Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[C:15]([O:23]C)[CH:14]=3)[O:10][N:9]=2)=[C:6]([CH3:25])[C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1.Cl>CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([OH:23])[C:16]([OH:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=3)[O:10][N:9]=2)=[C:6]([CH3:25])[C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=1
Reactant: COc1cc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Cc1nc(Cl)c(-c2noc(-c3cc(O)c(O)c([N+](=O)[O-])c3)n2)c(C)c1Cl
Temperature: 60 °C
Yield: 81.1 %

Procedure:
To an ice-cooled solution of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol (2.40 g, 5.84 mmol) in NMP (19 mL) was added aluminium chloride (0.977 g, 7.33 mmol) followed by addition of pyridine (1.93 mL). The reaction mixture was heated to 60° C. for 1 hour. It was cooled to room temperature and poured into 2 N HCl-solution (ca. 40 mL). The precipitate was filtered off, washed with water to and dried under vacuum. Recrystallization from acetic acid yielded 1.88 g (81%) of 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[CH:6]([C:19]([OH:21])=[O:20])[C:5]2=O)[CH2:3][CH2:2]1.C[N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=O>C(O)(C)C>[CH3:15][O:14][C:12]1[C:11]([N:24]2[CH2:25][C@@H:26]3[C@@H:27]([CH2:3][CH2:2][CH2:1][NH:4]3)[CH2:28]2)=[C:10]([F:17])[CH:9]=[C:8]2[C:7]([C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:13]=12)=[O:18]
Reactant: COc1c(F)c(F)cc2c1N(C1CC1)C(=O)C(C(=O)O)C2=O
Reactant: CN1CCCC1=O
Solvent: CC(C)O
Product: COc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-methoxy quinolone-3-carboxylic acid (100 grams), (S,S) Diazabicyclo nonane (60 grams) and 1,8-Diazabicyclo[5.4.0.]undec-7-ene(DBU) (10.gms) were added to N-Methylpyrolidinone (250 ml) and the reaction mixture was slowly heated to the 60–70° C. temperature and stirred till the reaction was substantially completed. 5% aqueous isopropyl alcohol was added to the reaction mass, and pH was adjusted towards basic with caustic lye. Then the reaction mass was filtered, through clarifying filter, washed with 5% aqueous isopropyl alcohol. Combined total filtrate and adjusted pH to 7.0 to 7.2 with aqueous Hcl. and isolated at a temperature of 10–15° C. to afford moxifloxacin. Moxifloxacin then treated with Hydrochloric acid in 10% aqueous methanol to yield corresponding hydrochloride salt. (Wet weight: 115 grams)
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:10]2[CH:22]=[CH:23][S:24][C:9]=2[C:8]=1Cl)=[O:6])([CH3:3])[CH3:2].C(OC(C1C(=O)N(CC2C=CC=C(F)C=2)C2C=CSC=2C=1[N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=O)C>>[CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:10]2[CH:22]=[CH:23][S:24][C:9]=2[C:8]=1[N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1c(Cl)c2sccc2n(Cc2cccc(F)c2)c1=O
Reactant: CCOC(=O)c1c(N2CCNCC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Product: CC(C)OC(=O)c1c(N2CCNCC2)c2sccc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 7-chloro-4-(3-fluoro-benzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid isopropyl ester (18) by applying the same procedure as described for 4-(3-fluoro-benzyl)-5-oxo-7-piperazin-1-yl-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (19). 1H-NMR (DMSO-d6) δ 1.28 (d, J=6.0 Hz, 6H), 2.81 (m, 4H), 3.22 (m, 4H), 5.07 (m, 1H), 5.36 (s, 2H), 7.10 (m, 3H), 7.29 (m, 1H), 7.35 (m, 1H), 7.98 (m, 1H); EIMS m/z 430 (M+1).
Reaction SMILES: [H-].[Na+].C1COCC1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12](S(C)(=O)=O)[N:11]=1.[CH3:22][C:23]([CH3:25])=[O:24]>O>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([CH2:22][C:23](=[O:24])[CH3:25])[N:11]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)nc(CC(C)=O)n1
Temperature: 30 °C
Yield: 22.4 %

Procedure:
In a reactor were placed 16.0 g (0.4 moles) of 60% sodium hydride, 400 ml of THF and 43.6 g (0.2 moles) of 4,6-dimethoxy-2-methanesulfonylpyrimidine. The reactor contents were heated to 30° C. Thereto was dropwise added 39.4 g (0.68 moles) of acetone, followed by a reaction for 2 hours. After the completion of the reaction, 350 ml of water was added and extraction with 500 ml of ethyl acetate was conducted. The ethyl acetate layer was concentrated. The concentrate was subjected to distillation under reduced pressure to obtain 8.8 g (44.9 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone. Refractive index n20D: 1.5181
Reaction SMILES: [ClH:1].CC(C)=O.[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O>CCOCC>[ClH:1].[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH2:18]
Reactant: Cc1ccc(NC(=O)CCNC(=O)OC(C)(C)C)c(O)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cc1ccc(NC(=O)CCN)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To 15 ml of a saturated solution of hydrogen chloride in ether, there were added 10 ml of acetone and 1.30 g (4.4 mmol) of N-(2-hydroxy-4-methylphenyl)-3-(tert-butoxycarbonyl)aminopropionamide and stirred at room temperature for 30 minutes. After the completion of the reaction, the crystals thus precipitated were filtered, washed with ether and dried. Thus 0.76 g (2.6 mmol) of N-(2-hydroxy-4-methylphenyl)-3-aminopropionamide hydrochloride was obtained. The yield was 59%.
Reaction SMILES: [NH2:1][CH:2]([C:4]1([CH2:8][NH2:9])[CH2:7][CH2:6][CH2:5]1)C.CO.C(N(CC)CC)C.C[O:20][C:21](=O)[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23]>N>[NH2:23][CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([NH:9][CH2:8][C:4]1([CH2:2][NH2:1])[CH2:5][CH2:6][CH2:7]1)=[O:20]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(N)C1(CN)CCC1
Agent: N
Solvent: CCN(CC)CC
Solvent: CO
Product: NCC1(CNC(=O)C(N)Cc2ccccc2)CCC1
Yield: 38.7 %

Procedure:
3.6 g (31.5 mmol) of 1 was mixed with 100 mL of methanol, followed by adding triethyl amine to adjust pH to 9-10 to obtain a first reaction solution. 5.1 g (28.7 mmol) of 2 was mixed with 100 mL of methanol to obtain a second reaction solution. The second reaction solution was added dropwisely into the first reaction solution to obtain a reaction mixture. The reaction mixture was subjected to reflux reaction at 60-70° C. for 19 hours, followed by evaporation to obtain a crude product. The crude product was dissolved in ammonia, followed by extracting with chloroform and water and evaporating to obtain a product of 2.9 g (11.1 mmol, 38.6%) of a light-yellow oil 3. The analytic data of the product are as follows: 1H-NMR (D2O, 400 MHz), δ(ppm): 7.29-7.15 (m, 5H, Ar), 3.57 (t, 1H, J=3, H2NCH), 3.20-2.95 (m, 2H, NHCH2), 2.89-2.76 (m, 2H, CH2Ar), 2.21-2.05 (m, CH2NH2), 1.69-1.66 (m, 2H, CH2CH2CH2), 1.52-1.45 (m, 4H, CH2CH2CH2); 13C-NMR (D2O, 100 MHz), δ(ppm): 176.88, 137.37, 129.38, 128.90, 127.11, 56.60, 45.82, 43.99, 42.36, 40.90, 26.59, 26.51, 14.27; ESI-MS (m/z): calcd. 261.36, found 262.18 [M+H]+; Anal. Calcd (Found) for C15H23N3O.HCl: C, 60.94 (60.49); H, 8.43 (8.12); N, 14.53 (14.11).
Reaction SMILES: C(O[SiH](OCC)OCC)C.C(OC1C=CC([C:21]2[O:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=CC=1)C=C>C1(C)C=CC=CC=1>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[CH:21]1
Reactant: C=CCOc1ccc(-c2nc3ccccc3o2)cc1
Agent: CCO[SiH](OCC)OCC
Solvent: Cc1ccccc1
Product: c1ccc2ocnc2c1
Temperature: 70 °C

Procedure:
A 250 ml round bottom flask, equipped with a reflux condenser and an oil bath with a magnetic stirrer was charged with 4.0 g (22 mmol) triethoxysilane and 5.0 g (20 mmol) of the above 2-(4-allyloxyphenyl)-benzoxazole in 100 ml of toluene under nitrogen atmosphere. The reaction mixture was heated to 70° C. and a catalytic amount of divinyl-tetramethyl disiloxane platinum complex was added. After the reaction mixture was heated for 2 hours, another 1.8 g (11 mmol) triethoxysilane were added and the reaction mixture was stirred over night. The product solution was evaporated, diluted with toluene and filtrated over Celite to yield 8 g (96%) of crude (4-(3-(triethoxysilyl)propyloxy])phenyl)-benzoxazole. UV (ethanol) 308 nm (23′468).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:31](=O)[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][OH:36]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)[CH:12]=[CH:11][C:10]=1/[C:31](=[N:35]/[OH:36])/[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)=O)c(OCc4ccccc4)c3)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(/C(C)=N/O)c(OCc4ccccc4)c3)c2)CCOCC1
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 7, 2'-benzyloxy-4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-2'-benzyloxy-4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]acetophenone oxime in 47% yield, m.p. 130°-131° C.;
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](/[CH:10]=[CH:16]/[N:17]([CH3:19])[CH3:18])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)/C=C/c1cc(Br)ccc1C#N
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2-methylbenzonitrile (1.0 g) dissolved in 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (2.11 ml) was stirred at 140° C. for 2 h (flask open to evaporate t-butanol). The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (350 mL). The organic was dried (MgSO4), filtered and evaporated to afford the crude product. The crude product was triturated with isohexane overnight to afford the subtitle compound (0.75 g) as a solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:12])[CH3:11].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[NH4+].[OH-]>OS(O)(=O)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[O:12])[CH3:11]
Reactant: CC(O)c1nc2ccccc2[nH]1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 16.2 g (0.1 mol) 1-(1H-benzimidazol-2-yl)ethanol (synthesised according to as described in A. Katrizky et al. Tetrahedron Assymetry, 8 (1997), 1491) in 200 ml 5% H2SO4 was treated with a solution of 39.6 g (75.5 mmol) potassium dichromate in 40% sulphuric acid. The reaction mixture was stirred at room temperature for 18 hours and neutralised with 190 ml conc. NH4OH. The formed precipitate was filtered, washed with 700 ml water and extracted with 700 ml 96% ethanol. The solvent was evaporated to c.a. 50–80 ml, the formed suspension cooled to −40° C., stirred for 10 min and filtered while cold. The solid was washed with 2×10 ml cold ethanol and dried under reduced pressure. Yield—9.3 g (58.1%). 1H NMR (250 MHz, CDCl3), δ, ppm: 2.84 (s, 3H), 7.38 (m, 2H), 7.56 (d, JHH=7.3 Hz, 1H), 7.89 (d, JHH=7.6 Hz, 1H), 11.08 (br.s 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[O:5][C:6]=1[CH:7]=O.Cl.NO.[N:16]1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C.Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[O:5][C:6]=1[C:7]#[N:16]
Reactant: c1ccncc1
Reactant: COC(=O)c1cc(Br)c(C=O)o1
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cc(Br)c(C#N)o1
Reaction time: 2.5 h

Procedure:
To a solution of 46.55 g (0.20 mol) of methyl 4-bromo-5-formyl-2-furoate in 465 mL of acetonitrile was added 15.28 g (0.22 mol) of hydroxylamine hydrochloride. To this suspension 96.6 mL (1.2 mol) of pyridine was added dropwise over a period of 35 min, at 20-25° C. After 90 min stirring neat trifluoroacetic anhydride (67.72 mL, 0.48 mol) was dropped in over 45 min at room temperature. After 2.5 hours stirring the reaction mass was poured in a mixture of HCl 1 M (0.75 L) and ethyl acetate (0.75 L); the aqueous layer was extracted again with 0.45 L of ethyl acetate. The organic extracts were washed with 0.45 L of 2 M HCl and the aqueous layer was back extracted with 0.3 L of ethyl acetate. The combined organic extracts were concentrated under reduced pressure to dryness. This crude material was dissolved in 100 mL of ethanol 95° and treated dropwise with 150 mL of water under efficient stirring at 40°-45° C. The resulting suspension was cooled to 0/+4° C. for 1 hour then filtered to afford, after drying, 44.2 g of product as light cream solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5](N)=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.N([O-])=O.[Na+].[PH2](O)=O>Cl>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[CH:5]=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Product: CC(C)c1cc(Br)cc(C(C)C)c1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
To a mixture of 4-bromo-2,6-bis(propan-2-yl)aniline (20.5 g, 80.02 mmol, 1.00 equiv) in 2N hydrochloric acid (210 mL) at −5° C. was added NaNO2 (13.8 g, 200.00 mmol, 2.50 equiv) in portions. The reaction was allowed stir at −5° C. for 10 min. Hypophosphorous acid (90 mL) was then added at −5° C. The reaction was warmed to room temperature and then stirred for 12 h. The resulting solution was extracted with 300 mL of ethyl acetate. The organic layer was concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:100) to give 12 g (62%) of 1-bromo-3,5-bis(propan-2-yl)benzene as a light brown oil. 1H NMR (300 MHz, CDCl3): δ 7.18 (s, 2H), 6.98 (s, 1H), 2.89-2.80 (m, 2H), 1.23 (d, J=6.9 Hz, 12H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][CH:19]([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:19]([F:18])[F:30])=[CH:26][CH:25]=2)=[O:29])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1ccc(OC(F)F)cc1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(OC(F)F)cc1

Procedure:
Example 16 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-(difluoromethoxy)-4-isocyanatobenzene (19.1 μl) to give the title compound (0.0252 g). LC-MS (System A): Rt 2.41 mins, Mass Spectrum m/z 460 [MH+].
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]1[CH:12]=[N:13][C:14]([N+:17]([O-])=O)=[CH:15][CH:16]=1)[CH2:6]2.[H][H]>C1COCC1.CO.[Pd]>[CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[N:13][CH:12]=1)[CH2:6]2
Reactant: CN1C2COCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN1C2COCC1CN(c1ccc(N)nc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 112i (800 mg, 3.0 mmol) in THF (80 ml) was added Pd/C (50 mg) in MeOH (20 ml) at room temperature. The reaction mixture was hydrogenated at atmospheric hydrogen pressure and stirred at room temperature overnight. The mixture was filtered and the filtrate was evaporated to give 112j as a colorless oil (680 mg, 90%).MS: [M+H]+: 235
Reaction SMILES: CC([O-])(C)C.[K+].[C:7](=O)([O:10]C)[O:8][CH3:9].[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][C:27](=[O:29])[CH2:28][CH:21]1[CH2:22][O:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C=O)C>C1(C)C=CC=CC=1>[CH3:9][O:8][C:7]([CH:26]1[C:27](=[O:29])[CH2:28][CH:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])[CH:25]1[CH2:24][O:23][CH2:22]2)=[O:10]
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)CC2COCC1N2C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a suspension of t-BuOK (1.82 g, 16.26 mmol) in toluene (30 mL) was added dimethyl carbonate (0.98 g, 10.84 mmol). The mixture was heated at 90° C. for 5 mins, and then 7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (1.3 g, 5.4 mmol) was added. After the resulting mixture was stirred at 90° C. for 30 mins, the mixture was turned to brown gel, and then DMF (1.5 mL) was added to get a brown solution. The mixture was stirred at 90° C. for 3 hours. After it was cooled to room temperature, silica gel (25 g, 100200 mesh) was added and the solvent was concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc in PE 0%˜70%) to give 7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-6,9-dicarboxylic acid 9-tert-butyl ester 6-methyl ester (Compound AO) as light yellow oil (0.8 g, 49%). LC/MS: calc'd 300 (MH+), exp 300 (MH+); 1HNMR (400 MHz, CDCl3) δ 1.40-1.45 (m, 9H), 2.29-2.41 (m, 1H), 2.68-2.84 (m, 1H), 3.47-3.79 (m, 7H), 3.88-3.96 (m, 0.5H), 4.09-4.16 (m, 0.3H), 4.30-4.45 (m, 1H), 4.55-4.67 (m, 0.8H), 11.86 (s, 0.3H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[C:41]([O:48][CH3:49])=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[C:41]([O:48][CH3:49])=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)c(OC)n1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)c(OC)n1
Yield: 72.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 3-chloromethyl-2,6-dimethoxypyridine (0.56 g) as starting materials, 5-benzyloxy-N-({1-[(2,6-dimethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g) was obtained.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:30][N:31]([CH:40]=[O:41])[O:32]CC2C=CC=CC=2)[C:8]([NH:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][C@@H:21]([CH2:27][CH3:28])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:13]=2[F:29])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:6][C@H:7]([CH2:30][N:31]([CH:40]=[O:41])[OH:32])[C:8]([NH:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][C@@H:21]([CH2:27][CH3:28])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:13]=2[F:29])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@H](Nc1nc(OC)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F)C(=O)N(C)C
Solvent: CO
Product: CC[C@H](Nc1nc(OC)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F)C(=O)N(C)C
Yield: 62.4 %

Procedure:
A solution of (2S)-2-{[6-{2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]hydrazino}-5-fluoro-2-(methyloxy)-4-pyrimidinyl]amino}-N,N-dimethylbutanamide (0.036 g, 0.063 mmol), and Pd(C) (0.008 g) in MeOH (10 mL) was run under standard hydrogenation conditions as in General Procedure A, Part C, to provide (2S)-2-{[6-[2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)hydrazino]-5-fluoro-2-(methyloxy)-4-pyrimidinyl]amino}-N,N-dimethylbutanamide as an orange solid (0.019 g, 63%). LCMS: (M+H)+=484.4.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4]1[CH:5]=[CH:6][C:7]([N+:29]([O-])=O)=[C:8]([C:10]2[CH:11]=[C:12]([CH:26]=[CH:27][N:28]=2)[C:13]([NH:15][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[O:14])[CH:9]=1)[CH3:2]>CO.[Pd]>[NH2:29][C:7]1[CH:6]=[CH:5][C:4]([N:3]([CH2:32][CH3:33])[CH2:1][CH3:2])=[CH:9][C:8]=1[C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][N:28]=1)[C:13]([NH:15][C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: CCN(CC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)c1ccc(N)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A mixture of (S)-2-(5-(diethylamino)-2-nitrophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide (4.73 g) and 10% Pd/C (1.3 g) in methanol (20 mL) was stirred under a hydrogen atmosphere for 2 h. The mixture was filtered and concentrated to give a brown solid (4 g, 91%).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH2:28]([SH:30])[CH3:29]>CN(C=O)C.O.[Cu]I>[Cl:10][C:8]1[CH:7]=[C:6]([CH3:11])[C:3]([C:4]#[N:5])=[C:2]([S:30][CH2:28][CH3:29])[CH:9]=1
Reactant: Cc1cc(Cl)cc(Cl)c1C#N
Reactant: CCS
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cc(Cl)cc(C)c1C#N
Temperature: 80 °C
Reaction time: 16 h
Yield: 22.8 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-benzonitrile (5.0 g, 26.9 mmol) in DMF (50 ml) in a sealed tube are added tripotassium phosphate (5.7 g, 26.9 mmol) and L-proline (0.62 g, 5.37 mmol) at RT. The reaction mixture is degassed and flushed with argon for 30 min and then are added CuI (0.51 g, 2.68 mmol) and ethanethiol (6.0 ml, 80.6 mmol) at RT. The reaction mixture is stirred at 80° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture is diluted with water (50 ml) and extracted with ethyl acetate (50×3 ml). The organic layer is washed with water (50 ml), brine (15 ml) dried over anhydrous sodium sulfate and evaporated to get the crude which is purified by column chromatography (silica gel, 5% acetone/hexane) to yield 4-chloro-2-ethylsulfanyl-6-methyl-benzonitrile (1.3 g, 6.14 mmol, 23%).