Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[CH3:13])[CH3:2]>[C].[Pd].C(O)C>[CH2:1]([O:3][C:4]1[C:5]([CH3:13])=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10])[CH3:2]
Reactant: CCOc1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCO
Product: CCOc1cccc(N)c1C
Temperature: 25 °C

Procedure:
A mixture of 1-ethoxy-2-methyl-3-nitrobenzene described in Reference Preparation example 2539.9 g, palladium-carbon (palladium 5%) 4 g and ethanol 200 mL was stirred at room temperature under hydrogen atmosphere for eighteen hours. The mixtures were filtered and the filtrates were concentrated to give 3-ethoxy-2-methylaniline 33.0 g.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=1[CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:10]2[C:11]([O:21]COC)=[C:12]([C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15])[S:13][C:9]=2[CH:8]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:2][C:3]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=1[CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:10]2[C:11]([OH:21])=[C:12]([C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15])[S:13][C:9]=2[CH:8]=1
Reactant: COCCNC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1OCOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCNC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A mixture of 6M HCl (3 mL), 6-((2,4-dichlorobenzyl)oxy)-N-(2-methoxyethyl)-3-(methoxymethoxy)-1-benzothiophene-2-carboxamide (170 mg) and THF (10 mL) was stirred at room temperature for 4 h. To the mixture was added saturated aqueous NaHCO3, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was collected by filtration and washed with hexane to give the title compound (150 mg). The obtained crystals were recrystallized from acetone-hexane.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][N:25]4[CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)=[O:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[ClH:48].O1CCOCC1>C(Cl)Cl>[ClH:48].[O:32]=[C:31]([N:33]1[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]1)[CH2:30][N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][C@@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:47])([F:46])[F:1])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)no2)cc1C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)N3CCNCC3)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tertiary-butyl 4-{[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetyl}piperazine-1-carboxylate (70.7 mg) in methylene chloride (1 ml) was added dropwise 10 equivalents of 4M HCl/dioxane, followed by stirring at room temperature for 3 hours. After 5 hours, the reaction solution was concentrated. With addition of diisopropyl ether, a white solid was precipitated. The white solid was washed with IPE to obtain 1-(2-oxo-2-piperazin-1-ylethyl)-4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole hydrochloride (58.9 mg) as a pale red solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1>[Pd].O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N2CCCC2)ncc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
A mixture of 4-methyl-5-nitro-2-pyrrolidin-1-ylpyridine (2.08 g, 10.0 mmol) and 10% palladium on carbon (208 mg) in tetrahydrofuran (10 mL) was stirred under hydrogen atmosphere at room temperature for 16 hr. Catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (1.76 g, 9.89 mmol, 99%), as a purple solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](C4C5C(=CC=CC=5)C=CN=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nccc4ccccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2nccnc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-isoquinolin-1-yl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (52 mg, 0.094 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL, 13.0 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylene diamine (0.4 mL, 6.0 mmol) was added. The reaction mixture was stirred for 1 h then quenched with water and extracted with CH2Cl2. The combined organics were concentrated and the residue was purified by silica gel chromatography with 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH) to afford 17 mg (43%) of 2-isoquinolin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as an off-white solid. MS (M+H)+=426; mp=180-185° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.02 (br. s., 1H), 9.09 (s, 1H), 8.91 (d, J=8.7 Hz, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.55 (d, J=9.1 Hz, 1H), 8.44 (d, J=7.6 Hz, 1H), 8.09 (d, J=7.9 Hz, 1H), 7.98 (d, J=5.7 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.66-7.77 (m, 1H), 4.40-4.70 (m, 3H), 4.12 (q, J=9.7 Hz, 1H), 3.93-4.04 (m, 1H), 3.74-3.88 (m, 1H), 1.22 (t, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:35][NH2:36]>CO>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:20][NH:36][CH3:35])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: CO
Product: CCCCc1nc(-c2ccc(OC[C@H](O)CNC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate A2) in 4 mL of methylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:75]=[C:74]([O:76][CH3:77])[CH:73]=[C:72]([O:78][CH3:79])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:31]([CH:34](/[CH:58]=[CH:59]/[C:60]1[C:65]([O:66][CH3:67])=[CH:64][C:63]([O:68][CH3:69])=[CH:62][C:61]=1[O:70][CH3:71])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([NH:43][C:44](=[O:57])[C:45]2[CH:50]=[C:49]([N+:51]([O-])=O)[CH:48]=[C:47]([N+:54]([O-])=O)[CH:46]=2)[CH:36]=1)(=[O:33])=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[C:20]([N+:27]([O-])=O)[CH:19]=2)[CH:9]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O.CC(C)=O>[CH3:79][O:78][C:72]1[CH:73]=[C:74]([O:76][CH3:77])[CH:75]=[C:3]([O:2][CH3:1])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:31]([CH:34](/[CH:58]=[CH:59]/[C:60]1[C:61]([O:70][CH3:71])=[CH:62][C:63]([O:68][CH3:69])=[CH:64][C:65]=1[O:66][CH3:67])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([NH:43][C:44](=[O:57])[C:45]2[CH:50]=[C:49]([NH2:51])[CH:48]=[C:47]([NH2:54])[CH:46]=2)[CH:36]=1)(=[O:32])=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:30])[C:18]2[CH:19]=[C:20]([NH2:27])[CH:21]=[C:22]([NH2:24])[CH:23]=2)[CH:9]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc(N)cc(N)c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc(N)cc(N)c3)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4,6-trimethoxystyryl-3-(3,5-dinitrobenzamido)-4-methoxy-benzylsulfone (example 5) (1.3 mmol) in acetone water (10:5) was heated to 50° C. After 30 min, sodiumhydrosulfite (Na2S2O4) (26.3 mmol) was added slowly, and the mixture was heated at reflux (50° C., 1 h.), cooled to room temperature and water was added. The product was rinsed with NaHCO3, and then isolated by extraction with ethyl acetate. The organic layer was dried over-anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was recrystallized from 2-propanol to yield pure (E)-2,4,6-trimethoxystyryl-3-(3,5,diaminobenzamido)-4-methoxy-benzylsulfone. m.p. 208-210° C. NMR (DMSO-d6) δ 3.76 (s, 3H), 3.80 (s, 6H), 3.82 (s, 3H), 4.4 (s, 2H), 5.9 (s, 1H), 6.2 (s, 2H), 7.05-8.26 (m, aromatic), 8.85 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])=[O:4].Cl.[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1>[C:15]([O:19][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COC(=O)CCCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Di-tert-butyl dicarboxylate (9.58 mL, 41.7 mmol) and 4-dimethylaminopyridine (1.02 g, 0.34 mmol) were successively added to a tert-butanol solution (56 mL) of 7-methoxycarbonylheptanoic acid (1) (5.00 mL, 5.24 g, 27.8 mmol) at room temperature under the argon atmosphere, and the mixture was stirred at room temperature for 1 hour. A 0.2 N hydrochloric acid solution (20 mL) was added to the reaction solution to make the mixture weakly acidic, and the reaction solution was concentrated to about ⅓ volume, and extracted with chloroform (50 mL) three times. The organic layer was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated. The resulting brown oily crude product (6.5 g) was separated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain t-butyl-7-methoxycarbonylheptanoate (2) as a colorless liquid substance (5.58 g, 82%).
Reaction SMILES: CC(CC)CC1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1.[CH2:21]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:21]([CH:26]1[CH2:27][CH2:28][CH:29]([OH:32])[CH2:30][CH2:31]1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCc1ccc(O)cc1
Agent: CCC(C)Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCC1CCC(O)CC1

Procedure:
4-(2-Methyl-butyl)-4'-biphenylcarboxylic acid in racemic form as a raw material was prepared according to a method described in the above Japanese patent No. 908,101 (Japanese patent publication No. Sho 52-41,256/1977). This product had a melting point of 223° C. and when melted, formed a smectic liquid crystal. Further 4-n-pentylcyclohexanol was synthesized by the catalytic hydrogenation of p-n-pentylphenol, and a mixture of 65% of trans-form substance with 35% of cis-form substance obtained by subjecting the above product to fractional distillation was employed.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([Cl:10])=[CH:5][N:4]=1.[CH3:11][NH2:12].C1CCCCC1.C(OCC)(=O)C>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:12][CH3:11])[C:6]([Cl:10])=[CH:5][N:4]=1
Reactant: CSc1ncc(Cl)c(Cl)n1
Reactant: CN
Solvent: CCO
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CNc1nc(SC)ncc1Cl

Procedure:
Prepared from 2-methylsulphenyl-4,5-dichloro-pyrimidine by reacting with methylamine in ethanol at 90° C., melting point: 241° C., Rf value: 0.59 (silica gel; cyclohexane/ethyl acetate=2:1)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[CH2:14][C:15]#[N:16]>CN(C)C=O.C(OCC)(=O)C>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:14][C:15]#[N:16])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A 0° C. solution of 4-hydroxyindole (20 g, 150 mmol) in 500 ml of dimethylformamide is treated with NaH (60% dispersion in mineral oil; 6.6 g, 165 mmol). After 30 minutes, bromoacetonitrile (11.5 ml, 165 mmol) is added, and the resulting mixture is allowed to slowly warm to ambient temperature and stir for 3 days. The reaction mixture is diluted with ethyl acetate and washed 3 times with H2O. The organic layer is dried over Na2SO4 and concentrated in vacuo. The crude residue is purified by normal phase HPLC (SiO2; 5% step gradient of 0 to 20% ethyl acetate in hexanes) to give 25 g of (1H-indol-4-yloxy)acetonitrile (97%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4](C(O)=O)[CH:3]=1>N1C2C(=CC=CC=2)C=CC=1.S([O-])([O-])(=O)=O.[Cu+].[Cu+]>[CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)c(C(F)(F)F)o1
Agent: [Cu+]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccc2ncccc2c1
Product: Cc1ccc(C(F)(F)F)o1
Yield: 53.9 %

Procedure:
To a solution of 5-methyl-2-(trifluoromethyl)-3-furancarboxylic acid (20 g, 103 mmol) in quinoline (36 ml) was added copper (I) sulfate (1 g, 6.3 mmol). While bubbling nitrogen, the mixture was immersed in an oil bath at 230° C. until gas generation ceased. The generated gas was collected and distilled again to give 2-methyl-5-(trifluoromethyl)furan (8.34 g, 54%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:23])=[C:15]([N+:20]([O-])=O)[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[OH-].[Na+]>CO.[Zn]>[NH2:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]2[O:3][C:2]([CH3:24])([CH3:1])[CH:6]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)[C:5]=2[C:14]=1[CH3:23]
Reactant: Cc1ccc(C2c3c(C)c([N+](=O)[O-])c(C)c(C)c3OC2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CO
Product: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Yield: 61.6 %

Procedure:
2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-5-nitro-2,3-dihydrobenzofuran (1.26 9, 3.9 mmol) was dissolved in methanol (30 ml). Zinc powder (1.3 9) and 1N sodium hydroxide (15 ml) were added to the solution and the mixture was heated under reflux for 3 hours. Insoluble materials were filtered off and water was added. The mixture was extracted with ethyl acetate. The extract was washed with water, dried and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 95:5) and crystallized from hexane to obtain the desired compound (710 mg, yield: 53.7%), m.p. 119°-120° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27](N3CCOCC3)[CH2:28][Br:29])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:36])[CH:10]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:7])[CH2:3][CH2:2]1.Cl.C[OH:50]>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([OH:50])[CH2:28][Br:29])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:36])[CH:10]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(CBr)N2CCOCC2)C1SC(=O)OCC1CC1
Reactant: CO
Agent: Cl
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1SC(=O)OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidine-1-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate (300 mg) in a mixture of methanol (22 ml) and methylene chloride (3.5 ml), and the mixture is stirred at room temperature under nitrogen atmosphere after addition of 10% hydrochloric acid (4ml). After 2 hours, the reaction mixture is poured into ice water, and is extracted with chloroform. The extract solution is washed with water, dried, and evaporated to give p-nitrobenzyl 4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxo-α-(2-bromo-1-hydroxyethylidene)azetidine-1-acetate (252 mg). Foam. Yield: 92.8%. IR: νmaxCHCl3 3426, 1781, 1710, 1690, 1601 cm-1. NMR: δCDCl3 0.23-1.33m5H, 3.84-4.36m4H, 4.55s2H, 5.10-5.32m3H, 5.88(5Hz)1H, 6.83-8.33m9H, 12.0s1H.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]#[N:19])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.BrC1C=CC(C2CCOCC2)=[N:25]C=1>>[NH2:25][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]#[N:19])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: N#CC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reactant: Brc1ccc(C2CCOCC2)nc1
Product: N#CC1(c2ccc(N)cn2)CCC2(CC1)OCCO2

Procedure:
In Reference Example 75(4), 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carbonitrile described in Reference Example 82 was used in place of 5-bromo-2-(tetrahydro-2H-pyran-4-yl)pyridine, and reacted and treated in a similar manner to give the titled compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[NH:12][C:13]2[C:18]([C:19](=O)[N:20]=1)=[C:17](OC)[C:16](OC)=[C:15](OC)[CH:14]=2.Cl[C:29]1C=C[N:32]=[C:31](CNC)[CH:30]=1>CCO>[CH:19]1[C:18]2[C:17]3[CH:29]=[CH:30][CH:31]=[N:32][C:16]=3[CH:15]=[CH:14][C:13]=2[N:12]=[CH:11][N:20]=1
Reactant: CNCc1cc(Cl)ccn1
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2c(OC)c1OC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc2ccc3ncncc3c2c1
Temperature: 90 °C

Procedure:
Diisopropylethylamine (0.15 mL, 0.86 mmol) was added to a mixture of 2-chloro-5,6,7-trimethoxy-1H-quinazolin-4-one (0.2 g, 0.78 mmol) and 4-chloro-2-methylaminomethylpyridine (0.13 g, 0.86 mmol) in EtOH (8 mL). The mixture was heated at 90° C. for 5 h. After cooling, the resulting white solid was filtered and washed with MeOH to provide quinazolino-pyridine compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](O)=O.[CH2:7]([NH2:11])[CH:8]([NH2:10])[CH3:9]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[NH:11][CH2:7][CH:8]([CH3:9])[N:10]=1
Reactant: COCC(=O)O
Reactant: CC(N)CN
Solvent: Cc1ccccc1
Product: COCC1=NC(C)CN1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 2-methoxyacetic acid (20 g, 222.0 mmol) in toluene (200 mL). Propane-1,2-diamine (50 g, 674.5 mmol) was added to the reaction. The reaction mixture was stirred overnight at 130° C., then concentrated under reduced pressure. This resulted in 25 g (crude) of the title compound as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O1CCCC1.B>O1CCCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[CH:7]=[O:8]
Reactant: O=C(O)c1cc(I)ccc1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Product: O=Cc1cc(I)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
To a solution of 5-iodo-2-nitrobenzoic acid (37 g, 126 mmol) (APIN) in anhydrous tetrahydrofuran (200 mL) at 0° C. was added borane tetrahydrofuran (1 M, 360 mL, 360 mmol) dropwise. The reaction mixture was then stirred at room temperature for 24 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO4, concentrated, and triturated. The precipitate 5-Iodo-2-nitro-phenyl)-methanol was collected as a yellow solid (20 g, 57%). The solid (5.5 g) was dissolved into dichloromethane (100 mL), and activated MnO2 (15 g) was added. The mixture was then heated at reflux for 4 h, cooled to room temperature, and filtered through a short pad of celite. The filtrated was concentrated to give 5-Iodo-2-nitro-benzaldehyde as a yellow solid (Yield 4.2 g, 76%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].C(OCC)(=O)C.C1COCC1>CCO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1(C2CCCC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(C2CCCC2)CC1

Procedure:
In a 250 mL round bottom flask with a magnetic stirrer, 5.4 g (16.7 mmol) 4-cyclopentyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester was dissolved in 40 mL EtOH. To the colourless solution 40 mL 4N NaOH was added. The orange solution was stirred under reflux for total of 6 days. The ethanol was removed and the reaction mixture was diluted with 100 mL ice water and extracted twice with 100 mL diethyl ether. The aqueous layer was acidified with 60 mL 4 N HCl to pH=2. A white precipitate formed and after addition of 200 mL ethyl acetate: THF 1:1 the white gelatinous suspension was filtered through a membrane filter. The aqueous layer from the filtrate was separated and extracted once with 100 mL ethyl acetate. The organic was layer dried with Na2SO4, filtered and concentrated under vacuum. The crude product (2.54 g, yellow viscous oil) was purified over silica chromatography eluting with a gradient formed from heptane and ethyl acetate to yield after evaporation of the product containing fractions 1.89 g (38%) of the title compound as off-white solid. MS ISP (m/e): 298.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([Cl:21])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[OH-].[Na+]>C(O)C.Cl>[NH2:18][C:16]1[C:15]([Cl:21])=[CH:14][C:13]([F:22])=[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:9])[F:10])[N:5]([CH3:11])[N:4]=2)[CH:17]=1
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(-c2cc(N)c(Cl)cc2F)c(Cl)c1OC(F)F
Yield: 77.6 %

Procedure:
To 4-chloro-3-(4-chloro-2-fluoro-5-nitrophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole (3.0 g, 8.5 mmoles) in a mixture of 15 ml ethanol and 15 ml conc. hydrochloric acid was added stannous chloride (7.70 g, 34 mmole) and the reduction was conducted under reflux for 8 hours. Then the product solution was poured into ice-cold water, the resulting mixture was made alkaline with 20% aqueous NaOH, and the objective product was extracted with ethyl acetate. Dehydration and concentration of the extract solution and purification of the residue by column chromatography gave the title compound (2.15 g), yield 78%.