Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:21])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24].[C:28](Cl)(=[O:31])[CH2:29][CH3:30].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:21])[C:10](=[N:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:28](=[O:31])[CH2:29][CH3:30])=[CH:18][CH:19]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:24])[CH3:25]
Reactant: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccc(O)cc3)n2C)ccc1Cl
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)Oc1ccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g (4.7 mmoles) of 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(4-hydroxyphenylimino)-3-methyl-4-thiazoline is suspended in 40 ml of dry chloroform. 0.4 g (4.7 mmoles) of propionyl chloride (dissolved in 10 ml of chloroform) and 1.4 g (18 mmoles) of pyridine are added in that order. A slightly exothermic reaction produces, temporarily, a solution from which a yellow solid precipitates. After stirring for 3 hours at room temperature, a further 0.4 ml of propionyl chloride is added. The resulting yellow solution is allowed to stand for 3 days at room temperature and then evaporated to dryness in vacuo, the residue is distributed between water and ethyl acetate, the organic phase is dried and evaporated and the residue is recrystallized from isopropanol. Colorless crystals of m.p. 155°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])[NH2:5].[CH3:11][O:12][C:13]([C:15]#[C:16][C:17](OC)=[O:18])=[O:14]>CO.CCCCCC>[Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[C:4]2[C:3]=1[C:17](=[O:18])[CH:16]=[C:15]([C:13]([O:12][CH3:11])=[O:14])[NH:5]2
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1cc(=O)c2c(Cl)c(Cl)c(Cl)cc2[nH]1
Temperature: 240 °C
Yield: 32.4 %

Procedure:
3,4,5-Trichloroaniline (25 g, 0.127 mol) and dimethylacetylene dicarboxylate (10.9 ml, 0.12 mol) were dissolved in dry methanol (300 ml) at 0° C. then heated at reflux for 14 h. The mixture was allowed to cool, then diluted with hexane (200 ml) and the yellow solid which precipated was collected by filtration and heated in diphenyl ether (200 ml) at 240° C. for 10 minutes. The reaction mixture was allowed to cool to room temperature and diluted with hexane. The solid which deposited was collected and recrystallised from acetone (500 ml) to give methyl 5,6,7-trichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (11.91 g), m.p. 295°-296° C. (decomp), δ (360 MHz, DMSO-d6) 3.96 (3H, s, CH3), 6.63 (1H, s, 3-H) and 8.17 (1H, s, 8-H) (Found C, 43.09; H, 1.70; N, 4.47%, C11H16NO3Cl3 requires C, 43.10; H, 1.97; N, 4.57%).
Reaction SMILES: [CH2:1]([C:3]([C:5](C1C=NC=CC=1)=[CH:6][N:7]([CH3:9])[CH3:8])=[O:4])[CH3:2].C(C(C[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=O)C>>[CH2:1]([C:3]([C:5]([C:26]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1)=[CH:6][N:7]([CH3:9])[CH3:8])=[O:4])[CH3:2]
Reactant: CCC(=O)C(=CN(C)C)c1cccnc1
Reactant: CCC(=O)Cc1cccnc1
Product: CCC(=O)C(=CN(C)C)c1ccncc1

Procedure:
A-11. 1-(3-Pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone using (3-pyridinyl)methyl ethyl ketone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[CH2:14][S:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:10])=[C:4]([C:28](=[O:45])[NH:29][C:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=3)[N:31]=2)[CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[CH2:14][S:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:10])=[C:4]([C:28](=[O:45])[NH:29][C:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:44])[F:42])[CH:36]=3)[N:31]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(4-chloro-2-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-ylcarbamoyl)phenylcarbamoyl)benzylthio)propanoate (150 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (4 mL), trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 48.9 mg (36%) of a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 12.21 (s, 1H), 11.73 (s, 1H), 11.56 (s, 1H), 8.68 (m, 1H), 8.49 (m, 1H), 8.10 (m, 3H), 7.92 (s, 1H), 7.73 (m, 7H), 7.01 (d, J=3 Hz, 1H), 3.86 (s, 2H), 2.59 (m, 2H). MS (ES, m/z): 625 [M+Na]+.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:34])[C:11]([CH3:33])([CH3:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[C:23]([CH3:29])([CH3:30])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([O:31][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([CH3:33])([CH3:32])[C:10]([O:9][CH2:7][CH3:8])=[O:34])[CH3:28]
Reactant: CCOC(=O)C(C)(C)CCCCCC(O)CCCCCC(C)(C)C(=O)OCC
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CCCCCC(CCCCCC(C)(C)C(=O)OCC)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Under nitrogen atmosphere, 3,4-dihydro-2H-pyran (10.2 g, 121 mmol) was added dropwise to a stirred solution of 8-hydroxy-2,2,14,14-tetramethypentadecanedioic acid diethyl ester (16.1 g, 40 mmol) and p-toluenesulfonic acid monohydrate (catalytic amounts) in methylene chloride (100 mL) under cooling with an ice bath. The reaction mixture was allowed to warm to room temperature and stirred overnight. After the reaction was completed (TLC), the solution was filtered through basic aluminum oxide (50 g), which was washed with methylene chloride (4×30 mL). The filtrate was concentrated in vacuo to give crude product (19.5 g), which was purified by chromatography (silica gel, 200 g, heptanes/ethyl acetate=20:1, 10:1) yielding 2,2,14,14-tetramethyl-8-(tetrahydropyran-2-yloxy)-pentadecanedioic acid diethyl ester as a colorless oil (12.1 g, 62%). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.69-4.59 (m, 1H), 4.11 (q, J=7.3 Hz, 4H), 3.98-3.82 (m, 1H), 3.65-3.40 (m, 2H), 2.00-1.18 (m, 26H), 1.24 (t, J=7.1 Hz, 6H), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 177.74, 97.36, 76.48, 62.61, 60.02, 42.05, 40.70, 40.63, 34.90, 33.38, 31.16, 30.32, 30.26, 25.48, 25.10, 24.86, 19.96, 14.23.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([NH2:13])[CH2:8][O:7]2)([O-:3])=[O:2].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:21][CH2:22][C:23]([NH:13][C@@H:9]1[CH2:8][O:7][C:6]2=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]2[CH2:10]1)=[O:24]
Reactant: NC1COc2nc([N+](=O)[O-])cn2C1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
Under argon protection, I-7-(S)-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-amine (134 mg, 0.73 mmol) was dissolved in anhydrous DMF (2 mL), added triethylamine (0.3 mL, 2.18 mmol), added dropwise chloroacetyl chloride (0.082 mL, 1.09 mmol) at 0° C., stirred for 2 h at room temperature, added saturated sodium bicarbonate solution, extracted by ethyl acetate, followed by anhydrous sodium sulphate drying and suction filtration, spun dry solvents, separated by column chromatography to give 92 mg yellow viscous liquid, yield was 50%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:35](OC(OCC)OCC)C>[Pt].C1(C)C=CC=CC=1>[N:14]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=[CH:35]1
Reactant: CCOC(OCC)OCC
Reactant: O=C(NCCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: O=C(NCCCCCn1cnc2cnc3ccccc3c21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
A catalytic amount of platinum on carbon was added to a suspension of N1-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide (5 g, 13.2 mmol) in toluene (250 mL). The reaction mixture was placed under a hydrogen atmosphere at 50 psi (3.4×104 pascals) on a Parr apparatus. After about 2 hours an oily ball had formed in the bottom of the Parr bottle. Magnesium sulfate and additional catalyst were added and the hydrogenation was continued overnight. The reaction mixture was filtered to remove the catalyst. The residue in the Parr bottle was combined with isopropyl alcohol (150 mL), heated on a steam bath and then filtered. HPLC analysis indicated that both filtrates contained product so they were combined and concentrated under vacuum to provide crude N1-{5-[(3-aminoquinolin-4-yl)amino]pentyl}benzamide. This material was combined with toluene (250 mL). Triethylorthoformate (4 g, 26.4 mmol) was added and the reaction mixture was heated at reflux with a Vigreux column for 2 hours. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration to provide 3.4 g of N1-[5-(1H-imidazo[4,5-c]quinolin-1-yl)pentyl]benzamide as a solid, m.p. 171.5-172.5° C. 1H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.43 (t, J=6.0 Hz, 2H), 8.38 (m, 1H), 8.18 (m, 1H), 7.80 (d, J=7.0 Hz, 2H), 7.73 (m, 2H), 7.51 (t, J=7.0 Hz, 1H), 7.45 (t, J=7.0 Hz, 2H), 4.72 (t, J=7.5 Hz, 2H), 3.25 (q, J=6.0 Hz, 2H), 1.94 (quintet, J=7.5 Hz, 2H), 1.58 (quintet, J=7.5 Hz, 2H), 1.40 (quintet, J=8.5 Hz, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])C(C(F)(F)F)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.[C:41](O)([C:43]([F:46])([F:45])[F:44])=O>C(Cl)Cl>[CH3:38][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:39])[NH:21][C:9]4[CH:10]=[C:41]([C:43]([F:46])([F:45])[F:44])[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M202) (285 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (67 mg, 29%).
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[F:28][C:29]1[CH:41]=[CH:40][C:32]2[S:33][CH:34]=[C:35]([CH2:36][CH2:37][CH2:38][NH2:39])[C:31]=2[CH:30]=1>CS(C)=O.C(=O)(O)[O-].[Na+]>[F:28][C:29]1[CH:41]=[CH:40][C:32]2[S:33][CH:34]=[C:35]([CH2:36][CH2:37][CH2:38][NH:39][CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[C:31]=2[CH:30]=1
Reactant: NCCCc1csc2ccc(F)cc12
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CNCCCc1csc2ccc(F)cc12)O3
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.6 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (151 mg, 0.669 mmol) and 3-(5-fluoro-benzo[b]thiophen-3-yl)-propylamine (140 mg, 0.335 mmol) in anhydrous dimethylsulfoxide (7 mL) was stirred at ambient temperature for three days without any apparent reaction occurring. The reaction was then heated at 40° C. for two days, resulting in complete conversion. The cooled reaction was diluted with saturated aqueous sodium bicarbonate (35 mL) and extracted with ethyl acetate (3×35 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacua. Flash chromatography on silica gel (2/2/96 methanol/2 M ammonia in methanol/methylene chloride) afforded 90 mg (63%) of the title compound as a yellow viscous oil, which was converted to its fumarate salt as a yellow solid: mp 117-120° C.; MS (ES) m/z 423 [M+H]+; [α]D −29.1° (c 0.94, DMSO)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][Si:22]([CH3:24])([CH3:23])[C:25]#[C:26][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1
Reactant: CCCS(=O)(=O)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)c1cccc(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-bromo-3-(propylsulfonyl)benzene (Intermediate 5; 23 g, 88 mmol) in THF (450 ml) was treated with Pd(dppf)Cl2 (3.9 g, 5.3 mmol), triethylamine (13.4 g, 132 mmol) and trimethylsilyl acetylene (8.64 g, 88 mmol). The reaction mixture was stirred at RT for 10 minutes, then cuprous iodide (1.0 g, 5.3 mmol) was added, the reaction mixture was heated at 60° C. for 24 h. The reaction mixture was filtered to remove the solid and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography using petroleum ether and ethyl acetate (98:2) as a eluent to afford the title compound as a brown oil.
Reaction SMILES: [CH3:1]N(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2.CI.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:1][O:19][C:18]([CH:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([O:7][CH3:6])[CH:9]=[CH:10][CH:11]=2)[CH2:16]1)=[O:20]
Reactant: COc1cccc2c1CC(C(=O)O)CC2
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)C1CCc2cccc(OC)c2C1
Reaction time: 8 h

Procedure:
To a DMF solution (30 mL) of 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (5.0 g, 24 mmol) was added MeI (7.1 g, 50 mmol) and K2CO3 (6.9 g, 50 mmol). The mixture was allowed to stir overnight and ethyl acetate (200 mL) was added. The resulting solution was washed with water (3×50 mL) and brine (50 mL) to provide 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester (6.6 g).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][C@@H:16]([OH:19])[CH2:17][CH3:18]>>[C@H:16]([O:19][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH2:17][CH3:18])[CH3:15]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CC[C@@H](C)O
Product: CC[C@@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example A14(c) from 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) and (R)-butan-2-ol. MS (m/e): 271.1 ([M−H]−, 100%)
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].CC[O-].[Na+].CN(C)[CH:11]=[C:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:13](=O)[CH3:14]>C(O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2[C:13]([CH3:14])=[N:1][C:2](=[O:3])[NH:4][CH:11]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=CN(C)C)C(C)=O)cc1
Reactant: NC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2c[nH]c(=O)nc2C)cc1
Temperature: 0 °C
Yield: 49.4 %

Procedure:
24.4 g of urea and 120 ml of a 25 percent ethanolic solution of sodium ethylate are added to a solution of 40.0 g of 4-dimethylamino-3-(4-methoxyphenyl)-3-buten-2-one in 120 ml of ethanol. The mixture is heated at the reflux temperature for 8 hours, then cooled to 0° C., and the reaction product is filtered off with suction and washed with cold ethanol. The residue is dissolved in water and, while cooling in ice, is neutralised with dilute hydrochloric acid. The precipitated product is filtered off with suction, washed with water and dried. 19.5 g of 5-(4-methoxyphenyl)-4-methyl-2-(1H)-pyrimidinone are obtained. Melting point 210° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([SH:9])=[N:5][S:6][C:7]=1[SH:8])#[N:2].[Na].[Na].Cl.Cl[CH2:14][C:15]([NH2:17])=[NH:16]>C(O)C>[C:15]([CH2:14][S:9][C:4]1[C:3]([C:1]#[N:2])=[C:7]([SH:8])[S:6][N:5]=1)(=[NH:16])[NH2:17]
Reactant: N=C(N)CCl
Reactant: N#Cc1c(S)nsc1S
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#Cc1c(SCC(=N)N)nsc1S
Reaction time: 2 h
Yield: 54 %

Procedure:
In 40 ml of 50% aqueous ethanol was dissolved 2.18 g of disodium 4-cyano-3,5-dimercaptoisothiazole, to which 1.29 g of α-chloroacetamidine hydrochloride was added. The mixture was stirred for 2 hours, concentrated under reduced pressure, diluted with water and adjusted to pH 5.2. The precipitating crystals were collected by filtration and washed with water and then ethanol to give 1.23 g of 3-amidinomethylthio-4-cyano-5-mercaptoisothiazole as gray crystals (mp 198°-201° C., decomp.).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:12]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(SC)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (prepared as in Example 89, 1.73 g, 5 mmol) in tetrahydrofuran/water (20 mL, 3:1) was treated with lithium hydroxide (419 mg, 10 mmol). The reaction was stirred at 25° C. for 24 h. At this time, the reaction was diluted with water (50 mL) and extracted with ether (1×50 mL). The aqueous layer was acidified to pH=2 with a 2N aqueous hydrochloric acid solution. The product was extracted into methylene chloride (3×75 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (3×100 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with 90/10 hexanes/ether to afford 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (1.05 g, 63.65%) as a white solid: mp 105–106° C.; EI-HRMS m/e calcd for C16H19F3O2S (M+) 332.1058, found 332.1055.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[Br:19][C:20]1[CH:21]=[C:22]([NH2:31])[CH:23]=[C:24]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:31][C:22]2[CH:23]=[C:24]([C:26]3[NH:30][N:29]=[N:28][N:27]=3)[CH:25]=[C:20]([Br:19])[CH:21]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: Nc1cc(Br)cc(-c2nnn[nH]2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cc(Br)cc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (250 mg, 1.1 mmol) in CH2Cl2 (6 mL) was added 3-bromo-5-(1H-tetrazol-5-yl)-phenylamine dihydrochloride (prepared as described in Part C, 365 mg, 1.32 mmol), HBTU (626 mg, 1.65 mmol) and DIPEA (0.576 ml, 3.3 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with CH2Cl2 and successively washed with 1M aqueous HCl solution (30 mL) and a saturated aqueous NaHCO3 solution. The organic phase was dried (phase separator) and evaporated under vacuum. The crude mixture was purified by preparative HPLC (C18 Nucleosil 100-10, flow: 40 ml/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA). After combination of the purified fractions, CH3CN was removed under vacuum and lyophilization gave the desired compound. MS (LC/MS): 447.1 [M−H]−; tR (HPLC conditions k): 4.62 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O>ClCCl>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[Br:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccsc1Br
Temperature: 65 °C

Procedure:
According to the method described in WO2005070916, A boiling solution of tert-Butyl-N-(thiophen-3-yl)carbamate (5.32 g, 26.70 mmol) in dichloromethane (260 ml) was treated portionwise with N-bromo-succinimide (4.73 g, 26.70 mmol) under vigorous stirring. After addition was complete, the heating bath temperature was raised to 65° C. and maintained for 20 minutes before allowing the reaction to cool to room temperature. The reaction mixture was washed with water, dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes:EtOAc) gave a clear oil which crystallized on standing (7.24 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][CH2:10][C@@H:9]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C@@H:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[NH:11][CH2:10][C@@H:9]3[CH2:13][NH:14][CH2:15][C@@H:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1NC[C@@H]1CNC[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-cis tert-butyl 6-methoxy-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate (25 mg, 0.082 mmol) in 4 mL methylene chloride was added 1 mL trifluoroacetic acid. The reaction was allowed to stir at ambient temperature for 2 h and then was concentrated in vacuo to afford a TFA salt. This material was free-based by partitioning between methylene chloride and aq. ammonium hydroxide. The organics were washed with brine, dried (Na2SO4) and concentrated to afford 10 mg (60%) of the title compound of Example 10. 1H NMR (CDCl3): δ 6.76-6.62 (m, 3H), 4.42 (broad s, 1H), 3.85 (s, 3H), 3.50-3.23 (overlapping m, 5H), 2.98-2.80 (m, 2H), 2.65-2.57 (m, 1H). LRMS (ESI): 205.3 (M+H)+.