Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:21][OH:22])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([C:14]2([CH2:24][NH:25][CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1([C:14]2([CH2:24][N:25]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:39])([F:40])[F:38])[CH:28]=3)[C:1](=[O:3])[CH3:2])[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH2:15]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)(F)c1cc(CNCC2(c3ccccc3)CCC3(CC2)OCCO3)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Acetic anhydride (2 mL) was added to a solution of N-[(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl]-3,5-bis(trifluoromethyl)benzenemethanamine (Example 19, 291 mg, 0.61 mmol) in pyridine (5 mL) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (25 mL). The mixture was washed with aqueous copper sulphate (5%, 2×25 mL) and brine (25 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (316 mg, 100%). m/z (ES+) 516 (M+1).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[CH:10][C:11]([OH:13])=O)[CH:2]=[CH2:3].C(N(CC)CC)C>ClCCl>[CH2:3]1[CH:2]2[CH2:1][CH:4]3[C:5]([CH:10]2[C:11]1=[O:13])=[CH:6][CH2:7][CH2:8][CH2:9]3
Reactant: C=CCC1CCCCC1=CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC2CC3CCCC=C3C12
Yield: 83.3 %

Procedure:
A solution of 2-(2-allylcyclohexylidene)acetic acid (800 mg, 4.44 mmol) in dichloromethane (200 mL) was added Ghosez reagent (5.77 mmol, 0.795 mL) at room temperature. The solution was stirred for 45 min until the acid chloride was formed. Then N,N-dimethylaminopyridine (55 mg, 0.45 mmol) was added and the solution was heated to reflux. A solution of triethylamine (8.9 mmol, 1.25 mL) in dichloromethane (3.75 mL) was added dropwise over 30 min. The solution was refluxed for another 1 h and solvent was distilled off. Purification by flash chromatography (pentane/Et2O 95/5) gave 1,2a,4,5,6,6a,7,7a-octahydrocyclobuta[a]inden-2-one (600 mg, 83%) as a colourless liquid, with 20% of the tetrasubstituted regioisomere. 1H NMR (400 MHz, CDCl3) 5.59 (1H, brs), 3.92 (1H, brs), 3.21 (1H, dddd), 2.92 (1H, m), 2.73 (1H, m), 2.51 (1H, m), 2.04 (4H, m), 1.79 (1H, m), 1.48 (2H, m), 1.05 (1H, m).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CN(C)C=O.[Se:10]1(=[O:19])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][Se:10](=[O:19])[C:14]=2[CH:15]=1)(=[O:22])[CH3:21]
Reactant: O=[Se]1C=Nc2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)[Se](=O)C=N2

Procedure:
12 grams (0.09 mol) of aluminum chloride are introduced into a ground-necked flask. 3.1 cm3 (0.04 mol) of dimethylformamide are added dropwise with stirring. After cooling, two grams (0.01 mol) of benzoselenazolinone are added and the mixture is homogenized. It is heated to 70°-80° C. on an oil bath with stirring, and 0.01 to 0.012 mol of acetyl chloride is then added. heating is maintained at a temperature of 80°-90° C. for a time T of approximately 4 h 30 min. The mixture is hydrolyzed on crushed ice. The product is drained, dried, and washed with boiling cyclohexane and recrystallized in toluene.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.F[B-](F)(F)F.[CH3:16][O+](C)C>CCOC(C)=O>[I:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:16])[N:7]=2)[CH:3]=1
Reactant: C[O+](C)C
Reactant: Ic1ccc2[nH]ncc2c1
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc2cc(I)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a solution of 5-iodo-1H-indazole (500 g, 2.05 mol) in EtOAc (4 L) is added trimethyloxonium tetrafluoroborate (450 g, 3.04 mol). After the resulting white suspension is stirred at room temperature for 2 h, it is concentrated under vacuum. Ice water (1 L) is added to the residue, and it is basified to pH 12 with 10% aqueous NaOH solution. The solids are collected by filtration, and redissolved in DCM (5 L). The insolubles are filtered off and the filtrate is washed with 10% aqueous NaOH solution (2×100 mL). The organic layer is dried over anhydrous Na2SO4, filtered through a short silica gel column, and concentrated. Methyl tert-butyl ether is added to the residue to give a slurry and the product is collected by filtration to give the title compound (360 g, 68.0%). MS (m/z): 259.0 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH3:18][Li].O>C(OCC)C>[OH:1][C:2]1([CH3:18])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1
Reactant: O=C1Cc2ccccc2C=Cc2ccccc21
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC1(O)Cc2ccccc2C=Cc2ccccc21

Procedure:
To a stirred solution of 5-oxo-dibenzo[a,e]cyclooctene (10.0 g) in dry diethyl ether at 0° C. under nitrogen, was added over 5 minutes, through a canula, a solution of methyl lithium (40 ml of a 1.4M solution in diethyl ether). After a further 10 minutes stirring water (40 ml) was added cautiously and the separated aqueous layer discarded. The organic layer was washed with water. then dried and evaporated. Crystallisation from diethyl ether/hexane gave the pure alcohol (6.2 g), mp 108°-109° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:8])[CH2:3][CH2:2]1.Cl.Cl[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[N:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][C:11]=3[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:20])=[O:8])[CH2:3][CH2:2]2)=[CH:33][CH:34]=1
Reactant: ClCc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)C1CCN(Cc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
3-((Piperidin-4-yl)carbonylamino)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 228 is suspended in N,N-dimethylacetamide (3 ml), and thereto are added 4-(chloromethyl)pyridine hydrochloride (45 mg), sodium carbonate (80 mg) and sodium iodide (41 mg), and the mixture is stirred at room temperature for 12 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, then 1/1) to give the title compound (109 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([Cl:20])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-])(=[O:12])=[O:11].P(Cl)(Cl)Cl.C(Cl)(Cl)Cl>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([Cl:20])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(C)c(C(Cl)S(=O)(=O)c2cccc[n+]2[O-])c1
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1ccc(C)c(C(Cl)S(=O)(=O)c2ccccn2)c1
Yield: 79.2 %

Procedure:
A mixture of 2.0 g (0.0064 mole) of 2-[(2,5-dimethylphenyl)-chloromethylsulfonyl]-pyridine N-oxide, 3.5 g (0.026 mole) of PCl3 and 15 ml of chloroform was refluxed for one hour. Addition of ethanol to destroy excess PCl3 and evaporation of the solvents left 2.6 g of crude product. The crude material was recrystallized from ethanol to give 1.5 g (79%) of crystalline material having a melting point of 117-119° C. Infrared and NMR spectra were in agreement with the structure. Analysis calculated for C14H14ClNO2S: C=56.85; H=4.77; N=4.74. Found: C=56.67; H=4.78; N=4.81.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:22])[C:5]2[CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:8]=[N:9][C:10]=2[CH:11]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:25][O:22][C:4]1[CH:3]=[C:2]([CH3:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[N:8]=[N:9]2
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)cc2nnc(-c3cccc(C(F)(F)F)c3)cc12
Yield: 15.7 %

Procedure:
To an acetone solution (5 mL) of 7-methyl-3-(3-trifluoromethylphenyl)cinnolin-5-ol (30.4 mg, 0.1 mmol) obtained in Example 70 were added methyl iodide (0.006 mL, 0.11 mmol) and potassium carbonate (13.8 mg, 0.11 mmol), followed by reaction at room temperature over night. To residue obtained by concentration of the reaction liquid under reduced pressure was added distilled water (1 mL) and extracted with ethyl acetate. Residue obtained after concentration of an organic layer under reduced pressure was purified with silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain an objective compound (5 mg, 15%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5](=[NH:8])[NH:6][OH:7].[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=O)=[CH:20][CH:19]=1)#[N:17].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:8]=[C:22]([C:21]3[CH:25]=[CH:26][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)[O:7][N:6]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C#N)cc3)n2)cc1Cl
Temperature: 110 °C
Yield: 84.7 %

Procedure:
3-Chloro-N-hydroxy-4-isopropoxybenzimidamide (10 g, 43.7 mmol) was dissolved in DMF (219 ml) under nitrogen. The mixture was heated at about 110° C. for about 10 min. A solution of 4-cyanobenzoyl chloride (7.24 g, 43.7 mmol) dissolved in DMF (30 mL) was added dropwise over about 20 min and the reaction heated at about 110° C. for about 4 h. until LCMS shows reaction complete. The reaction was cooled in an ice bath and poured into rapidly stirred water (1000 mL). The resulting white precipitate was collected by vacuum filtration and washed with water. The precipitate was dissolved in methylene chloride and washed with 1 N HCl and then brine. The methylene chloride was dried over sodium sulfate, filtered, and evaporated. Heptane and DCM were added to the residue and the mixture heated until the DCM had boiled off after which the mixture was allowed to cool. Solids did not dissolve in hot heptane. The resulting solid was collected by vacuum filtration and washed with heptane to provide 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile (12.568 g, 37.0 mmol, 85% yield) as a tan solid: LCMS (Table 1, Method a) Rt=4.58 min.; MS m/z: 340.20 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[S:18]1[CH:22]=[CH:21][C:20]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)=[CH:19]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: OB(O)c1ccsc1
Product: Oc1ccc2ncn(-c3ccsc3)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and thiophen-3-ylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=218.1 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=4[S:10][C:9]=3[NH:8][C:7]=2[CH:21]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C@H:32]2[CH2:37]N[CH2:35][CH2:34][NH:33]2)=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C.[OH-].[Na+]>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH2:31][CH2:30][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[CH2:37]3)[C:13]3[C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=4[S:10][C:9]=3[NH:8][C:7]=2[CH:21]=1
Reactant: COc1ccc(CC[C@H]2CNCCN2)cc1
Reactant: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CC[C@H]2CN(C3=Nc4ccc(F)cc4Nc4sc5ccccc5c43)CCN2)cc1
Temperature: 25 °C
Reaction time: 51 h
Yield: 38.1 %

Procedure:
Add 9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride (0.66 g, 2.1 mmol) to a solution of (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (0.91 g, 4.1 mmol) in dimethyl sulfoxide: toluene (1:8, 9 mL). Add diisopropylethylamine (0.36 mL, 2.1 mmol), heat to 110° C., and stir. After 51 hours, cool to ambient temperature, and dilute with ethyl acetate and 0.1 N NaOH. Separate the aqueous layer and extract it with ethyl acetate (2×). Wash all organics with a saturated solution of sodium chloride, and then dry (sodium sulfate), filter, and concentrate them under reduced pressure to an oil (1.27 g). Purify the oil by flash chromatography, eluting with a gradient of a 3% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane). Reconstitute the material in ethyl acetate and wash it with a saturated solution of sodium chloride (2×) to remove residual dimethylsulfoxide. Back extract the combined aqueous layers with ethyl acetate. Dry (sodium sulfate) the organic phases, filter, and concentrate them under reduced pressure to give the title compound (0.389 g): mass spectrum (APCI+, m/e): 487 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[N:17]=[C:16]([C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][CH2:24][N:25]3C(OC(C)(C)C)=O)=[CH:20][CH:19]=2)[CH:15]=[CH:14][C:13]=1[O:35][S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])=[O:11]>C(Cl)Cl>[NH:25]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([C:16]3[N:17]=[C:12]([C:10]([O:9][CH3:8])=[O:11])[C:13]([O:35][S:36]([C:39]([F:41])([F:42])[F:40])(=[O:38])=[O:37])=[CH:14][CH:15]=3)[CH:27]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)ccc1OS(=O)(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (18 mL) was added to tert-butyl 7-(6-(methoxycarbonyl)-5-(trifluoromethylsulfonyloxy)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29E) (2.00 g, 3.9 mmol) in anhydrous DCM (25 mL). The reaction mixture was stirred at rt for 1.5 hours, concentrated under reduced pressure, diluted with DCM, and washed with saturated NaHCO3. The aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure to provide the desired product methyl 6-(1,2,3,4-tetrahydroquinolin-7-yl)-3-(trifluoromethylsulfonyloxy)picolinate (29F) in sufficient purity for subsequent use. NMR (300 MHz, CDCl3) δ 7.88 (1H d), 7.66 (1H, d), 7.39 (1H, d), 7.29 (1H, dd), 7.08 (1H, d), 4.03 (3H, s), 3.39 (2H, m), 2.83 (2H, t), 2.02 (2H, m).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[NH2:16][C:17]1[CH:18]=[C:19]([C:24]([Br:27])=[CH:25][N:26]=1)[C:20]([O:22][CH3:23])=[O:21].O>CO>[CH3:23][O:22][C:20]([C:19]1[C:24]([Br:27])=[CH:25][N:26]2[CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:16]=[C:17]2[CH:18]=1)=[O:21]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1cc(N)ncc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Bromoacetophenone (17.29 g, 87 mmol) and NaHCO3 (8.03 g, 96 mmol) were added to a solution of methyl 2-amino-5-bromoisonicotinate (20.07 g, 87 mmol) in methanol (240 ml), and the mixture was heated to reflux (5 h). After cooling to r.t., water (75 ml) was added, and the brown suspension was stirred (15 min) and filtered. The precipitate was washed with a small amount of methanol. The title compound (10.11 g, 35%) was dried under vacuum and was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([F:27])=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][C:24]([F:27])=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Br
Yield: 59.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-fluorothiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.63 g, 1.2 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.23 g, 1.4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellowish solid (0.41 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Br)=[CH:11][N:12]=[C:13]2[C:18]=1[N:17]=[C:16]([O:19][CH3:20])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1CCOCC1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[OH-].[K+]>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].C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: COc1ccc2ncc(Br)c(OCc3ccccc3)c2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2ncc(O)c(OCc3ccccc3)c2n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 53 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (36 mg, 0.039 mmol, 0.02 eq) is added at room temperature to a stirred solution of 8-benzyloxy-7-bromo-2-methoxy-[1,5]naphthyridine (680 mg, 1.97 mmol, 1.0 eq) in water (10 mL), and dioxane (20 mL), followed by 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47 mg, 0.099 mmol, 0.05 eq) and a solution of potassium hydroxide (220 mg, 3.94 mmol, 2.0 eq) in water (10 mL). After 6 hours stirring at 90° C., the reaction mixture is quenched with a 1N hydrochloric acid aqueous solution (4 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 4:1, v/v) to afford 4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ol as a light yellow solid (278 mg, 53% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][CH3:23])[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C.O1CCCC1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][CH3:23])[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1cc(Nc2cccc(F)c2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCNc1cc(Nc2cccc(F)c2)ncc1C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of ethyl 6-((3-fluorophenyl)amino)-4-(propylamino)nicotinate (S15, 247 mg) in ethanol (3 mL) and tetrahydrofuran (1.5 mL), 2.0 mol/L aqueous sodium hydroxide (0.78 mL) was added at room temperature, and the mixture was stirred at 50° C. for 1 hour. To the reaction mixture, 2.0 mol/L aqueous sodium hydroxide (0.39 mL) was added at 50° C., and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was cooled to room temperature, and then 1.0 mol/L aqueous hydrochloric acid was added to the reaction mixture until the mixture became acidic. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 6-((3-fluorophenyl)amino)-4-(propylamino)nicotinic acid (S16, 130 mg).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([OH:16])=[O:15])[CH:8]=[CH:7]2.[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>O>[C:17]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([OH:16])=[O:15])[CH:8]=[CH:7]2)(=[O:19])[CH3:18]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
In a 100 ml-reaction vessel, 16.7 g (2.53×10-1M) of potassium hydroxide and 85 ml of water were placed, followed by cooling to 0° C. To the mixture, 20.0 g (1.06×10-1M) of 6-hydroxy-2-naphthoic acid was added and dissolved therein. To the solution, 10.9 g (1.07×10-1M) of acetic anhydride was added dropwise in 40 minutes at 0° C. followed by stirring for 2 hours. After stirring, the reaction mixture was acidified with 6N-hydrochloric acid to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and drying to obtain 18.3 g of 6-acetoxy-2-naphthoic acid (Yield: 74.4%).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH:28][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(Br)C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
55.9 g (326.1 mmol) of 2-bromopropionic acid chloride is added in drops at 0° C. to 100 g (296.4 mmol) of glycine benzyl ester-p-toluenesulfonic acid salt and 33.0 g (326.1 mmol) of triethylamine in 400 ml of methylene chloride. The temperature is not allowed to exceed 5° C. After addition is completed, it is stirred for 1 hour at 0° C., then for 2 hours at room temperature. 500 ml of ice water is added, and the aqueous phase is set at pH 2 with 10% aqueous hydrochloric acid. The organic phase is separated, washed once with 300 ml of 5% aqueous soda solution and 400 ml of water. The organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is recrystallized from diisopropyl ether.