Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](Cl)=[O:38].C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:37]([C:33]3[O:32][CH:36]=[CH:35][CH:34]=3)=[O:38])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.47 g, 5.50 mmol) (obtained as described in Reference Example 62(1)) in methanol (120 ml) was subjected to catalytic reduction in the presence of 20% palladium hydroxide (2.47 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (115 ml). To the mixture were added 2-furoyl chloride (0.65 ml, 6.60 mmol) and triethylamine (0.92 ml, 6.60 mmol), and the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (1.60 g, yield 60%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[NH:44][C:43]([CH3:45])=[N:42][N:41]=1)=[C:22]2[C:26]([O:28]CC1C=CC([N+]([O-])=O)=CC=1)=[O:27])([O:4]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].O1CCOCC1.P([O-])([O-])(O)=O.[K+:57].[K+]>[Pd].C(O)C>[OH:4][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[NH:44][C:43]([CH3:45])=[N:42][N:41]=1)=[C:22]2[C:26]([O-:28])=[O:27])([CH3:3])[CH3:1].[K+:57]
Reactant: Cc1nnc(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@@H](C(C)(C)OC(=O)OCc4ccc([N+](=O)[O-])cc4)[C@H]3C2)[nH]1
Agent: [Pd]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nnc(SC2=C(C(=O)[O-])N3C(=O)[C@@H](C(C)(C)O)[C@H]3C2)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-nitrobenzyl (5R, 6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(5-methyl-4H-1,2,4-triazol-3-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 mg) and 5% palladium on activated carbon (50 mg) in 0.048M aqueous dipotassium hydrogen phosphate (4.85 ml), ethanol (0.5 ml), and dioxane (6.0 ml) was shaken for 2 hours under a hydrogen atmosphere (40 psi) at ambient temperature. After the catalyst was filtered off, the filtrate was concentrated to half of the original volume. The aqueous concentrate was washed three times with diethyl ether and evaporated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion CHP-20P", eluting with water (100 ml) and 5% aqueous isopropyl alcohol (100 ml). The fractions, whose UV spectra showed λmax 292 nm, were combined and lyophilized to give potassium (5R, 6R)-6-(1-hydroxy-1-methylethyl)-3-(5-methyl- 4H-1,2,4-triazol-3-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (13.2 mg) as a yellow powder.
Reaction SMILES: [C:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O)([O:3][CH3:4])=[O:2].C(O)(=O)C(C)C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]=1[NH:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][CH3:4])=[O:2]
Reactant: NCc1ccccc1
Reactant: COC(=O)C1C(=O)CCc2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)C(=O)O
Product: COC(=O)C1=C(NCc2ccccc2)CCc2ccccc21
Yield: 102.4 %

Procedure:
To a solution of 1-carbomethoxy-2-oxo-1,2,3,4-tetrahydronaphthalene (10.2 g) and isobutyric acid (4.84 g) in toluene (150 mL) stirring at room temperature under argon, was added benzylamine (5.35 g). The resulting mixture was heated to reflux for 2 h with water removal using a Dean-Stark trap. The solvent was then evaporated under vacuum to provide the title compound (15 g) as a yellow gum.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[N:44]=[C:43]([C:45]3[CH:49]=[CH:48][S:47][CH:46]=3)[O:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[N:44]=[C:43]([C:45]3[CH:49]=[CH:48][S:47][CH:46]=3)[O:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2noc(-c3ccsc3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2noc(-c3ccsc3)n2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogen carbonate (1.27 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(4-butyl-2-methyl-6-oxo-1-{[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]methyl}-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.79 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.22 g, 25%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]1[O:16][C@@H:15]2[C@H:17]([OH:20])[CH2:18][O:19][C@@H:14]2[C@@H:13]1[OH:21].O>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:21][C@@H:13]2[CH2:12][O:16][C@@H:15]3[C@H:17]([OH:20])[CH2:18][O:19][C@H:14]23)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A solution of p-toluenesulfonyl chloride (24.8 g, 130 mmol) in pyridine (150 mL) was added to a stirred solution of isomannide (40) (19.0 g, 130 mmol) in pyridine (150 mL) over 1 hour at 0° C. then stirred at ambient temperature for 1 hour. The mixture was poured onto iced-water (1 L) then extracted with dichloromethane (3×300 mL). The organic phase washed with brine (300 mL), dried (MgSO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 50:50 gave monotosylate (50) (23.4 g, 60%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:3]1.CS(C)=[O:20].Cl>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:3]1=[O:20].[O:20]=[C:3]1[CH:4]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2]1
Reactant: COC(=O)CCCc1cn(C)c2ccccc12
Reactant: CS(C)=O
Agent: Cl
Product: CN1C(=O)C(CCCC(=O)O)c2ccccc21
Product: O=C(O)CCCC1C(=O)Nc2ccccc21

Procedure:
Reaction of the ester [II: R1 =R3 =H, R2 =(CH2)3COOMe, R3 =Me] with DMSO/HCl as above gave crude 4-(1-methyl-2-oxo-3-indolinyl)butanoic acid [III: R1 =R3 =H, R2 =(CH2)3COOMe, R3 =Me] (0.84 g, 91% yield) as a brown oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([O:33]CC3C=CC=CC=3)=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([OH:33])=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26]
Reactant: COc1ccc2c(c1CN)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc2c(c1CN)Oc1c(ccc(OC)c1CC(=O)O)C2(C)C
Yield: 95.3 %

Procedure:
A solution of 2 g (3.56 mmol) of benzyl 5-aminomethyl-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate trifluoroacetate in 70 ml of methanol was stirred at room temperature under hydrogen in the presence of 200 mg of palladium/charcoal (10%). After 30 minutes the catalyst was filtered off and the filtrate was concentrated. The residue was washed with ether and dried, whereby 1.6 g of 5-aminomethyl-3,6-dimethoxy-9,9-dimethylxanthene-4-acetic acid trifluoroacetate of m.p. 178°-184° (dec.) were obtained; IR 1680, 1630, 1608, 1496 cm-1 absorbed.,
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:14])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 100 °C
Yield: 45 %

Procedure:
To 5-bromo-3-nitropyridin-2-ol (78.A)(1 g, 5 mmol) was added 10 mL of phosphorus oxychloride. The reaction was heated at 100° C. for 1 hr., concentrated and worked up between EtOAc and saturated NaHCO3. The organic layer was concentrated, redissolved in DCM, filtered off the solids. The DCM layer was concentrated again to afford 450 mg (45%) of 78.B.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].ClC1C=CC=CC=1C1C(C2C=CC(Cl)=CC=2)=CC2N(C(=O)NN=2)N=1>>[Cl:1][C:2]1[C:3]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:4][C:5]2[N:6]([C:17](=[O:18])[NH:9][N:8]=2)[N:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(Cl)nn1
Agent: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Product: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Yield: 80 %

Procedure:
The title compound (900 mg, 80%) as a yellow solid was prepared from 1-(6-chloro-5-(4-chlorophenyl)pyridazin-3-yl)hydrazine (1.02 g, 4.0 mmol) and 1,1′-carbonyl diimidazole (3.24 g, 20.0 mmol) according to the procedures described for 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (Example 1G). LC/MS (method A): retention time=2.77 min, (M+H)+=281.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]2[C:17](Br)=[CH:16][N:15]=[C:14]([NH2:19])[N:13]=2)[NH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:5])[CH3:2].[CH:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[C:10]2=[CH:26][CH:27]=[C:17]3[C:12]([N:13]=[C:14]([NH2:19])[N:15]=[CH:16]3)=[C:9]2[NH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:5])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1c(-c2ccccc2)[nH]c(-c2nc(N)ncc2Br)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccccc2)[nH]c2c1ccc1cnc(N)nc12
Temperature: 110 °C
Yield: 30.3 %

Procedure:
To a solution of 5-(2-amino-5-bromo-pyrimidin-4-yl)-4-iodo-2-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (XXVIIA, R2=phenyl, R3=COOEt, 0.099 mmol) in dioxane (4 mL), under argon, vinyltributyltin (0.099 mmol), 2,6-di-tert-butyl-4-methylphenol (0.0045 mmol) and Pd(Ph3P)4 (0.01 mmol) were added. The reaction mixture was heated at 110° C. for 3 h, cooled to rt, the precipitate filtered through a celite pad and the resulting solution evaporated to dryness. The residue was chromatographed on silica gel (eluant: AcOEt/hexane 4:1) affording the title compound (0.03 mmol, 30% yield), ESI (+) MS: m/z 333 (MH+). 1H NMR: 1.20 (t, J=7.03, 3H), 4.19 (q, J=7.03, 2H), 6.55 (bs, 2H), 7.50 (d, J=8.60, 1H), 7.53-7.70 (m., 5H), 7.90 (d, J=8.60, 1H), 9.07 (s, 1H), 12.93 (s, 1H), and 5-amino-8-methylene-2-phenyl-3,8-dihydro-3,4,6-triaza-cyclopenta[a]indene-1-carboxylic acid ethyl ester (0.024 mmol) (XXVIII, R2=phenyl, R3=COOEt), ESI (+) MS: m/z 333 (MH+). 1H NMR: 1.14 (t, J=7.07 Hz, 3H), 4.16 (q, J=7.07 Hz, 2H), 6.02 (d, J=1.32, 1H), 6.43 (d, J=1.32, 1H), 6.57 (bs, 2H), 7.40-7.46 (m, 2H), 7.52-7.66 (m, 3H), 8.44 (s, 1H), 12.74 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:8]=2)[C:3]1=[O:15].[C:16]1([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH3:14][S:11]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH:2]3[S:24][C:23](=[N:22][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:3]3([OH:15])[C:4]=2[CH:5]=1)(=[O:13])=[O:12]
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Reactant: CS(=O)(=O)c1ccc2c(c1)C(=O)C(Br)C2
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)C1(O)C(C2)SC(=Nc2ccccc2)N1c1ccccc1
Reaction time: 8 h

Procedure:
1.45 g of 2-bromo-6-methanesulfonylindan-1-one are dissolved in 15 ml of acetone and treated with stirring with 1.25 g of N,N'-diphenylthiourea in 25 ml of acetone. The hydrobromide of 5-methanesulfonyl-3-phenyl-2-phenylimino-2,3,8,8a-tetrahydro-indeno[1,2-d]thiazol-3a-ol crystallizes out of the clear solution after about 2 hours. After standing overnight, it is filtered off with suction and washed with a little acetone. 1.7 g of hydrobromide (m.p. 247° C.) are dissolved in 10 ml of methanol and treated with 0.8 ml of triethylamine. After 15 min, 150 ml of water are added and the mixture is stirred for 30 min with ice-cooling. The product formed is filtered off with suction and washed with a little cold water. 5-Methanesulfonyl-3-phenyl-2-phenylimino-2,3,8,8a-tetrahydroindeno[1,2-d]thiazol-3a-ol of melting point 172° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([O:12]CC)=[O:11])=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:27])[CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:27])[CH:3]=1
Reactant: CCOC(=O)CSc1ccc(Cl)cc1Sc1ccc(S(=O)(=O)CC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2SCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the product from step (iv) (0.10 g), sodium hydroxide (0.018 g) in methanol (5 ml) and water (5 ml) was stirred at RT for 1 h. The mixture was partitioned between 2M hydrochloric acid/ethyl acetate, the organics separated, dried and evaporated under reduced pressure. The residue was purified by reverse phase HPLC. Yield 0.012 g
Reaction SMILES: C([O:5][C:6](=[O:29])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=2)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)[CH3:8])(C)(C)C.C(=O)([O-])N.FC1C(OC(=O)N([C@H]2[C@H](C3C=CC(Cl)=C(Cl)C=3)CN(C(C3CCN(C(C4(C)CC4)=O)CC3)=O)C2)C)=CC=CN=1.[F:73][C:74]1[CH:79]=[CH:78][C:77](O)=[CH:76][CH:75]=1.C(OC(=O)N([C@@H]1[C@@H](C2C=CC(Cl)=C(Cl)C=2)CNC1)C)(C)(C)C>>[F:73][C:74]1[CH:79]=[CH:78][C:77]([O:5][C:6](=[O:29])[N:7]([C@H:9]2[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=3)[CH2:12][NH:11][CH2:10]2)[CH3:8])=[CH:76][CH:75]=1
Reactant: Oc1ccc(F)cc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CN(C(=O)Oc1cccnc1F)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: NC(=O)[O-]
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(F)c1

Procedure:
After acidic cleavage of the Boc-protecting group from [(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester the intermediately built carbamate was prepared in analogy to the procedure described for the synthesis of {(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 2-fluoro-pyridin-3-yl ester (example 293, c) with 4-fluorophenol. In analogy to the procedure described for the synthesis of rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (example 1, e) the title compound was prepared from the intermediately built [(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester through cleavage of the benzyl group. MS m/e: 367.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20].[CH2:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:22]#[CH:23]>CN(P(N(C)C)(N(C)C)=O)C>[CH2:21]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:13]3=[C:14]4[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]3)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]4=[CH:4][C:3]=2[Cl:20])[CH2:26][CH2:25]1)[C:22]#[CH:23]
Reactant: CC1CCc2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C#CCN1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C#CCN1CCN(c2c(Cl)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Temperature: 160 °C
Reaction time: 5 h
Yield: 58.5 %

Procedure:
A mixture of 1.6 g of 8,9-dichloro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 3.2 g of 1-propargylpiperazine and 25 ml of HMPTA was heated with stirring at 160° C. for 5 hours under atmosphere of argon. After completion of the reaction, the solvent was removed by distillation and the residue was washed with water. The residue was dissolved in 100 ml of water and insoluble substances were removed by filtration. The aqueous fraction was extracted with 200 ml of chloroform and the chloroform fraction was dried over anhydrous sodium sulfate. After concentration, the concentrate was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyako Co., Ltd.; eluent: chloroform-methanol (9:1 by volume)) to obtain 1.2 g of 8-[4-(2-propynyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid having a melting point of 211° to 213° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][NH2:12].[CH:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])=[O:14]>O1CCCC1>[CH3:8][O:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH:18]=[O:19])=[O:14]
Reactant: O=Cc1cccc(C(=O)Cl)c1
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCNC(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To a mixture of 200 ml of tetrahydrofuran, 16.70 g of triethylamine and 12.40 g of 2-methoxyethylamine was added a solution of 16.00 g of 3-formylbenzoic acid chloride in 20 ml of tetrahydrofuran at room temperature. After stirred at room temperature for 6 hours, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 10.79 g of oily 3-[(2-methoxyethyl)aminocarbonyl]benzaldehyde [Compound No. (d)].
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([NH2:19])=O)=[N:12]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[OH:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]#[N:19])=[N:12]1
Reactant: Cc1cc(C(N)=O)nn1CCO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C#N)nn1CCO
Reaction time: 0.17 h
Yield: 183.8 %

Procedure:
Under a nitrogen atmosphere, triethylamine (17.9 g, 177 mmol) was added to a slurry of 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxamide (7.0 g, 41.4 mmol) in dichloromethane (70 mL). The mixture was cooled in an ice bath and then a solution of trifluoroacetic anhydride (15.6 g, 74.2 mmol) in dichloromethane (70 mL) was added over a period of 10 minutes. All of the solids dissolved to provide a cloudy solution. After 1 hour additional triethylamine (70.6 mmol) was added and the reaction mixture was cooled in an ice bath. Trifluoroacetic anhydride (35.3 mmol) was added neat over a period of 5 minutes. The reaction mixture was stirred for 10 minutes then the ice bath was removed and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with 2 M aqueous sodium carbonate (100 mL) and water (100 mL) then extracted with chloroform (×3). The extracts were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 11.5 g of 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carbonitrile a brown oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:14])[O:13][CH2:12]2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Cl-].[Mg+2].[Cl-].C1(SC)C=CC=CC=1>ClCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C2(C)CO2)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CSc1ccccc1
Product: CC(C)Cc1ccc(C(C)C=O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 98.3 %

Procedure:
To a solution of 38.0 g (0.2 mole) of 2-(4-isobutylphenyl)-1,2-epoxypropane in 130 ml of dichloromethane was added 3.43 g (0.036 mole) of anhydrous powdered (100 mesh, Tyler) magnesium chloride and 5.0 g (0.04 mole) of thioanisole and the mixture was stirred for 10 hours at room temperature. The reaction mixture was washed with dilute hydrochloric acid and then with aqueous sodium chloride several times until neutral, and subjected to distillation under atmospheric pressure to remove dichloromethane. The resulted residue was distilled under reduced pressure to afford 37.4 g of 2-(4-isobutylphenyl)propionaldehyde as colorless oil distilled at 127°-130° C. (8 mmHg). The yield is 98.5%