Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:6]([O:8][CH3:9])=[O:7].O>CO.C1COCC1.[C].[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(OC)c1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 104.1 %

Procedure:
To a solution of methyl 3-methoxy-4-nitrobenzoate (150 g) in methanol (600 mL) and THF (300 mL) was added 10% palladium-carbon (a 50% water-containing product, 15 g), and the reaction liquid was stirred at 50° C. to 64° C. under a hydrogen pressure of 0.9 MPa for 6.5 hours. The reaction liquid was allowed to stand to cool to room temperature and then filtered on celite, followed by concentrating the resultant filtrate under reduced pressure to provide 134 g of the title compound. The physical property values thereof agreed with reported values (CAS#41608-64-4).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5](N1C=CN=C1)(N1C=CN=C1)=[O:6].[N:17]1([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][NH2:35])[CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[N:17]1([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][NH:35][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(C)N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)NC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A solution of 0.113 g of isopropylamine in 2 ml of methylene chloride was added to a solution of 0.31 g of carbonyldiimidazole in 5 ml of methylene chloride, and the resulting mixture was cooled with ice, after which a solution of 0.500 g of 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine in 5 ml of methylene chloride was added. The reaction mixture was stirred at room temperature for 2 hours, after which it was poured into ice-water and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:20 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.41 g (yield 62%) of the title compound as a white powder, melting at 90°-92° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]([C:19]2[CH:24]=[CH:23][C:22]([NH:25]/[C:26](=[C:33]3\[C:34](=[O:42])[NH:35][C:36]4[C:41]\3=[CH:40][CH:39]=[CH:38][CH:37]=4)/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH3:18])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:43]C(OC(Cl)C)=O>ClCCl>[ClH:43].[ClH:43].[N:11]1([CH2:14][C:15]([N:17]([C:19]2[CH:24]=[CH:23][C:22]([NH:25]/[C:26](=[C:33]3\[C:34](=[O:42])[NH:35][C:36]4[C:41]\3=[CH:40][CH:39]=[CH:38][CH:37]=4)/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH3:18])=[O:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C(=O)CN1CCNCC1)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
390 mg (0.7 mmol) of (Z)-3-{1-[4-(N—(N-benzylpiperazinomethylcarbonyl)-N-methylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone are dissolved in 20 ml of dichloromethane and after the addition of 0.2 g (1.4 mmol) of 1-chloroethyl chloroformate heated for 30 minutes at ambient temperature and refluxed for 60 minutes. The solvent is concentrated by evaporation, the residue is combined with 10 ml of methanol and refluxed for 90 minutes. After 18 hours stirring at ambient temperature, the product is suction filtered, washed with methanol and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)ccc1Br
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(F)ccc1Br
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of 2-bromo-5-fluorophenol (20.0 g, 104.7 mmol) and potassium carbonate (21.71 g, 157.1 mmol) in acetone (200 mL) was added dimethyl sulphate (10.90 mL, 115.2 mmol). The resulting suspension was allowed to stir at 60° C. for 2 h before being allowed to cool and then concentrated in vacuo. The residue was dissolved in ether (200 mL) and water (100 mL). The organic phase was washed with aqueous hydrochloric acid (2 N, 50 mL), saturated sodium bicarbonate solution (50 mL) with the resulting organic phase being dried (MgSO4) and the solvent evaporated in vacuo to give a pale yellow oil (21.46 g, 100%). δH (300 MHz, CDCl3) 7.45 (1H, dd, Ar), 6.70-6.55 (2H, m, Ar), 3.90 (3H, s, OCH3).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Br-:1].[C:31]1([P+:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: BrCCCCCCCCCCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc(CCCCCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
Compound 11 (7.0 g) was dissolved in toluene (80 mL) and triphenylphosphine (6.8 g) was added thereto, followed by stirring at 100° C. for 12 hours. Triphenylphosphine (1.3 g) was further added, followed by stirring at 100° C. for 24 hours. After cooling the reaction solution to room temperature, the resulting precipitate was washed with toluene three times and the residue was dried under reduced pressure to obtain the title compound (7.2 g) having the following physical property values.
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[N:3]=1.[N+](=[CH:22][Si](C)(C)C)=[N-].CCCCCC>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[N:6]([CH3:22])[N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(Br)n2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a stirred suspension of tert-butyl 4-(5-bromo-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (26 g, 78.50 mmol) in toluene (200 mL) and methanol (50 mL) was added dropwise (diazomethyl)trimethylsilane 2M solution in hexane (43.2 mL, 86.35 mmol) under N2, keeping temperature around 20° C.: gas evolution and a small exotherm were observed. The yellow solution obtained was stirred at room temperature for 1 h. The solvent were evaporated and the resulting oil was purified on silica, eluting with 40% EtOAc in petroleum ether to afford tert-butyl 4-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (15.00 g, 55.3%) as an oil: 1H NMR Spectrum; (CDCl3) 1.46 (9H, s), 1.65-1.78 (2H, m), 1.90-2.01 (2H, m), 2.68-3.02 (3H, m), 3.83 (3H, s), 3.94-4.31 (2H, m); Mass Spectrum [M+H]+=no mass ion.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])=[C:37]([Cl:47])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Cl:47][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3-chloro-4-(2-ethoxyethoxy)phenyl borate (156 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) and recrystallized from ethanol to give colorless crystals of 7-[3-chloro-4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 67) (269 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].N[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=1.S(=O)(=O)(O)[OH:14]>>[Br:12][C:9]1[CH:10]=[C:11]([N+:1]([O-:4])=[O:2])[C:6]([OH:14])=[N:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(Br)cn1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(Br)cnc1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
34.5 ml (821.6 mmol) of fuming nitric acid (d=1.5 g/cm3) are added dropwise at 60° C. to 100 g (574.7 mmol) of 2-amino-5-bromopyridine in 300 ml of concentrated sulfuric acid (d=1.84 g/cm3), and the mixture is subsequently stirred at 60° C. for 2 hours. The reaction mixture is poured into ice water, and the precipitated solid is filtered off, washed with water and dried, giving 88.16 g of 5-bromo-2-hydroxy-3-nitropyridine. ##STR10##
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([CH:11]=O)=[CH:9][N:10]=1.Cl.[NH2:14]O>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([C:11]#[N:14])=[CH:9][N:10]=1
Reactant: O=Cc1cnc(-c2cccs2)s1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1cnc(-c2cccs2)s1
Yield: 72.3 %

Procedure:
6.6 g 2-thiophen-2-yl-thiazole-5-carbaldehyde, 2.8 g hydroxylamine hydrochloride in 45 ml dimethylformamide are heated to 150° C. for 2 hours. The solvent is removed under reduced pressure. The crude product is purified by flash column chromatography in ethylacetate:hexane=1:5. 4.7 g of 2-thiophen-2-yl-thiazole-5-carbonitrile (11) are obtained. 1H (CDCl3): 8.2, 1H, d; 7.6, 1H, d; 7.5, 1H, d; 7.1, 1H, dd. 13C (CDCL3) 166.8 Cq, 152.5 Cq, 135.6 CH, 130.7 CH, 129.0 CH, 128.5 CH, 111.9 Cq 104.4 Cq.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1.Cl>CO.C1COCC1.CCOC(C)=O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[S:14][C:13]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NOC[C@H](O)CO)c1c(Nc2ccc(I)cc2F)sc2ncccc12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of Example 22 (125 mg, 0.23 mmol) in methanol (5 mL) and THF (5 mL) was treated with 10% aq. HCl (5 mL). The reaction mixture was stirred for 3.5 h at r.t., then diluted with EtOAc (25 mL). The organic solution was washed with sat. brine (2×25 mL), then dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white powder, which was washed with EtOAc, then hexanes, and dried under suction (76 mg, 66%). δH (DMSO-d6) 11.31 (1H, s), 10.33 (1H, s), 8.34-8.33 (1H, m), 8.12-8.09 (1H, m), 7.79-7.76 (1H, m), 7.63-7.60 (1H, m), 7.45-7.40 (2H, m), 4.89-4.88 (1H, m), 4.62-4.59 (1H, m), 3.99-3.97 (1H, m), 3.85-3.80 (2H, m), 3.43 (2H, m). LCMS RT 3.38 minutes, (ES−) 502 (M−H)−, (ES+) 504 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:16])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:16]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][CH2:13][CH2:14][CH3:15])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCCCC(N)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCCC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a stirred solution of 1-(3′,4′-dimethoxyphenyl)pentylamine (0.3 grams, 1.34 mmol) and sodium carbonate (0.15 grams, 1.45 mmol) in a mixture of water (10 milliliters) and acetonitrile (10 milliliters) was added N-carbethoxyphthalimide (0.29 grams, 1.34 mmol). The resulting solution was stirred for 3 hours at room temperature, the acetonitrile was evaporated and a two phase mixture resulted. The organic phase was extracted into methylene chloride, dried over magnesium sulfate and concentrated to afford 0.41 grams of crude product as an oil. The crude product was purified by flash chromatography (silica gel, 30% ethyl acetate/hexane) to afford 0.18 grams (38%) of the product as an oil: 1H NMR (CDCl3) δ7.88-7.63(m, 4H), 7.20-7.07(m, 2H),6.82-6.76(m, 1H), 5.34-5.18(m, 1H), 3.89(s, 3H), 3.85(s, 3H),2.66-2.43(m, 1H),2.40-2.17(m, 1H), 1.50-1.20(m, 2H), 0.96-0.81(m, 3H). 13C NMR (CDCl3) δ1.68.5, 148.8, 148.5, 133.8, 132.5, 131.9, 123.1, 120.6, 111.6, 110.8, 55.9, 55.8, 55.0, 30.9, 29.2, 22.3, 13.9.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)=[O:42]>C(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:25])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:41]([O:43][C:44]3[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=3)=[O:42])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NCCCCCCO)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A solution of the alcohol (40.0 g, 88 mmol) produced in Example 4 and pyridine (7.1 ml, 88 mmol) in 300 ml of methylene chloride was added under nitrogen dropwise over one hour to a solution of 4-nitrophenyl chloroformate (17.7 g, 88 mmol) in 300 ml of methylene chloride at ice bath temperature. The reaction was stirred at ice bath temperature for two hours and overnight at room temperature. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 54.9 g of an off-white solid. Recrystallization from 1:1 ethyl acetatehexane gave 51.6 g (95%) of the title compound as a white crystalline solid, mp 117-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6]2
Reactant: CCOC(=O)CCl
Reactant: COc1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCc2cc(OC)ccc2C1

Procedure:
A solution of 6-methoxy-1,2,3,4-tetrahydroisoquinoline, Sall and Grunewald, J. Med. Chem. 1987, 30, 2208-2216 (1.1 mmol), ethyl chloroacetate (1.17 mmol), and K2CO3 (1.17 mmol) in CH3CN (10 mL) is stirred for 18 h. The mixture is partitioned between EtOAc and H2O. The organic phase is concentrated to an oil, which is purified by chromatography (silica gel, gradient, 20-80% EtOAc/hexane) to afford the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:63])/[C:16](/[C:38]3[N:39]=[C:40]([NH:43]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:41][CH:42]=3)=[N:17]\[O:18]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:12](=[O:64])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+].[C:66]([CH2:69][S:70][C:71]1[N:75]=[C:74]([SH:76])[S:73][N:72]=1)(=[NH:68])[NH2:67].C(O)=O>CN(C=O)C>[C:66]([CH2:69][S:70][C:71]1[N:75]=[C:74]([S:76][CH2:2][C:3]2[CH2:4][S:5][C@@H:6]3[C@H:13]([NH:14][C:15](=[O:63])/[C:16](/[C:38]4[N:39]=[C:40]([NH2:43])[S:41][CH:42]=4)=[N:17]\[OH:18])[C:12](=[O:64])[N:7]3[C:8]=2[C:9]([OH:11])=[O:10])[S:73][N:72]=1)(=[NH:67])[NH2:68]
Reactant: N=C(N)CSc1nsc(S)n1
Reactant: O=C([O-])C1=C(CO)CS[C@@H]2[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: N=C(N)CSc1nsc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)n1
Yield: 26.3 %

Procedure:
To a solution of 909 mg of sodium 3-hydroxymethyl-7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-trityloxyiminoacetamido]-3-cephem-4-carboxylate and 619 mg of 3-amidino methylthio-5-mercapto-1,2,4-thiadiazole in 8 ml of DMF was added 1.4 g of ethyl o-phenylenephosphate under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 4 hours and then subjected to a column chromatography on silica gel (150 g), being eluted with aceton/water (95:5). The eluate was concentrated to dryness under reduced pressure to obtain a powder to which was added 20 ml of formic acid. After stirring at room temperature for 14 hours, the mixture was distilled under reduced pressure to remove formic acid. The residue was added with water and THF, adjusted to pH 7 under ice-cooling, washed with ethyl acetate, concentrated under reduced pressure and then subjected to a column chromatography on XAD-II (140 mg), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated under reduced pressure and then lyophilized to give 155 mg of the title compound as a pale yellow powder.
Reaction SMILES: BrC1C=CC(S([O:11][C@H:12]2[C@@H:19]3[C@@H:15]([CH2:16][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=4)[CH2:18]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH3:30]O>>[CH3:30][O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=3)[CH2:18]2)[CH2:14][CH2:13]1
Reactant: CO
Reactant: O=S(=O)(O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(Br)cc1
Product: CO[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21

Procedure:
(3aR,4R,6aS)-2-[6-(Trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl 4-bromobenzenesulfonate (100 mg, 0.204 mmol) from Example 39 was heated at 85° C. for 3 days in methanol (0.3 mL) to give a colorless solution. The methanol was removed in vacuo, and the crude material was purified by silica gel chromatography using 100% dichloromethane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.57-7.53 (m, 1H), 7.01 (d, J=7.3, 1H), 6.54 (d, J=8.6, 1H), 3.58 (dd, J=11.0, 8.8, 1H), 3.52 (dd, J=7.1, 4.8, 1H), 3.47 (dd, J=10.7, 7.8, 1H), 3.28 (dd, J=11.1, 4.8, 1H), 3.24-3.18 (m, 4H), 2.81-2.64 (m, 2H), 1.93 (dq, J=12.9, 7.9, 1H), 1.80 (dtd, J=13.2, 7.8, 5.4, 1H), 1.68 (ddd, J=17.7, 11.3, 6.7, 1H), 1.38-1.25 (m, 1H); MS (ESI+) m/z 287 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].C(=S)([S-])[S-:6].[Na+].[Na+].[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)#[N:12]>ClCCl.CCCCCC>[C:3]([CH2:2][S:6][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([C:11]#[N:12])=[CH:14][CH:15]=1)#[N:4]
Reactant: N#CCCl
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: S=C([S-])[S-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: N#CCSC(=O)c1ccc(C#N)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
Chloroacetonitrile (13.1 ml; 0.203 mol) is added over 15 minutes to a cold (15° C.) 2 N solution of sodium trithiocarbonate (92.5 ml; 0.185 mol). The reaction mixture is stirred one hour at 5° C., extracted with ether, and the aqueous layer added dropwise to a solution of p-cyanobenzoyl chloride (20.9 g; 0.124 mol) in dichloromethane (40 ml). During addition, the temperature of the reaction mixture is held below 12° C. The reaction mixture is then held at 0°-5° C. for 2 hours, diluted with hexane (50 ml) and filtered to yield 26 g of a yellow solid. This solid is recrystallized from a mixture of acetone-methanol-water to afford 19.7 g of title product, a yellowish solid, melting point 129°-131° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>C1COCC1>[O:29]=[C:22]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)Cc1ccsc1
Reactant: O=C(Cl)c1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1cccnc1)c1ccsc1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of ethyl 2-(thiophen-3-yl)acetate (2.3 g, 16.2 mmol) in anhydrous THF (20 mL) was added LiHMDS (19.4 mL, 19.44 mmol) at −78° C. After stirring at that temperature for 0.5 h, a solution of nicotinoyl chloride (2.8 g, 16.2 mmol) in anhydrous THF (10 mL) was added into the reaction mixture and stirred at −78° C. for 4 hours. The mixture was quenched with NH4Cl solution, extracted with EtOAc. The organic layer was concentrated in vacuo and purified by silica gel column chromatography (1.7 g, yield 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.Cl.[CH3:28][N:29]([CH2:31][C:32](Cl)=[O:33])[CH3:30].C(=O)([O-])O.[Na+]>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][N:12]([C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)Cl
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CN(C)CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Reaction time: 2.5 h
Yield: 165.5 %

Procedure:
To a solution of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (0.52 g) and N,N-dimethylaniline (0.97 g) in methylene chloride (15 ml) is added dimethylaminoacetyl chloride hydrochloride (0.63 g) under ice cooling, and the mixture is stirred at the same temperature for 2.5 hours. To the reaction mixture is added aqueous sodium hydrogen carbonate solution, and is extracted with chloroform. The chloroform layer is washed, dried and distilled to remove the solvent. The residue is treated with hydrochloric acid and the resulting salt is recrystallized from ethanol-ether to give 2-(4-chlorophenyl)-4-(dimethylamino)acetyl-3,4-dihydro-2H-1,4-benzothiazine hydrochloride (0.63 g, yield 86%).