Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.OS(O)(=O)=O.O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[O:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A solution of 17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"methoxycyclohexyl)-1'-methylvinyl]-14-t-butyl-dimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Example 4) (30 gm, 0.0331 mol) in acetone (200 ml) was cooled to 0° C. To the solution was added 16.5 mL of Jones reagent (prepared by dissolving 26.72 g CrO3 in 23 mL of concentrated H2SO4, then diluting the solution to 100 mL with H2O) (The reaction was monitored by TLC 20% acetone/hexanes). After 60 minutes, the reaction was complete and excess oxidant was destroyed by slow addition of 10 mL of 2-propanol. After 10 min., the mixture had become bright green, and the reaction mixture was diluted with 800 mL of water and 1 L of ether. The layers were separated and the aqueous layer was washed with four equal portions of ether. Each ether layer was sequentially washed with two equal portions of water, then twice with 1 M KHCO3 solution, then with brine (Virtually all of the green color was removed following the KHCO3 washes). MS: 796 (M+7). The ether layers were combined, dried over MgSO4, and concentrated to a pale yellow gum that was lyophilized from benzene to afford 26.8 g (89%) of the title compound as a white solid. MS 796 (M+7).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[S:13]([NH:16][CH2:17][CH2:18][OH:19])(=[O:15])=[O:14].[H-].[Na+].[Na].[C:25]1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C=O)C.C(Cl)CCC.CCOC(C)=O>[CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[S:13]([N:16]([CH2:17][CH2:18][OH:19])[CH3:25])(=[O:15])=[O:14]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)N(C)CCO
Reaction time: 20 h

Procedure:
A solution of N,N-Dimethyl-2-[N-(2-hydroxyethyl)aminosulfonyl]-6-nitrobenzamide (3.97 g, 12.5 mmol) in dry DMF (40 ml) was added slowly to a stirred suspension of 50% NaH (0.60 g, 12.5 mmol) in dry DMF (10 ml) under N2 at 20-25°. After formation of the sodium salt was complete, a solution of methyl p-toluenesulfonate (2.40 g, 12.9 mmol) in DMF (4 ml) was added and the reaction mixture stirred at 20-25° for 20 hours and then at 60° for 23 hours. The orange solution was mixed with EtOAc (400 ml) and the white solid which formed was filtered off. This precipitate was washed with EtOAc (100 ml). The combined EtOAc solutions were washed with a saturated aqueous NaCl solution, dried (Na2SO4), filtered and concentrated under reduced pressure. Pure produced, mp 107-08°, 2.5 g (60%) was obtained by flash chromatography over silica gel and elution with a 65% n-butylchloride-35% acetonitrile solvent mixture.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:26])C(=O)C1>C(Cl)Cl>[Br:26][C:13]1[S:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c(Br)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution (0.2 M) of ethyl 4-[(tert-butoxycarbonyl)amino]thiophene-2-carboxylate in DCM was cooled to 0° C. and treated with NBS (1.1 eq.) then stirred at 0° C. for 30 min. The mixture was quenched with aqueous Na2S2O3 (saturated solution) and extracted with AcOEt. The organic phase was washed with aqueous Na2S2O3 (saturated solution) and brine then dried and concentrated. The residue was purified by flash chromatography on silica gel (1:12 AcOEt/petroleum ether) to afford the title compound (48%) as a solid. 1H NMR (300 MHz, DMSO-d, 300 K) δ 1.32 (t, J=7.07 Hz, 3H), 1.50 (s, 9H), 4.32 (q, J=7.07 Hz, 2H), 7.81 (s, 1H), 9.13 (bs, 1H); MS (ES+) m/z 350, 352 (M+H)+;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23](=[O:28])N(OC)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].OS([O-])(=O)=O.[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH:23]=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)OC)N(C(=O)OC(C)(C)C)C2)cc1
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CS[C@@H]2C[C@@H](C=O)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To 360 ml THF 30.8 ml LiAlH4 solution (30.8 mmol, 1M in THF, 1.2 eq) were added, the solution was cooled to −30° C. and 10.9 g (25.67 mmol) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 100 ml THF were added at that temperature, stirred for 30 min. The solution was cooled to −78° C. and a suspension of silica gel, MgSO4 and 10% KHSO4 solution was added, and slowly warmed to RT. The suspension was filtered, thoroughly washed with THF and evaporated. The crude product was redissolved in CH2Cl2 and dried over Na2SO4 and evaporated yielding 9 g (quant.) (2S,4R)-2-Formyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow oil, MS: 351 (M+).
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][NH:9][C:10]2=[O:13])=[CH:5][C:4]=1[NH2:14].C[C:16]([N:18](C)C)=O>[OH-].[Na+].[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[C:16]#[N:18])[C:10](=[O:13])[NH:9][CH:8]=[CH:7]2
Reactant: Nc1cc2cc[nH]c(=O)c2cc1Br
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [C-]#N
Product: N#Cc1cc2c(=O)[nH]ccc2cc1N
Temperature: 100 °C

Procedure:
A reaction vial was charged with 7-bromo-6-aminoisoquinolone hydrochloride (203 mg, 0.74 mmol), Zn(CN)2 (1.55 mmol) and Pd(Ph3P)4 (0.37 mmol) in 1.5 mL of dry dimethylacetamide. The vial was sealed and warmed to 100° C. for 20 minutes in a microwave. The reaction was recharged with additional Pd(Ph3P)4 (0.37 mmol) and warmed for another 20 minutes. The reaction was then diluted with 1 N aqueous NaOH and the resulting solids were isolated by filtration (615 mg). The desired product was present in both the solids as well as the filtrate. The solids were purified by suspension in dimethylacetamide, filtration to remove insoluble material and reverse phase HPLC chromatography of the filtrate to afford the desired product as a white solid (62 mg, 46%). The aqueous filtrate from above was neutralized with 1 N aqueous HCl and the resulting crude product was isolated by filtration (233 mg). This additional material was used without further purification.
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:10](=O)[CH2:11]OCC)\C(OC)=O)[CH3:3].CN(/C=C(/C(=O)CCCC)\C(OC)=O)C.Cl[C:32]1[C:37]([CH3:38])=[CH:36][N:35]=[C:34]([N:39]2[C:43]([CH2:44][O:45][CH2:46][CH3:47])=[C:42]([C:48]([NH:50][CH2:51][C:52]3[N:56]([CH3:57])[CH:55]=[N:54][CH:53]=3)=[O:49])[CH:41]=[N:40]2)[N:33]=1>>[CH2:46]([O:45][CH2:44][C:43]1[N:39]([C:34]2[N:33]=[C:32]([N:2]3[CH2:4][CH2:5][CH2:10][CH2:11][CH2:3]3)[C:37]([CH3:38])=[CH:36][N:35]=2)[N:40]=[CH:41][C:42]=1[C:48]([NH:50][CH2:51][C:52]1[N:56]([CH3:57])[CH:55]=[N:54][CH:53]=1)=[O:49])[CH3:47]
Reactant: CCOCc1c(C(=O)NCc2cncn2C)cnn1-c1ncc(C)c(Cl)n1
Reactant: CCOCC(=O)/C(=C/N(C)C)C(=O)OC
Agent: CCCCC(=O)/C(=C/N(C)C)C(=O)OC
Product: CCOCc1c(C(=O)NCc2cncn2C)cnn1-c1ncc(C)c(N2CCCCC2)n1

Procedure:
The title compound 99 was prepared by following the synthetic sequence and conditions described in Example 14 and Example 16 with the following modifications. First in Step 2 of Example 14, intermediate D.2 (R2=methyl, R3=H) was treated with (Z)-methyl 2-((dimethylamino)methylene)-4-ethoxy-3-oxobutanoate, instead of (Z)-methyl 2-((dimethylamino)methylene)-3-oxoheptanoate, to give D.3 (R2=methyl, R4=ethoxymethyl). This intermediate D.3 was converted to the corresponding D.5, 1-(4-chloro-5-methylpyrimidin-2-yl)-5-(ethoxymethyl)-N-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrazole-4-carboxamide, in three steps (Steps 3-5).
Reaction SMILES: C([O:4][CH:5]1[C:18]2[C:9](=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[C:15]([O:19][CH3:20])[CH:14]=[CH:13]3)[CH2:8][CH2:7][CH2:6]1)(=O)C.[OH-]>CO>[OH:4][CH:5]1[C:18]2[C:9](=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[C:15]([O:19][CH3:20])[CH:14]=[CH:13]3)[CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc2ncc3c(c2c1)C(OC(C)=O)CCC3
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ncc3c(c2c1)C(O)CCC3
Temperature: 60 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
To a solution of Compound 281a (7.10 g, 26.2 mmol) in dry methanol (200 mL) was added Dowex 1×8-200 hydroxide form (1.00 g) and the resulting mixture was heated at 60° C. for 24 hours. The warm reaction mixture was filtered and the filtrate was distilled until 100 mL remained. Ethyl ether (100 mL) was added to the residue and the resulting solution was allowed to stand in the refrigerator at zero degrees C for 16 hours. The crystalline precipitate was filtered off, washed with ethyl ether (50 mL) to give 5.03 g (84 percent) of Compound 282a: white crystalline solid; mp 189.5°-190.5° C.; Rf =0.21 (silica, ethyl ether); IR (CHCl3) νmax 3156, 2931, 1621, 1508 cm-1 ; 1H NMR (300 Mz, CDCl3) δ 8.45 (s, 1 H, H6), 7.96 (d, J=9.2 Hz, 1 H, H4), 7.50 (d, J=2.6 Hz, 1 H, H3), 7.31 (dd, J=9.2, 2.6 Hz, 1 H, H1), 5.37 (br s, 1 H, H10), 3.97 (s, 3 H, OCH3), 2.97-2.75 (m, 2 H, H7), 2.75-2.30 (br s, 1 H, OH), 2.30 (br d, J=10.6 Hz, 1 H, H9), 2.07-1.96 (m, 3 H, H8 and H9); 13C NMR (125 Mz, DMSO-d6) δ 157.1, 149.7, 142.5, 140.2, 130.2, 129.7, 128.1, 119.7, 103.0, 61.0, 55.3, 31.8, 26.6, 16.7; MS (FAB+) m/e (rel intensity) 230 (M+H, 100), 212 (10);HRMS for C14H16NO2 (M+H), calcd 230.1181, found 230.1189. Anal. Calcd for C14H15NO2 : C, 73.34; H, 6.59; N, 6.11. Found: C, 73.16; H, 6.73; N, 6.08.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[C@H:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[NH:7][C:8](=[O:13])[C:9]([NH2:12])([CH3:11])[CH3:10])[CH3:3].C(N(CC)CC)C.[C:30]([S:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])(=[O:32])[CH3:31].ON1C2N=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.O>[CH2:2]([O:4][C:5](=[O:22])[C@H:6]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[NH:7][C:8](=[O:13])[C:9]([NH:12][C:35](=[O:36])[C@@H:34]([S:33][C:30](=[O:32])[CH3:31])[CH:38]([CH3:40])[CH3:39])([CH3:11])[CH3:10])[CH3:3]
Reactant: CC(=O)S[C@H](C(=O)O)C(C)C
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)(C)NC(=O)[C@@H](SC(C)=O)C(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(2-amino-2-methyl-1-oxopropyl)-L-tyrosine ethyl ester monohydrochloride (1.33 g, 3.70 mmol) in dimethylformamide (50 mL) and triethylamine (0.52 mL, 3.70 mmol) is added (S)-2-acetylthio-3-methylbutanoic acid (0.65 g, 3.70 mmol). To this mixture is added 1-hydroxy-7-azabenzotriazole (0.55 g, 4.07 mmol) and 1,3-dicyclohexylcarbodiimide (0.84 g, 4.07 mmol). The mixture is stirred overnight and then water (50 mL) is added to the mixture. The solution is extracted with ethyl acetate (3×50 mL). The combined organic layers are washed with a saturated solution of sodium bicarbonate (20 mL), brine, dried over magnesium sulfate and the solvent is removed to give a yellow foam. The foam is purified by flash chromatography (SiO2 :hexane/ethyl acetate, 6:4) to give as a white solid N-[2-(2(S)-acetylthio-3-methyl-1-oxobutylamino)-2-methyl-1-oxopropyl]-L-tyrosine ethyl ester, m.p. 137°-138° C., the compound of formula II wherein R1 is 4-hydroxyphenyl, R2 is ethyl, R3 is acetyl, R4 is isopropyl, and R6 and R7 are methyl.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.CC1(C)O[C:31](=[O:33])[C:30](=[CH:34][NH:35][C:36]2[C:40]([CH3:41])=[CH:39][S:38][CH:37]=2)C(=O)O1>>[CH3:41][C:40]1[C:36]2=[N:35][CH:34]=[CH:30][C:31]([OH:33])=[C:37]2[S:38][CH:39]=1
Reactant: Cc1cscc1NC=C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1csc2c(O)ccnc12
Temperature: 235 °C
Reaction time: 0.08 h
Yield: 101.9 %

Procedure:
A solution of Dowtherm A (7 mL) was heated in oil bath at 235° C. under nitrogen. 2,2-dimethyl-5-((4-methylthiophen-3-ylamino)methylene)-1,3-dioxane-4,6-dione (5.0 g, 19 mmol) was added in portions over a 20 minutes period. After the last portion was added, the solution stirred at 235° C. for another 5 minutes. The solution was removed from the oil bath and allowed to cool to room temperature. Upon cooling, the product precipitated out of solution. Diethyl ether was added and the solid was filtered and dried to give the title compound (3.2 g) with residual amounts of Dowtherm A remaining.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH:10]2[CH2:12][N:13]([CH2:14][C:15]([O:17]CC)=[O:16])[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.CCO.[OH-].[Li+:24].Cl>C1COCC1.O>[O:1]=[C:2]1[CH2:11][CH:10]2[CH2:12][N:13]([CH2:14][C:15]([O-:17])=[O:16])[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[Li+:24]
Reactant: CCOC(=O)CN1CC2CC(=O)Nc3cccc1c32
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C([O-])CN1CC2CC(=O)Nc3cccc1c32
Reaction time: 0.25 h

Procedure:
To a solution of ethyl (4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer B, from Step E (55 mg, 0.211 mmol) in THF (1 mL), EtOH (1 mL) and H2O (1 mL) was added 1.0 N lithium hydroxide (0.232 mL, 0.232 mmol). After 15 min, 1 N aqueous HCl was added to adjust the solution to pH 7 and the mixture was concentrated in vacuo to give the title compound. MS: m/z=233 (M+1).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=O)[NH:11]2)(=[O:4])=[O:3].[BH4-].[Na+].C(O)(=O)C>O1CCOCC1>[CH3:1][S:2]([O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][NH:11]2)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cccc2c1CCC(=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CS(=O)(=O)Oc1cccc2c1CCCN2
Yield: 44.8 %

Procedure:
4.5 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyril was suspended in 90 ml of dioxane and 35 g of NaBH4 was added to the suspension then 5.3 ml of acetic acid was added dropwise to the mixture. After heat-refluxing the resulting mixture for 1 hour the solvent was removed under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue to form precipitates which were filtered and washed with chloroform. The filtrate was extracted with chloroform and the chloroform layer was dried over Na2SO4 followed by removing the solvent. The residue was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform) and the eluate thus-obtained was crystallized from petroleum ether. Recrystallization of the crystals thus-obtained from methanol gave 1.9 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline, colorless prisms having a melting point of 74° to 76° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(OC2CCNCC2)cc1
Reactant: O=C=NCc1ccccc1
Product: O=Cc1ccc(OC2CCN(C(=O)NCc3ccccc3)CC2)cc1
Yield: 80 %

Procedure:
The title compound (0.2 g, 80%) was prepared as a white solid from 4-(piperidin-4-yloxy)benzaldehyde (0.25 g) and benzyl isocyanate (0.084 ml), in a similar manner to that described in preparation 14.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][N:10]=[C:11]2[CH3:12]
Reactant: CC(=O)NCCc1ccccc1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2c(F)cccc21

Procedure:
In close analogy to the procedure described above, N-[2-(2-fluoro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: ClCCl.Cl.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:16]2[N:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.CN1CCOCC1.[CH3:39][N:40]([CH3:45])[S:41](Cl)(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.CCCCCC.O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:16]2[N:21]=[CH:20][C:19]([CH2:22][NH:23][S:41]([N:40]([CH3:45])[CH3:39])(=[O:43])=[O:42])=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine hydrochloride (60 mg, 0.135 mmol) obtained in Example 66 were added N-methylmorpholine (180 μl, 1.62 mmol), 4-dimethylaminopyridine (10 mg, 0.0819 mmol) and N,N-dimethylsulfamoyl chloride (66 μl, 0.609 mmol). The resulting mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:2 eluate was concentrated under reduced pressure to give the title compound (48 mg, 0.0930 mmol, 70%) as a white powder.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10](Cl)[CH:11]=[CH2:12]>O1CCCC1>[CH2:12]([C:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:11]=[CH2:10]
Reactant: C=CCCl
Reactant: O=C(O)C1CCCCC1
Solvent: C1CCOC1
Product: C=CCC1(C(=O)O)CCCCC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
300 cm3 of dry tetrahydrofuran (THF) and 40 g of diisopropylamine redistilled over calcium hydride were introduced into a 1 liter three-necked flask fitted with a condenser closed with a calcium chloride guard tube, a low-temperature thermometer, a mechanical stirrer and a nitrogen inlet tube. The solution was cooled to -20° C. and 220 cm3 of a 1.47 M solution of butyl-lithium in hexane were added. The addition was made in the course of 1 hour; the temperature of the mixture was kept at -10° C. 25.5 g (0.2 mole) of 1-cyclohexyl-carboxylic acid, dissolved in 50 cm3 of dry THF, were then introduced in the course of 20 minutes and the temperature of the whole was then raised gradually to 50° C. and this temperature was maintained for 2 hours. The yellow solution was cooled to -70° C. 15.3 g of dry allyl chloride were added and the mixture was stirred for a further 2 hours whilst allowing the temperature to return to ambient temperature, after which the whole was left to stand for 12 hours. The solution was concentrated in vacuo and then poured into 100 cm3 of ice-cold distilled water and 100 cm3 of hexane. The aqueous phase, which had been separated off, was acidified with dilute hydrochloric acid. The 1-allyl-1-cyclohexylcarboxylic acid obtained was extracted with ether. It was purified by distillation under reduced pressure and was in the form of a colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)[CH2:15][CH2:14]2)[CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[NH2:27])[CH2:17][CH2:18]2)[CH:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cc(F)cc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cc(F)cc2n1
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of 7-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline (0.046 g; 1 eq) in methanol (3 mL) was added dropwise to a suspension of iron powder (0.04 g; 7 eq) and ammonium chloride (0.04 g; 7 eq) in water (3 mL). The reactants were heated at reflux for 8 hours, with additional amounts of iron powder (total 0.04 g; 7 eq) and ammonium chloride (0.04 g; 7 eq) added in 3 portions during the reaction. The reaction mixture was cooled to room temperature and filtered using a Millipore filter. The filtrate was concentrated under reduced pressure, diluted with water (5 mL) and a saturated aqueous solution of sodium hydrogen carbonate (2 mL) and extracted into ethyl acetate (3×5 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure thus obtaining the title compound in 32% yield (0.012 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH3:25])[C:17]=2[O:16][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(N)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (4.78 g) and 2,3-dimethoxyaniline (3.68 g) were condensed in the same manner as described in Preparation Example 37 to give the title compound.