Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8]([CH:10]=[C:11]([CH3:21])[CH2:12]P(=O)(OCC)OCC)=[O:9])C.[CH3:22][C:23]([CH:27]=[CH:28][CH:29]=[C:30]([CH3:37])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:24][CH:25]=O.[OH-].[K+].Cl>CCCCCC.O.O1CCCC1>[CH3:21][C:11]([CH:12]=[CH:25][CH:24]=[C:23]([CH3:22])[CH:27]=[CH:28][CH:29]=[C:30]([CH3:37])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:10][C:8]([OH:7])=[O:9]
Reactant: CC(C)=CCCC(C)=CC=CC(C)=CC=O
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Agent: CC[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CC=CC(C)=CC=CC(C)=CC(=O)O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suspension of 30.0 g of sodium ethoxide in 300 ml. of tetrahydrofuran was added 118 g. of diethyl 3-ethoxycarbonyl-2-methyl-2-propenylphosphonate. To the mixture was added 67 g. of 3,7,11-trimethyl-2,4,6,10-dodecatetraen-1-al under stirring, chilling with ice and shielding from the light. After 1 hour, the reaction liquid was poured into 1 liter of water, and 1 liter of n-hexane was added for extraction. The n-hexane phase was separated, washed with two 100 ml. portions of a mixture of methanol and water (2:1), and concentrated to give 99 g. of a concentrate. To a refluxing solution of 8.2 g. of potassium hydroxide and 80 ml. of ispropyl alcohol was added 21 g. of the concentrate under shielding from the light. After 15 minutes, the reaction liquid was poured into 300 ml. of ice-water, made acidic by addition of hydrochloric acid, and extracted with 300 ml. of diethyl ether. The extract was washed with three 100 ml. portions of water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue was dissolved in 200 ml. of n-hexane and chilled to -20° C. to crystallize. There was obtained 9.8 g. of the desired product as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[N:13]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>N>[NH2:13][C:3]1[C:4](=[O:12])[N:5]([CH2:9][CH2:10][CH3:11])[C:6](=[O:8])[NH:7][C:2]=1[NH2:1]
Reactant: CCCn1c(=O)[nH]c(N)c(N=O)c1=O
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCCn1c(=O)[nH]c(N)c(N)c1=O
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-amino-5-nitroso-3-propyl-1,3-dihydropyrimidine-2,4-dione (5.4 g, 27 mmol) in 12.5% aqueous ammonia (135 ml) at 70° C. was added sodium dithionite (Na2S2O4, 9.45 g, 54 mmol) in portions over 15 minutes, and the mixture was stirred for 20 minutes. The solution was concentrated under reduced pressure, cooled to 5° C., the precipitate filtered off, and washed with cold water, to provide 5,6-diamino-3-propyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (12).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[N+:2]=[N-:3].[OH-].[Na+]>CO>[N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:2]=[N-:3]
Reactant: CCOC(=O)COCCN=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=NCCOCC(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.3 %

Procedure:
To a solution of ethyl 2-azidoethoxyacetate (6.56 g, 37.9 mmol) in MeOH (80 ml) was added 1N aq. NaOH (80 ml) and the mixture was stirred at room temperature overnight (17 h). After removing the insoluble material, the methanol was evaporated in vacuo and this was saturated with sodium chloride and washed with ether (30 ml×3). The aqueous layer acidified with 3N HCl (30 ml) was extracted with ether (40 ml×4). The ether extracts were washed with brine, dried (MgSO4) and evaporated to yield 4.25 g (29.3 mmol, 77.3%) of 2-azidoethoxyacetic acid as a colourless oil: 1Hmr (CDCl3) δ: 3.3-4.0 (4H, m, --OCH2CH2N3), 4.22 (2H, s, --COCH2O--), 9.52 ppm (1H, s, --CO2H, exchanged with D2O); ir (neat) νmax : 2600-3300 (br,--CO 2 H) 2100 (azide) and 1740 cm-1C=O-CO2H). This material was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14]C(C)([O-])C.[K+].CI>CN(C=O)C>[CH3:14][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]=[CH:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: C(=Nc1ncc[nH]1)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccnc1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
N-(2-imidazolyl)benzylideneamine (0.2 g) was dissolved in DMF (4 ml), and potassium t-butoxide (0.15 g) and methyl iodide (0.18 g) were added. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform). The resulting crude crystals were recrystallized from diethyl ether--hexane to give the title compound (0.1 g, 49.9%) as pale yellow needles.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[N:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:23]3[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:7][N:6]2[CH:8]=1
Reactant: c1cc[nH]c1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(-n3cccc3)ccc2n1
Yield: 7 %

Procedure:
As described for Example 60, 6-iodo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (80 mg, 0.2 mmol) was converted, using pyrrole instead of benzamide, to the title compound (5 mg, 7%) which was obtained as a light yellow solid. MS: m/e=341.3 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=5)[N:13]=[CH:12][C:11]4=[O:21])[CH2:6][CH2:7]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: NC1CCN(CCn2c(=O)cnc3cc(F)ccc32)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=c1cnc2cc(F)ccc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoroquinoxalin-2(1H)-one (Intermediate 145, 87 mg, 0.30 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (50 mg, 0.30 mmol), and sodium triacetoxy borohydride (200 mg, 0.90 mmol) were reacted as described for Example 69 to give the free base of the title compound as an oil. The free base was taken up in isopropanol (10 mL) and treated with 2.0M HCl in ether (3 eq). Solvent was removed under reduced pressure. The resulting solid was triturated with dichloromethane/hexanes (2 mL/10 mL). The precipitate was collected by filtration to give 45 mg (29%) of the bis-hydrochloride salt of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:39]=[CH:38][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.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]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:39]=[CH:38][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: Brc1ccc(OCCCN2CCNCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCNCC4)cc3)cc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 67.6 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (100 mg, 0.311 mmol), 1-(3-(4-bromophenoxy)propyl)piperazine (149 mg, 0.373 mmol), 2.0M aqueous potassium carbonate (0.5 mL, 1.0 mmol), and Pd(dppf)Cl2 (30 mg, 0.03 mmol) in toluene/ethanol (1.44 mL/0.48 mL) was stirred at 110° C. for 2.5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by preparative TLC to give the title compound (90 mg, 70% yield) as a white solid.
Reaction SMILES: [H-].[Na+].Cl[C:4](Cl)(Cl)[CH2:5][O:6][C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:53])[C@@H:16]([NH:32][C:33](=[O:52])[C@@H:34]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:19]=2)[NH:10]1)=[O:8].[CH2:56](O)[CH2:57]C=C>O1CCCC1>[CH2:5]([O:6][C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:53])[C@@H:16]([NH:32][C:33](=[O:52])[C@@H:34]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:19]=2)[NH:10]1)=[O:8])[CH2:4][CH:56]=[CH2:57]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)C(=O)N2CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N2)cc1
Reactant: C=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCOC(=O)[C@@H]1CCCN(C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)N1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
Sodium hydride (6 mg, 0.139 mmol) was added to a solution of (S)-1-{(S)-2-[(S)-2-tert-butoxycarbonylamino-3-(4-methoxy-phenyl)-propionylamino]-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (570 mg, 0.698 mmol) and 3-buten-1-ol (601 μL, 6.98 mmol) in tetrahydrofuran (10 mL) and the reaction stirred at 50° C. under nitrogen for 18 h. The reaction was cooled and the mixture passed through a plug of silica gel (eluting twice with ethyl acetate, 50 mL) to afford the title compound (438 mg, 85%) as a colourless oil (438 mg, 85%). 1H NMR (300 MHz, CDCl3) δ0.20 (s, 6H), 1.00 (s, 9H), 1.10-140 (m, 2H), 1.40 (s, 9H), 1.72-1.86 (m, 2H), 2.33-2.46 (m, 3H), 2.60-3.05 (m, 5H), 3.50 (d, 11.4 Hz, 1H), 3.80 (s, 3H), 4.15-4.35 (m, 4H), 4.95 (br s, 1H), 5.09-5.19 (m, 2H), 5.60-5.70 (m, 1H), 5.71-5.87 (m, 1H), 6.42 (d, J=8.0 Hz, 1H), 6.62-6.80 (m, 3H), 6.82 (d, J=8.7 Hz, 2H), 7.07-7.16 (m, 3H). LCMS (m/z) 739.40 [M+H], Tr=5.82 min.
Reaction SMILES: [CH3:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[NH:18]O)[C:5](=[O:20])[C:4]=2[CH:3]=1.CO.Cl>[Zn].O>[CH3:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[NH2:18])[C:5](=[O:20])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)C(=O)c1c(NO)cccc1C2=O
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1C)C(=O)c1c(N)cccc1C2=O
Temperature: 70 °C

Procedure:
50 Parts of 2,3-dimethyl-5-hydroxylaminoanthraquinone was added to a mixture of 600 parts of methyl alcohol, 200 parts of water and 60 parts of a 35 % aqueous hydrochloric acid and the mixture was heated with stirring to 70°C, then added thereto 15 parts of zinc dust little by little over 1 hour. The reaction mixture was maintained at 70°C for additional 3 hours and then cooled to 25°C and filtered. The residue was washed with water and dried to obtain 42.8 parts of 2,3-dimethyl-5-aminoanthraquinone of a purity of 95 %.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:21][CH2:20][C@@H:19]([O:22][Si](C(C)C)(C(C)C)C(C)C)[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]1[NH2:33].C(O)(C)C>O>[NH2:33][CH:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C@H:19]([OH:22])[CH2:20][CH2:21][C@H:11]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[F:3]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)C(N)c2cccnc21)(C(C)C)C(C)C
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: NC1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Temperature: 82 °C
Yield: 124.2 %

Procedure:
To a 250 ml flask was charged (6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-amine di HCl salt (15 g, 25.88 mmol) and a solution of isopropanol:water (45 mL:15 mL). The mixture was heated to 82° C. for 6 h then dried via azeotropic distillation at atmospheric pressure using isopropanol until the KF was less than <3%. After fresh isopropanol (25 ml) was added, the mixture was heated to 70° C. and then isopropyl acetate (45 ml) was added that resulting in a white slurry. The slurry cooled to 22° C. for 15 min to afford a white solid (9.33 g, 99%). 1H NMR (500 MHz CD3OD) δ 8.77 (d, J=5.7 Hz, 1H), 8.47 (d, J=7.9 Hz, 1H), 8.11 (dd, J=6.0, 8.2 Hz, 1H), 7.21-7.32 (m, 3H), 5.53 (dd, J=3.8, 9.8 Hz, 1H) 5.33 (d, J=9.8 Hz, 1H), 3.5 (bm, 1H), 2.25-2.40 (m, 2H), 2.15 (bm, 1H), 1.90 (bm, 1H); 13C NMR (125 MHz, MeOD) δ 159.4, 153.9, 151.9 and 151.8, 149.7, 143.6, 141.8, 135.7, 130.6, 127.7, 126.8, 118.9, 70.0, 54.9, 42.2, 34.5, 33.4.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].C([O:13][C:14]1[CH:19]=[CH:18][C:17]([S+:20]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C(C)(C)C)=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(C)(C)C.FC(F)(F)S(O)(=O)=O>CO>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([S+:20]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc([S+](c2ccc(OC(C)(C)C)cc2)c2ccc(OC(C)(C)C)cc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Product: Cc1ccc([S+](c2ccc(O)cc2)c2ccc(O)cc2)cc1
Yield: 96 %

Procedure:
A solution of 28.5 g (0.05 mol) of bis(p-tert-butoxyphenyl)(p-methylphenyl)sulfonium trifluoromethanesulfonate and 1.5 g (0.01 mol) of trifluoromethanesulfonic acid in 400 g of methanol was heated at 60° to 70° C. for 6.5 hours with stirring. The reaction mixture was evaporated in vacuo. The residual oil was washed two times with 200 g of diethyl ether. The amount of this crude product was 22 g (96% yield). Without further purification, the crude product was used in subsequent reaction.
Reaction SMILES: [Na].Cl[C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:6]=[C:5]([NH2:22])[N:4]=1.[CH3:23][OH:24]>C(OCC)(=O)C>[F:21][C:17]1[CH:16]=[C:15]([C:7]2[C:8]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[C:3]([O:24][CH3:23])[N:4]=[C:5]([NH2:22])[N:6]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CO
Reactant: Nc1nc(Cl)c(-c2ccncc2)c(-c2cccc(F)c2)n1
Agent: [Na]
Solvent: CCOC(C)=O
Product: COc1nc(N)nc(-c2cccc(F)c2)c1-c1ccncc1
Temperature: 62.5 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
After sodium (20 mg, 0.870 mmol) was dissolved in methanol (3 ml), 4-chloro-6-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine (50 mg, 0.166 mmol) was added thereto and the mixture was stirred under an atmosphere of nitrogen gas at 60 to 65° C. for 30 minutes. After cooling as it was, the reaction mixture was diluted with ethyl acetate. Then, the mixture was washed with an aqueous ammonium chloride solution thrice and brine, dried over anhydrous sodium sulfate and concentrated. To the residue was added diethyl ether, and the resulting precipitates were collected by filtration and washed with diethyl ether, to give the title compound (16 mg, 32%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.CO[CH:35]1[CH2:39][CH2:38][CH:37](OC)O1>C(O)(=O)C>[N:27]1([CH2:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19]/[C:12](=[C:6]3\[C:7](=[O:11])[NH:8][C:9]4[C:5]\3=[CH:4][CH:3]=[C:2]([N:1]3[CH:35]=[CH:39][CH:38]=[CH:37]3)[CH:10]=4)/[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:21][CH:22]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=C1Nc2cc(-n3cccc3)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reaction time: 2 h

Procedure:
0.5 g of 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone are dissolved in 20 ml of glacial acetic acid and 0.2 ml of 2,5-dimethoxytetrahydrofuran are added. The mixture is refluxed for 1 hour, concentrated by evaporation and the residue is taken up in 20 ml of water. After another 2 hours' stirring the mixture is made basic with 1N sodium hydroxide solution, the aqueous phase is extracted with methylene chloride and the organic phase is dried over sodium sulphate. After elimination of the solvent the residue is purified through a silica gel column with methylene chloride/methanol (4:1) as eluant.
Reaction SMILES: COC1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2SC=C(C(O)=O)N=2)CC1)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][N:37]=[C:36]2[C:42]([NH:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[O:57][C:56]([C:58]([O:60]CC)=[O:59])=[CH:55][CH:54]=2)[CH2:48][CH2:47]1)=[O:43]>CCO>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][N:37]=[C:36]2[C:42]([NH:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[O:57][C:56]([C:58]([OH:60])=[O:59])=[CH:55][CH:54]=2)[CH2:48][CH2:47]1)=[O:43]
Reactant: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)o1
Agent: COc1ccc2[nH]nc(C(=O)NCC3CCN(Cc4nc(C(=O)O)cs4)CC3)c2c1
Solvent: CCO
Product: COc1ccc2[nH]nc(C(=O)NCC3CCN(Cc4ccc(C(=O)O)o4)CC3)c2c1

Procedure:
5-{[4-({[(5-Methoxy-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}furan-2-carboxylic acid 24 was prepared, according to the procedure described for compound 8, starting from compound 23 and using EtOH as solvent. Yield: 64 mg, 84%.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]CCC)=O.[NH2:21][C:22]1[CH:27]=[N:26][CH:25]=[C:24]([Cl:28])[N:23]=1>>[Cl:28][C:24]1[N:23]=[C:22]([NH:21][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:27]=[N:26][CH:25]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from propyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.O1CCOCC1.N1C=CC=CC=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(N(CC)CC)C>[C:30]([O:8][C:5]1[CH:4]=[C:3]([O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Oc1cc(=O)[nH]cc1Cl)c1cccnc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(Oc1cc(OC(=O)c2cccnc2)c(Cl)cn1)c1ccccc1
Yield: 54 %

Procedure:
A 300 ml quantity of 5-chloro-4-nicotinoyloxy-2-pyridone was suspended in a mixture solvent of 30 ml of dioxane and 10 ml of pyridine and to the suspension were added 0.17 ml of benzoyl chloride and 0.83 ml of triethylamine. The mixture was refluxed for 3 hours. The resulting reaction mixture was concentrated and the concentrate was subjected to silica gel column chromatography using as an eluent, chloroform, thereby producing 230 mg of the title compound in a yield of 54%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[CH:6]=[CH:5]2.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[F-].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:18]3[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=3)[CH:3]=2)[C:8]1=[O:12]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cn1ccc2cc(Br)ccc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc3c(=O)n(C)ccc3c2)cn1
Temperature: 90 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
A mixture of 6-bromo-2-methylisoquinolin-1-one (3.8 g, 16 mmol), 1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.69 g, 32 mmol), CsF (7.29 g, 48 mmol), Pd(PPh3)2Cl2 (0.4 g, 1 mmol) in dioxane/H2O (60/10 mL) was stirred at 90° C. for 12 h under N2. The mixture was concentrated and the residue was purified by silica gel chromatography (PE:EA=2:1) to give the title compound (3.1 g, 81%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.40 (d, J=12 Hz, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.59-7.56 (dt, J1=4 Hz, J2=8 Hz, 2H), 7.07 (d, J=4 Hz, 1H), 6.48 (d, J=8 Hz, 1H) 3.98 (s, 3H), 3.61 (s, 3H). LCMS: 240.0 (M+H)+
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1.N1C=CC=CC=1.[CH3:37][N:38]1[CH:42]=[C:41]([S:43](Cl)(=[O:45])=[O:44])[N:40]=[CH:39]1>CO.C(OCC)(=O)C>[Cl:4][C:5]1[C:6]([CH:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:7][C:8]([NH:11][S:43]([C:41]2[N:40]=[CH:39][N:38]([CH3:37])[CH:42]=2)(=[O:45])=[O:44])=[N:9][CH:10]=1
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1cnc(S(=O)(=O)Nc2cc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a methylene chloride (5 ml) solution of the [5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine (93 mg, 0.217 mmol) obtained in Example 196 and pyridine (21 μl, 0.260 mmol) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (47 mg, 0.260 mmol). The resulting mixture was stirred at room temperature for 18 hours. After pyridine (1 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 7 hours, the reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added ethyl acetate. The resulting mixture was washed sequentially with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the methanol:methylene chloride (=1:50) eluate was concentrated under reduced pressure to yield a white solid. The resulting white solid was washed with ethanol, and collected by filtration to give the title compound (68 mg, 0.119 mmol, 55%) as a white powder.