Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][CH:1]([C:4]2[CH:17]=[CH:16][C:7]3[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=3[CH:5]=2)[CH3:2])=[CH:22][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cc2ccc(C(C)=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccc(C(C)NCc3ccc(OC)cc3)cc2s1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Ethyl 6-acetyl-1-benzothiophene-2-carboxylate (0.3 g, 1.21 mmol) was dissolved in DCE (3.0 mL). 4-methoxybenzyl amine was then added to the reaction followed by acetic acid (0.1 mL, 1.69 mmol) and NaBH(OAc)3 (0.41 g, 1.93 mmol). The reaction was allowed to stir for 5 d at room temperature before it was quenched with saturated sodium bicarbonate solution. The reaction mixture was then extracted with ethyl acetate (3×) and the combined organic layers was dried over Na2SO4. After concentrating in vacuo, the crude reaction mixture was purified by flash column chromatography to provide the amine. 1H (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 3.93 (q, J=6.5 Hz, 1H), 3.79 (s, 3H), 3.57 (dd, J=21.0, 12.9 Hz, 2H), 1.42-1.26 (m, 6H). MS: cal'd (MH+) 370, exp (MH+) 370.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:29]2[C:24]([CH2:25][NH:26][CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.[Cl:31][CH2:32][CH:33]=[C:34](Cl)C>CN(C)C=O>[CH3:30][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([CH2:34][CH:33]=[CH:32][Cl:31])[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:22])([OH:23])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: CC(Cl)=CCCl
Reactant: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CNCCC3C(C)(C)OC2=C1
Solvent: CN(C)C=O
Product: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CN(CC=CCl)CCC3C(C)(C)OC2=C1

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano[4,3-c]pyridin-10-ol (1 mole) and 1,3-dichloro-2-butene (0.5 mole) were reacted in dimethylformamide as described in Example 7 to give the desired product.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[CH3:21]O>>[CH3:21][O:15][C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCNC(=O)OCc1ccccc1

Procedure:
Prepared by the procedure described in Example 1, Step A from N-CBZ-β-alanine (5 g, 22.4 mmole), methanol and thionyl chloride to give the title compound. ##STR95##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])[N:4]=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])[N:4]=1
Reactant: [H][H]
Reactant: COc1nc(S(C)(=O)=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1nc(S(C)(=O)=O)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 2-methoxy-6-(methylsulfonyl)-3-nitropyridine (Preparation 83, 290 mg, 1.249 mmol) in EtOAc/EtOH (1:1, 10 mL) was added palladium on charcoal (10%, 100 mg). The flask was charged with hydrogen and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo to give the title compound (245 mg, 97%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[CH2:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:35]([O:42][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Product: Brc1ccc(OCc2ccccc2)nc1

Procedure:
A suspension of 2,5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-crown-6 (0.14 g, .05 equiv), benzyl alcohol (1.1 mL, 1.3 equiv), and potassium hydroxide (1.1 g, 2.4 equiv) in toluene (30 mL) were heated at reflux for 3 h in an apparatus fitted with a Dean-Stark trap. The suspension was cooled, concentrated, suspended in water, and extracted into methylene chloride. The combined organic phases were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.9 g (85%) which was used without purification. Mass spec.: 264.25 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:11])[CH3:10].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:38][CH2:39][CH2:40][CH2:41][C:42](=[CH:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH:57]=[C:56]([CH3:58])[N:55]=[CH:54]2)=[C:49]([O:59][CH3:60])[CH:48]=1)[C:43](O)=[O:44]>CN(C=O)C.C(OCC)(=O)C.O.C(Cl)CCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][C:43](=[O:44])[C:42](=[CH:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH:57]=[C:56]([CH3:58])[N:55]=[CH:54]2)=[C:49]([O:59][CH3:60])[CH:48]=1)[CH2:41][CH2:40][CH2:39][Cl:38])[CH3:10]
Reactant: COc1cc(C=C(CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Reactant: CC(N)c1cccc(F)c1F
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1cc(C=C(CCCCl)C(=O)NC(C)c2cccc(F)c2F)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2,3-difluorophenyl)ethylamine (purity: 72 wt %, 195 mg), IPEA (1 mL), EDC (257 mg) and HOBT (181 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (200 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,3-difluorophenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 30 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,3-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 95 mg of the title compound as a racemate. The compound (18 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: hexane:ethanol=5:5) to obtain the title optically active substance with a retention time of 28 minutes (7.5 mg; >99% ee) and the title optically active substance with a retention time of 37 minutes (7.5 mg; >90% ee). The physical properties of the compounds are as follows.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20](=[O:23])[CH2:21][CH3:22]>CC(C)=O>[CH2:21]([C:20]1[O:23][C:3](=[O:4])[C:5]2=[CH:9][CH:8]=[CH:7][N:6]2[CH:19]=1)[CH3:22]
Reactant: CCC(=O)CBr
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1cn2cccc2c(=O)o1
Temperature: 25 °C
Reaction time: 19 h
Yield: 102 %

Procedure:
To a slurry of 2-(trichloroacetyl)pyrrole (380 mg, 1.79 mmol) and K2CO3 (780 mg, 5.7 mmol) in 5 mL acetone was added a solution of 1-bromo-2-butanone (400 mg, 2.7 mmol) in 2 mL acetone. The mixture was stirred for 19 hours at room temperature before filtering and concentrating under reduced pressure to obtain 3-ethyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (298 mg, quantitative), which was used in the following step without purification.
Reaction SMILES: Br[C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.[CH3:40][CH2:41][CH2:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46]>O1CCCC1>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:6]1[CH2:7][CH2:8][CH2:9][C:10]2=[C:2]([C:43]([OH:47])([CH2:44][CH2:45][CH3:46])[CH2:42][CH2:41][CH3:40])[N:3]([CH3:20])[N:4]=[C:5]12
Reactant: CCCC(=O)CCC
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(Cl)c1
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (122 mg) and a crystal of 1,10-phenanthroline were dissolved in 3 mL of dry tetrahydrofuran and the solution was chilled to −78° C. under an atmosphere of argon. Then n-butyllithium (2.0 M in cyclohexane) was added until the dark color of the organolithium/phenanthroline complex persisted. An additional 0.17 mL of the butyllithium solution then was added. After 10 min, a solution of 4-heptanone (42.6 mg) in 1 mL tetrahydrofuran was added via syringe. The reaction mixture was allowed to stir at −780C for 15 min, then was allowed to warm to 0° C. After quenching with aqueous ammonium chloride, the reaction mixture was partitioned between ethyl acetate and brine. The ethyl acetate was dried with magnesium sulfate and concentrated on the rotary evaporator. The residue was chromatographed on silica gel eluting with 9:1 hexane/acetone to provide 76.0 mg of 4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo-[3,4-b]pyridin-3-yl]heptan-4-ol, which was recrystallized from hexane, mp 129-130° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1.C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C>[Br:20][C:7]1[C:5]2[CH2:6][C@@H:2]([CH3:1])[O:3][C:4]=2[C:10]([NH2:11])=[CH:9][C:8]=1[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(N)c2c(c1)C[C@@H](C)O2
Solvent: CN(C)C=O
Product: Cc1cc(N)c2c(c1Br)C[C@@H](C)O2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of (R)-2,5-dimethyl-2,3-dihydrobenzofuran-7-amine (3f) (1.3 g, 7.9 mmol) in DMF (16 mL) was added NBS (1.42 g, 7.9 mmol) at 0° C. It was stirred for 15 min at 0° C. The mixture was extracted with EtOAc (150 mL), washed with NaHSO3 (50 mL), water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1) to give the title compound (3g) as a solid. MS-ESI (m/z): 242 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[S:14]([N:13]1[CH:12]=[C:11]([CH2:25][NH:26][CH3:27])[CH:10]=[C:9]1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:16])=[O:15]
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2c(F)cccc2F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of tert-butyl ({5-(2-cyanopyridin-3-yl)-1-[(2,6-difluorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (213 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 160 mg, 86%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH2:6]([CH:8]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10](=[O:20])[CH:9]1[CH3:21])[CH3:7].C(Br)C#C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:6]([CH:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([CH2:3][C:2]#[CH:1])[C:10](=[O:20])[CH:9]1[CH3:21])[CH3:7]
Reactant: [Li]CCCC
Reactant: CCC1NC(c2ccccc2)=NC(=O)C1C
Agent: C#CCBr
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)C(C)C(CC)N=C1c1ccccc1
Reaction time: 0.25 h

Procedure:
Oven dried glassware and a nitrogen purge were utilized. 3.22 mL of 1.6 Molar n-butyl lithium in hexanes (5.15 mmol) was added dropwise to a solution of 1.06 g (4.93 mmol) of 6-ethyl-5-methyl-2-phenyl-5,6-dihydropyrimidin-4-one, in 15 mL of dry tetrahydrofuran, at -50 to -60° C. The mixture was stirred for 15 minutes and then 0.8 mL (5.38 mmol) of 80 wt.% propargyl bromide in toluene was added at -65° C. The ice bath was removed after 1.5 hours and the reaction mixture was stirred for an additional 20 hours. The solvent had evaporated overnight. Ether was added and the reaction mixture was washed three times with water followed by three times with 3 Molar hydrochloric acid. The acidic aqueous washes were combined, cooled externally, and 50% sodium hydroxide was added until the pH=10, then extracted three times with ether. The ether extracts were combined, dried over magnesium sulfate, and concentrated to yield 0.68 g of crude product. The crude product was combined with crude product obtained from previous reactions and purified on a six inch plug of basic alumina by washing with 400 mL of methylene chloride. The filtrate was concentrated to yield 6-ethyl-5-methyl-2-phenyl-3-propargyl-5,6-dihydropyrimidin-4-one (Compound 1), as a yellow solid, melting 62°-65° C.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:14]=2[O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[C:10]([Cl:31])[CH:9]=1>N1C=CC=CC=1>[Cl:31][C:10]1[CH:9]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:30]=[CH:29][C:11]=1[O:12][C:13]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:14]=1[O:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)COc1ccc(F)cc1Oc1ccc(N)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(Oc2cc(F)ccc2OCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethane sulphonyl chloride (0.05 ml) was added to a solution of the product from step (iv) (0.19 g) in pyridine (10 ml) and stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue dissolved in DCM (10 ml) and trifluoroacetic acid (10 ml). After stirring at RT for 2 h the solvent was removed and the residue purified by RPHPLC, yield 0.062 g.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[CH2:4][CH:5]([OH:16])[CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=[O:31])=CC=1.ClC1C=CC=C(C(OO)=O)C=1>C(O)C>[CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:31])[CH2:4][CH:5]([OH:16])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CCCSCCCN(CC)CC(O)COc1ccc(C#N)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: CCCS(=O)CCCN(CC)CC(O)COc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
2.45 g of 4-[3-[ethyl[3-(propylthio)propyl]amino]-2-hydroxypropoxy]-benzonitrile and 1.4 g p-toluenesulfonic acid were mixed in 50 ml of ethanol. The mixture was cooled to -10° C. and 1.7 g of m-chloroperbenzoic acid was added in small protions. The mixture was stirred for 0.5 hour at -10° C. and one hour at room temperature and then evaporated. The residue was dissolved in dichloromethane and washed with three portions of sodium carbonate and twice with water and thereafter dried over sodium sulfate, filtrated and evaporated. The residue, 2.3 g yellow oil, was purified by column chromatography. Yield: 1.4 g of the title compound.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:3]([OH:5])=O.[NH2:13][C:14]1[S:15][CH:16]=[C:17]([CH3:19])[N:18]=1.CCN(C(C)C)C(C)C.O>S(Cl)(Cl)=O.C(Cl)Cl>[Br:1][CH:2]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:3]([NH:13][C:14]1[S:15][CH:16]=[C:17]([CH3:19])[N:18]=1)=[O:5]
Reactant: COCCOCCC(Br)C(=O)O
Reactant: Cc1csc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: COCCOCCC(Br)C(=O)Nc1nc(C)cs1
Yield: 37.5 %

Procedure:
A stirred solution of 2-bromo-4-(2-methoxyethoxy)butanoic acid (Step 4) (200 mg, 0.83 mmol) in thionyl chloride (4 mL) was refluxed for 30 minutes. The reaction mixture was concentrated in vacuo to remove excess thionyl chloride. The residue was dissolved in DCM (2 mL) and was added slowly to a stirred solution of 2-amino-4-methylthiazole (99.5 mg, 0.871 mmol) and DIPEA (117.9 mg, 0.913 mmol) in DCM (4 mL). The reaction mixture was kept at ambient temperature for 1 h before water was added and the two phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with EtOAc/MeOH:1/1) to give the title compound as an oil (105 mg), 1H NMR (300 MHz, CDCl3) δ 6.57 (d, 1H), 4.72 (dd, 1H), 3.66 (m, 2H), 3.60 (m, 2H), 3.51 (m, 2H), 3.36 (s, 3H), 2.50 (m, 1H), 2.31 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][C:10]=3[O:18][CH3:19])[NH:8][C:4]=2[CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:35][N:36]1[C:41]([CH3:43])([CH3:42])[CH2:40][CH:39]([NH2:44])[CH2:38][C:37]1([CH3:46])[CH3:45]>CN(C=O)C.C1COCC1.C1COCC1>[Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([NH:44][CH:39]4[CH2:38][C:37]([CH3:45])([CH3:46])[N:36]([CH3:35])[C:41]([CH3:43])([CH3:42])[CH2:40]4)=[O:16])=[CH:11][C:10]=3[O:18][CH3:19])[NH:8][C:4]=2[CH:3]=1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: COc1cc(C(=O)O)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CC(C)(C)N(C)C(C)(C)C2)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 1 h
Yield: 47.6 %

Procedure:
A solution of 5,6-dichloro-2-(4-carboxy-2-methoxyphenyl)benzimidazole (0.8 g, 2,36 mmol), prepared as described in Preparation 6,1-hydroxybenzotriazole (0.32 g, 2.36 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.56 g, 2.9 mmol) in 80 ml of DMF/THF (50:50) was refluxed for 5 h. A solution of 1,2,2,6,6-pentamethyl-4-aminopiperidine (0.5 g, 2.9 mmol) in THF (5 ml) was added dropwise and the reaction was refluxed for additional 3 h. After cooling, solvent was removed under reduced pressure and the residue was treated with 1N NaOH (10 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was triturated with diisopropyl ether (150 ml), stirred for 1 h, filtered to give 0.55 g of the title compound (yield 47.6%), mp=285–286° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:15]([O-:17])=[O:16])=[N:13][OH:14])[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:6]=2[CH:25]=1.[CH3:26]COCC>O1CCCC1.[N+](=C)=[N-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:15]([O-:17])=[O:16])=[N:13][O:14][CH3:26])[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:6]=2[CH:25]=1
Reactant: CCOCC
Reactant: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Agent: C=[N+]=[N-]
Solvent: C1CCOC1
Product: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)[N+](=O)[O-]

Procedure:
A solution of diazomethane in ether was added to a suspension of 6 g (0.0163 mole) of 7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine in 100 ml of tetrahydrofuran. After sitting at room temperature for 1 hr in excess diazomethane was destroyed by addition of glacial acetic acid. The solvent was evaporated under reduced pressure and the residue was passed over 100 g of silica gel using methylene chloride. Crystallization from ether/hexane gave light yellow crystals with mp 130°-133° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH:17][N:18]=[CH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[NH:12][C:11]1=[O:30].N1CCCCC1.C(O)(=O)C>CN(C)C=O.C(O)(C)C>[CH3:9][N:10]1[C:15](=[O:16])[C:14]2=[C:1]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[N:18]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[N:17]=[C:13]2[NH:12][C:11]1=[O:30]
Reactant: O=Cc1ccncc1
Reactant: Cn1c(=O)cc(NN=Cc2cccc3ccccc23)[nH]c1=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Temperature: 120 °C
Yield: 62.6 %

Procedure:
Isonicotinaldehyde (0.87 g) was added to a solution of 1-naphthaldehyde (1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone (2.0 g) in dimethylformamide (66 ml) and isopropanol (16 ml). Piperidine (0.66 ml) was added followed by glacial acetic acid (0.08 ml). The solution was heated at 120° C. for 16 hours. Reaction cooled to room temperature, solids precipitated was filtered, and dried to give the subtitle compound (1.63 g). Mass: 383.93 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[N:4][N:3]=[N:2]1.S(Cl)([Cl:15])=O>C1C=CC=CC=1.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([Cl:15])=[O:12])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)CCCCn1cnnn1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCn1cnnn1

Procedure:
1 g of 5-(tetrazol-1-yl)-valeric acid in 12 ml of absolute benzene is heated at reflux temperature for 20 minutes with 0.6 ml of thionyl chloride and 2 drops of DMF. After concentration by evaporation under reduced pressure, the title compound is obtained.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH2:3][CH2:2]1.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]2[S:16][C:17]3[CH2:22][S@@:21](=[O:23])[CH2:20][CH2:19][C:18]=3[C:13]2=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:11]=1[Cl:32].C(N1C=CN=C1)(N1C=CN=C1)=O.O>CN(C=O)C>[Cl:32][C:11]1[C:12]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:13]2[C:18]3[CH2:19][CH2:20][S@:21](=[O:23])[CH2:22][C:17]=3[S:16][C:14]2=[N:15][C:10]=1[CH2:9][N:8]1[C:1](=[O:7])[CH2:2][CH2:3][C:4]1=[O:6]
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CC[S@](=O)C4)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CC[S@](=O)C4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of succinic anhydride (303.25 g) in DMF (3.5.L) was added (S)-2-(aminomethyl)-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridine (1134 g) and the mixture was stirred for 1 hour. To the mixture was slowly added carbonyldiimidazole (935.5 g), and stirred at room temperature for 22 hours and further at 36 to 38° C. for 5 hours. The reaction mixture was added dropwise to water (20 L). After stirring for 2.5 hours, crystals deposited were filtered off and washed with water (1277 g, 86.4%). This product was dissolved in a mixture of acetonitrile (8.7 L) and water (2.9 L) and treated with active carbon. Water (45 L) was added and crystals were filtered off. The crystals were suspended in acetone (2.9 L), stirred at 48 to 52° C. for 1 hour and cooled to room temperature. Crystals were filtered off to obtain the titled compound (997 g). Melting point 217-218.5° C. (decomp.) [α]D20−123.63 (c=0.00490, CHCl3).