Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)(Cl)Cl>[C:36]([NH:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc3c2CCCc2ccccc2-3)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(c(N3CCN(C(=O)OC(C)(C)C)CC3)n1)CCCc1ccccc1-2
Temperature: 60 °C

Procedure:
The product from Example 83A (20 mg, 0.051 mmol) was treated with CHCl3 (0.080 mL), pyridine (0.020 mL, 0.25 mmol), and acetic anhydride (0.006 mL, 0.061 mmol), then heated at 60° C. overnight, cooled and purified by chromatography (eluting with 9:1, 4:1 and 2:1 CH2Cl2:EtOAc) to provide the title compound. MS (M+H)+ m/z 438.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([C:15](=O)[CH3:16])[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([C:15](=[N:19][OH:20])[CH3:16])[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C1CN(Cc2ccccc2)CC12CC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=NO)C1CN(Cc2ccccc2)CC12CC2
Reaction time: 20 h
Yield: 73.5 %

Procedure:
1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethanone (Example A2a, 3.93 g, 17.1 mmol) and hydroxylamine hydrochloride (1.78 g, 25.7 mmol) are stirred in pyridine (10 mL) at 90° C. After 20 hours, the reaction mixture is diluted with ethyl acetate and the organic layer is washed with saturated NaHCO3, water, and brine. The organic layer is dried with MgSO4, filtered, and the filtrate concentrated to afford 1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethanone oxime as an oil (3.07 g). MSCI: m/z 245 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:23])[C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18]C(C)(C)C)=[O:17])=[N:14][CH:15]=1.CCOCC.[OH-].[Na+]>ClCCl>[F:23][CH:9]([F:8])[C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)c1cnc(C(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cnc(C(F)F)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of t-butyl 5-difluoromethylpyrazine-2-carboxylate (175 mg) in dichloromethane (1 mL), and the mixture was stirred at RT for 5 h. Ether and 5 N NaOH were added to the reaction solution. The aqueous layer was separated and made acidic with 5 N hydrochloric acid. EtOAc was added to the aqueous layer, and the organic layer was separated. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration. The filtrate was concentrated to obtain the title compound (100 mg).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]([NH:15][C@@H:16]([C:20]([F:23])([F:22])[F:21])[CH:17]([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[Cl-].[Li+].[NH:28]1[C:32](B(O)O)=[CH:31][CH:30]=[N:29]1>CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:19][CH:17]([CH3:18])[C@@H:16]([NH:15][C:6]1[C:5]2[CH:24]=[CH:25][C:2]([C:30]3[NH:29][N:28]=[CH:32][CH:31]=3)=[CH:3][C:4]=2[C:13]2[C:12](=[O:14])[NH:11][CH:10]=[CH:9][C:8]=2[N:7]=1)[C:20]([F:23])([F:22])[F:21]
Reactant: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2cc(Br)ccc12)C(F)(F)F
Reactant: OB(O)c1ccn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2cc(-c3ccn[nH]3)ccc12)C(F)(F)F
Temperature: 130 °C

Procedure:
To a solution of 9-bromo-6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}benzo[c]-1,6-naphthyridin-1(2H)-one (33 mg, 0.08 mmol) in DMF (1 mL) and sodium carbonate (0.5 mL, 2.0 M), were added lithium chloride (19.7 mg, 0.464 mg), 1H-pyrazol-5-ylboronic acid (17 mg, 0.16 mmol), and palladium tetrakis triphenylphosphine (27 mg). The mixture was degassed with nitrogen and heated in the microwave at 130° C. for 1 hr. The resulting black solution was filtered and purified by reverse phase HPLC to afford 6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}-9-(1H-pyrazol-5-yl)benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (600 MHz, CD3OD) δ 10.3 (s, 1H), 8.53 (d, 1H), 8.16 (d, 1H), 7.77 (s, 1H), 7.50 (d, 1H), 6.95 (s, 1H), 6.74 (d, 1H), 5.34 (m, 1H), 2.43 (m, 1H), 1.19 (d, 3H), 1.11 (d, 3H). LRMS (ESI) calc'd for (C20H19F3N5O) [M+H]+, 402.2; found 402.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Reactant: Brc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(Cl)c(Cl)cc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 72 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 72%). 1H NMR (300 MHz, CDCl3) δ 3.29-3.31 (m, 4H), 3.74-3.76 (m, 4H), 4.16 (s, 3H), 6.85-6.87 (m, 1H), 7.02-7.04 (m, 1H), 7.06-7.07 (m, 1H), 7.13-7.15 (m, 1H), 7.32 (br s, 1H), 7.86 (br s, 1H), 7.86 (br s, 1H), 7.91 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(=O)C)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[OH:26])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A mixture of potassium 7β-[2-(2-amino-4-thiazolyl)-2-(Z-trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (25 gm) and activated carbon (2.5 gm) was added to an aqueous acetone solution (1:1, 70 ml) containing p-toluenesulphonic acid (17.7 gm) at 50° C. The reaction mixture was heated to 70° C. in 20 minutes and maintained at this temperature for 35 minutes. After completion of the reaction, chilled ethylacetate (200 ml) having temperature −15° C. was added to the reaction mixture to reduce the temperature to 30–35° C. The carbon was filtered and the carbon bed was washed with water (50 ml). The filtrate was diluted with water (200 ml), warmed to 35° C. and pH of the solution was adjusted to 6.0–6.5 using aqueous ammonia solution (20%). The aqueous layer was separated and treated with carbon (2.0 gm) at 35° C. for 35 min. The carbon was filtered and the carbon bed was washed with water (50 ml). Acetone (25 ml) was added to the filtrate and 10% (w/v) solution of sulphuric acid was added dropwise to bring down the pH from 4.5 to 2.8 at 33–35° C., stirred for 30 minutes and adjusted the pH again to 2.6. The resulting slurry was stirred for 15–20 minutes at 33–35° C., cooled to 20–25° C., and stirred for 30 minutes. The product thus obtained was filtered, washed with water (50 ml) and dried at 35° C. under vacuum for 3–4 hours to get the title compound (9.0 gm, HPLC purity>99%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:24][C:25](=[O:43])[C@@H:26]([NH:34][C:35]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:36])[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:11]([OH:23])[C:12](=[O:22])[NH:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]([NH:24][C:25](=[O:43])[C@@H:26]([NH:34][C:35]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:36])[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:11](=[O:23])[C:12](=[O:22])[NH:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC(C)(C)NC(=O)C(O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC1CCCCC1)NC(=O)N1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)NC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC1CCCCC1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
N4-[(1S)-2-((1S)-1-[(benzyloxy)methyl]-2-hydroxy-3-oxo-3-[(1,1,3,3-tetramethyl butyl)amino]propylamino)-1-(cyclohexylmethyl)-2-oxoethyl]-4-Morpholinecarboxamide (260 mg, 0.4 mmole) was dissolved in CH2Cl2 (4 mL). Dess-Martin periodinane (550 mg, 1.2 mmole) was added. The solution was stirred for 2 h at room temperature and quenched with Na2S2O3 and saturated bicarbonate solution. After extracting with CH2Cl2, the organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, 1/3: Hexane/EtOAc, Rf=0.6) afforded N4-[(1S)-2-((1S)-1-[(benzyloxy)methyl]-2,3-dioxo-3-[(1,1,3,3-tetramethylbutyl)amino]propylamino)-1-(cyclohexyl-methyl)-2-oxoethyl]-4-morpholinecarboxamide as a white solid (170 mg, 71%).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C(OC(C)C)(C)C>>[O:16]([CH2:20][CH2:21][NH:22][C:9]([C:7]1[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:11])[N+:17]([O-:19])=[O:18]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(NCCO[N+](=O)[O-])c1ccc([N+](=O)[O-])o1
Yield: 28.7 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.56 g of 5-nitro-2-furancarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.25 g of the title compound was obtained as yellow plates (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:26])[CH2:10][CH2:11][C:12]([N:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13].C(N(C(C)C)CC)(C)C.[O:36]1[CH2:41]CCOO1.[Cl-].[NH4+]>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:26])[CH2:10][C@@H:11]([CH2:41][OH:36])[C:12]([N:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13]
Reactant: C1COOOC1
Reactant: C=C(CCC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(F)cc1F
Agent: [Ti+4]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C[C@@H](CO)C(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(F)cc1F
Temperature: -15 °C
Reaction time: 0.67 h

Procedure:
Titanium chloride solution (prepared from 33.8 ml of titanium chloride and 50 ml of dichloromethane) was added to a pre-cooled solution of (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4 (100 g) in dichloro methane (1000 ml) at −20 to −10° C. under nitrogen atmosphere and diisopropyl ethylamine (45.61 μm) was added to the reaction mixture and stirred for 40 minutes at −20 to −10° C. A trioxane solution (prepared from 52.94 g of trioxane and 150 ml of dichloro methane) was added to the reaction mixture at −20 to −10° C. and followed by titanium chloride solution (prepared from 33.8 ml of titanium chloride and 50 ml of dichloro methane) at −20 to −10° C. Temperature of the reaction mixture was raised to −5 to 0° C. and stirred for 2 hours at −5 to 0° C. After completion of the reaction, the reaction mixture was added to 10% ammonium chloride at 10-15° C. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloro methane. Both the dichloro methane layers were combined and washed with water followed by 10% sodium chloride solution. The obtained dichloro methane layer was taken to the next step without isolating the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)[CH:10]=1>CN(C)C=O>[Cl:1][C:19]1[S:18][C:17]([NH2:20])=[N:16][C:15]=1[C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nc(-c2cccnc2)cs1
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccnc2)c(Cl)s1
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
N-Chlorosuccinimide (14,7 g) was added all at once to a solution of 4-(pyridin-3-yl)-thiazol-2-amine (17,7 g) in N,N-dimethylformamide (130 ml) at 0°-5° C. After five minutes, the product precipitated, and after ten minutes, precipitation was completed by addition of water and ammonium hydroxide solution. The product was filtered and dried in vacuo at 60° C. to give 5-chloro-4-(pyridin-3-yl)-thiazol-2-amine, (18,2 g) Mp 202° C.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38](OC)=[O:39])=[CH:5][CH:4]=1.[Li+].[OH-].[CH2:46]1[CH2:50]OC[CH2:47]1.O>>[CH:46]([N:22]1[CH2:27][CH2:26][N:25]([C:38]([C:10]2[N:11]=[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)[NH:13][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:42])([F:43])[F:1])=[CH:4][CH:5]=2)=[O:39])[CH2:24][CH2:23]1)([CH3:50])[CH3:47]
Reactant: C1CCOC1
Reactant: COC(=O)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)n(COCC[Si](C)(C)C)c1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)N1CCN(C(=O)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate from step (d) above (500. mg, 0.794 mmol) in THF:H2O (5:1) was added LiOH (29 mg, 1.19 mmol, Aldrich) at 0° C. The mixture was stirred at RT for 16 h and the solvents were removed. The residue was dissolved in H2O (20 mL) and the aqueous solution was adjusted to pH ˜7. Then, the solvents were removed and the residue was purified on silica gel using ISCO Combiflash® system with EtOAc/Hexanes (1:4) as the eluant to give the title compound as a white solid. MS (ESI, positive ion) m/z: 616 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:19])[CH2:10][CH2:9]1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:16]([NH:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:17]([CH:27]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccn1)c1cc(Cl)ccc1NCC1CCNCC1
Reaction time: 24 h
Yield: 87 %

Procedure:
A solution of 2-(1-Boc-piperidin-4-ylmethylamino)-5-chloro-N-(2-pyridyl)benzamide (6.1 g, 14 mmol) in trifluoroacetic acid (125 mL) was stirred at 70° C. for 2 h, then at room temperature for 24 h. The solution was concentrated in vacuo, and the residue was directly applied to a silica gel column. Elution with dichloromethane—2 M ammonia in methanol (9:1) afforded 4.2 g (89%) of the pure title compound, as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=S)[NH:11][NH2:12].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[CH3:23][C:21]1[NH:12][N:11]=[C:10]([NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Cc1cccc(C)c1NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(C)cccc2C)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A mixture of 9.8 g (0.05 mole) of 4-(2,6-dimethylphenyl)-3-thiosemicarbazide and 8.48 g (0.05 mole) of ethyl 2-chloroacetoacetate (97%) in 75 mL of absolute ethanol was stirred under nitrogen atmosphere for one hour at room temperature. The reaction was slightly exothermic and the mixture changed from a white slurry to a yellow slurry as most of the solid dissolved. The mixture was treated with 40 mL of 2N ethanolic hydrogen chloride and allowed to stir at room temperature for 16 hr. The reaction mixture was heated at reflux for two hours; during this time it took on a dark orange color which cleared later as all the material dissolved (a small amount of insoluble material was also present). The reaction mixture was filtered and the solvent removed under reduced pressure leaving a yellow-orange solid. The solid was triturated with acetone which dissolved most the orange color. Filtration gave 12.6 g of pale yellow crystals, mp 131°-137° C. Recrystallization of the yellow solid from acetone gave two crops of soft, fluffy, white product. Both crops were combined and analyzed, yield 8.5 g (62%), mp 142°-144° C.
Reaction SMILES: [F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:19]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:3]2[O:4][C@H:5]([CH:8]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[OH:9])[C@@:6]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([OH:7])[C@:2]2([F:1])[CH3:18])[C:11](=[O:12])[N:13]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C[C@]1(F)[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@H](C(O)C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
2′-Deoxy-2′-fluoro-2′-C-methylcytidine (1.0 g, 1 eq) (Clark, J., et al., J. Med. Chem., 2005, 48, 5504-5508) was dissolved in 10 ml of anhydrous pyridine and concentrated to dryness in vacuo. The resulting syrup was dissolved in 20 ml of anhydrous pyridine under nitrogen and cooled to 0° C. with stirring. The brown solution was treated with benzoyl chloride (1.63 g, 3 eq) dropwise over 10 min. The ice bath was removed and stirring continued for 1.5 h whereby thin-layer chromatography (TLC) showed no remaining starting material. The mixture was quenched by addition of water (0.5 ml) and concentrated to dryness. The residue was dissolved in 50 mL of dichloromethane (DCM) and washed with saturated NaHCO3 aqueous solution and H2O. The organic phase was dried over NaSO4 and filtered, concentrated to dryness to give N4,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, Yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 85 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 4-fluorobenzoyl chloride, (0.018 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (35 mg, 82%). LCMS calculated for C22H20ClFN3O2 (M+H)+: m/z=412.1; Found: 412.1.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[C:6]1([NH2:24])[N:7]=[C:8]([NH2:23])[N:9]=[C:10]2[C:22]=1[C:21]1[C:20]3C[CH2:18][CH2:17][CH2:16][C:15]=3NC=1[CH:12]=[CH:11]2.[H-].[Na+].CI>C(O)(=O)C>[CH3:1][N:2]1[C:5]2[CH:12]=[CH:11][C:10]3=[N:9][C:8]([NH2:23])=[N:7][C:6]([NH2:24])=[C:22]3[C:21]=2[C:20]2[CH2:15][CH2:16][CH2:17][CH2:18][C:3]1=2
Reactant: Nc1nc(N)c2c(ccc3[nH]c4c(c32)CCCC4)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)O
Product: Cn1c2c(c3c4c(N)nc(N)nc4ccc31)CCCC2
Reaction time: 2 h

Procedure:
Dry dimethylformamide (150 ml.), 4.62 g. 8,9,10,11-tetrahydro-7H-pyrimido[4,5-c]carbazole-1,3-diamine and 0.96 g. ca. 50% sodium hydride-mineral oil dispersion are stirred, under nitrogen, for 1 hour. A solution of 2.84 g. methyl iodide in 10 ml. dry dimethylformamide is added during 10 minutes and stirring is continued for ca. 2 hours. Glacial acetic acid (20 ml.) is added and the solvent is removed. The residue is stirred with 12 g. sodium methoxide-150 ml. methanol for 2 hours and the mixture is diluted with 750 ml. water. The solids are collected, washed with water, dried, twice recrystallized from methanol and thoroughly dried to yield 1.96 g. title compound, m.p. 288°-292° (softens 285°).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:20][C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: Brc1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
4-Bromobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[Cl:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:26])=O>>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([Cl:26])=[O:19])=[CH:16][C:15]=1[Cl:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1Cl

Procedure:
To 1.0 g of this 4-n-dodecyloxy-3-chlorobenzoic acid was added 10 g of thionyl chloride, and the mixture was refluxed for 3 hours and unreacted thionyl chloride was removed under a reduced pressure. Thus, 4-n-dodecyloxy-3-chlorobenzoic acid chloride was quantitatively obtained. A solution of the so-obtained compound in toluene was added dropwise to a solution of 0.59 g of p-benzyloxyphenol and 0.3 g of triethylamine in toluene, and the mixture was stirred overnight. The thus-obtained solution was diluted with ethyl acetate, and the dilution was washed with 0.5N hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in succession, dehydrated on anhydrous sodium sulfate and concentrated under a reduced pressure to obtain p-benzyloxyphenyl 4-dodecyloxy-3-chlorobenzoate. The so-obtained ester was dissolved in ethyl acetate and 1 g of 5%-Pd/C was added to the solution, and the mixture was stirred at room temperature under a pressure of 3 atmospheres in a hydrogen atmosphere for three days and three nights. The Pd/C was removed by filtration and the filtrate was recrystallized from n-hexane to obtain 500 mg of 4-hydroxyphenyl 4-dodecyloxy-3-chlorobenzoate.