Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17](N)=[O:18])=[CH:11][CH:10]=1.Cl.C(O)(=[O:24])C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17]([OH:24])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(=O)O
Reactant: CC(CC(N)=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A mixture of 1 g. of 3-(2',4'-difluoro-4-biphenylyl)butyramide, 2 ml. of concentrated hydrochloric acid and 2 ml. of acetic acid is heated under reflux for 48 hours and, after addition of water, is worked up in the customary manner to give 3-(2' ,4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from (4-chloro-5-isobutylamino-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example C4) (1.93 g, 5.61 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a brown solid (1.30 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:5]([CH3:7])=O.[C:19]1(=[O:40])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:34])/[CH:30]=[C:31](\[NH2:33])/[CH3:32])[C:22](=[O:35])[C:21]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:20]12>C(O)C>[CH3:7][C:5]1[NH:33][C:31]([CH3:32])=[C:30]([C:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[C:19](=[O:40])[C:20]3=[CH:39][CH:38]=[CH:37][CH:36]=[C:21]3[C:22]2=[O:35])=[O:34])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Reactant: C/C(N)=C/C(=O)OCCCCN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCN2C(=O)c3ccccc3C2=O)C1c1ccccc1[N+](=O)[O-]

Procedure:
13.7 g (55 mmol) of 2-(2-nitrobenzylidene)-acetoacetic acid methyl ester and 16.6 g (55 mmol) of 3-aminocrotonic acid-(4-phthalimido-butyl)ester are boiled in 150 ml of ethanol for 18 hours. The orange yellow oil (28.7 g-98%) obtained after removal of the solvent by evaporation under vacuum is used for further reactions without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20].O>CC(C)=O>[CH2:20]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)[CH:19]=[CH2:18]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc(C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of 15.0 g (98.6 mmol) of methyl p-hydroxybenzoate and 13.0 g (94.1 mmol) of potassium carbonate mixed in 150 ml of acetone were added 13 ml (150 mmol) of allyl bromide and the whole was stirred at 80° C. for 2 hours under an argon gas atmosphere. Water was added to the solution and the whole was extracted with ethyl acetate. Then, the organic phase was washed with 5% aqueous solution of sodium hydroxide and saturated saline solution. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 18.6 g of methyl p-allyloxybenzoate (11) (yield: 96.6%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[Na+].[Na+].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]1([C:2]2[NH:3][C:4]3[C:9]([C:10]=2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)Cc1c(Br)[nH]c2ccccc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a solution of 2.0 g (7.1 mmol) of ethyl (2-bromoindol-3-yl)acetate in 40 ml of dioxane was added under argon 1.2 g (0.11 mmol) of Pd(PPh3)4 and 13.3 ml of 2.0 M sodium carbonate. After stirring at room temperature for ca. 15 min, 1.3 g (11 mmol) of benzeneboronic acid was added, and the mixture was heated at 80° C. under argon overnight. The mixture was cooled to room temperature and solids were removed by filtration. The filtrate was concentrated and chromatographed on silica gel with toluene as an eluent to yield 1.6 g (81%) of the 2-phenyl indole as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([OH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=O)=[C:4]([F:19])[CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH:9]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:17])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:19]
Reactant: O=S(Cl)Cl
Reactant: O=C1C2=C(CCCC2)C(O)N1c1ccc(Cl)cc1F
Solvent: ClCCl
Product: O=C1C2=C(CCCC2)C(Cl)N1c1ccc(Cl)cc1F
Yield: 87 %

Procedure:
In 30 ml of dichloromethane was suspended 21.0 g of 2-(4-chloro-2-fluorophenyl)-3-hydroxy-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one, and 7.5 ml of thionyl chloride was added to the suspension under stirring over a 20-minute period. The reaction mixture was warmed, stirred at 40° to 45° C. for 1 hour and concentrated to dryness under reduced pressure. The residue was dissolved in methylene chloride and, upon addition of hexane, there was produced insoluble matter, which was filtered out. The filtrate was concentrated to dryness under reduced pressure, thereby affording 19.5 g (yield of 87%) of crystals of the subject compound. Recrystallization from cyclohexane yielded white crystals, m.p. 89°-90° C.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH3:13])[C:3]1=[O:14].C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.ClCCl>[C:22]([O:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH3:13])[C:3]1=[O:14])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCN1C(=O)C(O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C

Procedure:
To a flame dried flask cooled under argon was added the crude 3-hydroxy-1-propylindolin-2-one (0.1 grams, 0.52 mmol) and DMAP (0.007 grams, 0.057 mmol). This was taken up in 5.0 mL of dichloromethane. While stirring at room temperature triethyl amine (78 μL, 0.57 mmol) was added followed by benzoyl chloride (67 μL, 0.57 mmol). The reaction stirred at room temperature until all of the starting material had been consumed. Once complete, the reaction was diluted with water, and the two layers separated. The aqueous layer was washed with dichloromethane twice. The combined organic solution was dried with sodium sulfate, filtered, and concentrated. Chromatography on silica gel using Hexanes/Ethyl acetate (8:2) afforded the desired compound. Yield, 67% for the two steps. 1H-NMR δ 8.11 (d, 2H), 7.58 (dd, 1H), 7.44 (m, 3H), 7.36 (t, 1H), 7.05 (t, 1H), 6.89 (d, 1H), 6.19 (s, 1H), 3.72 (m, 2H), 1.77 (m, 2H), 1.03 (t, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:9][CH2:8]1.C(N(CC)CC)C.[F:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:32])[F:31])[C:25]=1[C:33](Cl)=[O:34]>O1CCCC1>[CH:7]1([N:6]([CH2:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[Si:2]([CH3:15])([CH3:14])[CH3:1])[C:33]([C:25]2[C:26]([CH:30]([F:32])[F:31])=[N:27][N:28]([CH3:29])[C:24]=2[F:23])=[O:34])[CH2:8][CH2:9]1
Reactant: C[Si](C)(C)c1ccccc1CNC1CC1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nc(C(F)F)c(C(=O)N(Cc2ccccc2[Si](C)(C)C)C2CC2)c1F
Yield: 66.1 %

Procedure:
To 175 mg (0.80 mmol) of N-[2-(trimethylsilyl)benzyl]cyclopropanamine in 5 ml of dry tetrahydrofurane was added 0.234 ml (1.68 mmol) of triethylamine, followed by a solution of 187 mg (0.88 mmol) of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride in 3 ml of tetrahydrofurane. The reaction mixture was stirred under reflux for 3 hours. After cooling down, the reaction mixture was filtered, and the filtrate was evaporated under vacuum. The residue was dissolved in ethyl acetate/water. The aqueous phase was further extracted with ethyl acetate. The combined organic phase were dried and evaporated under vacuum to give 209 mg of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:21])[CH2:17][N:18]([CH3:20])[CH3:19])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1>CN1CCCC1=O.[OH-].[Na+]>[CH3:19][N:18]([CH3:20])[CH2:17][C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:31]([C:30]4[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=4)=[O:32])[CH:24]=[CH:23][CH:22]=3)=[N:11][N:10]2[CH:12]=1)=[O:21]
Reactant: CN(C)CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)CN(C)C)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-N2,N2-dimethylglycinamide (196 mg, 0.6 mmol) in N-methylpyrrolidone (5.0 mL) was added 1,3-dimethylpyrazole-5-carbonyl chloride (270 mg, 1.7 mmol), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→460/40) and precipitated from ethyl acetate to give the title compound (131 mg, 49%) as a white powder. melting point 210° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][CH2:29][CH2:30][C:31]4[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: NCCc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: Oc1cccc(CCNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)c1

Procedure:
Intermediate 7 was coupled with 3-(2-amino-ethyl)-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 390. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.8 (m, 5H) 8.4 (d, 1H) 7.4 (m, 2H) 7.3 (m, 1H) 7.0 (d, 1H) 6.9 (m, 1H) 3.7 (m, 2H) 3.4 (m, 1H) 3.1 (m, 2H) 2.9 (m, 3H) 2.1 (m, 1H) 1.8 (m, 2H) 1.5 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[I:9].[F:10][C:11]([F:23])([F:22])[C:12]1[N:17]=[C:16]([CH3:18])[C:15]([C:19](Cl)=[O:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19]([C:15]2[C:16]([CH3:18])=[N:17][C:12]([C:11]([F:23])([F:10])[F:22])=[CH:13][CH:14]=2)=[O:20])=[CH:4][C:3]=1[I:9]
Reactant: Nc1ccc(Cl)c(I)c1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(I)c1

Procedure:
Procedure D was performed with 4-chloro-3-iodoaniline (225 mg, 0.889 mmol) and 6-(trifluoromethyl)-2-methylpyridine-3-carbonyl chloride (237 mg, 0/93 mmol, 1.05 eq) at 0° C. for 30 minutes. The crude residue was purified by silica gel chromatography (2-50% ethyl acetate/hexanes) to yield N-(4-chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])/[CH:10]=[CH:11]/[C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:26][N:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:33]([N:27]1[CH2:28][C@@H:11]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])[CH2:26]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)c1ccccc1/C=C/C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a solution of (E)-ethyl 2-(3-(benzyloxy)-3-oxoprop-1-enyl)benzoate (1.44 g, 4.64 mmol)) in 20 mL of CH2Cl2 was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.78 mL, 6.96 mmol) and trifluoroacetic acid (0.072 mL, 0.93 mmol). The solution was allowed to stir at ambient temperature for 18 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.5 g, 2.1 mmol) and trifluoroacetic acid (2 drops) were added and the reaction was stirred at ambient temperature for 1 h. The reaction was evaporated and purified by ISCO (elution with 0-30% EtOAc/hexane) to afford 1.97 g (95%) of the title compound as an oil. LRMS (ES)+: 444.3 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:2].[C:11]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([O:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=1)=[O:16])([CH3:14])([CH3:13])[CH3:12].CN(C)C1C=CC=CC=1>C(#N)C>[C:11]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([O:24][C:25](=[O:26])[N:4]([CH2:3][C:1]#[N:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:21]=[CH:22][CH:23]=1)=[O:16])([CH3:14])([CH3:12])[CH3:13]
Reactant: N#CCNc1ccccc1
Reactant: CC(C)(C)C(=O)Nc1cccc(OC(=O)Cl)c1
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(OC(=O)N(CC#N)c2ccccc2)c1
Temperature: 0 °C

Procedure:
Into a solution of 13.2 g N-cyanomethylaniline in 150 ml acetonitrile is added 25.57 g chloroformic acid-[3-(tert.-butylcarbonylamino)-phenyl]-ester, then with further stirring 12.1 g N,N dimethylaniline is added dropwise and the mixture heated for an additional 15 minutes to boiling. The mixture is stirred after cooling in 1 l ice water, the substance which separates out is taken up and after drying in vacuum is recrystallized from a little acetonitrile.
Reaction SMILES: C([N:8]1[C:20]2[C:19]([OH:21])=[C:18]3[N:22](C(OC(C)(C)C)=O)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:37])[CH:13]=2)(OC(C)(C)C)=O.Br[CH2:39][CH2:40][CH2:41][NH:42]C(=O)OC(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[F:37][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:20]1[C:19]([O:21][CH2:39][CH2:40][CH2:41][NH2:42])=[C:18]3[NH:22][C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=4[C:17]3=[CH:16][C:15]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: NCCCOc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of 5,7-diBOC-2,10-difluoro-6-hydroxyindolo[2,3-b]carbazole (4.03 g, 8.0 mmol), tert-butyl 3-bromopropylcarbamate (2.20 g, 9.2 mmol), and Cs2CO3 (10.0 g, 31 mmol), and anhydrous MeCN (120 mL) was heated at 100° C. under Ar until the starting material disappeared (˜2 h). After cooled to RT, the inorganic salt was removed by filtration, washed with dichloromethane, and the combined filtrate was concentrated. The resulting residue 3-(2,10-difluoro-5,7-diBOC-indolo[2,3-b]carbazol-6-yloxy)propan-1-amine was dissolved in CH2Cl2 (100 mL). TFA (10 mL) was added and the solution was stirred at RT overnight. After evaporation, the residue was subjected to chromatography on silica gel, eluting with ethyl acetate/hexane/MeOH (10% cNH3.H2O) (50/50/10-100/0/10), giving 2.35 g (82%) of 3-(2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)propan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ 11.8 (br s, 2H), 8.56 (s, 1H), 7.89 (dd, J=9.4, 2.6 Hz, 2H), 7.44 (dd, J=8.6, 4.6 Hz, 2H), 7.17 (td, J=9.2, 2.4 Hz, 2H), 4.36 (t, J=6.2 Hz, 2H), 2.97 (t, J=6.2 Hz, 2H), 1.98 (pentalet, J=6.2 Hz, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.N1C=CC=CC=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>O1CCCC1>[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)=[O:19]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C(=O)n1cnc2ccccc21)c1ccccc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1H-benzo[d]imidazole (354 mg, 3 mmol) in tetrahydrofuran (15 ml) was added pyridine (0.367 ml, 4.50 mmol) followed by addition of methyl(phenyl)carbamic chloride (534 mg, 3.15 mmol). The reaction was heated to 80° C. for 20 hours. THF was removed by vacuum, the residue was partitioned between DCM and water. The organic phase was dried over MgSO4 and filtered. After evaporation the crude product was chromatographed in petroleum ether:EtOAc=2:1.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:10][CH:9]=1.OO>CS(C)=O>[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:2])=[CH:15][C:14]=2[C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccnc1-c1cc(C#N)ccc1Oc1ccc(Cl)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccnc1-c1cc(C(N)=O)ccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 145.8 %

Procedure:
Potassium carbonate (0.143 g, 1.0 mmol) was added to a solution of 4-(4-chlorophenoxy)-3-(3-methoxypyridin-2-yl)benzonitrile (Preparation 12, 0.175 g, 0.52 mmol) in DMSO, followed by dropwise addition of 30% hydrogen peroxide aqueous solution (3.1 mL, 3.1 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with aqueous potassium hydrogen sulfate (30 mL) and extracted with DCM (3×30 mL). The organic layer was washed with water (2×30 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (0.269 g). This was taken to the next step without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]1=[O:25])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]1=[O:25]
Reactant: COc1ccc2ncc(=O)n(CCCCO[Si](C)(C)C(C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCCCO)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
1-(4-{[Tert-butyl(dimethyl)silyl]oxy}butyl)-7-methoxyquinoxalin-2(1H)-one (363 mg, 1.0 mmol) was dissolved in tetrahydrofuran (10.9 ml). Tetrabutyl ammonium fluoride (1M tetrahydrofuran solution; 1.1 ml, 1.1 mmol) was added to this solution and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 247 mg (100%) of the title compound in the form of a light yellow syrup.
Reaction SMILES: [Li+].[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[F:7][C:8]1[CH:25]=[CH:24][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=O)=[CH:10][CH:9]=1>O1CCCC1>[C:2]1(=[C:12]([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3]1
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(F)cc2)cc1
Reactant: c1cc[cH-]c1
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=C2C=CC=C2)c2ccc(F)cc2)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A solution of 3.7 g (50 mmol) of lithium cyclopentadienylide in 90 ml of anhydrous tetrahydrofuran is added to a solution of 11.1 g (40 mmol) of 4-fluoro-4'-methylsulfonylbenzophenone, prepared in Example 2, in 70 ml of anhydrous tetrahydrofuran, cooled to 10° C. The reaction medium is stirred for 2 hours at this temperature and then for 24 hours at room temperature. It is subsequently poured onto ice. After dilution with water, the mixture is extracted with t-butyl methyl ether. The organic phase is dried over magnesium sulfate and then concentrated in the cold. The residue obtained is chromatographed on silica gel in dichloromethane. The resulting oil crystallizes from a petroleum ether/t-butyl methyl ether mixture to give 3.6 g of 4-[(cyclopenta-2,4-dienylidene)(4-fluorophenyl)methyl]methylsulfonylbenzene in the form of orange crystals melting at 110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[Br:11]Br>ClCCl>[Br:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: COc1cccc(C=O)c1
Reactant: BrBr
Solvent: ClCCl
Product: COc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.2 %

Procedure:
A stirred solution of 3-methoxybenzaldehyde (27.23 g) in dichloromethane (150 mL) at 0° C. is treated with a solution of bromine (32 g) in dry dichloromethane (50 mL) over 30 minutes. The reaction mixture is stirred at room temperature for 4 hours, combined with a previous preparation carried out on the same scale, and washed with saturated sodium metabisulphite solution (400 mL), with water (400 mL), brine (400 mL) and dried over magnesium sulphate. Evaporation and recrystallisation of the residue from petroleum ether (b.p. 40-60° C.) gives 2-bromo-5-methoxybenzaldehyde (45.25 g) as a white solid, m.p. 73-74° C.