Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.Cl.[NH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1)=O.[OH2:25]>>[NH2:14][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:25])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2
Reactant: NCC(=O)c1ccc(I)cc1
Reactant: O
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: Cl
Product: Nc1c(-c2ccc(I)cc2)nc2ccc(F)cc2c1C(=O)O

Procedure:
A basic aqueous solution of 3.8 g of 5-fluoroisatin in water was reacted with 9.8 g of 2-amino-1-(4-iodophenyl)ethanone hydrochloride by the procedure described in example 41, giving 7.0 g of the desiredcompound as a yellow solid, mp 251°-253° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27]1([CH:33]=[CH:34][C:35](Cl)=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:35](=[O:36])[CH:34]=[CH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccc(C(c2ccc(Cl)cc2)n2ccnc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(C=Cc1ccccc1)Nc1ccc(C(c2ccc(Cl)cc2)n2ccnc2)cc1
Yield: 83.8 %

Procedure:
To a stirred and cooled (0° C.) mixture of 14.6 parts of 4-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]benzenamine, 60.9 parts of benzene and 6.86 parts of pyridine was added a solution of 10.6 parts of 3-phenyl-2-propenoyl chloride in 17.4 parts of benzene under a nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was basified and extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from dichloromethane. The product was filtered off and dried, yielding 17.7 parts (83.8%) of N-[4-[(4-chlorophenyl) (1H-imidazol-1-yl)methyl]phenyl]-3-phenyl-2-propenamide; top. 244° C.(interm. 50).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=1[OH:19]>C(O)(=O)C>[OH:19][C:18]1[CH:17]=[C:16]([CH3:20])[CH:15]=[CH:14][C:13]=1[N:12]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: Cc1ccc(N)c(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 0 °C
Yield: 95.2 %

Procedure:
A solution of phthalic anhydride (14.81 g, 0.10 mole) and 6-amino-m-cresol (12.32 g, 0.10 mole) in 200 mL of acetic acid was stirred at ambient temperature for 30 minutes and then refluxed for 6 hours. The solution was cooled and poured into 500 mL ice-water with rapid stirring and the resultant solid was collected by suction filtration, washed with ice-cold water several times and air dried overnight to afford 24.1 g (95% yield) of product 1 as a light brown solid, mp 251-254° C. TLC (silica ; EtOAc), Rf=0.68.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH2:7]Cl)[CH:6]=1.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH2:7][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[CH:6]=1
Reactant: FC(F)(F)c1nn(CCl)cc1Br
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Br)c(C(F)(F)F)n1
Yield: 39.3 %

Procedure:
1.67 g of 4-bromo-1-(chloromethyl)-3-trifluoromethyl-1H-pyrazole and 1.03 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 18 ml of N,N-dimethylformamide. 1.74 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.97 g of [(4-bromo-3-trifluoromethyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (15), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[C:27]([F:30])([F:29])[F:28])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (500 mg, 1.31 mmol) and trimethyl(trifluoromethyl)silane (582 μL, 3.94 mmol) in tetrahydrofuran (6.5 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 131 μL, 0.131 mmol) at 0° C. After 15 min, hydrochloric acid (1.0 M, 2.0 mL) was added. After 30 min, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (590 mg, 1.30 mmol, 99%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].C(N(CC)CC)C.[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][C:18]=1O.O>C(Cl)Cl>[F:1][C:2]([F:8])([F:7])[S:3]([O:6][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[C:22]([CH3:23])[C:17]=1[CH3:16])(=[O:5])=[O:4]
Reactant: Cc1c(O)ccc([N+](=O)[O-])c1C
Reactant: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OS(=O)(=O)C(F)(F)F)ccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Anhydrous trifluoromethanesulfonate (3.17 ml, 18.8 mmol) and triethylamine (2.75 ml, 19.7 mmol) were added dropwise to a solution of 2,3-dimethyl-4-nitrophenol (3.0 g, 17.9 mmol) in methylene chloride (60 ml) at 0° C. and stirred at room temperature for 1 hour. Then, the reaction solution was poured into water and extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2,3-dimethyl-4-nitrophenyl trifluoromethanesulfonate (5.32 g, 99%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[N+:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([O:17][C:16]([F:15])([F:25])[F:26])[CH:19]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: Nc1cccc(OC(F)(F)F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc([N+](=O)[O-])c(Nc2cccc(OC(F)(F)F)c2)c1
Yield: 34.8 %

Procedure:
A solution of methyl 3-fluoro-4-nitrobenzoate (4.66 g, 23.4 mmol), 3-trifluoromethoxyaniline (4.98 g, 28.1 mmol) and N,N-diisopropylethylamine (4.84 mL, 28.1 mmol) in dimethyl sulfoxide (30 mL) was stirred at 120° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/tetrahydrofuran to give the title compound (2.90 g, yield 35%) as red crystals.
Reaction SMILES: [C:1]([NH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:14][NH:15][C:16](=O)[CH3:17])=[C:11]([CH:13]=1)[NH2:12])=[O:6])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:27][C:28]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Cl>CN(C)C=O.O>[ClH:27].[C:1]([NH:4][C:5]([C:7]1[CH:13]=[C:11]2[C:10]([CH2:14][N:15]=[C:16]([CH3:17])[N:12]2[CH2:30][C:29]2[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:28]=2[Cl:27])=[CH:9][CH:8]=1)=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(C(=O)NC(C)=O)cc1N
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC(=O)c1ccc2c(c1)N(Cc1ccc(Cl)cc1Cl)C(C)=NC2
Product: Cl
Temperature: 90 °C
Reaction time: 15 h
Yield: 30.1 %

Procedure:
5-(Acetylcarbamoyl)-2-(acetylaminomethyl)aniline (1.06 g), potassium carbonate (1.40 g), potassium iodide (0.8 g) and 2,4-dichlorobenzyl chloride (1.40 g) in a mixture of dimethylformamide (15 ml) and water (10 ml) were stirred at 90° C. for 15 hr. After concentration of the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The extract was concentrated, and methanol (5 ml) and concentrated hydrochloric acid (5 ml) were added. The mixture was refluxed for 1 hr. The reaction mixture was concentrated and purified by thin-layer chromatography to give the objective compound (0.46 g).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=1)=O.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCC1>C(O)C>[C:3]1([CH:1]=[C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:21]2=[O:29])[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2cccccc1-2
Reactant: O=C1Cc2ccccc2N1Cc1ccccc1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1C(=Cc2ccc3cccccc2-3)c2ccccc2N1Cc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
1-Formylazulene (1 mmol) was dissolved in 20 mL ethanol. 223 mg 1-benzylindolin-2-one (1 mmol) and 20 mL ethanol were then added. Next, a 2 mL solution (1 mmol) containing 1M pyrrolidine and ethanol was added to react at room temperature for three days. After removal of solvent, the resulting solution was extracted by 150 mL ethyl acetate and 50 mL water. The resulting solution was extracted again by 50 mL citric acid aqueous solution and ethyl acetate. The ethyl acetate layer was collected, dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. Next, methanol was added and ultrasonically shaken at 40° C. for 1 hour. After filtration, washing by methanol, and drying, Compound 002 (315 mg, 87%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: Cc1n[nH]c(=O)c(-c2ccc(F)cc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ccc(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
1.20 g of 5-(4-chlorophenyl)-4-(2,4-difluorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 1.22 g of 3-chloro-5-(4-chlorophenyl)-4-(2,4-difluorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (xv) of the present invention).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(Br)nc1
Reactant: OB(O)c1ccc(Br)cc1
Product: CCOC(=O)c1ccc(-c2ccc(Br)cc2)nc1
Yield: 98 %

Procedure:
In accordance with Example 11-(1), but using ethyl 6-bromonicotinate instead of 4-bromobenzylbromide, and 4-bromophenylboronic acid instead of [3-(hydroxymethyl)phenyl]boronic acid, the title compound (yield 98%) was afforded as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:18])=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Cl)ccc2c1cnn2Cc1ccccc1
Reaction time: 4 h
Yield: 37.7 %

Procedure:
A solution of 1-benzyl-1H-indazol-4-amine (0.080 g, 0.36 mmol) in DMF (2 mL) was treated with N-chlorosuccinimide (0.053 g, 0.39 mmol) at ambient temperature and stirred for 4 hours. The mixture was diluted with water, extracted with EtOAc, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (10-50% EtOAc in hexanes) to provide 1-benzyl-5-chloro-1H-indazol-4-amine (0.035 g, 38% yield).
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.[CH:10](=[O:12])[CH3:11]>O>[OH:12][CH:10]([C:7]1[O:8][C:2]([CH3:1])=[CH:3][C:4](=[O:5])[C:6]=1[OH:9])[CH3:11]
Reactant: CC=O
Reactant: Cc1cc(=O)c(O)co1
Solvent: O
Product: Cc1cc(=O)c(O)c(C(C)O)o1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
Allomaltol (12.6 g, 100 mmol, 1 eq.) was added to 100 ml water and the pH of the solution was adjusted to 10.5 using 50% aqueous sodium hydroxides. Acetaldehyde (5.5 g, 125 mmol, 1.25 eq.) dissolved in 25 ml water was slowly added dropwise over 1 hour and the solution allowed to stir overnight. After adjustment to pH 1 with 37% hydrochloric acid, the reaction mixture was extracted with 3×150 ml of dichioromethane. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated to yield the crude product. Recrystallisation from toluene afforded the pure product (14.1 g, 83%) as white needles. m.p. 127-130° C. [lit. 126-128° C.]. Ellis (1993)
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[SH:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:9]2[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=[CH:32][C:8]=2[N:7]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([S:5][C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:9]2[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=[CH:32][C:8]=2[N:7]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reactant: CCCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCSc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
Propyl iodide (0.37 g) was added to a solution of ethyl 2-mercapto-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylate (0.91 g) in ethanol (13 ml) containing 1N NaOH (4.0 ml) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to about pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration and purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane gave colorless prisms (0.4 g, 40%), m.p. 177°-178° C. (decomp.).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10]3[CH:13]=[N:14][C:15]([C:17]([OH:19])=[O:18])=[N:16][C:9]=3[C:8]=2[CH:7]=[C:6]([N+:20]([O-:22])=[O:21])[CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[CH2:28]([O:18][C:17]([C:15]1[N:14]=[CH:13][C:10]2[NH:11][C:12]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([N+:20]([O-:22])=[O:21])=[CH:7][C:8]=3[C:9]=2[N:16]=1)=[O:19])[CH3:29]
Reactant: O=C(O)c1ncc2[nH]c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3c2n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncc2[nH]c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3c2n1

Procedure:
Under argon, 0.2 g of 6,8-dinitro-5H-pyrimido[5,4-b]indole-2-carboxylic acid (Example 8) is refluxed in 20 ml of ethanol with the addition of 1 ml of concentrated sulfuric acid for 8 hours. Subsequently the solution is concentrated to half the quantity and dissolved in methylene chloride. The solution is washed first with water, then with sodium bicarbonate solution, and finally again with water, dried, and concentrated, yielding 0.18 g of 6,8-dinitro-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 295°-299° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2.C1C(=O)N([Cl:30])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:14]([Cl:30])=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Yield: 65 %

Procedure:
A mixture of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate [synthesized according to the procedure described in U.S. Pat. No. 8,084,620, Intermediate 48-1] (0.100 g, 0.277 mmol) and NCS (recrystallized from toluene; 0.037 g, 0.277 mmol) in CCl4 (10 mL) and DMF (2 mL) was stirred at room temperature for 112 h. The mixture was filtered, and the collected precipitate was washed with CCl4 and dried overnight under vacuum. The residue was purified by column chromatography on silica gel (40 g), eluting with hexanes, then with EtOAc-hexanes (30%, then 50%), to give ethyl 5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate as a fluffy white solid (0.071 g, 65% yield). Mass spectrum m/z 395, 397, (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.77 (d, J=8.6 Hz, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.36 (br. s., 1H), 8.29 (s, 1H), 7.89 (dd, J=8.4, 1.5 Hz, 1H), 7.74 (br. s., 1H), 4.38 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:7][CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[P:10]([OH:13])([OH:12])[OH:11].P(Cl)(Cl)Cl.CC(C)=O>O>[CH:1]1([NH:7][CH:8]([P:10]([OH:13])(=[O:11])[OH:12])[P:10]([OH:13])(=[O:12])[OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OP(O)O
Reactant: O=CNC1CCCCC1
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: O=P(O)(O)C(NC1CCCCC1)P(=O)(O)O
Yield: 25 %

Procedure:
127.2 parts of N-cyclohexylformamide and 81 parts of phosphorous acid were reacted with 137.3 parts of phosphorus trichloride at 70°C, and maintained for 5 hours at this temperature. The reaction product was dissolved in water, treated with acetone and the precipitate separated. A 25% yield of N-cyclohexyl-1-aminomethane-1,1-diphosphonic acid, based on PCl3, was obtained.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(O)(C)C>[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C@H:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][CH:1]=[O:10])=[CH:13]1
Reactant: Cn1ccc2ccccc21
Reactant: O=CC=Cc1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc([C@@H](CC=O)c2ccccc2)c2ccccc21
Yield: 83.5 %

Procedure:
Prepared according to the general procedure from cinnamaldehyde (190 μL, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.85 mL) and isopropanol (0.15 mL) at −55° C. for 45 h to provide, after silica gel chromatography (10:90 EtOAc/hexanes), the title compound as a colorless oil (110 mg, 84% yield, 90% ee). IR (film) 3051, 3026, 2945, 2888, 2822, 2733, 1722, 1616, 1604, 1547, 1474, 1429, 1376, 1331, 1245, 1225, 1156, 1131, 1013, 765, 740, 700 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.76 (dd, J=2.4, 2.4 Hz, 1H, CHO), 7.43 (dt, J=0.9, 8.1 Hz, 1H, ArH), 7.36-7.28 (m, 7H, ArH), 7.04 (ddd, J=1.2, 6.9, 8.1 Hz, 1H, ArH), 6.88 (s, 1H, NCH), 4.88 (t, J=7.5 Hz, 1H, ArCH), 3.76 (s, 3H, NCH3), 3.22 (ddd, J=2.7, 8.4, 16.5 Hz, 1H, CH2CO); 3.10 (ddd, J=2.7, 8.4, 16.5 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) δ 201.8, 143.5, 137.3, 128.6, 127.6, 126.8, 126.6, 126.4, 121.9, 119.4, 119.0, 116.6, 109.3, 50.0, 37.4, 32.9; HRMS (CI) exact mass calcd for (C15H17NO) requires m/z 263.1310, found m/z 263.1306. [α]D=+30.9 (CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (3:97 ethanol/hexanes, 1 mL/min); S isomer tr=48.5 min and R isomer tr=38.9 min.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:14][CH:15]=O)[C:4](=[O:17])[CH:3]=1.[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]([CH:37]3[CH2:42][CH2:41][N:40]([CH2:15][CH2:14][N:5]4[C:6]5[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=5)[C:2]([CH3:1])=[CH:3][C:4]4=[O:17])[CH2:39][CH2:38]3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COc1ccc2c(c1)c(C)cc(=O)n2CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(C)cc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To 25 mL of a chloroform solution containing 71 mg of (4-methyl-6-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde and 108 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 18 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 121 mg of sodium triacetoxyborohydride was added, and stirred for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1], to give 140 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-6-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.