Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22](OC)=[O:23])[C:9]=2[C:26](OC)=[O:27])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].CO>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:26][OH:27])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Br)c2)c1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(Br)c3)c2cc1OC
Yield: 90 %

Procedure:
To a suspension of 1-(2-bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (15.0 g) in tetrahydrofuran (150 ml) is added sodium borohydride (6.16 g), and the mixture is refluxed. To the mixture is added a mixture of methanol (60 ml) and tetrahydrofuran (60 ml) under reflux over a period of five hours. After the reaction is complete, the mixture is concentrated under reduced pressure to remove the solvent, and methyl chloride are an aqueous sodium hydrogen carbonate solution are added to the residue. The methylene chloride layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is crystallized from isopropyl ether to give 1-(2-bromo-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (11.86 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:24])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(=O)=O.CC(C)=O>C1COCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:24])[C:14]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(C#N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2c(O)c3cc(Br)ccc3[nH]c2=O)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of methyl 5-bromo-2-(2-(4-cyanophenoxy)acetamido)benzoate (0.240 g, 0.617 mmol, Intermediate 2: step b) in THF (6.65 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5 M in toluene, 3.66 mL, 1.83 mmol) over 1.5 minutes, and the mixture was stirred for 5 minutes. The dry-ice/acetone bath was replaced with wet-ice bath and the reaction was stirred for 1.5 hours. The reaction was then quenched with water and ethyl acetate was added. The organic layer was removed and the aqueous layer was acidified with 2 N HCl (kept pH above 2). An off-white precipitate was formed which was filtered and the solid was dried overnight in the air and 1 hour in an oven at 40° C. to give the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CO.[C:14](#[N:17])[CH:15]=[CH2:16].Cl>O1CCOCC1>[C:14]([CH2:15][CH2:16][C:2]([CH2:16][CH2:15][C:14]#[N:17])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])#[N:17]
Reactant: C=CC#N
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(CCC#N)(CCC#N)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of diethyl malonate (81 g) in 100 g of 1,4-dioxane containing Triton B (10g of 40% methanol solution) was added dropwise acrylonitrile (55 g) in a period of 30 minutes. The reaction is highly exothermic, and the temperature was controlled at 30°-40° C. by means of a water bath. The reaction mixture was stirred overnight, and later poured into 600 ml of ice-water containing hydrochloric acid (5 ml of conc. HCl). The white precipitate formed was collected by filtration and washed with water. The crude product (m.p. 61°-63° C., 100% yield) was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].CS(C)=O.S(=O)(=O)=O.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1c(CO)ccn1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C=O)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To a mixture of [2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (6.35 g), dimethyl sulfoxide (50 mL) and triethylamine (25 mL) was added sulfur trioxide.pyridine complex (4.57 g), and the mixture was stirred at room temperature for 12 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give a white title compound (yield 5.27 g, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH:16][CH:17]=O)=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][NH2:30]>CC(O)=O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[Cl:22])[N:30]=[CH:17][N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: NNc1ccccc1Cl
Reactant: O=CNC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Solvent: CC(=O)O
Product: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 65.2 %

Procedure:
To a solution of 9-bromo-N-formyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (350 mg, 1.04 mmol) in HOAc (10 ml) was added (2-chlorophenyl)hydrazine hydrochloride (557 mg, 3.13 mmol) in one portion. The resulting mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in MeOH and purified by chromatography on silica gel (Hexanes:EtOAc=10:1-1:1) to give 9-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 65%). LCMS (ESI): m/z 443.7 (M+H+)
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O>CN(C=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCn1ccc([N+](=O)[O-])n1
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A solution of 3-nitropyrazole (22.6 g.) in dry DMF (25 ml.) was added dropwise over 30 minutes to a suspension of sodium hydride (5.28 g.) in dry DMF (50 ml.) at 0°. The mixture was stirred for 30 minutes, ethyl 3-bromopropionate (36.8 g.) was added over 10 minutes, the mixture was kept at -15° for 17 hours and then allowed to warm to 20°. Water (550 ml.) was added, the solution was extracted with EtOAc (4×100 ml.) and the combined extracts were dried (MgSO4) and evaporated in vacuo to an oil. Fractionation on a silica medium pressure liquid chromatography column eluted with EtOAc/petrol (b.p.60°-80°) 1:1 v/v gave ethyl 3-(3-nitropyrazol-1-yl)propionate (19.2 g.) as a low melting solid. The n.m.r. spectrum in CDCl3 included the following resonances: 7 6 (d, 1H); 6.85 (d, 1H); 4.5 (t, 2H); 4.1 (q, 2H); 2.95 (t, 2H); 1.2 (t, 3H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.CO[C:12](=O)[CH2:13][N:14]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[NH2:30][CH2:31][CH2:32][NH:33][S:34]([C:37]1[C:38]2[CH:39]=[CH:40][N:41]=[CH:42][C:43]=2[CH:44]=[CH:45][CH:46]=1)(=[O:36])=[O:35]>>[C:18]([O:17][C:15](=[O:16])[N:14]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:13][CH2:12][NH:30][CH2:31][CH2:32][NH:33][S:34]([C:37]1[C:38]2[CH:39]=[CH:40][N:41]=[CH:42][C:43]=2[CH:44]=[CH:45][CH:46]=1)(=[O:36])=[O:35])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C)OC(=O)N(CCNCCNS(=O)(=O)c1cccc2cnccc12)c1ccc(Br)cc1
Yield: 71 %

Procedure:
By following similar procedure as described in Example 1, DIBAL-H reduction of [(4-bromo-phenyl)-tert-butoxycarbonyl-amino]-acetic acid methyl ester (aqueous Rochelle's salt work-up) and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine product as a solid (71% yield). ESIMS: m/z 549 [(M+H)+, 79Br], 551 [(M+H)+, 81Br].
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:17](C=O)C.N>C1COCC1>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH2:17])=[O:6]
Reactant: O=C(O)CCC(F)(F)F
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)CCC(F)(F)F
Reaction time: 4 h

Procedure:
To a solution of 4,4,4-trifluorobutanoic acid (19.9 g) in THF (200 mL) were added oxalyl chloride (30.5 mL) and DMF (0.54 mL) at 0° C., and the mixture was stirred for 4 hr. The obtained reaction mixture was added to 28% aqueous ammonia (150 mL) at 0° C., and the mixture was stirred for 1 hr. The reaction mixture was filtration, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained solid was suspended in diisopropyl ether. The precipitate was collected by filtration, washed with diisopropyl ether, and dried to give the title compound (17.9 g) as a solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([C:17](=[O:27])[N:18]([CH3:26])[CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:26][N:18]([CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:17]([CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][CH2:9]1)=[O:27]
Reactant: CN1CCC(N(C)C(=O)C2CN(C(=O)OC(C)(C)C)c3ccccc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(N(C)C(=O)C2CNc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of 3-[Methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (C) (3.93 g, 10.53 mmol) in dichloromethane (20 cm3) was cooled to 0° C. in an ice/water bath and trifluoroacetic acid (10 cm3) added. The solution was stirred at 0° C. for 1 hr before warming to room temperature. The solution was made basic with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3×100 cm3). The organic layer was then dried over magnesium sulfate, filtered and evaporated under reduced pressure to afford the title compound (D) (2.79 g, 10.2 mmol, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4].[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OCC)(=O)C>[Br:11][CH2:10][C:8]1[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:6][CH:7]=1
Reactant: COC(=O)c1cc(C)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CBr)cs1

Procedure:
A stirred mixture of 4-methyl-2-thiophenecarboxylic acid methyl ester (0.252 g) (Coll. Czechoslov. Commun. 1958, 23, 452, Synth. Commun. 1994, 24, 1721) and N-bromosuccinimide (0.287 g) in benzene (20 ml) was irradiated under a 500 W halogen lamp for 2 hours. The mixture was diluted with ethyl acetate, washed with water and dried (MgSO4). The residue was evaporated and purified by chromatography eluting with 50% ethyl acetate in isohexane. Yield 0.29 g.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:19])[N:15]=[C:16]([CH3:18])[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[N:23]=[C:24]([CH3:27])[S:25][CH:26]=1>>[CH3:27][C:24]1[S:25][CH:26]=[C:22]([NH:21][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:19])[N:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[N:23]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cc(C)nn1C
Reactant: Cc1nc(N)cs1
Product: Cc1ccc(Nc2cc(C)nn2C)c(C(=O)Nc2csc(C)n2)n1

Procedure:
The title compound, was prepared from 3-(2,5-Dimethyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid ethyl ester and 4-Amino-2-methylthiazole in accordance with the general method of Example 78, step 2 to yield the final compound as a light-yellow solid, MS (ISP): m/e=343.0 (M+H+).
Reaction SMILES: [F:1][CH2:2][C:3](=[CH2:14])[CH2:4][N:5]([CH2:11][CH:12]=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9].O.[NH:16]([CH2:18]C(O)=O)[CH3:17]>C1(C)C=CC=CC=1>[F:1][CH2:2][C:3]12[CH2:4][N:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH2:11][CH:12]1[N:16]([CH3:18])[CH2:17][CH2:14]2
Reactant: C=C(CF)CN(CC=O)C(=O)OCC
Reactant: CNCC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2N(C)CCC2(CF)C1

Procedure:
9.1 g (43 mmol) of ethyl N-(2-fluoromethylallyl) -N-(2-oxoethyl)-carbamate are heated under reflux overnight in a water separator with 3.9 g (43 mmol) of powdered sarcosine in 170 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:14]([OH:16])=[O:15])=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+].CO>O.[Ni]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:14]([OH:16])=[O:15])=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1
Reactant: Cn1cc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cc(C(=O)O)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 26 h

Procedure:
12 g 6-nitro-1-methyl-1H-indole-3-carboxylic acid are dissolved in 500 ml of water, 60 ml 1 N sodium hydroxide solution and 30 ml of methanol. 1.2 g Raney nickel are added and the mixture is hydrogenated for 26 hours at 1.5 bar. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is suspended in 100 ml of pyridine. 16.3 g 3,5-dichlorophenylsulphonyl chloride are added and the mixture is stirred overnight at ambient temperature. The pyridine is eliminated in vacuo. The residue is divided between water and ethyl acetate and the pH is adjusted to 5 by the addition of citric acid. The aqueous phase is extracted 3 times with ethyl acetate and the combined organic phases are dried on magnesium sulphate. After elimination of the solvents the residue is chromatographed on silica gel (dichloromethane/methanol/acetic acid 95:5:1 to 89:10:1)
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([NH2:14])[CH:13]=1)(C)(C)C.[C:18]([O:22][C:23]([N:25]([CH2:34][C:35](O)=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:24])[N:25]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:34][C:35](=[O:36])[NH:14][C:12]1[CH:13]=[C:8]([CH2:7][OH:6])[CH:9]=[CH:10][C:11]=1[CH3:15])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(F)c(F)c1
Reactant: Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1N
Product: Cc1ccc(CO)cc1NC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Yield: 58.8 %

Procedure:
Prepared according to the method of Example 3b), from 5-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-phenylamine (2.0 g) and [tert-butoxycarbonyl-(3,4-difluorophenyl)-amino]-acetic acid (2.30 g) to give the sub-title product (1.9 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:35][CH2:36][C:37](Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:37]([CH2:36][Cl:35])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 190.4 %

Procedure:
To a stirred solution of 7-(benzyloxy)-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (51.2 g, 0.141 mol) and triethylamine (39.94 g, 0.395 mol) in dichloromethane (410 mL) at 0° C. was added a solution of chloroacetyl chloride (8.67 g, 76.80 mmol) in dichloromethane (40 mL) drop wise by addition funnel. The reaction was stirred at ambient temperature for 17 hours then heated to reflux for 6 hours. The crude mixture was cooled to ambient temperature and partitioned between water and dichloromethane (200 mL). The layers were separated and the aqueous layer extracted with dichloromethane (2×300 mL). The organic layers were combined, washed with brine (2×300 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide 7-(benzyloxy)-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (61.7 g) as a brown solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[I:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:14][CH2:15][N:16]([C:24]([C:23]4[CH:27]=[CH:28][C:20]([I:19])=[CH:21][CH:22]=4)=[O:25])[CH2:17][CH2:18]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 90.9 %

Procedure:
Using 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (5.52 g) described in Preparation Example 88 and 4-iodobenzoyl chloride (6.35 g) and by the reaction and treatment in the same manner as in Preparation Example 114, the title compound (9.76 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)[CH3:22]>>[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:8]1[C:7]2[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1)[CH3:22]
Reactant: CCOc1ccccc1B(O)O
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: CCOc1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Yield: 74 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-ethoxybenzeneboronic acid according to the procedure described in example 8 gave 4-(2-ethoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (504) (I; Ar=2-ethoxyphenyl) in a 74% yield; mp (THF/CH2Cl2/hexane) 190–193° C. (dec). 1H NMR [(CD3)2SO] δ 11.71 (br s, 1H), 10.91 (br s, 1H), 9.23 (s, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.38 (td, J=7.8, 1.7 Hz, 1H), 7.33 (dd, J=7.5, 1.7 Hz, 1H), 7.07 (br d, J=6.7 Hz, 1H), 7.05 (dd, J=8.7, 2.3 Hz, 1H), 7.02 (dd, J=7.3, 6.6 Hz, 1H), 3.97 (q, J=6.7 Hz, 2H), 1.11 (t, J=6.9 Hz, 3H). Found: C, 70.63; H, 4.74; N, 6.88. C22H16N2O4.1/4 THF requires C, 70.76; H, 4.65; N, 7.18.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1>CN(C=O)C>[C:23]1([CH2:22][N:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][N:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:5][C:4]3=[O:12])[CH2:17][CH2:18]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: ClCCN1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Cc2ccccc2N1CCN1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Yield: 39 %

Procedure:
Sodium hydride (80% dispersion in mineral oil, 250 mg) was added to a solution of 1,3-dihydro-2H-indol-2-one (1.12 g) in dry DMF (5 ml at 0° C. The mixture was allowed to warm to room temperature and after 50 minutes a solution of 1-(2-chloroethyl)-4-(phenylmethyl)piperazine (2.02 g) in dry DMF (6 ml) was added. The reaction mixture was then heated at 80° C. for 2 hours and then evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on silica gel to afford the title compound (1.1 g, 40%) as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[C:17]([CH2:23]Br)[CH:16]=1>CN(C)C(=O)C.CCOCC>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:23]2
Reactant: BrCc1ccc(Br)cc1CBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (440 mg, 60% dispersion in mineral oil, 11 mmol) in N,N-dimethylacetamide (24 mL) was added, dropwise, a solution of p-toluenesulfonamide (1.45 g, 8.5 mmol) in N,N-dimethylacetamide (8 mL) over about 5 min. The frothy solution was stirred for 1 hr at room temperature then heated to 60° C. and stirred at this temperature for 0.5 hr. To this mixture was added, dropwise a solution of 4-bromo-1,2-bis(bromomethyl)benzene (2.9 g 8.4 mmol) in N,N-dimethylacetamide (6 mL). The resulting mixture was stirred for 1 hr then cooled to room temperature and stirred for 17 hr. The mixture was then diluted with ether, washed with water (2×) then brine, dried over sodium sulfate and concentrated. The residue was triturated with ethyl acetate and filtered to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([O:7][CH3:8])[C:3](Cl)=[N:4][OH:5].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]([CH3:9])([O:7][CH3:8])[C:3]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[N:4][OH:5]
Reactant: c1c[nH]cn1
Reactant: COC(C)(C)C(Cl)=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(C)(C)C(=NO)n1ccnc1
Yield: 85.2 %

Procedure:
A solution of 9.9 g (0.066 mol) of 2,2-dimethyl-2-methoxy-1-chloro-1-oximino-ethane is very slowly added dropwise to a mixture of 9.0 g (0.132 mol) of imidazole and 6.7 g (0.066 mol) of triethylamine in 50 ml of absolute tetrahydrofuran at 0° C., with stirring. The mixture is allowed to come to room temperature and is subsequently stirred for 10 hours. The reaction batch is filtered, the filtrate is concentrated and the concentrate is diluted with water. The product which has precipitated is filtered off with suction, washed with petroleum ether and dried. 10.3 g of 2,2-dimethyl-2-methoxy-1-(imidazol-1-yl)-1-oximino-ethane of melting point 155°-160° C. are obtained, that is to say 85% of theory. Intermediate: ##STR65##
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:27].[Na+].O>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH:18]([C:3]1[CH:2]([OH:1])[CH2:6][C:5](=[O:7])[C:4]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:27]
Reactant: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CCCCCCC1=C(C=O)C(O)CC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 13.5 parts of dl-methyl 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoate, 17.8 parts of sodium periodate, 55 parts of water, 160 parts of dioxane and 2 parts by volume of a 2% osmium tetroxide in dioxane solution is stirred at room temperature under nitrogen for about 4 hours. The reaction mixture is extracted with ether and the ether solution is dried over anhydrous sodium sulfate, then concentrated to dryness under reduced pressure. The resulting residue is purified by dry column chromatography on silica gel containing 8% of water, using 50% ethyl acetate in benzene, thus affording dl-methyl 2-formyl-3-hydroxy-5-oxocyclopent-1-eneheptanoate, characterized by an ultraviolet absorption maximum at about 228 millimicrons with a molecular extinction coefficient of about 10,200.