Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[CH:9]([CH3:22])[C:10]([NH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[CH3:21])=[O:11].[Cl-].[NH4+]>O1CCCC1>[NH2:6][C:5]1[N:12]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=2[CH3:21])[C:10](=[O:11])[CH:9]([CH3:22])[C:4]=1[C:3]#[N:7]
Reactant: Cc1cc(Br)cc(C)c1NC(=O)C(C)Br
Reactant: N#CCC#N
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1N1C(=O)C(C)C(C#N)=C1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a suspension of NaH (17.2 g) in tetrahydrofuran (500 mL) was added a solution of malononitrile (28.4 g) in tetrahydrofuran (100 mL) under ice-cooling and the mixture was stirred at room temperature for 1 hour. 2-Bromo-N-(4-bromo-2,6-dimethylphenyl)propionamide (120 g) was added and the mixture was heated at reflux for 1 hour. With ice-cooling, an ammonium chloride aqueous solution was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with a mixture of diisopropylether and ethyl acetate and filtered, dried to give 2-amino-1-(4-bromo-2,6-dimethylphenyl)-4-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitrile (110.1 g).
Reaction SMILES: CS(C)=O.[F:5][C:6]1[C:7]([C:12]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-:19].[K+].[K+].OO>O.C(OCC)(=O)C>[F:5][C:6]1[C:7]([C:12]2([C:16]([NH2:17])=[O:19])[CH2:15][CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1(c2ncccc2F)CCC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)C1(c2ncccc2F)CCC1
Temperature: 0 °C
Yield: 58.8 %

Procedure:
To a 250 mL round bottom flask containing DMSO (60 mL) was added 1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (2.96 g, 16.8 mmol, 1.0 equiv) and the mixture was stirred until homogenous. Potassium carbonate (7.0 g, 50.4 mmol, 3.0 equiv) was then added and the reaction mixture was cooled to 0° C., followed by the addition of 35% hydrogen peroxide (6.5 mL). The reaction was stirred at 0° C. for 30 min and then warmed to room temperature. At this time, the reaction was diluted with water (50 mL) and ethyl acetate (100 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (3×50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel chromatography (10% EtOAC/hexanes) to afford 1.92 g (59%) of 1-(3-fluoropyridin-2-yl)cyclobutanecarboxamide as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C)C=O>[CH2:20]([O:9][C:8]([C:7]1[CH:6]=[CH:5][O:4][C:3]=1[Si:2]([CH3:12])([CH3:11])[CH3:1])=[O:10])[CH3:21]
Reactant: CCI
Reactant: C[Si](C)(C)c1occc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccoc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.3 %

Procedure:
2-Trimethylsilyl-3-furancarboxylic acid (16.4 g) (synthesized in accordance with the method described in J. C. S. Perkin, 1, 1125 (1981)) was dissolved in N,N-dimethylformamide (50 ml), and potassium carbonate (12.3 g) and iodoethane (13.9 g) were added. The mixture was stirred at room temperature for 15 hours, poured into ice water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) as oil. 2-Trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) was dissolved in acetonitrile (75 ml), and sulfuryl chloride (10.9 g) in acetonitrile (25 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-chloro-3-furancarboxylic acid ethyl ester (3.5 g) as oil. 2-Chloro-3-furancarboxylic acid ethyl ester (3.5 g) was dissolved in ethanol (25 ml), and 1N aqueous sodium hydroxide (25 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with diisopropyl ether-hexane to give 2-chloro-3-furancarboxylic acid (2.2 g) as crystals. mp 138°-141° C.
Reaction SMILES: C[C@H:2](NC([C@@H](NC([C@@H](NC(N[C@H](C(O)=O)CC(C)C)=O)[C@H]1NC(=N)NCC1)=O)CCC(N)=O)=O)[CH:3]=[O:4].[CH3:37][CH:38]([C:52]([OH:54])=[O:53])[C:39]1C=CC(C2C=CC=CC=2)=C(F)C=1.C[C@H]1[C@](O)(C(COP([O-])(O)=O)=O)[C@]2(C)[C@H]([C@H]3[C@](F)([C@@H](O)C2)[C@]2(C)C(=CC(C=C2)=O)CC3)C1.[Na+].C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@@H](CN)[C@@H](O)[C@H](O)[C@H]3N)[C@H]2O)[C@@H](O)[C@@H]1N.OS(O)(=O)=O>>[C:52]([O:54][CH2:2][CH2:3][OH:4])(=[O:53])[C:38]([CH3:37])=[CH2:39]
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CC(C)C[C@H](NC(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C=O)[C@@H]1CCNC(=N)N1)C(=O)O
Agent: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)COP(=O)([O-])O
Agent: NC[C@@H]1O[C@H](O[C@H]2[C@@H](O)[C@H](O[C@@H]3[C@@H](O)[C@H](N)C[C@H](N)[C@H]3O[C@H]3O[C@H](CN)[C@@H](O)[C@H](O)[C@H]3N)O[C@@H]2CO)[C@H](N)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Product: C=C(C)C(=O)OCCO

Procedure:
A mixture was prepared by combining aprotinin 1 g.; elastatinal 0.1 g.; flurbiprofen 0.1 g.; dexamethasone sodium phosphate 0.1 g.; neomycin sulfate; and physiological saline up to 100 g. A contact lens form the crosslinked polymer of 2-hydroxyethyl methacrylate (38 percent by weight of equilibrium water) was swelled in the given solution for 24 hours. The contact lens was used for the treatment of nonhealing corneal erosions. Within a week after application the reepithalization was sped up. Extraordinary results were attained after severe etching and burning of the anterior segment of the eye. The intraocular inflammation did not develop, the cornea did not exhibit ulceration and healed with a scar to place within a month. The transparency recovered in the periphery of the cornea.
Reaction SMILES: B.C1COCC1.[CH2:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=1[CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])=[O:11])[CH3:8]>C1COCC1>[CH2:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=1[CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cccc(O)c1CCCC(=O)O
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(O)c1CCCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Borane THF complex (56 ml of 1M in THF, 56 mmol) was slowy added to a solution of 4-[2-ethoxycarbonyl-6-hydroxyphenyl]butanoic acid in THF at 0° C. The solution was stirred for 2 hr and allowed to warm to room temperature. The reaction was quenched slowly with aqueous acetic acid (5 ml of 50%) and stirred until the bubbling subsided. The mixture was concentrated in vacuo to a slurry, which was dissolved in cold 10% potassium carbonate. The solution was extracted with ethyl acetate twice. The organic extracts were dried with brine and concentrated in vacuo to a tan oil that solidified upon standing (5.14 g, 84.9%).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])C([O-])=O.[Na+].CN(C=O)C>[Cu]I.C1(C)C=CC=CC=1>[F:16][C:12]([F:17])([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:11]([F:19])([F:18])[F:10]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: N#Cc1ccc(I)cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 160 °C
Yield: 52.3 %

Procedure:
A mixture of 4-iodobenzonitrile (10.0 g, 43.7 mmol), sodium pentafluoroproprionate (15.4 g, 82.9 mmol), and copper(I) iodide (16.6 g, 87.3 mmol), DMF (160 mL), and toluene (60 mL) was heated at 160° C. for 16 h, allowing most of the toluene to distil off. After cooling, ethyl acetate (200 mL) was added, and the mixture was filtered through diatomaceous earth, and the filtrate was partitioned between ethyl acetate/heptane and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (5.05 g 52%). Yellow oil, MS (EI) 221.1 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:12]1([S:18]([CH2:21][C:22]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([OH:33])[C:25]([C:34]3[CH:38]=[CH:37][O:36][CH:35]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:12]1([S:18]([CH2:21][C:22]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([O:33][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:25]([C:34]3[CH:38]=[CH:37][O:36][CH:35]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A solution of 2-[N-(t-butoxycarbonyl)amino]ethyl bromide (0.032 g) in DMF (0.5 ml) was added to a stirred cooled solution of ethyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 36, 0.05 g) and cesium carbonate (0.065 g) in DMF (0.5 ml) at 0° C. The resultant mixture was allowed to warm to room temperature, stirred for 3 hours then partitioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 20-25% to give ethyl 6-(benzenesulphonylmethyl)-2-[2-(t-butoxycarbonyl)amino-ethoxy]-3-(furan-3-yl)-benzoate (0.031 g) as a colourless gum.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:32]([C:34]1[CH:39]=[C:38]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)[CH:37]=[CH:36][CH:35]=1)#[N:33]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(C#N)c3)c2c1
Yield: 3.4 %

Procedure:
N-[3-(3-Cyanophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.75 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 380 mg of 3-cyanophenylboronic acid, 30 ml of dimethylformamide, 2.85 ml of a saturated aqueous sodium hydrogencarbonate solution and 37 mg of tetrakis(triphenylphosphine)palladium[0]. 20 mg of N-[3-(3-cyanophenyl)-1 H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 240° C. (analysis C21H16N4O4S2.H2O % calculated C, 53.61; H, 3.86; N, 11.91; O, 17.00; S, 13.63. % found C, 53.95; H, 3.85; N, 11.68; S, 13.18).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][O:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.Cl[CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>CC#N>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][O:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[CH2:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Reactant: ClCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCN1CCOCC1)Cc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Yield: 6.8 %

Procedure:
The product from step (v) of example 29 (360 mg, 0.78 mmol) was dissolved in MeCN (10 mL) and 4-(3-chloropropyl)morpholine hydrochloride (187 mg, 0.94 mmol) added at rt. Anhydrous K2CO3 (323 mg, 2.34 mmol) and sodium iodide (117 mg, 0.78 mmol) were added. The mixture was refluxed for 15 h. After cooling to room temperature, the crude product was purified by RPHPLC and the resulting residue was triturated with diethyl ether:EtOAc (5:1) at 0° C. The suspension was filtered to afford the title compound as a pale yellow solid (31 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])=[CH:16][CH:17]([C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:28][CH:29]=2)[C:18]=1C(OCC)=O)=[O:7])(C)(C)C.CCOC(C)=O>CC#N.O>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[CH2:35][C:15]1[CH:16]=[C:17]([C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:28][CH:29]=2)[C:18]2[C:6](=[O:7])[N:8]3[C@@H:9]([CH2:10][CH2:11][CH2:12]3)[C:13]=2[N:14]=1
Reactant: CCOC(=O)C1=C([C@@H]2CCCN2C(=O)OC(C)(C)C)NC(Cc2ccc(F)cc2F)=CC1c1cnc(C(=O)OCC)cn1
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(-c2cc(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Ethyl 5-[2-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-6-(2,4-difluorobenzyl)-3-(ethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2-pyrazinecarboxylate (1.3 g, 2.17 mmol) was dissolved in 8 mL of CH3CN and 4 mL of H2O. Ceric ammonium nitrate (2.38 g, 4.34 mmol) was added and the reaction mixture stirred at ambient temperature for 30 min and then EtOAc was added and the organics extracted and washed with H2O, brine, and then dried (Na2SO4), filtered and concentrated to a brown solid. The solid was subjected to TFA (4.5 mL in 1 mL CH2Cl2) for 1 h and then concentrated. The residue was redissolved in CH2Cl2 (5 mL) and treated with Et3N (3 mL). After 16 h the reaction mixture was concentrated to a brown foam. The residue was redissolved in EtOAc and washed 1× pH 4.5 buffer, 1× brine and the organics dried (Na2SO4), filtered and concentrated to yield 0.250 g (26% yield) of the title compound as a tan solid. 1H NMR (CDCl3, 400 MHz) δ 9.41 (s, 1H), 9.34 (s, 1H), 7.58 (s, 1H), 7.26–7.21 (m, 1H), 6.80 (dd, J=16.4, 7.4 Hz, 2H), 4.75 (dd, J=10.3, 6.2 Hz, 1H), 4.51 (dd,J=14.2, 7.1 Hz, 2H), 4.27 (s, 2H), 3.78–3.68 (m, 1H), 3.45–3.39 (m, 1H), 2.54–2.43 (m, 1H), 2.37–2.32 (m, 2H), 1.46–1.38 (m, 1H), 1.23 (t, J=7.2 Hz, 3H); ESMS m/z 451 (M+H)+, 449 (M−H)+.
Reaction SMILES: O.Cl.CO[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[N:14]([CH3:22])[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.[OH-].[Na+].[CH2:25]([OH:27])C>[Fe]>[CH3:25][O:27][C:9]1[CH:10]=[CH:5][C:6]([N:14]([CH3:22])[CH:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)=[CH:7][C:8]=1[NH2:11]
Reactant: COc1ccc([N+](=O)[O-])cc1N(C)C1CCN(C)CC1
Reactant: CCO
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(N(C)C2CCN(C)CC2)cc1N
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a 250 mL three necked round bottomed flask, added iron powder (1.99 grams, 6.81 mmol) and 10 mL of demineralized water. Stirred the mass for 5 minutes and added concentrated hydrochloric acid (12 mL) drop-wise. The reaction was exothermic. Further, heated the reaction mass to 50° C. and added a solution of 2-methoxy-5-nitro-N-methyl-N-(1-methyl piperidin-4-yl)phenylamine (1.9 grams, 6.81 mmol) obtained at step (IV) was dissolved in ethanol (20 mL), drop-wise through addition funnel. The reaction mass was heated at 78-80° C. for 4 hours. After completion of reaction (thin layer chromatography), ethanol was distilled off completely under reduced pressure to obtain oily mass. Added water (50 mL) and basified to pH: 9 using 50% aqueous sodium hydroxide solution. Filtered the inorganic and washed the cake with ethyl acetate (2×50 mL). The organic layer was separated and dried over anhydrous sodium sulfate and concentrated to obtain 2.31 grams of oily product.
Reaction SMILES: [CH3:1][N:2]1[CH2:33][CH2:32][CH2:31][C@@:3]1([CH3:34])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:27]([CH3:30])[CH2:28][CH3:29])[C@H:16]([O:25][CH3:26])[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[CH2:33][CH2:32][CH2:31][C@@:3]1([CH3:34])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:27]([CH3:30])[CH2:28][CH3:29])[C@H:16]([O:25][CH3:26])[CH2:17][C:18]([OH:20])=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Yield: 152 %

Procedure:
According to the general procedure B, from #202 (5.2 g, 10.77 mmol, 1 eq.), dichloromethane (45 mL), and trifluoroacetic acid (20 mL) was synthesized the crude desired material, to obtain #203 (7 g, quantitative yield) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[C:29]1[S:33][C:32]([CH3:34])=[N:31][CH:30]=1)=[O:4].Cl[C:36]1[CH:45]=[CH:44][C:43]2[CH2:42][CH2:41][N:40]3[C:46]4[CH:47]=[CH:48][CH:49]=[C:50]([F:53])[C:51]=4[CH:52]=[C:39]3[C:38]=2[N:37]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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]>[F:53][C:50]1[C:51]2[CH:52]=[C:39]3[C:38]4[N:37]=[C:36]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]6[O:7][C:6]([C:29]7[S:33][C:32]([CH3:34])=[N:31][CH:30]=7)=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:10]=5)[CH:45]=[CH:44][C:43]=4[CH2:42][CH2:41][N:40]3[C:46]=2[CH:47]=[CH:48][CH:49]=1
Reactant: CNC(=O)c1c(-c2cnc(C)s2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2cnc(C)s2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
To a degassed solution of N-methyl-6-(N-methylmethylsulfonamido)-2-(2-methylthiazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (200 mg, 0.40 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (113 mg, 0.41 mmol), Na2CO3 (84 mg, 0.79 mmol), K2CO3 (109 mg, 0.79 mmol) in 1,4-dioxane (5 mL) and H2O (0.1 mL) were added Pd2(dba)3 (10 mg) and X-Phos (10 mg) under N2. Then the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O and dried over Na2SO4. After concentrated, the residue was purified by prep-HPLC to give the product (30 mg, yield: 12%). 1H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 7.89 (s, 1H), 7.62˜7.68 (m, 2H), 7.45 (d, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.12˜7.20 (m, 2H), 6.74˜6.81 (m, 1H), 6.22 (d, J=4.0 Hz, 1H), 4.32 (t, J=6.4 Hz, 2H), 3.32 (s, 3H), 3.27˜3.31 (m, 2H), 3.02 (d, J=4.8 Hz, 3H), 2.75 (s, 3H), 2.74 (s, 3H). MS (M+H)+: 616.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:33]=[N:32][C:31]([OH:34])=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:15][CH2:16][N:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[CH:30][C:31](=[O:34])[N:32]([CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48])[N:33]=4)=[CH:24][CH:23]=3)=[O:21])[CH2:18][CH2:19]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: O=C(c1ccc(-c2ccc(O)nn2)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCn1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3)cc2)ccc1=O
Yield: 34.8 %

Procedure:
6-[4-({4-[(5-Chloro-1H-indol-2-yl)sulphonyl]piperazin-1-yl}carbonyl)phenyl]-pyridazin-3-ol (see WO 99/57113, 0.054 gram, 0.11 mmol), 0.016 gram of anhydrous potassium carbonate (0.11 mmol, 1.0 eq.) and 0.02 gram of 1-bromo-2-(2-methoxy-ethoxy)ethane (0.11 mmol, 1.0 eq.) were mixed in 1.5 mL of dry N,N-dimethylform-amide. The mixture was treated with microwave at 150° C. for 1 hour. Without any work-up, purification was performed on preparative HPLC, which gave 0.023 gram of 6-{4-[4-(5-chloro-1H-indole-2-sulphonyl)-piperazine-1-carbonyl]-phenyl}-2-[2-(2-methoxy-ethoxy)-ethyl]-2H-pyridazin-3-one (yield 36%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=1)[CH:14]=[CH:13]2.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O.CCOCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[O:25])=[CH:27][CH:28]=1)[CH2:14][CH2:13]2
Reactant: NC(=O)c1ccc(Cn2ccc3cc(CNCCc4cccs4)ccc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC(=O)c1ccc(CN2CCc3cc(CNCCc4cccs4)ccc32)cc1
Yield: 70.1 %

Procedure:
Mix 4-{5-[(2-Thiophen-2-yl-ethylamino)-methyl]-indol-1-ylmethyl}-benzamide (0.20 g, 0.51 mmol) and acetic acid (5 mL) in a flask. Add sodium cyanoborohydride (0.09 g, 1.52 mmol) and stir for 3 hrs. Neutralize reaction with 5M aqueous NaOH (10 mL) and dilute with water (50 mL). Extract with CH2Cl2 (3×50 mL). Purification on silica using 40:1 CH2Cl2/2M NH3 in CH3OH to 20:1 CH2Cl2/2M NH3 in CH3OH gradient eluent yields the product as an oily substance. Trituration with ether gives the product as a white solid (0.14 g, 72%). Mass spectrum (ion spray): m/z=392.2 (M+1); 1H NMR (DMSO-d6) 7.91 (bs, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.38 (d, J=7.9 Hz, 2H), 7.30 (bs, 1H), 7.27 (d, J=4.8 Hz, 1H), 6.99 (s, 1H), 6.92-6.87 (m, 2H), 6.82 (d, J=2.2 Hz, 1H), 6.46 (d, J=7.9 Hz, 1H), 4.25 (s, 2H), 3.54 (s, 2H), 3.21 (t, J=8.1 Hz, 2H), 2.92-2.81 (m, 4H), 2.69 (t, J=7.1 Hz, 2H).