Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([C:17]3[S:21][C:20]4[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)=[O:16])[C:9]=2[CH3:26])[N:5]=[C:4]([O-])[C:3]1=[O:28].[Na+].P(Br)(Br)([Br:32])=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:32][C:4]1[C:3](=[O:28])[N:2]([CH3:1])[CH:7]=[C:6]([C:8]2[C:9]([CH3:26])=[C:10]([NH:14][C:15]([C:17]3[S:21][C:20]4[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:5]=1
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c([O-])n1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Br)n1
Yield: 49.9 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 10 (6.55 g, 15.7 mmol) and anhydrous methylene chloride (60 mL). To the resulting suspension phosphorous oxybromide (9.95 g, 34.3 mmol) and N,N-dimethylformamide (190 mg, 2.60 mmol) were added and the reaction was then heated at reflux for 4 h. After this time the reaction mixture was poured into a 10% aqueous potassium carbonate solution (100 mL) and methylene chloride (75 mL) was added. The resulting suspension was filtered through Celite 521 and the layers separated. The aqueous layer was extracted with methylene chloride (2×100 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with a 2:1 solution of ethyl acetate/hexanes (10 mL) and filtered. The filter cake was washed with the 2:1 ethyl acetate/hexanes solution (20 mL) and dried to a constant weight under vacuum to afford a 50% yield (3.59 g) of 11 as a light yellow solid: mp 240-241° C., 1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 7.28 (m, 3H), 3.57 (s, 3H), 2.76 (t, 2H, J=5.5 Hz), 2.61 (t, 2H, J=5.5 Hz), 2.18 (s, 3H), 1.76 (m, 4H); MS (ESI+) m/z 458(M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C:15]=1[F:28].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:28][C:15]1[CH:16]=[C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]=1[CH2:13][N:3]1[C:4]([O:9][CH2:10][CH2:11][CH3:12])=[CH:5][C:6](=[O:8])[N:7]([CH2:30][C:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[O:32])[C:2]1=[O:1]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCCOc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a mixture of 4′-[(2,4-dioxo-6-propoxy-3,4-dihydropyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.55 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.4 g) and N,N-dimethylformamide (25 mL) was added 60% sodium hydride (0.087 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.45 g, 59%).
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:16]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:7][C:8]([N:11]([CH3:15])[CH2:12][CH2:13][OH:14])=[N:9][CH:10]=1.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>N1C=CC=CC=1>[CH2:35]([NH:37][C:38](=[O:39])[O:14][CH2:13][CH2:12][N:11]([C:8]1[CH:7]=[C:6]([CH:16]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C:5]([Cl:4])=[CH:10][N:9]=1)[CH3:15])[CH3:36]
Reactant: CN(CCO)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNC(=O)OCCN(C)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 19 h
Yield: 74 %

Procedure:
To a methylene chloride (1.0 ml) solution of 2-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl](methyl)amino]ethanol (73 mg, 0.15 mmol) was added pyridine (0.5 ml), followed by further addition of ethyl isocyanate (100 μl). The resulting mixture was stirred for 19 hours. After the reaction mixture was concentrated under reduced pressure, the residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to yield the title compound (65 mg, 74%) as an oil.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[C:6]1([CH2:12][CH2:13][CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(#N)C>[S:1]([O:15][CH2:14][CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)OCCCc1ccccc1
Yield: 48 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride in solution prepared in (a) was reacted as in Example 12 with 16.4 g (0.118 mole) of 3-phenyl-1-propanol (98%) using 46.4 g (0.459 mole) of triethylamine in 100 ml of additional acetonitrile followed by using the extracting, washing and concentration procedures of Example 12 through the first evaporation. The viscous, oily residue was partitioned between water and ethyl ether (300 ml each). The organic layer was separated and washed with four 200 ml portions of water, the aqueous wash being finally neutral to pH paper. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 19.5 g of a light-yellow, viscous oil which solidified on standing. The solid was recrystallized using ethyl ether and petroleum ether (bp range 30°-60° C.) to give 12.1 g (48%) of title compound as white solid, mp 56.5°-58° C.
Reaction SMILES: Cl.[N:2]1[CH:3]=[C:4]([C:11](Cl)=[O:12])[N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[NH2:14][C:15]1[CH:16]=[C:17]([CH:35]=[CH:36][C:37]=1[Br:38])[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:19]>N1C=CC=CC=1>[Br:38][C:37]1[CH:36]=[CH:35][C:17]([C:18](=[O:19])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[CH:16][C:15]=1[NH:14][C:11]([C:4]1[N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=[N:2][CH:3]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccn12
Reactant: CN1CCN(c2ccccc2CNC(=O)c2ccc(Br)c(N)c2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(Br)c(NC(=O)c3cnc4ccccn34)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Imidazo[1,2-a]pyridine-3-carbonyl chloride hydrochloride (0.97 mg, 4.46 mmol) was slowly added in portions to a stirred solution of 3-amino-4-bromo-N-(2-(4-methylpiperazin-1-yl)benzyl)benzamide (step 1) (900 mg, 2.23 mmol) in dry pyridine (15 ml). The reaction was stirred at RT for 18 hrs and quenched with water. The solvent removed in vacuo. The residue was treated with a small amount of MeOH to dissolve insoluble material then partitioned between aq. NaHCO3 and DCM. The organic extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product mixture was crystallised from MeOH to give a white solid;
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([C:48](=[O:52])[C:49](Cl)=[O:50])=[CH:40]1.CO>C(Cl)Cl>[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([C:48](=[O:52])[C:49]([N:16]2[CH2:15][C:14]([CH3:28])([CH3:27])[C:13]3[N:12]=[C:11]([CH:29]([CH3:31])[CH3:30])[C:10]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])=[C:19]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[C:18]=3[CH2:17]2)=[O:50])=[CH:40]1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)C(=O)c1c[nH]c3ccccc13)CC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10 mg, 0.023 mmol) in CH2Cl2 (5 mL) was added Et3N (0.020 mL, 0.140 mmol) and the resulting mixture cooled to 0° C. Added to this was 2-(1H-indol-3-yl)-2-oxoacetyl chloride (14.5 mg, 0.070 mmol) and the mixture stirred at room temperature (mixture became a clear colorless solution over time). After 1 h, 0.5 mL MeOH was added and the mixture was concentrated under a stream of air, taken up in MeOH and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm column). The product was repurified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm column). The product-containing fractions were combined, concentrated to remove the organic solvent and the resulting precipitate collected by filtration to give 2-(6-(2-(1H-indol-3-yl)-2-oxoacetyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-tert-butoxyacetic acid (2.4 mg, 16% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (0.5H, d, J=5.80 Hz), 8.13 (0.5H, d, J=7.32 Hz), 8.05 (0.5H, s), 7.82 (0.5H, s), 7.48-7.68 (2H, m), 7.24-7.48 (4H, m), 7.09 (0.5H, t, J=5.80 Hz), 6.80-6.92 (0.5H, m), 6.71-6.80 (0.5H, m), 6.59-6.71 (0.5H, m), 4.72 (0.5H, s), 4.58 (0.5H, d, J=18.01 Hz), 4.37 (1H, dd, J=17.24, 8.09 Hz), 3.96 (0.5H, d, J=16.79 Hz), 3.77-3.93 (1H, m), 3.55-3.72 (2.5H, m), 1.49 (3H, d, J=7.02 Hz), 1.23-1.38 (6H, m), 1.17 (3H, t, J=5.80 Hz), 0.85-1.05 (9H, m). 19F NMR (500 MHz, CD3OD) δ ppm −115.51. LCMS (M+H) calcd for C35H39FN3O5: 600.28. found: 600.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1[CH:34]=[O:35].[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:38]=1[CH:39]=[C:40](B1OC(C)(C)C(C)(C)O1)[NH:41]2>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:36][C:37]1[C:38]2[CH:39]=[C:40]3[C:2]4[N:7]=[C:6]([C:8]5[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])=[CH:10][C:11]6[O:15][C:14]([C:16]7[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=7)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=6[CH:27]=5)[CH:5]=[CH:4][C:3]=4[CH:34]([OH:35])[N:41]3[C:42]=2[CH:43]=[CH:44][CH:45]=1
Reactant: CC1(C)OB(c2cc3c(F)cccc3[nH]2)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C=O)c(Cl)n3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C4O)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 22.4 %

Procedure:
To a degassed solution of 5-(6-chloro-5-formylpyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.29 mmol) and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (94 mg, 0.35 mmol) in 1,4-dioxane (3 mL) and water (200 μL) was added CS2CO3 (189 mg, 0.58 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (30 mg, 0.05 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred for 3 hours. The reaction was cooled, filtered through a pad of celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. Preparative TLC (eluted with (30% ethyl acetate/DCM) to provide 5-(10-fluoro-5-hydroxy-5H-pyrido[2′,3′:3,4]pyrrolo[1,2-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (40 mg, yield: 22%) MS (M+H)+: 615.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([NH:17][C:18]2[NH:22][C:21]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][CH:30]([CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29]4)[C:25]([Cl:27])=[CH:26][C:20]=3[N:19]=2)[CH:11]=1)(C)(C)C>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH2:8])=[CH:11][C:12]=1[NH:17][C:18]1[NH:22][C:21]2[CH:23]=[C:24]([N:28]3[CH2:32][CH2:31][CH:30]([CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29]3)[C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1
Reactant: CN(C)CC1CCN(c2cc3[nH]c(Nc4cc(CNC(=O)OC(C)(C)C)ccc4Cl)nc3cc2Cl)C1
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CC1CCN(c2cc3[nH]c(Nc4cc(CN)ccc4Cl)nc3cc2Cl)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
6 M aq. HCl-solution (1.0 ml) was added to N-{4-chloro-3-[5-chloro-6-(3-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-carbamic acid tert-butyl ester (130 mg, 0.2 mmol) in THF (2 mL) and stirred at 50° C. for 1 h. The reaction mixture was concentrated to give the sub-title compound.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22]C(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Al](C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Pd]
Agent: C[Al](C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(C)nc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 2155.9 %

Procedure:
A suspension of methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.34 mmol, 1.00 equiv), Pd2(dba)3 (12 mg, 0.01 mmol, 0.04 equiv), x-phos (6 mg, 0.01 mmol, 0.04 equiv), and Al(CH3)3 (0.5 mL, 3.00 equiv, 2.5M) in 1,4-dioxane (3 mL) was placed in a 10-mL sealed tube under an inert atmosphere allowed to react, with stirring, for 6 hr while the temperature was maintained at 100° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate:petroleum ether (1:1)). The resulting mixture was concentrated under vacuum. The residue was purified via silica gel column (ethyl acetate/petroleum ether (1:20)) yielding 60 mg (64%) of methyl 3-methyl-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:35][CH2:34][C@@H:33]([OH:36])[CH2:32]1>>[N:25]1([C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][N:31]5[CH2:35][CH2:34][C@@H:33]([OH:36])[CH2:32]5)=[CH:12][C:11]=4[CH:13]=3)=[CH:22][CH:21]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: O[C@@H]1CCNC1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CC[C@@H](O)C4)cc3c2)cc1)N1CCOCC1

Procedure:
The product from Example 23D and 3-(R)-pyrrolidinol were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.55 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.78 (s, 1H), 3.35-3.8 (m, 17H), 2.3-2.4 (m, 2H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[NH2:17].[H-].[Na+]>CN(C)C=O>[CH:12]1[C:11]2[O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3](=[O:2])[NH:17][C:16]=2[CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1ccccc1Oc1cnccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccncc2Oc2ccccc21
Reaction time: 1 h

Procedure:
A solution of 2-(4-amino-3-pyridyloxy)benzoic acid methyl ester (7.5 g) in dimethylformamide (25 ml) was slowly added to a suspension of sodium hydride (60%) oil dispersion, 1.4 g), washed with hexanes, in dimethylformamide (5 ml). After one hr, the reaction mixture was stirred with ice-water and extracted with chloroform. The organic extract was washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate; filtered, and evaporated to 5.5 g (84%) of product. Recrystallization from absolute ethanol gave the analytical sample, mp 253°-254° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:22]4[N:21]([CH3:23])[C:20]5[C:15](=[CH:16][C:17]([O:24][CH3:25])=[CH:18][CH:19]=5)[C:14]=4[C:13]4[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:12]=4[C:11]=3[C:5]=2[CH:4]=1.[CH3:31]OC1CC(=O)C2NC3C4N(C)C5C(=CC(OC)=CC=5)C=4C4CN(C)C(=O)C=4C=3C=2C=1.COC1C=CC2NC3C4NC5C(=CC(OC)=CC=5)C=4C4C(=O)N(C)C(=O)C=4C=3C=2C=1.CI.S(OC)(OC)(=O)=O.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:22]4[N:21]([CH3:23])[C:20]5[C:15](=[CH:16][C:17]([O:24][CH3:25])=[CH:18][CH:19]=5)[C:14]=4[C:13]4[C:26](=[O:30])[N:27]([CH3:31])[C:28](=[O:29])[C:12]=4[C:11]=3[C:5]=2[CH:4]=1
Reactant: COC1=Cc2c([nH]c3c2c2c(c4c5cc(OC)ccc5n(C)c34)CN(C)C2=O)C(=O)C1
Reactant: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(C)c35)C(=O)NC4=O)c2c1
Agent: COc1ccc2[nH]c3c4[nH]c5ccc(OC)cc5c4c4c(c3c2c1)C(=O)N(C)C4=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(C)c35)C(=O)N(C)C4=O)c2c1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
6,7,12,13-tetrahydro-3,9-dimethoxy-12-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole; yellow crystals; m.p. >330° C. The 6,7,12,13-tetrahydro-3,9-dimethoxy-6,12-dimethyl-5,1-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole used as starting material is prepared by the methylation of 6,7,12,13-tetrahydro-3,9-dimethoxy-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole (precursor for Example 7) with methyl iodide or dimethyl sulphate in the following manner: A solution of 1 g (2.5 mmol) 6,7,12,13-tetrahydro-3,9-dimethoxy-6-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole in 50 ml dry dimethylformamide is added dropwise at 20° C. to a suspension of 91 mg (3.0 mmol) sodium hydride (80% in paraffin oil) in 5 ml dimethylformamide under an atmosphere of argon. After stirring for 1 hour at 200° C., 0.2 ml (3.2 mmol) methyl iodide are added thereto and the reaction mixture is stirred for 16 hours at 20° C. It is then evaporated in a vacuum and the residue is partitioned between ethyl acetate and water. The ethyl acetate phase is separated off, dried over anhydrous sodium sulphate, filtered and evaporated. The residue is stirred with 30 ml diisopropyl ether/ethyl acetate (2:1 v/v) and the undissolved product is filtered off. 6,7,12,13-Tetrahydro-3,9-dimethoxy-6,12-dimethyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole is obtained in the form of a pale brown amorphous powder. The methylation can also be carried out in an analogous manner with dimethyl sulphate as alkylation agent.
Reaction SMILES: [Cl-].[NH4+].O.[CH3:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:10]([N+:27]([O-])=O)[CH:9]=1)(=[O:7])=[O:6]>[Fe].C(O)(C)C>[NH2:27][C:10]1[CH:9]=[C:8]([S:5]([CH3:4])(=[O:6])=[O:7])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCOc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCOc1ccc(S(C)(=O)=O)cc1N

Procedure:
A mixture of 25.2 g of iron powder, 1 g of ammonium chloride, 25 ml of water and 250 ml of isopropanol was heated and stirred in a nitrogen stream. To the mixture 23.1 g of dodecyl 4-methylsulfonyl-2-nitrophenyl ether was added. After the conclusion of the addition and a 1-hour stirring, the resulting solution was filtrated out by a Nusche coated sellaite therein. The reaction mixture was concentrated, and to the mixture methanol was added to deposit 17.5 g of dodecyl 2-amino-4-methylsulfonylphenyl ether crystal.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1>>[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
A round bottom flask was charged with chlorosulfonic acid (170 mL, 2.57 mol) at 0° C. and 4-methyl benzoic acid (50 g, 0.37 mol) was added portion wise. The reaction mixture was heated at 130° C. for 5 h. The reaction mixture was then poured over ice and stirred for 10 minutes. The solids formed were filtered, washed with cold water and dried to afford 4-methyl-3-(chlorosulfonyl)benzoic acid as a white powder. This compound (80 g, 0.34 mol) was then charged into a round bottom flask containing sodium sulfite (200 g, 2.05 mol) and water (80 mL) portion wise. Aqueous sodium hydroxide (6 N) was then added dropwise till the pH of the reaction mixture reaches 10 and the reaction was stirred overnight. The reaction was then made acidic (pH 2) by addition of 2N HCl. The solids formed were filtered and dried to get 4-methyl-3-sulfinobenzoic acid as a white solid. This compound (55 g, 0.275 mol) was charged into a round bottom flask containing potassium carbonate (75.8 g, 0.55 mol) and N,N-dimethylformamide (450 mL). Methyl iodide (68.1 mL, 1.10 mol) was added slowly and the reaction was stirred for 4 hours. The reaction mixture was then diluted with water and extracted with EtOAc. The solvents were removed under reduced pressure to get the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[F:23][C:24]1[C:25](=[O:40])[N:26]([CH3:39])[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1>O1CCOCC1.C(=O)(O)[O-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:3][C:2]=1[C:28]1[CH:29]=[C:24]([F:23])[C:25](=[O:40])[N:26]([CH3:39])[CH:27]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(F)c1=O
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cc(F)c(=O)n(C)c2)c1
Yield: 35.4 %

Procedure:
N-[3-Bromo-4-(2,4-difluorophenoxyl)phenyl]ethanesulfonamide (77 mg, 0.2 mmol), the title compound of Example 119, step 2 (50 mg, 0.2 mmol), and Pd(dppf)Cl2 (14 mg, 10%) in 1,4-dioxane (1 mL) and saturated bicarbonate solution (aq) (333 μL) were reacted, worked up and purified in a manner similar to Example 117. The title compound (31 mg, 27%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.22 (t, J=7.3, 3 H) 3.11 (q, J=7.3 Hz, 2H) 3.55 (s, 3H) 6.86 (d, J=8.6 Hz, 1H) 7.02-7.12 (m, 1H) 7.13-7.23 (m, 2H) 7.26 (d, J=2.8 Hz, 1H) 7.35-7.52 (m, 1H) 7.60 (m, 1H) 7.79 (s, 1H) 9.48-9.96 (m, 1H). LCMS (M+H)+=439.