Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:22])[C@@H:12]1[CH2:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]1[CH2:20][CH3:21].ClC1C([C:30]([F:33])([F:32])[F:31])=CC=CC=1CN>>[Cl:1][C:2]1[C:7]([C:30]([F:33])([F:32])[F:31])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:22])[C@@H:12]1[CH2:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]1[CH2:20][CH3:21]
Reactant: CCN1C(=O)C(C)(C)C[C@H]1C(=O)NCc1ccc(F)cc1Cl
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Product: CCN1C(=O)C(C)(C)C[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl

Procedure:
N-{[2-Chloro-3-(trifluoromethyl)phenyl]methyl}-1-ethyl-4,4-dimethyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide (E130) but using {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine in the place of [(2-chloro-4-fluorophenyl)methyl]amine.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[C:12](I)[C:11]([Cl:15])=[CH:10][N:9]=1.[NH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[C:25](=[O:27])[N:24]([CH3:28])[CH2:23][CH2:22]2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:7][C:8]1[CH:13]=[C:12]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[C:25](=[O:27])[N:24]([CH3:28])[CH2:23][CH2:22]3)[C:11]([Cl:15])=[CH:10][N:9]=1
Reactant: CN1CCc2cccc(N)c2C1=O
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN1CCc2cccc(Nc3cc(Cl)ncc3Cl)c2C1=O
Temperature: 80 °C
Yield: 71.8 %

Procedure:
Palladium(II) acetate (0.093 g, 0.41 mmol) was added to 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.360 g, 0.62 mmol), cesium carbonate (6.76 g, 20.74 mmol), 2,5-dichloro-4-iodopyridine (2.84 g, 10.37 mmol) and 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (1.827 g, 10.37 mmol) in dioxane (100 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 18 hours then allowed to cool to room temperature. The mixture was filtered and then evaporated. The residue was dissolved in EtOAc (100 mL), and washed sequentially with a saturated solution of NaHCO3 (50 mL), water (50 mL), and finally with a saturated solution of NaCl (50 mL). The organic layer was separated, dried over MgSO4, and then evaporated. The residue was triturated with Et2O to leave a solid. The solid was purified by chromatography on silica, eluting with a gradient of 0-5% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to afford 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (2.398 g, 72% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.97 (2H, t), 3.05 (3H, s), 3.57 (2H, t), 7.00 (1H, m), 7.34 (1H, s), 7.44-7.51 (2H, m), 8.31 (1H, s), 11.63 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=322.29 and 324.28 and 326.29.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:29][CH2:30][C@H:31]([OH:41])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[OH:41][C@H:31]([CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[CH2:30][NH:29][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2)CC1
Product: O=S(=O)(Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1)c1ccc(-c2ccccn2)s1

Procedure:
The title compound was prepared from 5-pyridin-2-yl-thiophene-2-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 227) and 4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtained in Example 5) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.80–1.90 (m, 2 H), 2.40–2.80 (m, 5 H), 3.50–3.60 (m, 2 H), 3.70–3.90 (m, 3 H), 4.99 (brs, 1 H), 6.66 (d, J=8.0 Hz, 2 H), 6.75 (d, J=8.0 Hz, 2 H), 6.83 (d, J=9.0 Hz, 2 H), 6.96 (d, J=9.0 Hz, 1 H), 7.36 (dd, J=4.4, 1.7 Hz, 1 H), 7.41 (d, J=4.0 Hz, 1 H), 7.76 (d, J=4.0 Hz, 1 H), 7.88 (dd, J=8.0, 1.7 Hz, 1 H), 8.00(d, J=8.0 Hz, 1 H), 8.54 (d, J=4.4 Hz, 1 H), 8.89 (s, 1 H); MS (ES) m/z: 580.9 (MH+); HRMS Calcd. for C29H33N4O5S2 (MH+): 581.1892. Found: 581.1910.
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:47])[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]([S:34]([C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1[O:45][CH3:46])(=[O:36])=[O:35])[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1COCC1>[Cl:27][C:25]1[CH:26]=[C:21]2[C:22](=[CH:23][CH:24]=1)[N:28]([S:34]([C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1[O:45][CH3:46])(=[O:36])=[O:35])[CH:29]([C:30]([O:32][CH3:33])=[O:31])[C:20]2([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])[OH:47]
Reactant: COC(=O)CN(c1ccc(Cl)cc1C(=O)c1ccccc1Cl)S(=O)(=O)c1cc(OC)ccc1OC
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1N(S(=O)(=O)c2cc(OC)ccc2OC)c2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 1 h

Procedure:
In a parallel procedure, 400 mg of the compound prepared in step B are dissolved in 3 ml of anhydrous THF at -78° C. under argon and 2.2 ml of the solution prepared above are added over 5 minutes, followed by 0.4 ml of HMPA. After 1 hour, a further 0.5 ml of the solution prepared above is added, the mixture is then left to stand for 1 hour at -78° C. and, finally, water is added and the mixture is extracted with ether.
Reaction SMILES: Br[CH2:2][C:3](=[O:7])[C:4]([OH:6])=[O:5].[CH3:8][N:9]1[C:14](=[O:15])[N:13]2[CH:16]=[N:17][C:18]([C:19](=[S:21])[NH2:20])=[C:12]2[N:11]=[N:10]1>C(#N)C>[NH:20]=[C:19]([C:18]1[N:17]=[CH:16][N:13]2[C:14](=[O:15])[N:9]([CH3:8])[N:10]=[N:11][C:12]=12)[S:21][CH2:2][C:3](=[O:7])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(=O)CBr
Reactant: Cn1nnc2c(C(N)=S)ncn2c1=O
Solvent: CC#N
Product: Cn1nnc2c(C(=N)SCC(=O)C(=O)O)ncn2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromopyruvic acid (1.388 g; 8.3 mmol) in dry acetonitrile (20 mL) was added 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (1.000 g; 4.8 mmol). The mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The residue was washed with DCM (3×15 mL) and diethyl ether (2×20 mL) and the pale yellow solid (1.20 g; 84%) was used without further purification.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:7][C:6]([CH:9]=[N:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:5][CH:4]=1>CO>[C:3]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:4]=[CH:5][C:6]([CH2:9][NH:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:7][CH:8]=1
Reactant: C(=NC1CN2CCC1CC2)c1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(-c2ccc(CNC3CN4CCC3CC4)cc2)cc1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Sodium borohydride (260 mg) was added to a stirred solution of 3-[(biphenyl-4-ylmethylene)amino]quinuclidine (990 mg) in methanol (50 ml) and the reaction mixture stirred for 2 hours. The methanol was evaporated and the residue dissolved in 1M hydrochloric acid (12 ml). The aqueous solution was washed with diethyl ether (3×25 ml) before the addition of excess sodium hydroxide solution (density 1.35 g/cm3) to pH 14. The mixture was extracted with diethyl ether, the ether separated, dried (Na2SO4) and evaporated. An excess of saturated ethereal hydrogen chloride was added to precipitate a solid which was crystallised from methanol/ethyl acetate to give 3-[(biphenyl-4-ylmethyl)amino]quinuclidine (820 mg) as a colourless solid, m.p. 180°-181° C., microanalysis, found: C, 62.8; H, 7.3; N, 7.4%; C20H24N2 2HCl.H2O requires: C, 62.7; H, 7.3; N, 7.3%; NMR: ([CD3 ]2SO): 1.7-2.0(3H, m), 2.2-2.4(1H, m), 2.6(1H, s), 3.1-3.8(8H, m) 4.2(2H, s), 7.3-7.5(3H, m) and 7.6-7.8(6H, m); m/z 293 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]>C1COCC1>[OH:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:12][CH:11]=1
Reactant: CCOc1ccc(C(=O)O)cc1
Reactant: NCCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)NCCCCO)cc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A 22-L, 3-necked, round-bottom flask equipped with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, was charged with 1.16 kg of 4-ethoxybenzoic acid and 11 L of THF. A total of 1.403 kg (8.65 mole, 1.24 eq) of 1,1′-carbonyldiimidazole was added at ambient temperature in 4 portions (to control CO2 evolution) to attain a conversion of 98% to the activated acid. After the yellow solution was cooled to −5° C., a solution prepared from 684.5 g (7.68 mole, 1.10 eq) of 4-amino-1-butanol in 0.5 L of THF was added over a period of 50 min while maintaining a temperature of −7 to −3° C. The gummy mixture was allowed to warm to room temperature and stir overnight. The light-yellow solution was concentrated (45° C., 50 mbar) to 3.22 kg of an orange oil that was charged to an extractor along with 5.7 kg of 10% HCl and 6 L DCM. The aqueous phase was extracted with 3 L DCM. The DCM extracts were combined, washed with 5 L of 0.5 N HCl, washed with 5 L of saturated aq. NaHCO3, dried (MgSO4), filtered, concentrated (45° C., 25 mbar), and air dried to give 1.52 kg (91.9%) of crude product as a white solid. Impurities were removed by saponification. A 12-L, 3-necked, round-bottom flask equipped with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, was charged with 1.52 kg of crude product, 5.5 L of IPA and 156.5 g of 50% NaOH. The mixture was heated for 30 min at 55-78° C. After cooling to 37° C., the hazy solution was charged into an extractor along with 7.8 L of water and 17 L of DCM. After the phases were separated, the aqueous layer was is extracted with 6 L of DCM. The organic extracts were combined, washed with 7.8 L-of water, dried (MgSO4), filtered, concentrated (50° C., 25 mbar) and air dried to give 1.453 kg (87.7%) of N-(4-hydroxybutyl)-4-ethoxybenzamide (V-5) as a white lumpy solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[NH2:18][C:16](=[NH:15])[S:17][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NC(N)=S
Reactant: CCOC(=O)c1c(C)nn(C)c1CCl
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(C)c1CSC(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.4 %

Procedure:
A solution under nitrogen was prepared from 10.7 g of the compound produced in Example 1 and 3.95 g of thiourea in 200 ml of ethanol. After refluxing the solution four hours, it was allowed to stir at room temperature overnight. The solvent was removed under reduced pressure. Then, the residue was triturated with hexane to give 16 g of solid (wet weight), m.p. 175°-180° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].CN[CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][CH:9]5[CH2:2][CH2:3][O:5][CH2:44][CH2:43]5)[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CC5CCOCC5)c4)cc23)CC1
Yield: 16.4 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl(tetrahydro-2H-pyran-4-ylmethyl)amine (129 mg, 1.0 mmol) for N-methylethanamine to afford 11.0 mg of the title compound (16.4%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:3]1[CH3:17].C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:17][C@H:3]1[C:2](=[O:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: C[C@H]1[C@@H](O)CCN1C(=O)OCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a solution (150 mL) of benzyl (2S,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (20.5 g) in acetonitrile were added molecular sieves 4A powder (25 g) and 4-methylmorpholine-N-oxide (20.4 g), and the mixture was cooled to 0° C. tetra-n-Propylammonium perruthenate (3.0 g) was added, and the mixture was stirred at 0° C. for 1 hr and at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate. The insoluble material was filtered through Hyflo Super-Cel. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1→2/1) to give the title compound as a colorless oil (yield: 18.0 g, yield: 89%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].FC1[CH:17]=[C:18](C=CC=1OCCOC)[C:19](O)=[O:20].FC1C=C(C=CC=1F)C(O)=O>>[CH2:19]([O:20][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])[CH2:18][CH3:17]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: COCCOc1ccc(C(=O)O)cc1F
Agent: O=C(O)c1ccc(F)c(F)c1
Product: CCCOc1ccc(C(=O)O)cc1C(F)(F)F

Procedure:
3-Methoxypropan-1-ol (217 mg, 2.40 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (500 mg, 2.40 mmol), and NaH (240 mg, 6.0 mmol) were combined in THF (10 mL) and DMF (1 mL) at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was partitioned between ethyl acetate and a 1M aqueous solution of hydrochloric acid. The layers were separated and then the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude material was purified by column chromatography utilizing a gradient of 0-5% methanol in dichloromethane to yield 4-(3-methoxypropoxy)-3-(trifluoromethyl)benzoic acid (213 mg, 32%) as a white solid. ESI-MS m/z calc. 278.1. found 279.3 (M+1)+; Retention time: 1.38 minutes (3 min run). 4-Propoxy-3-(trifluoromethyl)benzoic acid was prepared from 4-fluoro-3-(trifluoromethyl)benzoic acid and 3-fluoro-4-(2-methoxyethoxy)benzoic acid was prepared from 3,4-difluorobenzoic acid using the procedure described above.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([CH2:42][OH:43])[CH2:22][CH2:21][N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([CH2:42][OH:43])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:3][CH2:2]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(CO)CCN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC3)ccc2n1CC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(CO)CCNCC3)ccc2n1CC1CC1
Reaction time: 0.33 h
Yield: 105.2 %

Procedure:
To a solution of (4-(1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)-1-tritylpiperidine-4-yl)methanol (STEP F, 300 mg, 0.453 mmol) in dichloromethane (6 mL) was trifluoroacetic acid (2 mL). After 20 min, the mixture was concentrated in vacuo and the residue was diluted with methanol and the solution was filtered through strong cationic exchange column (SCX). The column was washed with 1 mol/L ammonia methanol to wash out the product. The filtrate was concentrated in vacuo to give the title compound (200 mg, quantitative yield).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[C:16]([O:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][O:21][C:18]1[N:17]=[C:16]([O:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)[C:15]([S:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:36])=[O:5])(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: COc1ccc(S(=O)(=O)N[C@H](C=O)CC(=O)OC(C)(C)C)c(OCCc2ccnc3ccccc23)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@H](C=O)CC(=O)O)c(OCCc2ccnc3ccccc23)n1

Procedure:
(S)-3-[6-Methoxy-2-(2-quinolin-4-yl-ethoxy)-pyridin-3-sulfonylamino]-4-oxo-butyric acid tert-butyl ester (0.18 g, 0.35 mmol) was stirred in 5 mL of a solution of 25% TFA in CH2Cl2 at room temperature for 2 h. Analytical HPLC indicated the reaction was complete. The reaction mixture was concentrated. Residual TFA was azeotroped with toluene. The crude product was purified by preparative-scale reverse phase HPLC (0 to 30% acetonitrile in H2O with 0.1% TFA over 2.5 hours at 15 mL/min on Vydac 2.5×25 cm C18 column) to give 0.053 g (0.12 mmol, 33%) of (S)-3-[6-methoxy-2-(2-quinolin-4-yl-ethoxy)-pyridin-3-sulfonylamino]-4-oxo-butryric acid as a fluffy white solid. MS (APCI) m/z 460.2 (M+1). 1H NMR (300 MHz) CD3OD 9.03 (m, 1H), 8.63 (d, J=8.4 Hz, 1H), 7.94-8.23 (m, 5H), 6.39 (d, J=8.4 Hz, 1H), 4.97 (m, 2H), 4.43 (dd, 1H), 3.96 (m, 2H), 3.88 (d, 3H), 3.48 (m, 1H), 2.46-2.60 (m, 1H), 2.24-2.38 (m, 1H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH:16][CH:17]1[CH:22]([OH:23])[CH:21]([OH:24])[CH:20]([CH2:25][OH:26])[O:19][C:18]1=[O:27]>CO.C(=O)([O-])[O-].[Na+].[Na+]>[OH:19][CH:20]([CH:21]([OH:24])[CH:22]([OH:23])[CH:17]([OH:16])[CH2:18][OH:27])[C:25]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:26]
Reactant: O=C1OC(CO)C(O)C(O)C1O
Reactant: NCCCCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCCCCCCCCCCNC(=O)C(O)C(O)C(O)C(O)CO
Temperature: 25 °C
Reaction time: 30 h

Procedure:
3.5 g of 12-aminododecanoic acid are dissolved in 500 ml of methanol and, with 2.7 g of finely powdered sodium carbonate and 4.8 g of 3,4,5-trihydroxy-6-hydroxymethyltetrahydropyran-2-one, stirred at room temperature for 30 hours. The mixture is filtered off, the filtrate is concentrated and the residue is dissolved in 70 ml of water. With ice-cooling, 1N hydrochloric acid is added gradually until the pH is 1-2 (about 50-55 ml). The free acid precipitates out and is filtered off with suction, washed with a little cold water, and dried under high vacuum at 35° C. This gives 9 of molecular weight 393.48 (C18H35NO8); MS (ESI+): 394 (M+H+); (ESI+):392 (M−H)−.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (69 mg, 80%), MS (ISP) m/z=347.4 [(M+H)+], mp 235.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[O:7])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[O:7])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Product: CC(C(=O)O)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To fuming nitric acid (150 ml) was added p-chlorobenzoylpropionic acid (20.0 g), slowly portionwise at 0° C. After the addition was completed the resulting mixture was stirred at 0° C. for 30 minutes and the resulting white solid was suction filtered and washed with water until the pH of the washing liquids was neutral, then dried to yield 3-(4-chloro-3-nitrobenzoyl)propionic add as a white solid (13.0 g).
Reaction SMILES: C([S:4][CH:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11](=[O:24])[CH2:10][CH2:9]1)(=O)C.C[O-].[Na+]>CO>[O:24]=[C:11]1[CH2:10][CH2:9][C@H:8]([CH2:7][CH2:6][CH:5]([SH:4])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)SC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(S)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC

Procedure:
A solution of 606 mg. of ethyl 15-acetylthio-9-oxoprostanoate (Example 113) in 20 ml. of reagent methanol is treated, under nitrogen atmosphere, with 1.6 ml. of 1N methanolic sodium methoxide. After 10 minutes the reaction is quenched by the addition of 0.3 ml. of glacial acetic acid and taken to dryness. A solution of the residue in ether is washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to afford 428 mg. (89%) of an oil; λmax. 4.0 (sulfhydryl) and 5.78 μ (carbonyls).