Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[C:24]([O:38][CH3:39])[CH:23]=2)[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=[C:8]2[N:7]=1)C.[OH-].[K+]>C(O)CO.O>[CH3:39][O:38][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[CH2:21][N:20]1[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=[C:8]2[N:7]=[C:6]1[NH2:5]
Reactant: CCOC(=O)Nc1nc2cc(-c3ccccc3)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccccc5)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
To a stirred solution of ethyl(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.090 g, 0.17 mmol) in ethylene glycol (10 mL) and water (10 mL) was added potassium hydroxide (1.00 g, 17.82 mmol). The mixture was heated to 100° C. After 48 h, the mixture was allowed to cool to room temperature and was diluted with water (30 mL). The mixture was extracted with dichloromethane (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to afford 0.027 g (34%) of the product as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 8.21 (s, 1H), 7.87 (s, 1H), 7.70-7.68 (m, 3H), 7.50 (s, 2H), 7.40 (s, 1H), 6.90-6.77 (m, 4H), 5.31 (s, 2H), 5.05 (s, 2H), 4.77 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H) ppm; (M+1)=468.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16]O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:25]>C(OCC)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][Br:25])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCc1cccc(Oc2ccccc2)c1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: BrCCCc1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 209.4 %

Procedure:
To a mixture of 21.0 grams (0.092 mole) of 3-(3-phenoxyphenyl)propanol and 1 mL of pyridine which had been cooled to 0° C. was added dropwise during a 20 minute period 8.27 grams (0.031 mole) of phosphorus tribromide. This mixture was stirred at 0° C. for 90 minutes and then at ambient temperature overnight. The reaction mixture was then diluted with 200 mL of diethyl ether, and the solution was washed successively twice with 50 mL of water, four times with 25 mL of a saturated, aqueous solution of sodium bicarbonate, once with 50 mL of water, and once with an aqueous solution of sodium chloride. After being dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under reduced pressure, leaving 18.9 grams of 3-(3-phenoxyphenyl)propyl bromide as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30](S(C)(=O)=O)[N:29]=1>O1CCCC1>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:30]1[N:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:28]([O:27][CH3:26])[N:29]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCOC(=O)Cc1ccccc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(c1nc(OC)cc(OC)n1)c1ccccc1C
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
n-Butyllithium (10 ml of 2N solution in pentane) was added dropwise to a stirred solution of di-isopropylamine (2.0 g) in dry tetrahydrofuran (40 ml) under nitrogen at -10° C. After stirring at this temperature for 15 minutes, the solution was cooled to -75° C., and a solution of ethyl (2-methylphenyl)acetate (3.56 g) in tetrahydrofuran (20 ml) was added dropwise. After stirring at -75° C. for one hour, 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine (4.36 g) was added in one portion, and the resulting suspension was allowed to warm slowly to room temperature before stirring overnight. The reaction mixture was then poured onto water (400 ml) and the resulting oil was extracted into ether (2×150 ml). The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated to give a yellow oil which was purified by chromatography to give 3.8 g of the desired product as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[CH:3]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>ClCCl>[Si:20]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[CH:3]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2ccsc2c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2ccsc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
6-Hydroxybenzothiophene (22, 8.55 g, 56.9 mmol) and imidazole (4.65 g, 68.3 mmol) were dissolved in dichloromethane (120 mL) and TBDMS-Cl (9.73 g, 62.6 mmol) dissolved in dichloromethane (50 mL) was slowly added at 0° C. The reaction mixture was agitated at 0° C. for 1 hour. After adding water and transferring the resulting solution to a separatory funnel, the dichloromethane layer was separated. The remaining organic compound was extracted three times with dichloromethane. After removing water using sodium sulfate, the solvent was removed under reduced pressure. Column chromatography yielded 6-(t-butyldimethylsilyloxy)benzothiophene (23, 13.6 g, 90%) as a liquid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3([C:34]#[N:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[N:6][C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH3:21])=[CH:15][CH:14]=2)[CH:9]=1.[OH-:36].[Na+]>CO.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3([C:34]([NH2:35])=[O:36])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:23]=2)=[N:6][C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH3:21])=[CH:15][CH:14]=2)[CH:9]=1
Reactant: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C#N)CCOCC5)c4)cnc3N)on2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C(N)=O)CCOCC5)c4)cnc3N)on2)cc1
Temperature: 100 °C

Procedure:
4-[4-[5-amino-6-[3-[4-(methylaminomethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-2-pyridyl]tetrahydropyran-4-carbonitrile (Trifluoroacetic Acid (1)) (18 mg, 0.03002 mmol) was dissolved in methanol (1 mL) and then 1 M sodium hydroxide solution (300.2 μL of 1 M, 0.3002 mmol) was added. The reaction mixture was heated in the microwave to 100° C. for 45 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracted organic layer was dried over MgSO4, filtered and concentrated in vacuo to a solid. Compound was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% trifluoroacetic acid in water; solvent B: acetonitrile) over 16 minutes at 25 mL/minutes], combined fractions were then freeze-dried to give 4-[4-[5-amino-6-[3-[4-(methylaminomethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-2-pyridyl]tetrahydropyran-4-carboxamide Compound I-13 as a yellow solid (6 mg, 31.37%). 1H NMR (400.0 MHz, DMSO-d6) δ 2.2-2.25 (m, 2H), 2.45-2.5 (m, 2H), 2.65-2.7 (m, 3H), 3.6-3.75 (m, 4H), 4.28-4.33 (m, 2H), 7.18-7.2 (m, 1H), 7.27-7.3 (m, 1H), 7.35-7.39 (m, 1H), 7.7 (d, 2H), 7.85 (s, 1H), 8.05 (d, 1H), 8.1 (s, 1H), 8.18 (d, 2H), 8.7 (d, 1H), 8.88 (br s, 2H), 9.05 (s, 1H); LC/MS m/z 486.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:4]([CH2:14][CH2:15][CH3:16])[CH:3]=1.[F:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:24]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[N:23]=2)=[O:25])=[C:4]([CH2:14][CH2:15][CH3:16])[CH:3]=1
Reactant: CCCc1cc(Cl)nnc1CNCC(C)C
Reactant: O=C(O)c1cccc(F)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCc1cc(Cl)nnc1CN(CC(C)C)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (6-chloro-4-propyl-pyridazin-3-ylmethyl)-isobutyl-amine (940 mg, 3.89 mmol) and 6-fluoro-pyridine-2-carboxylic acid (663 mg, 4.7 mmol) in CH2Cl2 (10 ml) is added EDCI (783 mg, 4.7 mmol) and DMAP (244 mg, 2 mmol). The mixture is stirred at room temperature overnight. Water (10 ml) is added and the layers are separated. The organic layer is washed with brine (10 ml), then dried (Na2SO4) and evaporated. Flash column purification of the residue (2:1 of hexane: ethyl acetate) provides the title product. 1H NMR (CDCl3) (mixture of rotamers) 7.89 (q, 0.7H), 7.81 (q, 0.3H), 7.69 (dd, 0.3H), 7.53 (dd, 0.7H), 7.34 (s, 0.7H), 7.20 (s, 0.3H), 6.99 (dd, 0.7H1), 6.91 (dd, 0.3H), 5.19 (s, 0.6H), 5.07 (s, 1.4H), 3.41 (d, 0.6H), 3.31 (d, 1.4H1), 2.75 (t, 1.4H1), 2.48 (t, 0.6H), 2.08-2.17 (m, 1H), 1.69-1.75 (m, 1.4H1), 1.54-1.60 (m, 0.6H), 1.02 (t, 2.11H), 0.99 (d, 1.8H), 0.97 (t, 0.9H), 0.80 (d, 4.2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:12][C:11]=2[C:23]([NH2:25])=[O:24])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl>[F:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[C:13]1[O:14][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][S:40]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)(=[O:42])=[O:41])=[CH:9][CH:8]=2)=[C:11]([C:23]([NH2:25])=[O:24])[N:12]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a suspension of 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide hydrochloride (0.030 g, 0.082 mmol) in DCM (2 mL) was added triethylamine (25 uL, 0.18 mmol) followed by 4-fluorobenzenesulfonyl chloride (0.016 g, 0.082 mmol) and the resulting mixture stirred at room temperature overnight. Triethylamine (13 uL, 0.093 mmol) followed by 4-fluorobenzenesulfonyl chloride (0.016 g, 0.082 mmol) was then added and the reaction stirred for a further 3 hours. After 2 hours triethylamine (6 uL, 0.043 mmol) and 4-fluorobenzenesulfonyl chloride (0.008 g, 0.041 mmol) was added. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-((4-fluorophenylsulfonamido)methyl)phenyl)oxazole-4-carboxamide (0.0230 g, 0.047 mmol, 57%) as a white solid. 1H NMR (DMSO) 4.07 (2H, d), 7.39 (6H, m), 7.74 (3H, m), 7.85 (2H, m), 8.13 (2H, d), 8.32 (1H, t). LCMS (2) Rt: 3.07 min; m/z (ES+) 488.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]1[CH2:12][O:11][CH:10]=[CH:9][CH2:8]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.C1COCC1>[O:11]1[CH2:12][CH2:7][CH2:8][CH2:9][CH:10]1[O:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: C1=COCCC1
Reactant: O=C(O)CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a mixture of 3-hydroxypropanoic acid (7.2 g, 80 mmol, TCI, TOKYO KASEI) and DHP (13.4 g, 160 mmol, Alfa) in dichloromethane (100 mL) and THF (100 mL) was added PPTS (2 g, 8 mmol, Aldrich) in portions. The reaction mixture was stirred at rt overnight, and was quenched with 50 mL of saturated NaHCO3 aqueous solution. The resulted mixture was extracted with dichloromethane (50 mL×5). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:1 (v/v) petroleum ether/EtOAc) to give colorless oil (7.8 g, 56%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18]O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:32][O:33][C:34](=[O:41])[CH2:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>C1COCC1>[CH3:32][O:33][C:34](=[O:41])[CH2:35][CH:36]1[CH2:40][CH2:39][N:38]([CH2:18][CH2:17][CH2:16][N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:37]1
Reactant: COC(=O)CC1CCNC1
Reactant: OCCCN1c2ccccc2CCc2ccccc21
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.1 %

Procedure:
3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propanol (2.0 g, 0.0079 mol, prepared as described in example 10) was dissolved in dry THF (25 ml) under an atmosphere of nitrogen, and triethylamine (2.75 ml) was added. Methanesulfonyl chloride (0.61 ml, 0.0079 mol) was added dropwise and when addition was complete the reaction mixture was stirred for 45 minutes. The mixture was filtered and 3-pyrrolidinacetic acid methyl ester (2.4 g, 0.012 mol) was added to the filtrate. The mixture was heated at reflux temperature for 4 h and then stirred at room temperature for 48 h. Triethylamine (2.2 ml) was added and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature the solvent was removed by evaporation in vacuo. The residue was purified by column chromatography on silica gel (125 g) using a mixture of dichloromethane and methanol (9:1) as eluent, affording 0.9 g (27%) of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-3-pyrrolidinacetic acid methyl ester as an oil. Rf : 0.15 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].BrCCC=C.O>O1CCCC1>[CH3:2][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: CCc1ccccn1
Reactant: [Li]CCCC
Agent: C=CCCBr
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(C)c1ccccn1
Temperature: -20 °C

Procedure:
A solution of 8.46 ml (0.074 mol) of 2-ethylpyridine in 35 ml of tetrahydrofuran was cooled to −20° C. and 47 ml of n-butyllithium (15 w.-% in hexane, 0.074 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature, stirred for another one hour and subsequently cooled back down to −20° C. A solution of 7.52 ml (0.074 mol) of 4-bromo-1-butene in 10 ml of tetrahydrofuran was then added at such a rate that the temperature remained at −20° C. The mixture was allowed to warm to room temperature, stirred for a further 14 hours and hydrolyzed with 50 ml of water. The organic phase was separated off and the aqueous phase was extracted three times with 30 ml each time of diethyl ether. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. The residue obtained in this way was distilled at 98-100° C./14 torr. This gave 8.95 g (75%) of 2-(1-methyl-4-pentenyl)pyridine.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.CS(O)(=O)=O.CS(O)(=O)=O.[CH3:34][C:35]1([N:39]([CH3:41])[CH3:40])[CH2:38][NH:37][CH2:36]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:37]5[CH2:38][C:35]([CH3:34])([N:39]([CH3:41])[CH3:40])[CH2:36]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN(C)C1(C)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Product: CN(C)C1(C)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)C1
Yield: 75.6 %

Procedure:
1-Cyclopropyl-7-fluoro-8-(3-methyl-3-dimethylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.58 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.45 g of 3-methyl-3-(dimethylamino)azetidine dimethanesulphonate. 1.55 g of 1-cyclopropyl-7-fluoro-8-(3-methyl-3-dimethylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 268° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20]1>C(Cl)Cl>[N:19]1([C:2]2[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=2)[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24]1
Reactant: C1=CCNCC1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A suspension of 10 g. of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 40 ml. of methylene chloride is treated with 20 ml. of 1,2,5,6-tetrahydropyridine and stirred at room temperature under an argon atmosphere for 16 hours. The resulting precipitate is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 203° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]3[C:16]([C:17]=2[O:18]C)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](OCC)(=O)[CH3:24]>S(=O)(=O)(O)O.C(O)C.O>[CH2:23]([O:22][C:20]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=1)=[O:21])[CH3:24]
Reactant: CCOC(C)=O
Reactant: COc1c(Cc2ccccc2)cc(C(=O)O)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(Cc2ccccc2)c(O)c2ccccc12
Yield: 62 %

Procedure:
A solution of the compound of Example 95 (2.55 g, 9.2 mmole) and concentrated sulfuric acid (3 drops) in ethanol (125 mL) was heated at reflux for 80 hours. The mixture was cooled and diluted with water, and the crude product was isolated by extraction with ethyl acetate. This was chromatographed (9:1 hexane/ethyl acetate) and recrystallized (hexane) to provide the title compound (1.74 g 62%) as white needles, mp 79°-80°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:30][C:31]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:34]([NH2:35])=[C:33]([O:41][CH3:42])[CH:32]=1>CC(O)CCC>[Br:30][C:31]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:34]([NH:35][C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH3:17])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(Br)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 73.5 %

Procedure:
A solution of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate 130, 0.829 g, 3.40 mmol), p-toluene sulphonic acid monohydrate (0.924 g, 4.86 mmol) and 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 0.8 g, 3.24 mmol) was heated at reflux in 2-pentanol (32 mL) under an atmosphere of N2 for 18 h. The mixture was then allowed to cool, and was then concentrated in vacuo. The resulting residue was triturated with CH3CN until a yellow precipitate formed. This solid was collected by filtration and was washed with diethyl ether. The solid was suspended in 10% CH3OH in CH2Cl2 and washed with saturated aqueous NaHCO3 (2×) followed by water. The organic solution was then concentrated in vacuo, and the resulting residue was triturated in CH3CN/water. The mixture was then filtered, and the collected solid was washed with CH3CN followed by diethyl ether and was then air dried to give the title compound (1.082 g, 74%) as a yellow solid; 1H NMR: 3.90 (3H, s), 4.05 (3H, s), 7.15-7.21 (1H, m), 7.26-7.31 (1H, m), 7.36 (1H, d), 7.52 (1H, s), 7.56 (1H, d), 8.34 (1H, s), 8.39 (1H, s), 8.40-8.45 (2H, m), 9.20 (1H, s); m/z: ES+ MH+ 454/456.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[F:22][C:23]([F:29])([F:28])[S:24](O)(=[O:26])=[O:25]>C1(C)C=CC=CC=1>[F:22][C:23]([F:29])([F:28])[S:24]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:26])=[O:25]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 5 liter four-necked flask equipped with a thermometer, a Dimroth condenser, a calcium chloride tube and a stirrer, 190.0 g (0.904 moles) of dimethyl 5-hydroxyisophthalate, 3 liters of dehydrated toluene and 214.7 g (2.718 moles) of dehydrated pyridine were placed and the resultant mixture was cooled at −30° C. under stirring. To the cooled mixture, 510.2 g (1.808 moles) of anhydrous trifluoromethanesulfonic acid was slowly added dropwise with sufficient care so that the temperature did not exceed −25° C. It took 1 hour to complete the addition. After the addition was completed, the temperature of the reaction was elevated at 0° C. and the reaction was allowed to proceed for 1 hour. Then, the temperature was elevated to the room temperature and the reaction was allowed to proceed for 5 hours. The obtained reaction mixture was poured into 4 liters of ice water and separated into an aqueous layer and an organic layer. The aqueous layer was treated twice by extraction with 500 ml of toluene and the extract was combined with the organic layer. The obtained organic layer was washed twice with 3 liters of water and dried with 100 g of anhydrous magnesium sulfate. From the resultant mixture, anhydrous magnesium sulfate was removed by filtration and toluene was removed by distillation using a rotary evaporator. After drying under a reduced pressure, 294.0 g of dimethyl 5-trifluoromethanesulfonyloxyisophthalate was obtained as a light yellow solid substance (the yield: 95%). The crude product obtained above was recrystallized from hexane and white needle crystals were obtained. The obtained crystals were used for the next reaction.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:19]=[O:20].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[CH:4][C:3]=2[CH:19]=[O:20])=[CH:29][CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(Oc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2C=O)cc1
Temperature: 160 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A mixture of 4-fluoro-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde (750 mg, 2.639 mmol), 4-(tert-butyl)phenol (436 mg, 2.903 mmol), potassium carbonate (547 mg, 3.958 mmol) and dimethylacetamide (4 ml) was stirred at 160° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=15:1) to give the title compound (598 mg, 54.7%) as a pale yellow solid.