Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:61]1([CH2:66][C:67](O)=[O:68])[CH:65]=[CH:64][CH:63]=[N:62]1>CC(N(C)C)=O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:67](=[O:68])[CH2:66][N:61]2[CH:65]=[CH:64][CH:63]=[N:62]2)=[CH:7][C:6]=1[C:8]1[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(N)ccc1Oc1ccc(F)cc1F
Reactant: O=C(O)Cn1cccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(=O)n(C)cc1-c1cc(NC(=O)Cn2cccn2)ccc1Oc1ccc(F)cc1F
Yield: 39 %

Procedure:
A solution of Example 1G and DIPEA (0.15 M and 0.43 M in DMA, respectively, 257 μL, 0.04 mmol Example 1G (1.0 equivalent) and 0.12 mmol DIPEA (3.0 equivalents)), HATU (0.2 M in DMA, 257 μL, 0.052 mmol, 1.3 equivalents), and 2-(1H-pyrazol-1-yl)acetic acid (0.40 M in DMA, 121 μL, 0.048 mmol, 1.2 equivalents) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0 2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction was loaded directly into an injection loop and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at a flow rate of 30 mL/min (0-0.5 min 5% A, 0.5-6.5 min linear gradient 5-60% A, 6.5-7.0 min linear gradient 60-100% A, 7.0-8.9 min 100% A, 8.9-9.0 min linear gradient 100-5% A, 9.0-10 min 5% A) to yield the title compound (7.33 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6/D2O) δ 7.76 (d, J=2.3 Hz, 1H), 7.60-7.45 (m, 4H), 7.37-7.28 (m, 1H), 7.07-6.87 (m, 3H), 6.31 (t, J=2.1 Hz, 1H), 5.82 (s, 1H), 5.00 (s, 2H), 3.93 (q, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (ESI) m/z 481.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.S(=O)(=O)(O)O.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[O:14]=[C:3]1[C:2]2[N:1]=[C:20]([C:19]3[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=3)[O:21][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)c2oc(-c3ccc(F)cc3)nc21
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of 6.22 g (30 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene in 60 mL of nitrobenzene, 18.00 mL (150 mmol) of 4-fluorobenzoic acid chloride are added with protection from light. After 10 min of stirring with reflux, 0.20 mL of concentrated sulfuric acid is added. After 12 h and complete cooling, ether is added to obtain a yellow precipitate which is filtered through fritted glass, washed with ether and purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 60/40). The yellow powder obtained after evaporation of the solvent is uncolored, recrystallized in dichloromethane to produce 2.90 g of 4,9-dihydro-4,9-dioxo-2-(4-fluorophenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:24]=[CH:23][C:15](/[CH:16]=[CH:17]/[C:18]4[N:19]=[N:20][NH:21][N:22]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:8][C:7]=2[CH:33]=1.IC.[C:36]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:24]=[CH:23][C:15](/[CH:16]=[CH:17]/[C:18]4[N:22]([CH3:36])[N:21]=[N:20][N:19]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:8][C:7]=2[CH:33]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:24]=[CH:23][C:15](/[CH:16]=[CH:17]/[C:18]4[N:22]=[N:21][N:20]([CH3:36])[N:19]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:8][C:7]=2[CH:33]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3nn[nH]n3)cc2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3nnn(C)n3)cc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3nnnn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %
Yield: 39 %

Procedure:
To a 30 mL vial containing (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-2H-tetrazole (15 mg, 0.03 mmol) in DMF (2 mL) was added with iodomethane (2.260 μL, 0.04 mmol) and K2CO3 (13.62 mg, 0.10 mmol) and the reaction was stirred at room temperature for 18 h. The reaction was quenched with sat. aq. NH4Cl (15 mL) and extracted with DCM (25 mL). The organic phase was collected (phase separator) and concentrated in vacuo to afford the crude product. The crude product was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl-1H-tetrazole (8 mg, 0.08 mmol, 52% yield) and (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-2-methyl-2H-tetrazole (6 mg, 0.01 mmol, 39% yield) both as a white solids.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(#N)C>[Cl-:8].[CH2:1]([N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCCCCCCCCl
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCC[N+](CC)(CC)CC
Product: [Cl-]
Temperature: 80 °C
Reaction time: 96 h
Yield: 24.1 %

Procedure:
A nitrogen-purged 500 ml flask was charged with 28.96 g (0.286 mol) of triethylamine, 55.23 g (0.371 mol) of 1-chlorooctane and 78.11 g of acetonitrile. The mixture was stirred at 80° C. under nitrogen for 96 hours. The volatile constituents of the reaction mixture were then drawn off under reduced pressure and the residue was washed with heptane and ethyl acetate to obtain 10.34 g (0.069 mol) of triethyloctylammonium chloride (white hygroscopic salt). The yield was 24%, based on triethylamine.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[S:26][C:27]5[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=5[N:29]=4)=[CH:21][C:20]=3[CH2:34][CH2:35][CH3:36])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.O[Li].O>C1COCC1.O>[CH2:34]([C:20]1[CH:21]=[C:22]([C:25]2[S:26][C:27]3[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=3[N:29]=2)[CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH2:16][CH2:15][O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:37])=[O:2])[CH:6]=[CH:7]2)[CH2:35][CH3:36]
Reactant: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(ccn2CC(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
To a solution of methyl(5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)phenoxy]propoxy}-1H-indol-1-yl)acetate (Example 55, 145 mg, 0.28 mmol) in THF (4.8 mL), was added LiOH.H2O (39 mg, 0.84 mmol) in water (1.6 mL), and the mixture was stirred for 12 h at rt. The solvents were evaporated and a small volume of water was added to the residue. The pH of the mixture was adjusted to 3 with 1 N HCl. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, filtered, and concentrated to give 140 mg (99%) of the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.30 (d, 1H), 7.25-7.15 (m, 3H), 7.10 (d, 1H), 6.92 (dd, 1H), 6.45 (d, 1H), 6.20 (d, 1H), 4.85 (s, 2H), 4.40-4.32 (m, 2H), 4.32-4.22 (m, 2H), 2.90-2.80 (br, 2H), 2.80-2.70 (br, 2H), 2.50-2.40 (m, 2H), 2.25-2.05 (m, 2H), 1.95-1.75 (br, 4H), 1.60-1.40 (m, 2H), 0.90 (t, 3H). LC/MS m/z 505.2 (M+H)+, RT 3.88 min.
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].[Si:5](Cl)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].N1C=CN=C1>C(Cl)(Cl)Cl>[Si:5]([O:4][CH2:3][CH2:2][I:1])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCI
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCCI
Yield: 99.9 %

Procedure:
A mixture of 2-iodoethanol (12.4 g, 72 mmol) and tert-butyldimethylsilyl chloride (11.94 g, 79 mmol) in chloroform (10 ml) was treated with imidazole (5.39 g, 79 mmol) which produced a white suspension. This was filtered and washed with chloroform. The filtrate was evaporated under reduced pressure to give the product as a colourless liquid (20.592 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[N:15]=[C:14]([OH:20])[CH:13]=[C:12]3[Br:21])=[CH:4][CH:3]=1.[CH3:29]N(C)C=O.C([O-])([O-])=O.[Cs+].[Cs+].CI>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[N:15]([CH3:29])[C:14](=[O:20])[CH:13]=[C:12]3[Br:21])=[CH:4][CH:3]=1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4,8-dibromoquinolin-2-ol (360 mg, 0.67 mmol, 1.00 equip), N,N-dimethylformamide (15 mL), Cs2CO3 (654 mg, 2.01 mmol, 3.00 equip), and CH3I (190 mg, 1.34 mmol, 2.00 equip). The resulting solution was stirred overnight at 80° C. The resulting solution was diluted with water (80 mL). The solids were collected by filtration to yield 6-[bis(4-chlorophenyl)methyl]-4,8-dibromo-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 552 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27](Cl)[CH:26]=4)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[O-:32][CH2:33][CH3:34].[Na+].[CH3:36][CH2:37][OH:38]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:32][CH2:33][CH3:34])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([O:38][CH2:37][CH3:36])[CH:26]=4)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCO
Reactant: CC[O-]
Reactant: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)c5)CC4)nc23)c(Cl)c1
Agent: [Na+]
Product: CCOc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(OCC)c5)CC4)nc23)c(Cl)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution of 8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyridin-4-yl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 58) (46 mg, 0.10 mmol) in EtOH (1 mL) was added sodium ethoxide solution (21% in ethanol, 56 L, 0.15 mmol) and the reaction mixture was stirred under Argon in a sealed tube at 60° C. for 16 h. After cooling to room temperature the mixture was heated in the microwave to 150° C. for 45 minutes and then sodium ethoxide solution (21% in ethanol, 56 uL, 0.15 mmol) was added and the mixture heated to 150° C. for another 30 in the microwave. The mixture was then evaporated and diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 20 g, 0 to 100% ethyl acetate in heptane) afforded the title compound (17 mg, 35%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7]([C:8](=O)[CH:9]=[CH:10][C:11]=3[S:17]([CH3:20])(=[O:19])=[O:18])=[N:6][C:5]=2[CH:4]=1>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17]([CH3:20])(=[O:19])=[O:18])[NH:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2sc3c(S(C)(=O)=O)ccc(=O)c-3nc2c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)Nc1cccc(S(C)(=O)=O)c1S2
Yield: 35.7 %

Procedure:
2-Methoxy-6-methylsulphonylphenothiazine (m.p. 204°-206°C.; 16.05 g.) is prepared by reduction of 2-methoxy-6-methylsulphonyl-9-oxophenothiazine (47 g.) by means of zinc powder (28 g.) in dimethylformamide (175 cc.), acetic acid (73 cc.) and distilled water (73 cc.).
Reaction SMILES: [F:1][C:2]1[C:3]([C@H:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:32]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10](=[O:21])[NH:9][C@H:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=2)=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:34])[CH3:33]
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)cc1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
To a solution of (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-hydroxy-3-nitrobenzamide (83 mg, 0.191 mmol) and DCM (5 mL) were added acetic anhydride (0.2 mL, 2.120 mmol) and DIPEA (0.15 mL, 0.861 mmol). After stirring for 45 min, the reaction was quenched with water and after stirring for 3 days, the aqueous solution was filtered to give the title compound as a yellow solid. The resulting product was used in the next step without further purification. MS (ESI pos. ion) m/z: 478.1 (M+H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=O)[N:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:6]1=[O:7].FC(F)(F)C(O[C:29](=O)[C:30](F)(F)F)=O.[C:37](=[O:40])(O)[O-:38].[Na+].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.ClCCl>[C:12]1([N:9]2[C:10]([C:30]3[C:29]([C:37]([OH:38])=[O:40])=[CH:4][CH:5]=[CH:6][N:8]=3)=[C:5]([CH2:4][CH2:3][CH2:2][CH3:1])[C:6](=[O:7])[N:8]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C([O-])O
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCc1c(-c2ncccc2C(=O)O)n(-c2ccccc2)n(-c2ccccc2)c1=O
Reaction time: 1 h
Yield: 154.2 %

Procedure:
Phenylbutazone (1,2-diphenyl-3,5-pyrazolidinedione; 11.00 g, 0.035 mole) was treated with 11.55 g (0.055 mole) of trifluoroacetic anhydride. The resulting solid suspension was shaken or mechanically stirred until a homogeneous solution was obtained, then it was stirred with a magnetic stirrer at room temperature in a tightly closed flask for one hour. The solution was concentrated in vacuo for one hour and the oily residue obtained was dissolved in 50 ml of acetone and allowed to react with 12.5 g (0.055 mole) of nicotini anhydride. The initial suspension became homogeneous after 0.25 hours with concomitant formation of a yellow color. After an additional one hour at room temperature, the yellow solution was concentrated in vacuo and the residue was dissolved in 200 ml of dichloromethane. The dichloromethane solution was extracted first with an aqueous sodium bicarbonate solution (12.2 g, 0.145 mole in 150 ml), then with an aqueous sodium hydroxide solution (28 g, 0.07 mole in 56 ml) and subsequently dried over sodium sulfate. The dichloromethane solution was concentrated in vacuo and the residue was crystallized from dichloromethane petroleum ether bp 30°-60° C. to give 11.16 g (mp 139°-141° C., 77.5% yield) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[C:9]([CH3:44])=[N:8]1.CCN(C(C)C)[CH:51]([CH3:53])[CH3:52].C([OH:59])C>>[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:29][CH2:30][N:31]([CH2:52][C@@H:51]([OH:59])[CH3:53])[CH2:32][CH2:33]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:35])=[O:36])[CH:14]=2)[C:9]([CH3:44])=[N:8]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 82 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (197 mg, 0.294 mmol), DIPEA (76 mg, 0.588 mmol) and ethanol (4 mL) to get 167 mg (82.0%) of the titled compound. MS: m/z=693.7 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][CH2:11][CH3:12])[C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[C-:16]#[N:17].[Na+]>CN(C)C=O.O>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][CH2:11][CH3:12])[C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1)#[N:17]
Reactant: CCOC1Oc2ccc(Br)cc2C1(C)C
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1Oc2ccc(C#N)cc2C1(C)C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethyl-2-ethoxybenzofuran (4.7 g, 0.017 mole) was heated under reflux with cuprous cyanide (2.7 g, 0.03 mole) in dimethyl formamide (10 ml) as in example 2 for 3 hours. A warm solution of sodium cyanide (5 g) in water (20 ml) was added with stirring and stirring was continued for 1 hour at ambient temperature. The solution was diluted with water and extracted with ether. The extracts were washed with water, dried over magnesium sulphate and run down yielding 3.6 g crude product. Purification was accomplished by silica gel chromatography in 1:4 ether/petroleum ether (b.p. 40°-60° C.). The yield of pure title product was 2.9 g (79%).
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[N+:6]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>CO>[CH3:1][O:17][C:16](=[O:18])[CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Trimethylsilyl chloride (5.6 mL, 2.0 equiv.) was added to a stirred solution of (3-nitrophenyl)acetic acid (4.0 g) in methanol (60 ml). The resulting solution was stirred at room temperature for 18 hours, then concentrated at reduced pressure and partitioned between DCM and aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound as a colourless liquid (4.2 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[S:16][C:27]3[CH2:28][CH2:29][CH2:30][CH:25]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=4)[C:26]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Solvent: CCO
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2F)cn1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A suspension of [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (125 mg, 0.50 mmol) and of 2-bromo-6-phenyl-cyclohexanone (253 mg, 1.00 mmol) in ethanol (4 mL) was stirred at room temperature for 30 minutes and then heated for two days to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified on silica gel using dichloromethane and then dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (200 mg, 99%) as a white solid. MS ISP (m/e): 405.4 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.40 (s, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.38 (t, 1H), 7.32 (t, 2H), 7.10-7.21 (m, 4H), 4.04 (m, 1H), 2.70 (m, 2H), 2.13 (s, 3H), 2.11 (m, 1H), 1.70-1.89 (m, 3H).
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.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[NH2:21][C:22]1[CH:27]=[C:26]([C:8]2[C:7]3[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=3[C:5]3[C:4]4[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[CH:9]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)c1
Yield: 62 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 3-aminobenzeneboronic acid according to the procedure described in example 8 gave 4-(3-aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (15) (I, Ar=3-aminophenyl) in a 62% yield; mp 279–284° C. 1H NMR δ [(CD3)2SO] 11.70 (s, 1H), 10.96 (s, 1H), 9.22 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.10–7.03 (m, 2H), 6.77–6.74 (m, 1H), 6.72–6.68 (m, 1H), 6.61 (dd, J=8.1, 2.3 Hz), 1H), 5.11 (br s, 2H). Found: C, 69.41; H, 4.12; N, 10.73. C20H13N3O3 requires C, 69.96; H, 3.82; N, 12.24.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH:23]2[CH2:35][OH:36])=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][CH:23]2[CH:35]=[O:36])=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)CC1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1CN(Cc2ccccc2)CCN1C(=O)Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 107.8 %

Procedure:
A solution of dimethylsulphoxide (369 mg) in dry dichloromethane (3 ml) was added to a stirred solution of oxalyl chloride (300 mg) in dry dichloromethane (7 ml) at -60° under nitrogen and the resulting solution was stirred at -60° to -64° for 30 minutes. The product of stage (i) (774 mg) in dry dichloromethane (5 ml) was added dropwise and the reaction mixture was stirred between -60° to -63° for 2.5 h. Triethylamine (995 mg) was added and the mixture was allowed to warm to -20°, and quenched with water (15 ml). The layers were separated and the aqueous phase was further extracted with dichloromethane (2×15 ml). The combined organic extracts were dried and evaporated to give the title compound as an oil (830 mg).