° C. 3.75 ml diethyl ether are added and the reaction mixture is warmed to −10° C. over one hour. The reaction is quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer is extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (acetone in hexane 0 to 80%) yields 410 mg of 5-{[(2-Fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-1H-quinolin-2-one.
Reaction SMILES: C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:25]=[C:26]1[NH:30][CH2:29][CH:28]([C:31]([OH:33])=O)[S:27]1.[N+]([O-])(O)=O.[N+:38]([O:41][CH2:42][CH2:43][NH2:44])([O-:40])=[O:39]>O1CCCC1>[N+:38]([O:41][CH2:42][CH2:43][NH:44][C:31]([CH:28]1[S:27][C:26](=[O:25])[NH:30][CH2:29]1)=[O:33])([O-:40])=[O:39]
Reactant: O=C1NCC(C(=O)O)S1
Reactant: NCCO[N+](=O)[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Product: O=C1NCC(C(=O)NCCO[N+](=O)[O-])S1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.4 %

Procedure:
0.85 ml of triethylamine and 0.53 ml of diphenylphosphoryl azide were added, whilst ice-cooling, to a suspension of 0.30 g of 2-oxothiazolidine-5-carboxylic acid (prepared as described in Preparation 3) and 0.41 g of N-(2-nitrooxyethyl)amine nitrate in 10 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 2.5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. The crude crystals thus obtained were triturated with diisopropyl ether, collected by filtration and washed to give 0.40 g of the title compound as a colorless powder, melting at 114°-115° C.
Reaction SMILES: [CH3:1][S:2][CH2:3]Cl.CN(CCCCl)C.[CH3:12][C:13]1[CH:29]=[C:16]2[NH:17][C:18](=[O:28])[C:19]3[CH:24]=[N:23][C:22]4[NH:25][N:26]=[CH:27][C:21]=4[C:20]=3[N:15]2[N:14]=1.C(N1C2N=CC3C(=O)NC4N(N=C(C)C=4)C=3C=2C=N1)C>>[CH3:12][C:13]1[CH:29]=[C:16]2[N:17]([CH2:3][S:2][CH3:1])[C:18](=[O:28])[C:19]3[CH:24]=[N:23][C:22]4[NH:25][N:26]=[CH:27][C:21]=4[C:20]=3[N:15]2[N:14]=1
Reactant: Cc1cc2[nH]c(=O)c3cnc4[nH]ncc4c3n2n1
Reactant: CSCCl
Agent: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Agent: CN(C)CCCCl
Product: CSCn1c(=O)c2cnc3[nH]ncc3c2n2nc(C)cc12

Procedure:
By substituting methylthiomethyl chloride for the dimethylaminopropyl chloride in the procedure of Example 4 and substituting the 2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one obtained in Example 8 for the 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one, 2-methyl-4-methylthiomethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:22])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][S:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:16]=2[NH:22][C:10]1=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSc1c(N)cccc1N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CSc2c(N)cccc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-3-(2,6-diamino-phenylsulfanyl)-propionic acid (1.0 g, 3.1 mmol) in DMF (12 mL) was added DIEA (1.6 mL, 9.1 mmol), HOBT.H2O (859 mg, 6.2 mmol) and HBTU (2.3 g, 6.2 mmol). The mixture was stirred under an atmosphere of N2 at room temperature for 3 h. The reaction was poured into H2O and extracted with EtOAc. The organic extracts were combined, washed with 0.5 M HCl, H2O, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography by silica gel chromatography to give the title compound (560 mg, 59%).
Reaction SMILES: [NH:1]1CCO[CH2:3][CH2:2]1.[SH:7][C:8]1[NH:9][C:10](=[O:19])[CH:11]=[C:12]([CH2:16][CH2:17][CH3:18])[C:13]=1[C:14]#[N:15].BrCC#N.BrCC(N)=O>>[C:2]([CH2:3][S:7][C:8]1[NH:9][C:10](=[O:19])[CH:11]=[C:12]([CH2:16][CH2:17][CH3:18])[C:13]=1[C:14]#[N:15])#[N:1]
Reactant: C1COCCN1
Reactant: CCCc1cc(=O)[nH]c(S)c1C#N
Agent: N#CCBr
Agent: NC(=O)CBr
Product: CCCc1cc(=O)[nH]c(SCC#N)c1C#N

Procedure:
The morpholine salt of 2-mercapto-6-oxo-4-propyl-1,6-dihydro-pyridine-3-carbonitrile (see above) was reacted with 2-bromoacetonitrile as described above for 2-bromoacetamide to provide 2-cyanomethylsulfanyl-6-oxo-4-propyl-1,6-dihydro-pyridine-3-carbonitrile. This nitrile (19.02 g, 81.53 mmol) and N-phenyltrifluoromethanesulfonimide (29.59 g, 82.00 mmol) were dissolved in 100 mL of dry dioxane. Diisopropylethylamine (19.3 mL, 135 mmol) was added and the mixture was stirred at room temperature under argon for 4 h. The solvent was concentrated. The residue was dissolved in EtOAc and ether and the resulting solution was filtered through a pad of silica gel which was washed with ether. The filtrate was concentrated and the resulting yellow solid was collected by filtration and dried under vacuum to provide trifluoro-methanesulfonic acid 5-cyano-6-cyanomethylsulfanyl-4-propyl-pyridin-2-yl ester (18.45 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=O.C([O-])(=[O:25])C.[NH4+:27]>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12]1)=[N:27][OH:25]
Reactant: O=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Reactant: CC(=O)[O-]
Reactant: [NH4+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
To the compound (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone (22 g) in 95% ethanol (350 ml) and water (100 ml) was added NH2OHHCl (10.1 g) and ammonium acetate (12.7 g, 2.1 eq). The resulting mixture was refluxed for 3.5 hours. The mixture was then allowed to stir at room temperature for 24 hours. The reaction mixture was concentrated to remove ethanol, poured into water (500 ml), and extracted with dichloromethane (500 ml). This was followed by washing with water, brine, and drying over magnesium sulfate. The product was concentrated to an oil and purified by column chromatography to yield 12 g of (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime.
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.O.[F-:13].[K+]>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(F)c1ccc(I)cc1

Procedure:
p-Iodobenzenesulfonyl chloride (593 g, 1.96 mol), prepared as described in Example 1(a) above, is dissolved in 2.5 L of acetone and placed in a 5 L three-neck round-bottom flask fitted with a heating mantle, mechanical stirring and a water-cooled condenser. Potassium fluoride (126 g, 2.17 mol) and about 25 mL of water is added and the reaction is heated at reflux for approximately 5 hours. On cooling, the reaction mass is filtered and the solvent removed to provide a crude solid, which on purification, by distillation under high vacuum, affords p-iodobenzenesulfonyl fluoride as a white solid; yield 504 g (90%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11])[CH3:2].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:12]([N:14]1[CH2:15][C:16](=[O:17])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[C:10]1=[S:11])[CH3:13]
Reactant: CCNCC(=O)O
Reactant: CCc1ccccc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1ccccc1N1C(=O)CN(CC)C1=S
Yield: 36.8 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 16.3 g of 2-ethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-10% ethyl acetate in hexane). Crystallization from diethyl ether afforded the title compound (9.12 g) as a white solid, m.p. 71°-73° C. Anal. Calcd. for. C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.81; H, 6.43; N, 11.17. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.O.[OH-].[Na+]>C(O)(=O)C>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[CH2:21][C:9]1[C:10]([O:17][CH:18]([F:19])[F:20])=[N:11][C:12]2[C:7]([C:8]=1[CH3:30])=[C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(F)cc3F)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(Cc2ccc(F)cc2F)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12

Procedure:
A solution of [3-(2,4-difluorobenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.20 g), methanol (10 mL), water (0.8 mL) and 5.0 M aqueous sodium hydroxide solution (0.4 mL) was stirred at room temperature for 2 hour. The pH of the mixture was adjusted to 5 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water and the solid collected by filtration, washed with water and dried to afford title compound as a white solid, 0.030 g.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].[N+](C1C=C[C:20]([O:23]C(Cl)=O)=CC=1)([O-])=O.CCN(CC)CC.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([CH2:53][C:54]2([C:58]([OH:60])=[O:59])[CH2:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>C(Cl)Cl>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:20]([NH:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][C:54]3([C:58]([OH:60])=[O:59])[CH2:57][CH2:56][CH2:55]3)[CH2:49][CH2:48]2)=[O:23])[C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: NCC1CCN(CC2(C(=O)O)CCC2)CC1
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)O)CCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 216.7 %

Procedure:
A mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (486 mg, 2.8 mmol) and chloroformic acid 4-nitrophenyl ester (556 mg, 2.8 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 5 min. To this mixture, Et3N (0.84 mL, 6.1 mmol) was added slowly and this mixture became a solution. This solution was added to a mixture of 1-{[4-(aminomethyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid 4-methylbenzene sulfonate (1.1 g, 2.8 mmol, Step 7) in CH2Cl2 (5 mL) at room temperature. After stirring for 10 min, Et3N (0.38 mL, 2.8 mmol) was added and the resulting mixture was stirred at room temperature for 2 hr. This mixture was washed with 0.5 N HCl aq (10 mL) and saturated NaHCO3 aq (10 mL) then the organic layer was concentrated. To the residue, saturated NaHCO3 aq (15 mL) and heptane (15 mL) was added at room temperature and it was stirred for 6 hrs at that temperature. Solid was observed and this mixture was filtered. The obtained solid was washed with H2O and heptane. After drying, crude material was obtained (1.0 g, 82%) as white solid. This crude material (4.0 g) was purified by recrystallization from toluene (36 mL) to give 2.6 g of the titled compound (66%) as white solid.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N)(OC(C)(C)C)=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:17])[CH3:2]
Reactant: O=CCc1ccccc1C1CCNCC1
Reactant: CC(C)(C)OC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ccccc1C1CCNCC1

Procedure:
A solution of 4-(2-oxoethylphenyl)-piperidine-N-Boc-amine was stirred in a solution of DCM (3 mL) and trifluoroacetic acid (1 mL) for 1 h, concentrated under reduced pressure, residual solvent was coevaporated twice from methanol, and dried under high vacuum to provide the N-deprotected 4-(2-acetylphenyl)piperidine. Using standard reductive amination conditions 4-(2-acetylphenyl)piperidine was reacted with N-[2-(S)-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-3-cyano-1-naphthamide and converted to the citrate salt. MS m/z 612 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:23][CH2:22]2)[C:17]1=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(F)cc4)cc3Cl)C2=O)CC1
Yield: 73.8 %

Procedure:
Treat a solution of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 29) (0.10 g, 0.19 mmol) in CH2Cl2 (3 mL) with methanesulfonyl chloride (0.02 mL, 0.28 mmol) and triethylamine (0.07 mL, 0.48 mmol) and stir the reaction for 1 hr at room temperature. Quench the reaction with 1N HCl and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 0.07 g (73%) of product. MS (m/e): 500 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][NH2:8])[CH:4]=[N:3]1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1cc(CN)cn1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 8 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (1-methyl-1H-pyrazol-4-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 8% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J=8.1 Hz, 1H), 8.31 (br s, 2H), 7.69 (s, 1H), 7.50-7.30 (m, 5H), 6.30 (dd, J=8.1, 2.7 Hz, 1H), 6.13 (d, J=2.7 Hz, 1H), 5.13 (s, 2H), 3.82 (s, 2H), 3.77 (s, 3H), 2.52 (s, 3H); MS (ES+) m/z 436.1 (M+1).