Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13](CNC2N=C(C3C=NC=CN=3)C=CN=2)=[CH:12][CH:11]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([NH:43]C3C=CC(C(O)=O)=CC=3)[N:38]=2)[CH:32]=1>>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:13]3[CH:12]=[CH:11][C:10]([C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH2:1])=[O:30])=[CH:15][CH:14]=3)[N:38]=2)[CH:32]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: Nc1ccccc1NC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1

Procedure:
Title compound was obtained in 54% yield according to the procedure described for the synthesis of compound 26a (scheme 6, step 4) replacing acid 25a by the acid 343. Characterization of the title compound is provided in the Table 12.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[CH:24][N:23]=1>CN(C=O)C>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Temperature: 60 °C

Procedure:
18.6 mL triethylamine and piperazine-1-carboxylic acid tert-butyl ester were added to 9.7 g 4-chloro-6-methoxy-pyrimidine in 50 mL DMF. The reaction was stirred over night at 60° C. The reaction was cooled and the precipitate was filtered. The filtrate was evaporated. The residue was dissolved in DCM, extracted with water and washed with sodium chloride solution. The solvent was evaporated and the residue was crystallized with a mixture of petrolether and diethylether (8:2) to yield 8.7 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([Si](C)(C)C)=[CH:5][C:6]=1[C:7]1[C:11]([F:13])([F:12])[C:10]([F:15])([F:14])[C:9]([F:17])([F:16])[C:8]=1[C:18]1[CH:22]=[C:21]([Si](C)(C)C)[S:20][C:19]=1[CH3:27].Br>C(Cl)(Cl)Cl>[CH3:27][C:19]1[S:20][CH:21]=[CH:22][C:18]=1[C:8]1[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[C:11]([F:13])([F:12])[C:7]=1[C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH3:1]
Reactant: Cc1sc([Si](C)(C)C)cc1C1=C(c2cc([Si](C)(C)C)sc2C)C(F)(F)C(F)(F)C1(F)F
Agent: Br
Solvent: ClC(Cl)Cl
Product: Cc1sccc1C1=C(c2ccsc2C)C(F)(F)C(F)(F)C1(F)F
Yield: 98 %

Procedure:
1,2-bis(2-methyl-5-trimethylsilyl-3-thienyl)hexafluorocyclopentene (2.16 g, 0.005 mol) was dissolved in chloroform (200 ml) and was allowed to react for 6 hours under refluxing conditions by adding concentrated hydrobromic acid (10 ml) to the solution. After the completion of the reaction, the chloroform layer was washed with an aqueous solution of sodium bicarbonate and the chloroform was removed under reduced pressures. The reaction product was purified by silicagel column chromatogram to give 1,2-bis(2-methyl-3-thienyl)hexafluorocyclopentene (1.8 g, 0.0049 mol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:49].[K+].Cl>O1CCOCC1.CCOC(C)=O.O.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:49])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Brc1cc(OCc2ccccc2)cc2ncsc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Oc1cc(OCc2ccccc2)cc2ncsc12
Temperature: 90 °C
Reaction time: 0.58 h

Procedure:
5-(benzyloxy)-7-bromobenzo[d]thiazole (0.65 g, 2.0 mmol), Pd2(dba)3 (95 mg, 0.10 mmol), and 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (180 mg, 0.42 mmol) were taken up in 1,4-dioxane (7.2 mL) under Ar. Aqueous 2 M KOH (3 mL, 6 mmol) was added and the mixture was heated to 90° C. After 35 min, the mixture was cooled to r.t. and was diluted with EtOAc (20 mL), water (15 mL), and brine (15 mL). The aqueous phase was and acidified with 3 M aqueous HCl (3 mL, 9 mmol). The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (10-60% EtOAc in hexanes) to provide 5-(benzyloxy)benzo[d]thiazol-7-ol 4.03B. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H12NO2S: 258.1; found 257.8.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH:9](=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:10].Cl>CS(C)=O>[CH3:10][CH:9]1[CH2:2][C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC=C(C(=O)OCC)C(=O)OCC
Reactant: C[S+](C)(C)=O
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CC1C
Reaction time: 2 h

Procedure:
To a solution of 50.6 g of trimethylsulphoxonium iodide in 400 cm3 of dimethyl sulphoxide there are added, in one go, 8.84 g of 60% sodium hydride in oil. The reaction mixture is stirred for 2 hours and then a solution of 43.3 g of diethyl ethylidenemalonate in 200 cm3 of dimethyl sulphoxide is added dropwise over a period of 15 minutes. After stirring for 16 h, a mixture of ice and 100 cm3 of 1N hydrochloric acid is added and then the reaction mixture is extracted with ether (3×200 cm3). The combined organic phases are washed with sodium chloride solution and then dried over sodium sulphate and evaporated. Chromatography on silica gel (dichloromethane/cyclohexane: 75/25) allows 37.5 g of expected product to be isolated.
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][NH:10][CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>>[C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][N:10]([C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])[CH2:9][CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc(C23CCCC2CNCC3)cc1
Product: O=C(C1CC1)N1CCC2(c3ccccc3)CCCC2C1

Procedure:
Following the procedure outlined in Example 28, 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine was acylated with cyclopropanecarboxylic acid chloride to provide 4a-phenyl-2-cyclopropanecarbonyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine. Reduction of the acylated pyrindine intermediate by reaction with lithium aluminium hydride afforded the corresponding 2-alkyl pyrindine, which when reacted with hydrobromic acid provided 4a-phenyl-2-cyclopropylmethyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindinium bromide. M.P. 240°-241° C.
Reaction SMILES: FC1C(O[C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[Cl:27])=C(F)C(F)=C(F)C=1F.[CH3:33][C:34]1([CH3:42])[O:38][CH:37]([CH2:39][O:40][NH2:41])[CH2:36][O:35]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:16][C:14]1[C:13]([F:17])=[C:12]([F:18])[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[Cl:27])=[C:10]([CH:15]=1)[C:9]([NH:41][O:40][CH2:39][CH:37]1[CH2:36][O:35][C:34]([CH3:42])([CH3:33])[O:38]1)=[O:28]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Reactant: CC1(C)OCC(CON)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)OCC(CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Reaction time: 20 h
Yield: 67.9 %

Procedure:
To a stirring solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid pentafluorophenyl ester (5.80 g, 9.51 mmol) is freshly distilled tetrahydrofuran (40 mL) was added O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (1.54 g, 10.5 mmol) and diisopropylethylamine (1.8 mL, 10.5 mmol). After 20 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water and twice with saturated brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by crystallization in ethyl acetate/hexanes affording 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide as a white solid (3.7 g, 67.9%): 1H NMR (400 MHz; CDCl3) δ 9.82 (bs, 1H), 8.10 (bs, 1H), 7.68 (s, 1H), 7.47 (bs, 1H), 7.40-7.43 (m, 1H), 6.44-6.47 (m, 1H), 4.40 (bs, 1H), 3.97-4.20 (m, 3H), 3.77 (t, 1H, J=8.0), 1.44 (s, 3H), 1.37 (s, 3H); MS (APCI+)=573.0/575.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[C:14]([CH:21]4[O:25][CH2:24][CH2:23][O:22]4)[CH:15]=[CH:16][C:17]=3[O:19][CH3:20])[CH2:12][CH2:11][C:10]2=[O:26])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[CH3:75][NH:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[C:18]2[C:13]=1[CH2:12][CH2:11][C:10](=[O:26])[N:9]2[CH2:8][C:5]1[CH:6]=[N:7][C:2]([N:76]([CH3:75])[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[CH:3][CH:4]=1
Reactant: CNc1ccccc1
Reactant: COc1ccc(C2OCCO2)c2c1N(Cc1ccc(Cl)nc1)C(=O)CC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCCO2)c2c1N(Cc1ccc(N(C)c3ccccc3)nc1)C(=O)CC2
Yield: 94.6 %

Procedure:
1-(6-Chloropyridin-3-ylmethyl)-5-[1,3]dioxolan-2-yl-8-methoxy-3,4-dihydro-1H-quinolin-2-one (0.4 g), tris(dibenzylideneacetone)dipalladium (48.8 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (92.6 mg) and sodium tert-butoxide (0.15 g) were suspended in toluene (10.6 ml). N-methylaniline (0.17 g) was added, and the resulting mixture was heated under reflux in an argon atmosphere for 13 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1→dichloromethane:methanol=20:1). The purified product was concentrated under reduced pressure to thereby obtain 0.45 g (yield: 95%) of 5-(1,3-dioxolan-2-yl)-8-methoxy-1-[6-(N-methyl-N-phenylamino)pyridin-3-ylmethyl]-3,4-dihydro-1H-quinolin-2-one as an amorphous solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Li+].Cl.[C:19]1([C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N+]=[N-])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[OH:1][C@H:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@H](O)CCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@H](O)CCc1ccccc1
Reaction time: 3.5 h
Yield: 38.4 %

Procedure:
Dissolve (R)-2-hydroxy-4-phenylbutyric acid, ethyl ester (4.16 g, 20 mmol) in methanol (40 mL). Add 1N lithium hydroxide (25 mL, 25 mmol) and stir under an atmosphere of argon for 3.5 hours. Acidify with 1N hydrochloric acid (25 mL), saturate with sodium chloride and extract with ethyl acetate (3×25 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Take up the residue in methylene chloride (20 mL) and add diphenyldiazomethane (3.36 g, 17.3 mmol). Stir overnight and wash with saturated sodium hydrogen carbonate (2×). Dry (MgSO4), evaporate the solvent in vacuo and recrystallize (methylene chloride/hexane then again with cyclohexane) to give (R)-2-hydroxy-4-phenylbutyric acid, diphenylmethyl ester as white needles (2.3 g, 38%); mp 82°-84° C.
Reaction SMILES: C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:23][O:24][C:25](=[O:60])[N:26]=[C:27]([S:58][CH3:59])[C:28]([C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH2:47][CH2:48][O:49][Si](C(C)(C)C)(C)C)[C:39]=1[F:57])=[N:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:23][O:24][C:25](=[O:60])[N:26]=[C:27]([S:58][CH3:59])[C:28](=[N:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=1)[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH2:47][CH2:48][OH:49])[C:39]=1[F:57]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCO)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
After adding 0.09 ml of acetic acid and 1.3 ml of TBAF (1.0 M, THF solution) to a solution of 616 mg of (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-(4-cyanophenylimino)-1-methylsulfanylethylidene)carbamic acid methyl ester (Example (181a)) in 5 ml of THF, the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (394 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: CN(C=O)C.CC([CH2:9][CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:32]2([CH3:33])[C@H:17]([C@H:18]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:21](C[C@H](C[CH2:26]2)O)=[CH:20][CH2:19]3)CC1)C)C.[C:34]([O-:37])(=[O:36])[CH3:35]>CO>[CH3:17][C:18]1[CH2:19][CH2:20][CH2:21][C:27]([CH3:26])([CH3:28])[C:29]=1/[CH:30]=[CH:31]/[C:32](/[CH3:33])=[CH:14]/[CH:12]=[CH:11]/[C:10](/[CH3:9])=[CH:35]/[C:34]([OH:37])=[O:36]
Reactant: CC(=O)[O-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Solvent: CN(C)C=O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1

Procedure:
40 mg of hapten are solubilized in 2 ml of anhydrous methanol and 2 ml of anhydrous DMF containing 1 μl of radioactive tracer (cholesterol: ref. NET 725, Dupont de Nemours). 80 mg of PL dissolved in 2 ml of 1.5 M acetate buffer are then added dropwise. After thorough stirring, the conjugates are purified by dialysis. The first dialysis solution consists of a mixture of 1/3 of methanol, 1/3 of DMF and 1/3 of water. The following two solutions consist solely of water.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.CN.[CH3:33][N:34](C)C=O>CO>[CH3:33][NH:34][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12](=[O:30])[C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: O=C(Nc1ccc(C(=O)N2CCC(=O)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Agent: CN
Solvent: CO
Product: CNC1CCN(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-oxo-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline(0.5 g) are added 40% solution of methylamine in methanol (5 ml), molecular sieves 4A (1 g) and dimethylformamide (6 ml), and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is filtered and to the filtrate is added sodium borohydride (80 mg), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated and water is added to the resulting residue, and extracted with ethyl acetate. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to give 4-methylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.2 g) as colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:13][NH2:14])=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:15].[Si:16]([O:23][CH2:24][C:25]1([CH3:34])[S:31][CH2:30][CH2:29][N:28]=[C:27](SC)[CH2:26]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:28]4[CH2:29][CH2:30][S:31][C:25]([CH2:24][O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([CH3:34])[CH2:26][C:27]4=[N:14][N:13]=3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:15]
Reactant: CSC1=NCCSC(C)(CO[Si](C)(C)C(C)(C)C)C1
Reactant: NNC(=O)C1(c2ccc(Br)c(F)c2)CC1
Solvent: CCCCO
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)c(F)c4)CC3)n2CCS1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of the compound (4.1 g, 15 mmol) obtained in Example 25-2) and 7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-methyl-5-(methylthio)-2,3,6,7-tetrahydro-1,4-thiazepine (4.79 g, 15 mmol) in n-butanol (30 mL) was stirred at 140° C. for 3.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Isco Combiflash, 40 g, ethyl acetate:dichloromethane=0:100 to 100:0, gradient) to obtain the title compound (3.47 g, 44%) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH2:16])([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:17][O:14][C:13]([C:10]1([NH2:16])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)O)C1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.6 %

Procedure:
In a round-bottomed flask 3-aminopyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (0.20 g, 0.87 mmol) was dissolved in dichloromethane (3.2 mL) and MeOH (1.6 mL). (Trimethylsilyl)diazomethane (2.0 M in hexanes, 0.75 mL, 1.5 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with a small portion of acetic acid and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous Na2CO3. The aqueous layer was extracted with dichloromethane and the combined organics were dried over Na2SO4 and concentrated to afford 0.218 g of 3-amino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a light yellow oil.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:8]([OH:9])[CH2:7][O:6][CH2:5][O:4]1)[CH3:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C[O-].[Na+].C1(C)C=CC=CC=1>[CH2:10]([O:9][C@H:8]1[CH2:7][O:6][CH2:5][O:4][C@H:3]1[CH2:1][CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: CC[C@@H]1OCOC[C@@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC[C@@H]1OCOC[C@@H]1OCc1ccccc1
Yield: 63.6 %

Procedure:
The procedure of Example XVIII was followed using 4.5 g of cis-4-ethyl-5-hydroxy-1,3-dioxane and 8.1 g of a methanolic solution 25% in sodium methylate, and 4.3 g of benzyl chloride in 180 ml of dry toluene. The reaction product was distilled under reduced pressure to give in free fractions 4.8 g of cis-5-benzyloxy-4-ethyl-1,3-dioxane; bp 96°-100°/0.01 mm; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CO.ClCCl.C(OCC)C>[CH2:33]([N:15]1[CH2:16][CH2:17][C:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)(=[O:10])=[O:11])([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:13][CH2:14]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.6 %

Procedure:
The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidine hydrochloride (100 mg, 0.245 mmol) obtained in Example 260, triethylamine (0.070 ml, 0.50 mmol) and benzaldehyde (0.050 ml, 0.428 mmol) were added to dichloromethane (5 ml), followed by the addition of sodium triacetoxyborohydride (110 mg, 0.500 mmol) at room temperature. The resulting mixture was stirred at room temperature for 14 hours. A 1N aqueous sodium hydroxide solution (3.0 ml) was then added. The resulting mixture was stirred at room temperature for 30 minutes. After diethyl ether was added, the resulting mixture was washed with a 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography, and the fraction obtained from the dichloromethane:methanol=50:1 eluate was concentrated under reduced pressure, whereby the title compound (87 mg, 0.19 mmol, 77%) was obtained as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[N:25]1([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH:29]=[CH:28][N:27]=[CH:26]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:37][CH:36]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Solvent: CCOC(C)=O
Product: O=c1c2cnc(Nc3ccc(Cn4ccnc4)cc3)nc2n2ccnc2n1-c1ccccc1Cl

Procedure:
A mixture of Example 1E (0.060 g, 0.167 mmol) and 4-((1H-imidazol-1-yl)methyl)aniline (0.046 g, 0.267 mmol) was heated in a capped vial at 100° C. for 1 hour. The reaction mixture was treated with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified on a 12 g column using the ISCO Companion flash system eluting with methanol/ethyl acetate (5:95 to 10:90) to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 5.23 (s, 2H), 7.00 (s, 1H), 7.04 (d, J=1.9 Hz, 1H), 7.14 (s, 1H), 7.35-7.29 (m, 2H), 7.61-7.51 (m, 3H), 7.71-7.64 (m, 1H), 7.87-7.75 (m, 4H), 9.14 (s, 1H). MS (ESI+) m/z 468.8 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[N:7][CH:8]=1
Reactant: OCc1ccc(CF)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(CF)cn1
Reaction time: 7 h

Procedure:
Manganese dioxide (1.4 g) is added in a single portion to a solution of compound (5) (0.3 g) in chloroform (5 ml) at room temperature. The suspension is stirred vigorously for 7 hours and then diluted with chloroform and filtered through Celite. The filtrate is concentrated under vacuum and the yellow oil obtained (0.25 g) is used in its present form in the following reductive amination step.