Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([CH2:6][C:7](Cl)=[O:8])CCCC1.[N:10]1[CH:11]=[CH:12][N:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]([C:23]3[S:24][C:25]([C:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=4)=[CH:26][CH:27]=3)=[O:22])=[CH:15][C:14]=12.NC1C=CC(C(OC)=O)=CC=1>>[C:7]([N:31]1[CH2:30][CH:29]=[C:28]([C:25]2[S:24][C:23]([C:21]([NH:20][CH2:19][C:16]3[CH:17]=[CH:18][N:13]4[CH:12]=[CH:11][N:10]=[C:14]4[CH:15]=3)=[O:22])=[CH:27][CH:26]=2)[CH2:33][CH2:32]1)(=[O:8])[CH3:6]
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2=CCNCC2)s1
Reactant: O=C(Cl)CC1CCCC1
Agent: COC(=O)c1ccc(N)cc1
Product: CC(=O)N1CC=C(c2ccc(C(=O)NCc3ccn4ccnc4c3)s2)CC1

Procedure:
The title compound was prepared as described in Example 52A, substituting acetyl chloride for 2-cyclopentylacetyl chloride and N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide for methyl 4-aminobenzoate. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.13-9.06 (m, 1H), 8.48 (d, J=7.0 Hz, 1H), 7.88 (s, 1H), 7.72 (d, J=3.9 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.38 (s, 1H), 7.15 (t, J=4.2 Hz, 1H), 6.83 (dd, J=7.0, 1.6 Hz, 1H), 6.28-6.21 (m, 1H), 4.46 (d, J=5.9 Hz, 2H), 4.15-4.04 (m, 2H), 3.61 (dt, J=11.3, 5.6 Hz, 2H), 2.63-2.35 (m, 2H), 2.07-1.99 (m, 3H); MS (ESI)(+)) m/e 381 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([CH3:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].[NH4+].[Cl-]>C(Cl)Cl>[CH3:37][S:38]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([CH3:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)OCC(C)(c1ccncc1)C2CCCCCCCCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)OCC(C)(c1ccncc1)C2CCCCCCCCCOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 380.3 %

Procedure:
To a solution of 4-(9-hydroxynonyl)-7-methoxy-3-methyl-3-(4-pyridyl)chroman (108 mg, 0.272 mmol) in methylene chloride (2 mL) were added under ice-cooling triethylamine (0.057 mL, 0.41 mmol) and methanesulfonyl chloride (0.032 ml, 0.41 mmol), which was then stirred for 30 minutes. After the reaction was completed, saturated aqueous NH4Cl solution was added, the resulting mixture was then extracted with methylene chloride and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 4-(9-methanesulfonyloxynonyl)-7-methoxy-3-methyl-3-(4-pyridyl)chroman (492 mg, yield 38%).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]=2[CH:6]=[CH:5]1)([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:23]O>>[CH3:23][O:16][C:15]([C:8]1[C:7]2[CH:6]=[CH:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[CH:11]=[C:10]([O:13][CH3:14])[CH:9]=1)=[O:17]
Reactant: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Yield: 32.4 %

Procedure:
To a stirred suspension of 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg, 3.00 mmol) in MeOH was added H2SO4 (440 mg, 4.50 mmol) and then heated at reflux for 3 h. Methanol was distilled off completely under reduced pressure and the residue basified with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 100-200) by eluting 5% ethyl acetate in petroleum ether to afford 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid methyl ester (240 mg, 32.4%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (d, J=6.8 Hz, 6H), 3.84 (s, 3H), 3.88 (s, 3H), 4.81-4.78 (m, 1H), 6.86 (d, J=3.2 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.54 (d, J=3.6 Hz, 1H). LCMS (ES+): m/z=248.16[M+H].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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:14][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[N:3]=[C:4]([S:15][CH3:16])[N:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(Cl)n1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1nc(Cl)c(-c2ccccc2)c(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35.1 %

Procedure:
To a mixture of 4,6-dichloro-2-(methylthio)-5-phenylpyrimidine (2.71 g, 10.0 mmol), 4-chlorophenylboronic acid (1.72 g, 11.0 mmol) and tetrakis(triphenylphosphine)palladium (578 mg, 0.50 mmol) in toluene (25 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 10 mL, 20.0 mmol). The resulting reaction mixture was stirred at 100° C. under argon for 6 h, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to obtain 1.22 g of the title compound as a white solid. HPLC/MS: retention time=4.32 min, [M+H]30 =347.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:9]=2)=[O:4].[C:26]([Cu])#[N:27].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccccc3OC)ccc2c1O
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
4-Hydroxy-1-iodo-7-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (150 mg, 0.33 mmol) and CuCN (60 mg, 0.67 mmol) were suspended in DMF (1.3 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 100 mg. MS: (−) m/z 349.28 (M−1).
Reaction SMILES: [S:1]1[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH:3]=[C:2]1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O.C(Cl)(Cl)Cl>CN(C)C=O>[S:1]1[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH:3]=[C:2]1[C:13]([Cl:18])=[O:15]
Reactant: O=C(O)c1cc2oc3ccccc3c2s1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2oc3ccccc3c2s1

Procedure:
A suspension of 15.5 g thieno[3,2-b]benzofuran-2-carboxylic acid, 16.9 g of thionyl chloride, 150 ml of chloroform and 1 ml of dimethylformamide is refluxed 5 hours, the reaction mixture is screened and the solvent removed from the filtrate to yield thieno[3,2-b]benzofuran-2-carboxylic acid chloride as a brown solid. 5.1 g of the above mentioned acid chloride is added portionwise over 30 minutes to a stirred mixture of 2.7 g of 2-aminothiophenol, 50 ml of toluene and 5 ml of pyridine cooled in an ice bath. The mixture is then stirred at ambient temperature for 17 hours, cooled, filtered and the residue washed with ligroin to yield the amide of formula (X) ##STR18## as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+].[CH3:49][S:50]([CH3:52])=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:49][S:50][CH3:52])[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OCSC)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (25 mg, 0.054 mmol) in DMSO (0.2 mL) was added a mixture of acetic acid and acetic anhydride (1:5.6) (0.17 mL). After stirring for 1.5 h at room temperature it was held at 40° C. for 5 h. It was cooled to room temperature and stirred for 16 h. The mixture was cooled in ice-bath and NaHCO3 solution was added carefully. It was extracted with ether. The extract was washed with water and brine, dried over MgSO4 and evaporated. Pure 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(trans-4-methylsulfanylmethoxy-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester was obtained by chromatography over silica gel (hexane:EtOAc=−4:1) (22 mg, 77%).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][NH2:28].[Cl:30][C:31]1[CH:32]=[C:33]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:34][N:35]([CH3:46])[C:36]([C:38]1[CH2:39]N(C)[C:41](=[O:44])[C:42]=1[OH:43])=[O:37]>>[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][N:28]1[CH2:39][C:38]([C:36](=[O:37])[N:35]([CH2:34][C:33]2[CH:47]=[CH:48][C:49]([Cl:50])=[C:31]([Cl:30])[CH:32]=2)[CH3:46])=[C:42]([OH:43])[C:41]1=[O:44]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)CCN
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: COC(=O)CCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 17 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and β-alanine methyl ester as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber oil (34.3 mg, 17% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (m, 2H), 7.09 (m, 1H), 4.59 (s, 2H), 4.27 (s, 2H), 3.77 (m, 2H), 3.67 (s, 3H), 3.03 (s, 3H), 2.69 (t, 2H, J=6.22). HRMS (M+H) calcd for C17H19N2Cl2O5: 401.0671. found: 401.0669.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]([NH:23]C(=O)C)[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]([CH3:22])([N+:19]([O-:21])=[O:20])[CH3:18])=[CH:7][CH:6]=[N:5]1>O.CO>[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]([CH3:22])([N+:19]([O-:21])=[O:20])[CH3:18])[NH2:23])=[CH:7][CH:6]=[N:5]1
Reactant: CC(=O)Nc1ccc(OCC(C)(C)[N+](=O)[O-])c(-c2ccnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nccc1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Temperature: 140 °C
Yield: 72.4 %

Procedure:
A solution of sodium hydroxide (70 mg, 1.74 mmol) in water (0.15 mL) was added to a suspension of N-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)acetamide (84 mg, 0.29 mmol) in methanol (1 mL) and the mixture was stirred at 140° C. in a screw capped vial for 90 min. The mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and water, the organic layer was dried with sodium sulfate, filtered and evaporated to dryness to afford the title compound (62 mg, 0.21 mmol, 74%) as a yellow oil which was used without further purification. LCMS m/z (%)=291.3 (M+H 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2C=CC[NH:9][CH2:8][C@H:7]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]1=[O:28].C(N(CC)CC)C.[C:37]1([CH2:43][CH2:44][C:45](Cl)=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[C:14]2[CH:13]=[CH:18][CH:17]=[CH:16][C:15]=2[N:9]([C:45](=[O:46])[CH2:44][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:8][C@H:7]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:6]1=[O:28]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CNCC=Cc2ccccc21
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A solution of (3S)-2-oxo-3-(benzoylamino)-2,3,4,5-tetrahydro-1H-1,5-benzodiazecine-1-acetic acid methyl ester 200 mg, 0.57 mmol) in CH2Cl2(10 ml) was treated with triethylamine (1-9 mg, 1.13 mmol) and 3-phenylpropionyl chloride (114 mg, 0.68 mmol). The reaction was stirred at RT for 30 min and diluted with CH2Cl2. The solution was washed wIth*. aq. 10% HCl, sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4 and concentrated in vacuo to give 240 mg (87%) of 602a as a white foam.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:11][CH:10]=[N:9][C:8]=1[O:12][CH2:13][CH:14]1[CH2:16][O:15]1.[CH3:17][CH:18]([Si:20](Cl)([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH3:19]>C1COCC1>[CH:18]([Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[C:10]1[S:11][C:7]2[CH:14]([CH2:16][OH:15])[CH2:13][O:12][C:8]=2[N:9]=1)([CH3:19])[CH3:17]
Reactant: Brc1scnc1OCC1CO1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](c1nc2c(s1)C(CO)CO2)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., a soln. of n-BuLi in hexanes (2.18 M, 16.7 mL, 36.4 mmol) was added over 30 min to a soln. of 5-bromo-4-(oxiran-2-ylmethoxy)thiazole (7.17 g, 30.4 mmol) in THF (564 mL). The mixture was stirred at −78° C. for 2 h, then, TIPSCl (6.63 mL, 31.0 mmol) was added, the mixture was allowed to warm to RT and stirred at RT for 30 min. Subsequently, the mixture was cooled to −78° C. and treated with a soln. of n-BuLi in hexanes (2.18 M, 13.9 mL, 30.4 mmol). The mixture was stirred at 0° C. for 2 h, then, it was quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was purified by means of CC (100 g KP-Sil, EtOAc/Hept 5-50%), followed by CC (5-50% EtOAc/Hept) to provide a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8](Cl)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>O.C(O)C(C)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCCCCCCCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)CO
Product: CCCCCCCCCCN1CCN(C)CC1
Temperature: 150 °C
Yield: 74.9 %

Procedure:
100 g (1 mole) of 1-methyl-piperazine and 176.5 g (1 mole) of decyl chloride were heated under reflux, at an external temperature of 150° C, until the reaction mixture had ceased boiling. After cooling, the solid product was extracted by shaking with a mixture with 40 g (1 mole) of sodium hydroxide in 500 ml of water and 500 ml of isobutanol. The organic phase was separated off and concentrated, and the residue was extracted with petroleum ether. After evaporating the petroleum ether solution, 180 g (75% of theory) of 1-methyl-4-decyl-piperazine were obtained in a form which was pure according to thin layer chromatography.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Mg].[CH2:9](OS(C1C=CC(C)=CC=1)(=O)=O)[CH:10]([CH3:12])[CH3:11]>C(OCC)C>[CH2:9]([C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7])[CH:10]([CH3:12])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)C)cc1
Reactant: Cc1ccsc1Br
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccsc1CC(C)C
Yield: 48 %

Procedure:
A part of a solution containing 2-bromo-3-methylthiophene (1.5 g, 8.5 mmol) in dry diethyl ether is added drop-wise to a suspension of magnesium (308 mg, 12.7 mmol, 1.5 equiv.) in dry diethyl ether until the mixture starts to reflux. The remaining solution is added dropwise. A solution of toluene-4-sulfonic acid isobutyl ester (2.9 g, 12.7 mmol, 1.5 equiv.) in dry diethyl ether is added dropwise at room temp., then the mixture is further refluxed for two hours. After cooling to room temp., the mixture is quenched with sat. ammonium chloride solution and extracted with tert. butylmethylether. The combined organic extracts are washed with water, brine, dried over magnesiumsulfat-dihydrate, filtered and evaporated to give a yellow oil. After Kugelrohr-distillation, 630 mg of the title compound is obtained as a colorless oil. GC-MS (EI): M=154
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:9]=2[S:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH:16][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:15][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC1=CSc2cc(N)ccc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1=CSc2cc(NS(C)(=O)=O)ccc2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of (7-amino-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (Example 8c, 2.38 g, 9.51 mmol) in dichloromethane (80 mL) was cooled to 0° C. and treated with triethylamine (3.1 g, 30.4 mmol) followed by dropwise addition of methanesulfonyl chloride (1.37 g, 9.51 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and allowed to warm to 25° C. The reaction mixture was concentrated in vacuo and purified by flash chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/hexanes) to afford the desired product, (7-methanesulfonylamino-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (2.2 g, 6.7 mmol, 71% yield) as a light tan solid. 1H NMR (400 MHz, CDCl3) δ 1.31 (t, 3H, J=7.0 Hz), 3.00 (s, 3H), 3.43 (s, 2H), 4.19 (quartet, 2H, J=7.1 Hz), 4.73 (s, 1H), 6.28 (s, 1H), 6.85 (d, 1H, J=8.5 Hz), 6.99 (dd, 1H, J1=8.5 Hz, J2=2.4 Hz), 7.12 (d, 1H, J=2.3 Hz), 10.64 (bs, 1H). LC-MS (ESI) calcd for C13H16N2O4S [M+H+] 329.06. found 329.10 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([O:27]C)=O)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:38][NH2:39]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:38][NH2:39])=[O:27])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:34])([F:35])[F:36])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Temperature: 80 °C

Procedure:
To a solution of methyl 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido-[2,3-b][1,5]benzodiazepine-8-carboxylate (intermediate 56, 0.11 g, 0.21 mmol) in ethanol (1.0 mL) at rt was added hydrazine hydrate (0.460 mL). The mixture was heated at 80° C. for 18 h, cooled to rt, and the precipitate was collected by filtration to provide the title compound. LC/MS: m/e 520.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 8.00 (1H, s), 7.78 (1H, d, J=8.3 Hz), 7.65 (1H, d, J=7.5 Hz), 7.10-7.16 (3H, m), 6.90-6.95 (3H, m), 4.45-4.70 (2H, br), 1.24 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11](CCl)[CH:12]=[O:13].[OH-].[Na+].[CH2:18](O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:18]=[C:12]([OH:13])[CH:11]=[N:10]1
Reactant: CCO
Reactant: O=CC(CCl)=NNc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cnn(-c2ccc(Cl)cc2Cl)c1
Yield: 87 %

Procedure:
27.0 g of 3-chloropyruvaldehyde 2,4-dichlorophenylhydrazone is suspended in 100 ml of ethanol. To the suspension is added at room temperature 12 g of sodium hydroxide dissolved in 10 ml of water. After stirring the mixture for 2 hours ethanol is distilled off, and water is added to the resultant residue to dissolve it. Insolubles are removed by filtration, and the filtrate is neutralized with glacial acetic acid. The precipitate is recovered by filtration, washed with water and dried. Recrystallization from toluene results in 17.3 g of the subject compound in the yield of 87%.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>ClCCl>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Yield: 52.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-octadecanol (36 grams, 210 mmol), pyridine (20 milliliters), and dichloromethane (500 milliliters) was heated to reflux. The alcohol dissolved and the solution was allowed to cool 5° C. 4-Nitrobenzoyl chloride (39.0 grams, 210 mmol) was added in portions over a twenty minute period. The reaction mixture was heated to reflux for sixteen hours. The reaction mixture was washed with 250 milliliters of water. The aqueous layer was washed with 250 milliliters of dichloromethane. The organic layers were combined and concentrated under reduced pressure to a light tan solid. Added 500 milliliters of hexane and heated to reflux. A white precipitate formed as the solution was cooled to room temperature. Filtered off the white precipitate and concentrated the filtrate to a light tan solid. The solid was recrystallized from ethanol (500 milliliters) to obtain 46 grams of octadecyl 4-nitrobenzoate as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:31])=[C:3]([N:8]1[C@H:11](SC)[C@@H:10]([C@H:14]([O:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[CH3:15])[C:9]1=[O:30])[C:4]([O:6][CH3:7])=[O:5].[Cl:32]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:32][CH:11]1[N:8]([C:3](=[C:2]([CH3:31])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9](=[O:30])[C@@H:10]1[C@H:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])[CH3:15]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C1Cl
Temperature: 0 °C

Procedure:
To a solution of methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-2-oxoazetidin-1-yl]but-2-enoate (481 mg) in dichloromethane (5 ml) was added a solution of chlorine (83 mg) in carbon tetrachloride (0.65 ml) at -78° C. The solution was allowed to warm to 0° C. during 45 minutes and evaporated in vacuo. The residue was chromatographed on silica gel (12 g) eluting with 10-33% ethyl acetate in hexane to give methyl 2-[(3S)-4-chloro-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate [a mixture (55:45) of (4R) isomer and (4S) isomer] (394 mg).