Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27])=[CH:14][CH:13]=1.O>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:2][OH:3])=[O:27])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCCCCCCCC(=O)Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCCCCCCCC(=O)NO)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a cold stirring suspension of 1 gm hydroxylamine hydrochloride and 1.3 gm sodium carbonate in 25 ml CH2Cl2 was added dropwise 1.58 gms 9(4-methoxyphenyl)nonanoyl chloride over a period of 15 min. The mixture was then stirred in the cold for a further 45 min, then 1.5 ml H2O was added, the mixture was allowed to warm up to room temperature, and stirring was continued for 72 hrs. The precipitated solid was filtered, washed with water, and crystallized twice from CH2Cl2 to give A. The filtrate from the reaction mixture was evaporated in vacuo to give a granular solid which was also crystallized twice from CH2Cl2 to give B. A and B were shown to be the same by spectral comparison. Total yield (A+B)=1.58 gm (51%) m.p. 96°-98° C. Elemental analysis: calculated C 67.90, H 8.90, N 4.95. Found C 67.96, H 9.08, N 4.95 (calculated for 0.2 moles H2O).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.CI.[C:28](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C(=O)/C=C/c2cn(C)c3ccccc23)cc(OC)c1OC
Yield: 81.6 %

Procedure:
Compound 1 (1.0 g) obtained in Example 1 was dissolved in acetone (50 ml), and methyl iodide (1.42 g) and potassium carbonate (1.0 g) were added thereto, followed by heating under reflux for 72 hours. Insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate (20 ml) in a condition of heating under reflux, and insoluble matters were filtered off. Hexane (25 ml) was added to the filtrate, and the precipitated crystals were collected by filtration to give Compound 2 (0.85 g).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:19][CH:20]([F:24])[C:21](F)=[O:22]>C1(C)C=CC=CC=1>[F:19][CH:20]([F:24])[C:21](=[O:22])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(F)C(F)F
Reactant: COC(=O)C=CN1CCCCC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
Methyl 3-piperidin-1-ylacrylate (99%, 8.7 g, 51 mmol) and pyridine (4.26 g, 54 mmol) was initially charged in toluene (150 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (10 g, 61 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (200 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. This gave methyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 12.0 g; purity according to GC: 97.7%; yield: 93.2%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.CCN(CC)CC.[C:39](Cl)(=[O:47])[O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:12]([C:11]1[CH:15]=[CH:16][C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:39](=[O:47])[O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:3]2)=[N:9][C:10]=1[NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:23]=1)(=[O:13])[NH2:14]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)Oc3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
To a suspension of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (140 mg, 0.330 mmol) and Et3N (0.069 mL, 0.495 mmol) in CH2Cl2 (3 mL) was added phenyl carbonochloridate (51.6 mg, 0.330 mmol) at 0° C. and stirred for 10 min. The reaction mixture was quenched with satd. NaHCO3, extracted with CH2Cl2, separated, and concentrated. The residue was purified (ISCO, 100% ethyl acetate, 12 g silica gel column) to obtained 93 mg of (R)-phenyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate as a white solid. LCMS: (M+H)+=545.31. 1H NMR (400 MHz, CDCl3) δ ppm 11.20 (1H, s), 7.69 (2H, d, J=8.79 Hz), 7.50 (1H, d, J=8.79 Hz), 7.31-7.39 (4H, m, J=7.91, 7.91 Hz), 7.19 (1H, t, J=7.47 Hz), 7.08 (2H, d, J=7.47 Hz), 6.10 (1H, d, J=8.79 Hz), 5.64 (1H, s), 5.35 (1H, d, J=7.47 Hz), 5.30 (1H, s), 4.03 (1H, dd, J=12.96, 2.86 Hz), 3.78-3.91 (1H, m), 3.64 (7H, s), 3.38-3.53 (2H, m), 1.98-2.12 (1H, m), 1.76-1.87 (1H, m), 1.63-1.76 (1H, m), 1.19-1.34 (1H, m).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:9]Cl)[CH2:3][CH2:2]1.[C-:18]#[N:19].[Na+]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:9][C:18]#[N:19])[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:3][CH2:2]1
Reactant: FC(F)Oc1ccc(CCl)cc1OCC1CC1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To 3-cyclopropylmethoxy-4-difluoromethoxybenzyl chloride (26 g) in dimethylflormamide (150 mL) under an argon atmosphere was added sodium cyanide (9.7 g, 198 mmol). The resulting mixture was stirred at room temperature and heated gently for 2 h, then cooled and concentrated. The mixture was partitioned between basic brine and ether and extracted twice. The organic extract was washed with brine and was dried (sodium sulfate). The solvent was removed in vacuo to provide an orange-brown oil (24 g), which was used without purification.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2].[CH2:15]([Mg]Br)C>>[CH2:11]([C:6]1[NH:7][C:8]([C:9]#[N:10])=[C:4]([C:1](=[O:3])[CH2:2][CH3:15])[N:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Reactant: CC[Mg]Br
Product: CCCCc1nc(C(=O)CC)c(C#N)[nH]1
Yield: 51.9 %

Procedure:
Following a procedure similar to that described in Preparation 24(i), but using ethylmagnesium bromide instead of methylmagnesium bromide, the title compound, melting at 84°-85° C., was obtained in a 51.9% yield.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([S:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[OH-].[K+]>C(O)C.O>[CH:14]1([S:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=2)[C:3]([OH:19])=[O:2])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A solution of rac-cyclopentylsulfanyl-(3,4-dichloro-phenyl)-acetic acid methyl ester (50 mg, 0.16 mmol) in ethanol (3 mL) at 25° C. was treated with a solution of potassium hydroxide (44 mg, 0.79 mmol) in water (1 mL) and the mixture was stirred at 25° C. After 3 h, the reaction was diluted with water and evaporated under reduced pressure. The concentrate was acidified to pH 2 with art aqueous solution of 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) to afford rac-cyclopentylsulfanyl-(3,4-dichloro-phenyl)-acetic acid (43 mg, 90% yield) as a colorless oil: EI-HRMS m/e calcd for C13H14Cl2SO2 (M+) 304.0091, found 304.0101.
Reaction SMILES: ClC1C=CC=CC=1N1C(C2C=CC(S(C)(=O)=O)=CN=2)=NN=C1C=CC1[O:29][C:28]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)=[N:27][N:26]=1.NN.O>CO>[C:34]([C:33]1[CH:32]=[CH:31][C:30]([C:28]([NH:27][NH2:26])=[O:29])=[CH:37][CH:36]=1)#[N:35]
Reactant: CS(=O)(=O)c1ccc(-c2nnc(C=Cc3nnc(-c4ccc(C#N)cc4)o3)n2-c2ccccc2Cl)nc1
Agent: NN
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-Cyano-benzoic acid methyl ester 1 (1.0 g, 13 mmol) in 30 mL of MeOH was added 3 mL of H2NNH2.H2O. The mixture was stirred at ambient temperature for 16 h. The solid was collected and washed with CH3OH to give 4-Cyano-benzoic acid hydrazide 2 as a solid. Yield: 0.8 g, 80%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[Br:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>CN(C)C=O>[Br:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])=[CH:21][C:17]=1[C:18]([N:10]1[C:11](=[O:12])[C:6]2=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]2[C:8]1=[O:9])=[O:19]
Reactant: O=C(Cl)c1cc(Oc2ccc(Br)cc2[N+](=O)[O-])ccc1Br
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Oc2ccc(Br)cc2[N+](=O)[O-])ccc1Br)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of 4-nitrophthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-bromo-5-(2-nitro-4-bromophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-bromo-5-(2-nitro-4-bromophenoxy)benzoyl]-4-nitrophthalimide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][CH:12]=1)=[O:9].[Br:21]NC(=O)CCC(N)=O>C(#N)C>[Br:21][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[NH:10][C:8]([NH:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: NC(=O)CCC(=O)NBr
Reactant: O=C(Nc1cnccn1)Nc1ccnc2ccccc12
Solvent: CC#N
Product: O=C(Nc1cnccn1)Nc1c(Br)cnc2ccccc12
Yield: 79 %

Procedure:
1-(Pyrazin-2-yl)-3-(quinolin-4-yl)urea (220 mg, 0.754 mmol) was dissolved in acetonitrile (3 mL) and N-bromosuccinamide was added (201 mg, 1.13 mmol). The resulting solution was heated at 80 C under microwave irradiation for 35 mins. The cooled solution was then partitioned between NaHCO3 solution and dichloromethane. The organic layer was separated, dried (MgSO4), filtered and concentrated to give the product. Yellow solid. Amount 204 mg. Yield 79%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]=[O+][O-]>CO.ClCCl>[C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC1(C(=O)OC(C)(C)C)CC1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CC=O)CC1

Procedure:
A solution of 5.7 g (31.3 mmol) of 1-allyl-cyclopropanecarboxylic acid tert-butyl ester in 50 mL methanol and 50 mL dichloromethane under nitrogen was taken to −78° C. where ozone was bubbled in for 1 hour. Nitrogen was bubbled in until the familiar blue color dissipated. Three drops of pyridine followed by 2 mL of dimethyl sulfide were added and the cooling bath removed. After 2 hours the reaction was poured into aqueous saturated ammonium chloride solution, extracted with dichloromethane, dried and concentrated to deliver a quantitative yield of the desired aldehyde as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[CH2:24]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][N:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:36]([C:35]1[CH:34]=[N:33][C:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:40][CH:39]=1)=[O:37])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: O=C(O)c1ccc(OCc2ccccc2)nc1
Product: CCOC(=O)C(C(=O)c1ccc(OCc2ccccc2)nc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1

Procedure:
The title compound, a colorless oil (1.5 g, 62%), was prepared in analogy to intermediate 8A by reaction of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) with 6-(benzyloxy)nicotinic acid. MS: 543.2 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][OH:12])[N:5]=1)(=[O:3])[CH3:2].[C:13](Cl)([Cl:15])=[O:14]>ClCCl.C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][O:12][C:13]([Cl:15])=[O:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)n(CCO)n1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C)n(CCOC(=O)Cl)n1
Reaction time: 1.5 h

Procedure:
3-Acetyl-1-(2-hydroxyethyl)-5-methylpyrazole (505 mg, prepared as described in Example 12, Preparation 1) in dry dichloromethane (5 ml) under an atmosphere of argon was treated with a solution of phosgene in toluene (12.5% w/w, 5.22 ml) and the mixture stirred for 1.5 h. The solvents were then removed, dichloromethane was added and removed using a rotary evaporator to give 3-acetyl-1-[2-(chlorocarbonyloxy)ethyl]-5-methylpyrazole; νmax (CH2Cl2) 1777 and 1684 cm-1.
Reaction SMILES: [N:1]([C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[N+:2]=[N-:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:9][C@H:5]1[C@H:4]([N:1]=[N+:2]=[N-:3])[NH:7][C:6]1=[O:8]
Reactant: [N-]=[N+]=N[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=N[C@@H]1NC(=O)[C@H]1N

Procedure:
To a solution 1.3 g of (3S,4S)-4-azido-3-tritylamino-2-oxoazetidine in 15 ml of acetone is added 0.736 g of p-toluenesulfonic acid monohydrate. The mixture is treated in a same manner to Reference Example 45B to give 0.886 g of tosyl salt of (3S,4S)-3-amino-4-azido-2-oxoazetidine.
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:4]2[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[C:10]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:23]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN1C(=O)CCC1>[CH3:22][C:17]1[C:16]([C:10]2[C:11]([O:14][CH3:15])=[CH:12][C:13]3[C:4]4[N:3]([C@@H:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH3:25])[C:2]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[N:23][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: C1CCNCC1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n([C@H](C)c3ccccc3)c12
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N3CCCCC3)n([C@H](C)c3ccccc3)c12
Temperature: 150 °C
Yield: 53.6 %

Procedure:
2-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline (30 mg, 0.069 mmol) (for a preparation see Intermediate 12) was dissolved in NMP (0.5 ml), piperidine (0.2 ml, 2.020 mmol) was added and the mixture was heated at 150° C. for 30 min, then cooled, added to water (10 ml) and extracted with EtOAc (10 ml). The solvent was washed with water (2×10 ml), dried and evaporated. The residue was dissolved in DCM (2 ml), loaded onto a 10 g silica column, eluted with 2M methanolic ammonia/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-2-(1-piperidinyl)-1H-imidazo[4,5-c]quinoline (18 mg, 0.037 mmol, 53.9% yield) as a amber solid. LCMS (formate) Rt 1.05 min, MH+ 482
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=[CH:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1)=[CH:6]2.[C:26]1(=[O:32])[NH:30][C:29](=[O:31])[CH:28]=[CH:27]1>>[N+:20]([C:18]1[CH:19]=[C:14]([CH:13]2[CH:28]3[C:29](=[O:31])[NH:30][C:26](=[O:32])[CH:27]3[C:6]3[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[CH2:12]2)[CH:15]=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1)([O-:22])=[O:21]
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc2[nH]c(C=Cc3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)cc2c1
Product: COc1ccc2[nH]c3c(c2c1)C1C(=O)NC(=O)C1C(c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C3
Yield: 89 %

Procedure:
The reaction of 5-Methoxy-2-[2-(3,5-dinitrophenyl)ethenyl]-1H-indole (II; Ar=3,5-dinitrophenyl) (40) prepared as described in example 46 with maleimide using the procedure described in example 69 gave 4-(3,5-Dinitrophenyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H,3aH)-dione (IV; Ar=3,5-dinitrophenyl, R10═H) (41) in a 89% yield as a glassy solid which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)[CH:22]=[C:21]([CH3:29])[N:20]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][C:25]([C:23]3[CH:24]=[C:19]([CH3:18])[N:20]=[C:21]([CH3:29])[CH:22]=3)([OH:26])[CH3:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1cc(C2(C)CO2)cc(C)n1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cc(C)nc(C)c2)CCN(C)C1
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF and sodium hydride (120 mg, 3 mmol) was added. The reaction mixture was stirred for 10 min and 2,6-dimethyl-4-(2-methyloxiran-2-yl)pyridine (210.6 mg, 1.3 mmol) was added dropwise to it with constant stirring. The reaction mixture was stirred at RT overnight. The reaction mixture was poured on crushed ice and the precipitate obtained was filtered under vacuum; washed with water and hexane to obtain 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(2,6-dimethylpyridin-4-yl)propan-2-ol (260 mg), which was dissolved in DCM (3 mL) and cooled to 0° C. Thionylchloride (3 mL) was added dropwise to it and the reaction mixture cooled to RT. The reaction mixture was stirred at RT for 2 h. Thionylchloride was evaporated under vacuum by azeotropic distillation with DCM. 1N NaOH solution was added to basify (pH-12-13) the reaction mixture and extracted with EtOAc (40 mL×2). The organic layer was concentrated under vacuum to get the desired product. The crude compound was further purified through reverse phase HPLC. Yield: 13 mg (HCl salt). 1H NMR (CD3OD, D1-HCl salt) δ (ppm): 8.0 (s, 2H), 7.70 (s, 1H), 7.30 (s, 1H), 7.10 (s, 2H), 4.76 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.28 (m, 1H), 3.20 (m, 1H), 3.16 (s, 3H), 2.80 (s, 6H), 2.42 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([OH:19])=[O:18].O>CN(C)C=O>[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([O:19][CH3:5])=[O:18]
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)cc(OC)cc1OC
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Dimethyl sulfate (1.04 ml, 11.0 mmol) was added dropwise to a mixture of potassium carbonate (3.34 g, 24.2 mmol) and 2-amino-4,6-dimethoxybenzoic acid (2.56 g, 11.0 mmol) in dimethylformamide (70 ml) at 0° C. The reaction was stirred for 1 hour, then poured into water. The resulting precipitate was filtered, washed with water and dried in vacuo. The filtrate was extracted with ethyl acetate, and the combined organic extracts were dried (magnesium sulphate) and concentrated in vacuo. The combined solids were dried in vacuo to yield methyl 2-amino-4,6-dimethoxybenzoate (1.8 g, 77% yield) as a yellow crystalline solid:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH3:5].Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2>>[Br:1][C:2]1[CH:8]=[C:9]2[C:5](=[CH:4][CH:3]=1)[N:12]([CH2:13][CH2:14][CH2:15][CH3:7])[CH:11]=[CH:10]2
Reactant: CCCCBr
Reactant: Brc1ccc2[nH]ccc2c1
Product: CCCCn1ccc2cc(Br)ccc21

Procedure:
The title compound was prepared from 1-bromobutane (11 mL, 101 mmol) and 5-bromoindole (20 g, 101 mmol) in substantially the same manner, as described in Step 1 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 252. 1HNMR (300 MHz, DMSO-d6): δ 7.71 (d, 1H, J=1.9 Hz), 7.46 (d, 1H, J=8.7 Hz), 7.42 (d, 1H, J=3.1 Hz), 7.22 (dd, 1H, J=6.7 Hz and J=2.0 Hz), 6.40 (d, 1H, J=3.1 Hz), 4.15 (t, 2H, J=7.0 Hz), 1.70 (q, 2H, J=7.0 Hz), 1.19 (h, 2H, J=7.47 Hz), and 0.85 ppm (t, 3H, J=7.47 Hz).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]([CH2:23][C:24]([OH:26])=[O:25])([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:11][CH2:10]2.[CH3:27]O>>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:18][C:19]([F:20])([F:21])[F:22])[CH2:11][CH2:10]2
Reactant: O=C(O)CC1(CC(F)(F)F)CCc2cc(O)ccc2C1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1(CC(F)(F)F)CCc2cc(O)ccc2C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
Sulfuric acid (2 mL) was added to a solution of 1E (8.5 g, 28.1 mmol) in methanol (80 mL), and the mixture was stirred at 80° C. for 3 h. Methanol was removed from reaction mixture under reduced pressure, and the residue was diluted with ethyl acetate and extracted with saturated NaHCO3 solution and brine solution. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (8.5 g, 91%) as a syrup. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 6.75 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 6.65 (s, 1H), 3.57 (s, 3H), 3.05-2.78 (m, 4H), 2.73-2.55 (m, 2H), 2.32 (m, 1H), 2.09 (m, 1H). ESI-MS m/z: 317 (M+H)+.