Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([OH:25])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13])[N:8]=[CH:7]2.[N+:26]([O-])([O-:28])=[O:27].[Na+].O>O1CCCC1.C(O)(=O)C>[OH:25][C:3]1[C:2]([N+:26]([O-:28])=[O:27])=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])[O-]
Reactant: C[C@@H](Cn1ncc2ccc(O)c(Br)c21)NC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(O)c([N+](=O)[O-])c21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of the product from Step B (3.76 g, 9.3 mmol) in tetrahydrofuran (20 mL) and acetic acid (10 mL) was cooled in an ice bath, sodium nitrate (1.93 g, 27.9 mmol) was added and the reaction mixture was stirred for 1 h followed by warming to room temperature and stirring for one hour. Water (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate (2×100 m), dried over magnesium sulfate, filtered, and evaporated to an oil (2.87 g). This residue was purified by chromatography (silica gel, hexane/ethyl acetate) to give a tan foam (2.44 g, 71%): LC/MS m/z 371. This was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[S:33])[CH:27]=[C:28]([CH3:30])[CH:29]=1.C(N(CC)CC)C>>[CH3:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:33])[CH:27]=[C:28]([CH3:30])[CH:29]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: Cc1cc(C)cc(N=C=S)c1
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cc(C)cc(C)c4)CC3)nc21

Procedure:
Pipemidic acid (45 mg, 0.148 mmol), 3,5-dimethylphenyl isothiocyanate (24 mg, 0.148 mmol) and triethylamine (41 μL, 296 mmol) were used. Purification on silica yielded compound 22 in Table 1, below (41.6 mg, 67%). 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 1H), 8.66 (s, 1H), 7.48 (s, 1H), 6.86-6.75 (m, 3H), 4.33 (q, J=7.10 Hz, 2H), 4.22-3.91 (m, 8H), 2.30 (s, 6H), 1.48 (t, J=7.11 Hz, 3H) ppm.
Reaction SMILES: [NH:1]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>C(O)C.O.[Li+].[OH-]>[N:1]1([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: C1CNCCNCCCNCCNC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(CN2CCCNCCNCCCNCC2)cc1
Reaction time: 5 h
Yield: 66.6 %

Procedure:
To solution of Cyclam (0.913 g, 4.5 mmol) dissolved in a mixture of ethanol:water (5:1 by vol.) (18 ml) was added a solution of 4-chloromethylbenzoic acid (0.157 g, 0.92 mmol) in aqueous LiOH (53 mg in 4 ml of water). This mixture was thereafter refluxed vigorously with stirring for 5 hours. Then the solvent was removed at reduced pressure, and the residue was dissolved in 13 ml of water. The aqueous solution obtained was then extracted with chloroform (10 times 3 ml) and the aqueous layer was concentrated at reduced pressure down to 2 ml. The product as a white solid was precipitated by adding the solution of concentrated HCl and ethanol and purified by recrystallizing from ethanol/water/HCl to yield 0.205 g of the title compound. According to the LC-MS, the assay of 4-(1,4,8,11-tetraazacyclotetradec-1-ylmethyl)-benzoic acid hydrochloride was >95%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:24].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:24])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 283.4 %

Procedure:
To a solution of 4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017 mol) in 10 mL of DMSO was added hydrogen peroxide (0.24 mL of 30% aqueous solution, 1.7 mmol) and potassium carbonate (0.04 g, 0.4 mmol) at 0° C. The mixture was stirred for 1 hour while allowing it to warm to room temperature. Water was added and the precipitate was collected by filtration and air-dried to give 0.32 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide as a white solid (67% yield), mp: 230–231° C. Anal. Calc'd for C15H11FN4O: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)O)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:31])[CH3:30])[N:21]=[CH:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])(C(C)(C)C)(C)C.[CH:43](O)=[O:44]>CC(=O)OCC.O.[Zn]>[CH:43]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH2:32][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:30])[CH3:31])[N:21]=[CH:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])=[O:44]
Reactant: O=CO
Reactant: CC(C)c1ccccc1-c1ncc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1ccccc1-c1ncc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 50 °C
Yield: 56 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-5-((4-chlorophenyl)(hydroxy)methyl)-6-(2-isopropylphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 0.0247 mmol) in HCOOH (1 mL) was added Zn dust (8 mg, 0.123 mmol). The reaction was heated at 50° C. for 1 h, cooled to RT then diluted with EA (5 mL) and water (1 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 3-(5-(4-chlorobenzyl)-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (7 mg, 56% yield) as a colorless oil. LCMS: MH+ 506 and TR=2.225 min.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl.[H][H].CCOCC>C(O)C.CO.[Pd]>[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[CH:30][CH:31]=1
Reactant: c1ccc(COc2ccc(OCCN3CCC(Cc4ccccc4)CC3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: Oc1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 1-[2-(4-benzyloxyphenoxy)ethyl]-4-benzylpiperidine hydrochloride (401 mg, 1.0 mmol) in 25 mL of ethanol was added 1.0 mL of 1 M HCl in methanol and 100 mg of 10% Pd/C. The resulting mixture was hydrogenated at 30 psi of hydrogen for 2 h. The catalyst was removed through a short column of celite (5 g) and washed with methanol (3×15 mL). The combined flitrate was evaporated in vacuo to give an oil and then ether (30 mL) was added to the residue. The resulting mixture was allowed to stir at rt overnight. The white solid was collected by filtration and dried in vacuo, giving 330 mg (100%) of the title product. mp 212-215° C. 1H NMR (CDCl3 +DMSO-d3) 1.656 (m, 3 H), 1.829 (m, 2 H), 2.425 (s, 2 H), 2.626 (m, 2 H), 3.187 (m, 2 H), 3.4 (brs, 1 H), 4.253 (s, 2 H), 6.549 (m, 4 H), 6.942-7.092 (m, 5 H), 12.0 (brs, 1 H).
Reaction SMILES: Br[C:2]1[S:19][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:9]([CH3:11])[O:10][C:4]=2[C:3]=1[CH:20]([CH3:22])[CH3:21].[CH3:23]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[CH3:11][CH:9]1[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]2[S:19][C:2]([CH3:23])=[C:3]([CH:20]([CH3:22])[CH3:21])[C:4]=2[O:10]1
Reactant: CB(O)O
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2sc(Br)c(C(C)C)c2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1sc2c(c1C(C)C)OC(C)CN(C(=O)OC(C)(C)C)C2
Yield: 81.8 %

Procedure:
A solution of tert-butyl 7-bromo-2-methyl-8-(1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (390 mg), methylboronic acid (239 mg), potassium phosphate (849 mg), tetrakis(triphenylphosphine)palladium (116 mg) and DME (4 mL) was stirred at 80° C. for 20 hr, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 3→7% ethyl acetate/hexane) to give the title compound (266 mg, 82%) as a solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.[N:16]1[N:17]([CH:21]([CH3:26])[C:22](OC)=[O:23])[N:18]=[N:19][CH:20]=1.Cl>O1CCCC1.O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:22]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:11])[F:12])=[CH:9][CH:8]=2)([OH:23])[CH:21]([N:17]2[N:18]=[N:19][CH:20]=[N:16]2)[CH3:26])=[CH:6][CH:5]=1
Reactant: COC(=O)C(C)n1ncnn1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(n1ncnn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of 4-trifluoromethoxybromobenzene (45.79 g) in dry tetrahydrofuran (200 cm3) was added carefully to a stirred mixture of magnesium turnings (4.56 g), iodine (1 crystal) and dry tetrahydrofuran (70 cm3). The reaction commenced after about 20 cm3 of the solution had been added, and the reaction was maintained at the reflux temperature whilst the remainder of the solution was added, and thereafter for a further 1 hour. The mixture was cooled to the ambient temperature and a solution of methyl 2-(1,2,3,4-2H-tetrazol-2-yl)propionate (13.95 g), in dry tetrahydrofuran (60 ml) added dropwise, after which the mixture was heated at the reflux temperature for 30 minutes. The mixture was cooled and poured into water (500 cm3) and acidified with 2N hydrochloric acid (250 cm3). The aqueous mixture was extracted with diethylether (3×400 cm3), the ethereal extracts combined, dried over anhydrous magnesium sulphate, and concentrated by removal of the solvent by evaporation under reduced pressure. The residual oil (30.5 g) was subjected to purification by chromatography using a silica gel column eluted with a mixture of hexane (4 parts by volume) and ethylacetate (1 part by volume), and by hplc to yield 1,1-bis(4-trifluoromethoxyphenyl)-2-(1,2,3,4-2H-tetrazol-2-yl)propan-1-ol as a colourless oil (10 g) which crystallized on standing (mp. 55°-58° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[N:17]=[CH:16][NH:15][C:14]=1[CH:18]=O>>[Cl:1][C:2]1[C:3]2[C:10](=[CH:18][C:14]3[NH:15][CH:16]=[N:17][C:13]=3[CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1nc[nH]c1C=O
Reactant: O=C1Cc2c(Cl)ncnc2N1
Product: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Yield: 76.9 %

Procedure:
4-Chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1 eq.) was condensed with 5-methyl-3H-imidazole4-carbaldehyde (1 eq.) at room temperature to give (76.9%) of 4-chloro-5-(5-methyl-3H-imidazol-4-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2.[OH-].[K+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cc(F)ccc2n1Cc1ccncc1
Yield: 78.8 %

Procedure:
A solution of 2.1 g (7.04 mmol) of ethyl 5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylate (WO 2007/010144) and of 1.18 g (21.12 mmol) of potassium hydroxide in 80 ml of ethanol and 2 ml of water is refluxed for 2 hours. The reaction mixture is subsequently concentrated under reduced pressure. 100 ml of water are added and the pH of the solution is brought to pH 8 by the addition of a concentrated hydrochloric acid solution. A precipitate is recovered by filtration and is washed with water and then dried under reduced pressure. 1.5 g of the expected product are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][CH3:24])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:31])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][CH3:24])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COCCN1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COCCN1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(2-methoxyethyl)piperazin-1-yl]quinolin-7-yl}ethanone (22 mg, 0.063 mmol) and ammonium acetate (48.8 mg, 0.632 mmol) in methanol (0.36 mL) and acetonitrile (0.36 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (7.95 mg, 0.126 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness (22 mg, 99%). The residue was used directly in the next step. LCMS calculated for C18H26ClN4O(M+H)+: m/z=349.2; found: 349.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].Cl[CH:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21](O)=[O:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:21](=[O:22])[CH:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)CC(Cl)C(=O)O
Reactant: CC(C)CN
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(CC(C)C)C(=O)N1CC(C)C

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-isobutyl-1,3-thiazolidin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:73][O:74][CH2:75][CH2:76]O.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:76][CH2:75][O:74][CH3:73])=[O:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: COCCO
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOC(=O)CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoic acid (300 mg, 0.56 mmol) in 10 ml of anhydrous DMF were added HATU (255 mg, 0.67 mmol) and N,N-diisopropylethylamine (217 mg, 1.68 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 2-methoxyethanol (0.50 ml, 6.3 mmol). The mixture was heated at 66° C. for 1 hour, and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with ethyl acetate to give 2-methoxyethyl 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate as white solid. Yield: 215 mg, 65%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2([C:11](OCC)=[O:12])[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[N:17]=2)[N:3]=1.CC(C)([O-])C.[K+].O.C(O)(=O)C>C1COCC1>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[CH2:25][N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:4]2[N:5]=[CH:6][C:7]3[C:8]4([CH2:9][CH2:10]4)[C:11](=[O:12])[NH:1][C:2]=3[N:3]=2)=[N:17]1
Reactant: CCOC(=O)C1(c2cnc(-c3nn(Cc4ccc(F)cc4F)c4ncccc34)nc2N)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2nc(-c3nn(Cc4ccc(F)cc4F)c4ncccc34)ncc2C12CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The intermediate from Step b) was taken up in 20 ml of THF, 109 mg (0.974 mmol) of potassium tert-butoxide were added under an atmosphere of argon and the mixture was stirred at RT for 2 h. Water was added, and the pH of the reaction mixture was adjusted to pH=5 with acetic acid. The mixture was stirred at RT for 10 min and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase:acetonitrile/water with 0.1% formic acid, gradient 50:50→70:30). This gave 101 mg of the title compound (25% of theory).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1([F:37])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([NH:35]N)[C:28]=2[O:27]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:37][C:26]1([F:25])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([N:35]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[C:28]=2[O:27]1
Reactant: NNc1cccc2c1OC(F)(F)O2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4c3OC(F)(F)O4)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=473.2 (M+H)+
Reaction SMILES: P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C.[C:18]([C:21]1[N:30]=[C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]3[O:39][CH2:40][O:41][C:35]=3[CH:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:42])[CH:27]=2)[N:22]=1)(O)=[O:19].[NH2:43][CH2:44][CH2:45][S:46]([O-:49])(=[O:48])=[O:47].[Na+].Cl>CN(C)C=O.O>[ClH:42].[S:46]([CH2:45][CH2:44][NH:43][C:18]([C:21]1[N:30]=[C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]3[O:39][CH2:40][O:41][C:35]=3[CH:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:42])[CH:27]=2)[N:22]=1)=[O:19])([OH:49])(=[O:48])=[O:47]
Reactant: NCCS(=O)(=O)[O-]
Reactant: O=C(O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCS(=O)(=O)O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Yield: 173.8 %

Procedure:
0.60 ml (3.8 mmol) of diethyl cyanophosphate and 0.90 ml (6.4 mmol) of triethylamine were dropped, in this order, into a solution of 0.50 g (1.4 mmol) of 2-carboxy-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline and 0.28 g (1.9 mmol) of sodium 2-aminoethanesulfonate in 15 ml of dimethylformamide under cooling with ice and stirring. The obtained mixture was stirred at room temperature for several days, followed by the addition of 10 ml of 1N hydrochloric acid and water. The crystals thus precipitated were recovered by filtration, washed with water and air-dried to give 0.61 g of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([NH2:10])[CH2:5]1)[CH:2]=[CH2:3].C(O[CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([NH:10][CH:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCCC(N)C1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: C=CCN1CCCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
Refluxing 1-allyl-3-aminopiperidine and 9-acetoxyxanthene in dry toluene for 24 hours and working up by the procedure of Example 1 gives N-(N-allyl-3-piperidinyl)-9-xanthenylamine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=[C:27]2[C:31]=1[NH:30][CH:29]=[CH:28]2>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:30]3[C:31]4[C:27](=[CH:26][C:25]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:24][C:23]=4[F:22])[CH:28]=[CH:29]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CS(=O)(=O)c1cc(F)c2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)cc(F)c43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06) and 7-Fluoro-5-(methylsulfonyl)-1H-indole (intermediate-22) (0.060 g, 23%).