Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C:24]([S:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:7][P:8]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C:24]([S:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:43])=[O:25])[CH2:7][P:8]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:9])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CN(CP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)SCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CN(CP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)S(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl-N-[(benzylthio)carbonyl]-N-[bis(phenoxy)phosphinylmethyl]-glycinate (1.0 g.; 0.002 mol.) dissolved in 10 ml. of methylene chloride at 0° C. was slowly added a solution of metachloroperbenzoic acid (0.4 g.; B 0.002 mol.) dissolved in 100 ml. of methylene chloride. The reaction mixture was stirred for one hour and allowed to gradually warm to 25° C. The mixture was washed with 5% sodium hydroxide, dried, then concentrated in vacuo. The resulting oil was extracted into hot petroleum ether and allowed to crystallize for 16 hours to yield ethyl-N-[(benzylsulfinyl)carbonyl]-N-[bis-(phenoxy)phosphinylmethyl]-glycinate as a solid having a melting point of 106°-115° C. and the folloing analysis:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=[O:12])(=O)(O)[OH:9]>>[CH:5]1[CH:6]=[C:1]([OH:7])[C:2]([S:8]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)(=[O:12])=[O:9])=[CH:3][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Product: O=S(=O)(c1ccc(O)cc1)c1ccccc1O

Procedure:
The mixture containing 4,4′-dihydroxydiphenylsulfone, 2,4′-dihydroxydiphenylsulfone, phenolsulfonic acid and phenol which is obtained by adding phenol and sulfuric acid to the filtrate formed by filtration of 2,4′-dihydroxydiphenylsulfone, followed by the dehydration of the resultant mixture, can be treated in the same manner as that in the treatments of the mixture containing 4,4′-dihydroxydiphenylsulfone, 2,4′-dihydroxydiphenylsulfone, phenolsulfonic acid and phenol which is obtained by the dehydration of phenol and sulfuric acid. 4,4′-Dihydroxydiphenylsulfone is separated by crystallization to obtain a mixture having a content of 2,4′-dihydroxydiphenylsulfone greater than the content of 4,4′-dihydroxydiphenylsulfone. 2,4′-Dihydroxydiphenylsulfone is crystallized by adjusting the composition of the mixture so that the ratio of the amounts by weight of phenol to water is in the range of 10:90 to 90:10; and the formed crystals are separated by filtration. The filtrate formed above by the filtration and containing phenol and phenolsulfonic acid can be used repeatedly as the raw material for producing dihydroxydiphenylsulfone by the dehydration of phenol and sulfuric acid and/or phenolsulfonic acid.
Reaction SMILES: [CH2:1]([C@H:4]([C@H:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[CH:31][CH:30]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29](/[CH:3]=[CH:2]/[CH2:1][C@H:4]([C@H:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])=[CH:30][CH:31]=1)[CH3:37]
Reactant: CCOc1ccc(Br)cc1
Reactant: C=CC[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C/C[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of diisopropyl (2R,3S)-2-allyl-3-hydroxybutanedioate (3.0 g; 11.6 mmol; 1.0 eq.) and DIEA (3.86 mL; 28.9 mmol; 2.4 eq.) in CH3CN (30.0 mL) was added 4-bromophenetole (2.0 mL; 13.9 mmol; 1.2 eq.). To this solution was added a mixture of tri-o-tolylphosphine (0.35 g; 1.16 mmol; 0.1 eq.) and palladium(II) acetate (0.03 g; 0.12 mmol; 0.01 eq.) in CH3CN (3.0 mL) which was sonicated before the addition to the reaction mixture. The reaction was stirred under argon at reflux for 2.5 h, cooled to RT and the solvents were evaporated under reduce pressure. The resulting residue was then taken up in EtOAc and washed with an aqueous saturated solution of NaCl. Evaporation of the solvent gave an oil (4.3 g). Purification by chromatography (SiO2, gradient from 20/80 EtOAc/c-hex to 100/0 EtOAc/c-hex) gave the title product as a colorless oil (4.41 g, 100%). M+(ESI): 379.3. 1H NMR (CDCl3, 300 MHz) δ 7.14 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 6.46 (d, J=15.6 Hz, 1H), 6.00-5.86 (m, 1H), 5.05-4.83 (m, 2H), 4.13 (dd, J=7.0 Hz, J=3.0 Hz, 1H), 3.90 (q, J=7.0 Hz, 2H), 3.10 (d, J=7.2 Hz, 1H), 2.89-2.78 (m, 1H), 2.70-2.55 (m, 1H), 2.52-2.35 (m, 1H), 1.27 (t, J=7.0 Hz, 3H), 1.22-1.00 (m, 12H).
Reaction SMILES: [CH2:1]([C:3]1([C:33]([O:35]CC)=[O:34])[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:30][O:31][CH3:32])[C:18]4[S:22][C:21]([NH:23][C:24](=[O:28])[NH:25][CH2:26][CH3:27])=[N:20][C:19]=4[CH:29]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+]>CCO.O>[CH2:1]([C:3]1([C:33]([OH:35])=[O:34])[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:16]=[C:17]([CH2:30][O:31][CH3:32])[C:18]4[S:22][C:21]([NH:23][C:24](=[O:28])[NH:25][CH2:26][CH3:27])=[N:20][C:19]=4[CH:29]=3)=[CH:13][N:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(COC)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(COC)c2s1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 64.5 %

Procedure:
Ethyl 4-ethyl-1-[5-[2-(ethylcarbamoylamino)-7-(methoxymethyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (23 mg, 0.042 mmol) was dissolved in EtOH (1 mL) and 2M aqueous NaOH (330 μL, 0.66 mmol) added. The reaction mixture was stirred at 70° C. for 15 mins before additional 2M NaOH (670 μL, 1.34 mmol) was added and the reaction continued for 1.5 h then temperature increased to 100° C. and reaction continued for 4 h after which time the reaction was allowed to cool to rt overnight. After this time LCMS indicated small amount of starting material still present and the reaction was completed by heating to 100° C. for a further 2 h after which time the reaction was cooled to rt, diluted with water and extracted with DCM (3×). The aqueous layer was acidified with 10% HCl (aq) before extracting with EtOAc (3×) and the combined EtOAc extracts dried and the solvent evaporated to yield the Compound 203 (13.5 mg, 64%). 1H NMR (MeOD) δ 8.54 (s, 2H), 7.66 (bd, J=1.4 Hz, 1H), 7.28 (s, 1H), 4.68 (s, 2H), 4.48 (dt, J=13.7, 3.6 Hz, 2H), 3.35-3.28 (m, 2H), 3.22-3.11 (m, 2H), 2.20-2.13 (m, 2H), 1.60 (q, J=7.5 Hz, 2H), 1.44-1.34 (m, 2H), 1.21 (t, J=7.2 Hz, 3H), 0.89 (t, J=7.5 Hz, 3H). MS: 499.12 [M+H]+
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:9][NH:10][CH3:11].[OH-].[Na+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:10]([CH3:11])[CH3:9])=[O:6]
Reactant: CNC
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCCl
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To a solution of 4-chloro-butyryl chloride (1.12 ml, 10.0 mmol) and dimethyl-amine hydrochloride (4.1 g, 50.0 mmol) in THF at 5° C. was added 2M NaOH (30 ml, 60.0 mmol) dropwise over 30 minutes while maintaining reaction temperature between 5-10° C. The reaction was stirred for additional 1.5 h and was concentrated, extracted with EtOAc (×2). The combined organic layer was washed with 1M HCl (×2), brine, dried over Na2SO4, and concentrated in vacuo to yield the title compound as colorless oil (1.5 g, ˜100%). The crude was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][C:38]2([CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCCl>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][C:38]2([CH2:45][CH2:44][CH:43]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:42][CH2:41]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
3,4-Dichloroaniline (364 mg, 2.2 mmol), sodium triacetoxyborohydride (889 mg, 4.20 mmol) and acetic acid (0.24 mL, 4.20 mmol) were added to a solution of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (561 mg, 2.10 mmol) in 1,2-dichloroethane (30 mL) with crunched 4A mol sieves (10 g). The mixture was stirred a room temperature over night. Additional 4A mol sieves (12 g) and sodium triacetoxyborohydride (445 mg) was added and the mixture was stirred over night. The reaction was quenched with water and 5% citric acid was added. The mixture was filtered through kieselguhr and the filtrated was evaporated until only the aqueous layer remained. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with brine, dried with sodium sulphate, filtered and evaporated to give the crude product. Flash chromatography (ethyl acetale/heptane) gave 9-(3,4-dichloro-phenylamino)-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (258 mg, 0.624 mmol, 30%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH2:18][N:19]2C(=O)C4C(=CC=CC=4)C2=O)[CH2:10]3)=[CH:5][CH:4]=[N:3]1.CO.O1CCCC1.NN>>[NH2:19][CH2:18][C@@H:17]([N:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)[C:12]1=[O:16])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1ccc2c(c1)CN([C@H](CN)Cc1cccc(F)c1)C2=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
The product of Step D (0.72 g, 1.45 mmol) was dissolved in methanol (4 mL, 100 mmol) and tetrahydrofuran (4 mL, 50 mmol). To the resulting solution was added hydrazine (2 mL, 60 mmol). The solution was stirred at 50° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by combi-flash chromatography eluting with MeOH/EtOAc (20-60%). The product was further purified by prep.-LC/MS (pH=10). The purification afforded 345 mg (37.3% yield) of the final product as white solid. LC-MS found: 365.2 (M+1)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.70 (d, J=3.6 Hz, 1H), 7.66 (s, 1H), 7.58 (dd, J1=7.8 Hz, J2=1.2 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.23 (dd, J1=7.8 Hz, J2=6.3 Hz, 1H), 7.03 (m, 2H), 6.93 (ddd, J1=8.7 Hz, J2=8.4 Hz, J3=2.4 Hz, 1H), 6.45 (d, J=2.1 Hz, 1H), 4.46 (s, 2H), 4.40 (m, 1H), 3.86 (s, 3H), 3.04 (dd, J1=14.4 Hz, J2=5.1 Hz, 1H), 2.88 (dd, J1=14.40 Hz, J2=4.5 Hz, 1H), 2.82 (d, J=6.9 Hz, 2H).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][C:11](=[O:18])[O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][C:11](=[O:18])[O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)COC(=O)Nc1cccc(C)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)COC(=O)Nc1cccc(C)c1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Methoxycarbonylmethyl (2-hydroxymethyl-3-methylphenyl)carbamate (6.8 g) is introduced in dichloromethane (60 ml) and treated dropwise with thionyl chloride (3.4 ml). The mixture is then stirred at RT for a further 1 h. The solvent is then distilled off and the residue is treated 2 times with dichloromethane (50 ml each) and the mixture is in each case concentrated again on a rotary evaporator. 7 g (96%) of the title compound of m.p. 114-116° C. are obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[CH:10]=[C:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.O>CN1C(=O)CCC1>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:27]([NH:26][CH2:25][CH2:24][NH:23][C:2]2[C:3]3[N:11]([CH3:12])[CH:10]=[C:9]([C:13]4[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=4[CH3:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: COc1cc(C)c(-c2cn(C)c3c(Cl)nc(C)nc23)c(C)c1
Reactant: COc1ccc(CC(=O)NCCN)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CC(=O)NCCNc2nc(C)nc3c(-c4c(C)cc(OC)cc4C)cn(C)c23)cc1

Procedure:
Heat a solution of 4-chloro-7-(4-methoxy-2,6-dimethyl-phenyl)-2,5-dimethyl-5H-pyrrolo[3,2-d]pyrimidine (120 mg, 0.38 mmol) and N-(2-amino-ethyl)-2-(4-methoxyphenyl)-acetamide (125 mg) in NMP (2 mL) for 14 h at 130° C. Pour into water (5 mL) and extract with EtOAc (2×10 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate under reduced pressure to obtain the title compound which is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19](F)=[C:18]([F:24])[C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2].[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([N:26]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:18]([F:24])[C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2]
Reactant: C1CNCCNC1
Reactant: CCOC(=O)c1cn(CC)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(CC)c2nc3c(F)c(N4CCCNCC4)c(F)cc3cc2c1=O
Yield: 46.1 %

Procedure:
The 7,9-difluoro-3-ethoxycarbonyl-1-ethyl-4-oxo-8-(perhydro-1,4-diazepin-1-yl)-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 5, but starting from 3 g of 3-ethoxycarbonyl-1-ethyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 2 g of hexahydro-1,4-diazepine. 1.7 g of 3-ethoxycarbonyl-1-ethyl-7,9-difluoro-4-oxo-8-(perhydro-1,4-diazepin-1-yl)-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 190° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[C:18]([F:25])=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21]>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:24]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([F:25])[CH:17]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: N#Cc1cccc(Br)c1F
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OCC(=O)Nc2ccc(-c3ccc(C#N)c(F)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-bromo-2-fluorobenzonitrile generally according to the coupling procedure described in examples 82 and 1. 1H NMR (DMSO-d6): δ 10.08 (s, 1H), 7.92-7.99 (m, 2H), 7.77-7.79 (m, 1H), 7.64-7.69 (m, 2H), 7.22 (d, J=8.39 Hz, 1H), 4.28 (s, 2H), 1.62 (s, 6H). MS (ESI) m/z 311 ([M+H]+); MS (ESI) m/z 309 ([M−H]−).
Reaction SMILES: F[C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)=[CH:25][C:24]=1[O:35][CH3:36]>>[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[NH:30][CH2:31][CH2:32][N:33]([C:20]3[CH:2]=[CH:3][C:4]4[C:5]([CH:19]=3)=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=4)[CH2:34]2)=[CH:25][C:24]=1[O:35][CH3:36]
Reactant: COc1cc(C2CNCCN2)ccc1N
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Product: COc1cc(C2CN(c3ccc4cc5c(=O)c(C(=O)O)cn(C)c5nc4c3)CCN2)ccc1N
Yield: 76.2 %

Procedure:
Working under the conditions of Example 16, but starting with 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.16 g) and (RS)-2-(4-amino-3-methoxyphenyl)piperazine (1.82 g), (RS)-8-[3-(4-amino-3-methoxyphenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.40 g) is obtained in the form of a yellow solid, decomposing at 259° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[Br:21]Br.O>O>[Br:21][C:17]1[C:18]([Cl:20])=[CH:19][C:4]2[N:3]=[C:2]([Cl:1])[N:6]([C@@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:5]=2[CH:16]=1
Reactant: BrBr
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)ccc32)[C@H](O)[C@@H]1O
Solvent: O
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Br)cc32)[C@H](O)[C@@H]1O
Reaction time: 6 h

Procedure:
To a suspension of 0.110 g (0.313 mmol, as C12H12Cl2N2O4MeOH) of 2,5-dichloro-1-β-D-ribofuranosylbenzimidazole in 3 mL of H2O was added dropwise 10 mL of a sat. solution of Br2 /H2O at room temperature. After the addition has been completed, stirring was continued for 6 h. The reaction mixture was filtered and the solid was washed with portions of H2O, and then recrystallized from MeOH to give 0.091 g (73%, 2 crops) of 99 as white crystalline needles. MP 158°-159° C. MS (El) m/e 395.9274 (5% M+ =395.9279). 1H NMR (DMSO-d6): δ8.69 (s, 1, 7-H), 7.96 (s, 1, 4-H), 5.88 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.41 (t, 5'-OH, J5'-5'OH =4.5 Hz), 5.30 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.42 (m, 1, 2'-H, J2'-3' =5.5 Hz), 5.30 (d, 1, 3'-OH, J3'-4' =1.5 Hz), 4.01 (m, 1, 4'-H, J4'-5' =J4'-5'=2.5 Hz), 371 (m, 2, 5'-H and 5"-H, J5'-5" =1.20 Hz). Anal. Calcd. for C12H11BrCl2N2O4 : C, 36.21; H, 2.79; N, 7.04. Found: C, 36.14; H, 2.90; N, 6.90.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([NH:29][C:30]([CH3:35])([CH3:34])[C:31]([NH2:33])=[O:32])[CH:26]([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:30]([CH3:35])([CH3:34])[C:31](=[O:32])[N:33]=3)[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)CNC(C)(C)C(N)=O
Product: Cc1c(C2=NC(=O)C(C)(C)N2CC(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 12 was synthesized from 4a (248 mg, 0.66 mmol) and 5g (160 mg, 1.01 mmol) as a white solid (110 mg, 33%) in a manner similar to that described in Example 36. 1H NMR (600 MHz, CDCl3) δ 7.46 (d, 1H), 7.29-7.24 (m, 3H), 7.11 (d, 1H), 7.06 (d, 2H), 3.78-3.75 (m, 2H), 2.34 (s, 3H), 2.03-2.01 (m, 1H), 1.44 (s, 6H), 0.85-0.82 (d, 6H); ESMS m/z: 503.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3ccccc3)no2)CC1
Yield: 53 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-(2-methoxyphenyl)piperazine (19.2 mg, 0.10 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (32 mg, 0.15 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16.5 hr and followed the same processes as in Example 1 to obtain 10 mg (53.0%) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.C(O[CH2:31][CH3:32])(=O)C>CCCCCC>[C:7]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:13]5[C:18]([C:19]=4[CH:20]=3)=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:4][CH:3]=2)[C:31]2[C:32](=[CH:6][CH:5]=[CH:8][CH:20]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc(-c5cccc6ccccc56)cc4)ccc32)cc1

Procedure:
The Rf values of the objective substance and 3-(4-bromophenyl)-9-phenyl-9H-carbazole were respectively 0.57 and 0.65, which were obtained by silica gel thin layer chromatography (TLC) (with a developing solvent containing ethyl acetate and hexane in a 1:10 ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(F)cc1
Product: O=C(Cl)CCc1ccc(F)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A mixture of 3-(4-fluorophenyl)propionic acid (275.1 g, 1.6 mol) and thionyl chloride (300 mL, 4.1 mol) was heated to reflux for 3 h, cooled to room temperature and distilled under aspirator vacuum to give 287.6 g (96%) of 3-(4-fluorophenyl)propionyl chloride as a pale pink oil, b.p., 120°-122° C./15 mm Hg:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11](=[O:14])(O)[O-:12].[Na+]>C(OCC)(=O)C.O>[C:4]([O:12][C:11](=[O:14])[NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[Br:2])([CH3:7])([CH3:5])[CH3:3]
Reactant: NCc1ccccc1Br
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 2-bromobenzylamine hydrochloride (5.00 g) and di-tert-butoxycarbonyl (5.39 g) in ethyl acetate (30 ml) was added saturated sodium bicarbonate solution (30 ml), and stirred at room temperature for 16 hours. The obtained reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a colorless liquid (6.48 g, 95%).