Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:21]1[O:32][C:31]2[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=2[O:22]1>>[CH2:21]1[O:32][C:31]2[CH:30]=[CH:29][C:25]([C:26]([N:20]=[C:16]([N:7]3[CH2:6][C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=4[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[CH2:8]3)[O:17][CH2:18][CH3:19])=[O:27])=[CH:24][C:23]=2[O:22]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc2c(c1)OCO2)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,4-methylenedioxybenzoyl chloride, there is obtained ethyl N-(3,4-methylenedioxybenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 414 (5), 385 (7), 194 (100), 149 (33);
Reaction SMILES: [C:1]1([Si:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:9][CH2:10][O:11]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]1([Si:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:9][CH2:10][OH:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCC=C[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCC=C[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
The crude acetoxy compound from Example 14 is dissolved in 250 mL methanol, and 25.0 g of potassium carbonate is added all at once. After stirring for 2 hours, the reaction mixture is filtered and concentrated. The concentrated residue is partitioned between 200/200 mL water/ethyl acetate. The organic layer is removed, washed with brine, dried and concentrated. The crude material is purified by flash chromatography using silica gel to afford the pure product.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:35](=[O:38])(=[O:37])[NH2:36])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)[C:12]([O:14]CC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:35](=[O:38])(=[O:37])[NH2:36])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:23][CH:22]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(NCc2ccccc2)c(Oc2ccc(OCc3ccccc3)cc2)c(S(N)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccc(OCc2ccccc2)cc1
Reaction time: 40 h

Procedure:
A solution of ethyl 3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoate (2 g) in 1N sodium hydroxide (45 ml) was left standing at room temperature for 40 hours. Then the reaction mixture was adjusted to a pH of 2.5 by addition of 4N hydrochloric acid. The precipitated 3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. After drying, the compound was obtained with a melting point of 249°-251°C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH:16]([OH:17])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2 ml) solution of 3-bromopyridine (286 μl, 3 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 60 minutes. Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was added dropwise to the resulting brown solution. The temperature of the reaction mixture was raised gradually to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride and then, the mixture was extracted with ethyl acetate. The solvent was dried, followed by concentration under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1), whereby the title compound (296 mg, 45%) was obtained as needle crystals.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:18][C:19]1[C:20]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C2CCCCO2)=[O:29])[CH:24]=1>C(O)C>[F:18][C:19]1[C:20]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:39])=[O:40])[C:28]([NH:30][OH:31])=[O:29])[CH:24]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@](CCn1cc(F)c(-c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Yield: 52734.1 %

Procedure:
Pyridinium p-toluenesulfonate (22 mg, 0.088 mmol) was added to a solution of (2R)-4-(5-fluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (197 mg, 0.422 mmol). The solution was heated to reflux in ethanol (10 ml) and stirred at this temperature until complete. The solution was cooled to RT, and the volatiles were removed in vacuo. The solid was triturated in ethanol (5 mL), collected via filtration, then washed with ethanol (3×5 mL), hexanes (10 mL), and ether (3×10 mL). The solid was dried under vacuum to afford a white solid (85.1 g, 76.4%). LC-MS m/z 383.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3 H) 2.11-2.23 (m, 0 H) 2.41-2.55 (m, 1 H) 3.12 (s, 3 H) 3.73-3.84 (m, 1 H) 3.99-4.11 (m, 1 H) 6.53 (d, J=7.61 Hz, 1 H) 7.41-7.73 (m, 5 H) 8.04 (d, J=6.44 Hz, 1 H) 9.24 (s, 1 H) 11.10 (s, 1 H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH:8]([C@@H:11]1[CH2:15][O:14][C:13](=[O:16])[N:12]1[C:17]1[CH:18]=[C:19]([CH:23]2[C:32]([CH3:34])([CH3:33])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:35](O)=[O:36])[CH:29]=3)[NH:24]2)[CH:20]=[CH:21][CH:22]=1)([CH3:10])[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH:8]([C@@H:11]1[CH2:15][O:14][C:13](=[O:16])[N:12]1[C:17]1[CH:18]=[C:19]([CH:23]2[C:32]([CH3:34])([CH3:33])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:35]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:36])[CH:29]=3)[NH:24]2)[CH:20]=[CH:21][CH:22]=1)([CH3:10])[CH3:9]
Reactant: CS(N)(=O)=O
Reactant: CC(C)[C@@H]1COC(=O)N1c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1COC(=O)N1c1cccc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of 60% sodium hydride (290 mg, 7.3 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (703 mg, 7.4 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (300 mg, 0.74 mmol) and 1,1′-carbonyldiimidazole (300 mg, 1.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (71 mg, 20%) as a white solid: LC/MS m/e calcd for C25H31N3O5S (M+H)+: 486.61, observed: 486.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[CH3:1][C:2]1[N:3]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(C)c(C)cc2[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(C)nc2cc(C)c(C)cc21
Yield: 93.4 %

Procedure:
2,5,6-Trimethylbenzimidazole (9.4 g) and sodium hydride (2.1 g, 80% suspension in oil) were sonicated in dry tetrahydrofuran (150 ml) for 1 hour. Ethyl 2-bromoacetate (9.8 g) in dry tetrahydrofuran (50 ml) was added and the reaction sonicated at 40° C. for 2 hours. The reaction was partitioned between ethyl acetate (300 ml) and water (100 ml), the organic phase dried over magnesium sulphate and the solvent removed under reduced pressure to yield ethyl 2-(2,5,6-trimethylbenzimidazol-1-yl)acetate (13.5 g).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH2:28][CH3:29])=[N:17][N:18]3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)=[O:5])C.O1CCCC1.[OH-].[Na+]>CO>[CH2:28]([C:16]1[C:15]2[C:19](=[CH:20][C:12]([C:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH:8]=3)=[CH:13][CH:14]=2)[N:18]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[N:17]=1)[CH3:29]
Reactant: CCOC(=O)C1CC=C(c2ccc3c(CC)nn(-c4ccc(F)cc4)c3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nn(-c2ccc(F)cc2)c2cc(C3=CCC(C(=O)O)CC3)ccc12
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a stirred solution of 1.13 g (2.87 mmol) of 4-(3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl)-cyclohex-3-ene-carboxylic acid ethyl ester dissolved in 50 mL of methanol and 15 mL of tetrahydrofuran was added 8.62 mL (8.61 mmol) of 1N sodium hydroxide and reaction mixture heated to reflux for 3 hr. After 3 hr, the reaction mixture was concentrated on a rotary evaporator, diluted with 200 mL of H2O, acidified to pH 1 with 1N HCl and extracted 2×200 mL ethyl acetate. The organic extracts were combined, washed with water, brine and dried over Na2SO4. Filtration, concentration and drying gave crude product. Recrystallization from ethyl acetate/hexane gave 0.31 grams of white crystalline product. mp=214-216° C.; MS, m/z 365 (M+H+, base).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)#[N:2].[OH:42]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)(=[O:42])[NH2:2]
Reactant: OO
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Br)ccc32)C1c1cccc(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Br)ccc32)C1c1cccc(Cl)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.14 g, 0.22 mmol) prepared in Example 118 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.37 g, 3.3 mmol), then aqueous solution (1N) of NaOH (1.1 mL, 1.1 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield 0.12 g, 83%)
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][C:12]([NH2:14])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C(#N)C>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([NH:10][CH2:11][C:12]([NH2:14])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)CNc1ncccc1N

Procedure:
A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (19.6 g, 0.1 mole) in 160 ml of ethyl acetate was hydrogenated over 5% palladium on carbon (2.0 g) at ~55° C. overnight. The reaction mixture was warmed with acetonitrile and filtered through a Celite pad. The pad was washed with hot acetonitrile and the filtrate was evaporated to a solid. A 1.2-g sample of this solid was recrystallized from methanol-acetonitrile to give a light yellow solid, which was dried under high vacuum at room temperature to give 0.4 g, of title compound, m.p. 153°-55° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:21][O:22][C:23]1[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([NH:29][C:24]1[C:23]([O:22][CH3:21])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:7]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC2)cc1C(=O)O
Reactant: COc1cccnc1N
Product: COc1ccc(S(=O)(=O)N2CCCCC2)cc1C(=O)Nc1ncccc1OC

Procedure:
The entitled compound was produced according to the method of Example 92 but using 2-methoxy-5-(piperidin-1-ylsulfonyl)benzoic acid and 3-methoxypyridine-2-amine as the starting materials.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14])=[O:6].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>CN(C)C=O>[CH3:14][C:8]1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=1[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Cc1ccc(C(=O)CCCCl)c(C)c1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)CCCn2ccnc2)c(C)c1
Yield: 59 %

Procedure:
1-Chloro-4-(2,4-dimethylphenyl)-4-butanone (5.16 g) and imidazole (8.34 g) in dimethylformamide (10 ml) at 0° C. were stirred overnight at ambient temperature, then one day at 80° C. The resulting mixture was poured into water (200 ml), extracted with ether (3×75 ml) and the extracts were dried (magnesium sulfate) and evaporated. Chromatography of the product on silica gel eluting with 7% methanol in methylene chloride gave 3.5 g of 1-[4-(2,4-dimethylphenyl)butan-4-on-1-yl]imidazole.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C@@H:31]([C:33]1[CH:44]=[CH:43][C:36]2[O:37]C(C)(C)[O:39][CH2:40][C:35]=2[CH:34]=1)[OH:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([N:8]([CH2:30][C@H:31]([OH:32])[C:33]1[CH:44]=[CH:43][C:36]([OH:37])=[C:35]([CH2:40][OH:39])[CH:34]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCCOCCCc3cccc(S(N)(=O)=O)c3)Cc3ccccc3)ccc2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cccc(CCCOCCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(O)c(CO)c2)c1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a stirred, ice-cooled solution of 3-{3-[(7-{Benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}benzenesulfonamide (97.2 g) in IMS (417 ml) was gradually added aqueous 1M hydrochloric acid (417 ml) keeping the temperature below 15° C. The mixture was then stirred at room temperature for ca 5 h. Saturated sodium bicarbonate (417 ml) and ethyl acetate (1000 ml) were then added to the mixture. The organic layer was separated off, washed with water (400 ml), brine (400 ml) and finally dried (Na2SO4). Concentration in vacuo gave the title compound (87.9 g)—LC RT=4.01 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.[Li]C(C)(C)C.CCCCC.CON(C)[C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29]>CCOCC>[NH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29]
Reactant: CON(C)C(=O)C1CCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: Nc1ccccc1C(=O)C1CCCC1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To a stirred solution of phenyl-carbamic acid tert-butyl ester (1.2 g, 6.2 mmol) in Et2O (12 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (8.4 mL, 14.3 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopentanecarboxylic acid methoxy-methyl-amide (1.07 g, 6.8 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 1.03 g (68%) of (2-amino-phenyl)-cyclopentyl-methanone as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[F:34][C:35]([F:41])([F:40])[CH2:36][C:37](Cl)=[O:38]>>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:37](=[O:38])[CH2:36][C:35]([F:41])([F:40])[F:34])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Reactant: O=C(Cl)CC(F)(F)F
Product: COc1cccc2[nH]c(CCCN(C)CC[C@]3(OC(=O)CC(F)(F)F)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12

Procedure:
Prepared according to procedure P1.4 in Example 1A using rac-(1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol and 3,3,3-trifluoropropionyl chloride.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22]>>[CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([NH:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: CC(C)(CNC(=O)NCc1ccccc1)C(=O)O
Product: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C(C)(C)CNC(=O)NCc1ccccc1)OCC
Yield: 86.7 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 3-(3-benzylureido)-2,2-dimethylpropanoic acid (Compound VI-3) (152 mg, 0.61 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) (200 mg, 0.41 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=90:10) to obtain the title compound (258.1 mg, 88%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[I:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[I:14])[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a solution of 1.00 g (2.82 mmol) (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester in 10 ml DMF were added 0.12 g (3.1 mmol) sodium hydride (60% in mineral oil) at −10° C. (The preparation of (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester has been described in US 2002/0022624 A1.) The reaction mixture was allowed to warm to room temperature. After 1 h, the mixture was cooled back to −10° C., and 0.44 ml (7.1 mmol) iodomethane were added during 5 min. The reaction mixture was allowed to warm to room temperature. After 2.5 h at room temperature, the reaction was quenched by addition of 10 ml of a saturated aqueous solution of NaHCO3 and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, hexanes/ethyl acetate=4:1) to give 1.06 g (100%) of the title compound as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[SH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: OCCCCCCS
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cc(C)cc(SCCCCCCO)c1
Yield: 88.9 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), 6-mercaptohexanol (137 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 6-(3,5-dimethylphenyl)mercaptohexanol (212 mg, 92% yield) as colorless oil. Column chromatographic solvent (hexane/ethyl acetate=3/1). Rf=0.4 (hexane/ethyl acetate=2/1). 1H NMR (CDCl3, 300 MHz) δ 6.92 (s, 2 H), 6.78 (s, 1 H), 3.62 (q, 2 H, J=4.8 Hz), 2.90 (t, 2 H, J=7.2 Hz), 2.27 (s, 6 H), 1.30-1.68 (m, 9 H). 13C NMR (CDCl3, 75 MHz)δ 138.6, 136.5, 127.8, 126.7, 63.2, 33.8, 33.0, 29.5, 28.9, 25.7, 21.7. IR (neat, cm−1) 3320 (broad), 3060, 3022, 2972, 2847. MS (EI) m/z (relative intensity) 238 (40), 138 (100). Anal Cald for C14H22OS, Cald. C: 70.54, H: 9.30; Found C: 70.29, H: 9.33.