Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])[CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>>[O:23]=[S:22]1(=[O:24])[CH2:21][CH2:20][CH2:19][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1N1CCOC1=O
Reactant: O=S(=O)(Cl)CCCCl
Product: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1N1CCOC1=O

Procedure:
To a mixture of methyl 2-bromo-4-nitrobenzoate (2 g), oxazolidin-2-one (0.67 g), potassium carbonate (2.06 g), copper(I) iodide (0.73 g) and N,N′-dimethylethylenediamine (0.83 mL) was added toluene (16 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give methyl 4-nitro-2-(2-oxo-oxazolidin-3-yl)benzoate (960 mg). To a solution of ethanol (24 mL) and water (5 mL) were added ammonium chloride (0.11 g) and iron (0.79 g), and a solution of the obtained methyl 4-nitro-2-(2-oxooxazolidin-3-yl)benzoate (960 mg) in ethanol (19 mL) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give methyl 4-amino-2-(2-oxooxazolidin-3-yl)benzoate (730 mg). Using the obtained methyl 4-amino-2-(2-oxooxazolidin-3-yl)benzoate (730 mg) and 3-chloropropane-1-sulfonyl chloride (0.49 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (495 mg) was obtained.
Reaction SMILES: [B:1]1([CH2:10][CH2:11][CH2:12][CH2:13][Br:14])OC2C(=CC=CC=2)O1.[OH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[Br:14][CH2:13][CH2:12][CH2:11][CH2:10][B:1]1[O:22][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:15]1
Reactant: BrCCCCB1Oc2ccccc2O1
Reactant: CC(C)(O)C(C)(C)O
Solvent: C1CCOC1
Product: CC1(C)OB(CCCCBr)OC1(C)C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
After gently warming until melted, 4-bromo-1-butylboronic acid catechol ester (112.2 g, 0.44 mol, 1.0 equiv), while under a stream of nitrogen, was added to a 3-necked 500 mL round-bottomed flask, diluted with freshly distilled THF (150 mL, 3.0 M) and treated with pinacol (104.0 g, 0.88 mol, 2 equiv) in one portion. After stirring for 16 h under a nitrogen atmosphere the resulting solution was concentrated. The crude product was diluted with heptane (500 mL) and cooled in an ice-water bath. After 1 h, the precipitated catechol was removed by filtration and the remaining solution was filtered through a short pad of silica gel (500 g) wetted with heptane. After eluting with solutions of 5% ethyl acetate in heptane (700 mL) and 10% ethyl acetate in heptane (700 mL), the filtrate was concentrated to give 2-(4-bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil (112.7 g, 97%). 1H NMR (CDCl3, 300 MHz) δ 3.38 (t, J=6.6 Hz, 2H), 1.90-1.78 (m, 2H), 1.58-1.44 (m, 2H), 1.26 (s, 12H), 0.78 (t, J=7.5 Hz, 2H); ESI-LCMS m/z calcd for C10H20BBrO2: expected 262.1. found 263.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:20])([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[O:8][CH2:7][CH2:6]2.C(O)(=[O:23])C>O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:20])([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[O:8][CH2:7][C:6]2=[O:23]
Reactant: CC(=O)O
Reactant: COc1cc2c(cc1OC)C(C)(CCC(=O)O)OCC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: COc1cc2c(cc1OC)C(C)(CCC(=O)O)OCC2=O
Reaction time: 1.5 h

Procedure:
A solution of chromium trioxide (25.7 g) in a mixture of acetic acid (120 ml) and water (35 ml) is added dropwise to a solution of 6,7-dimethoxy-1-methylisochroman propionic acid (27.0 g), described in Example 16, in acetic acid (140 ml) keeping the temperature of the mixture below 20° C. The mixture is kept at room temperature for 1.5 hr. and then poured into water and extracted with chloroform. The extracts are thoroughly washed with water, dried and evaporated. The residue is crystallized from benzene to give the title compound, m.p. 172°-173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([OH:13])[C:11]3[S:14][CH2:15][CH2:16][S:17][C:10]=3[C:9]2=[O:18])=[N:6][CH:7]=1.[H-].[Na+].Cl[C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23].C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]([O:18][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[C:10]3[S:17][CH2:16][CH2:15][S:14][C:11]=3[C:12]2=[O:13])=[N:6][CH:7]=1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc(Cl)cn1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (15.0 g.) in anhydrous tetrahydrofuran (150 cc.) is treated for 15 minutes at about 10°-15°C with sodium hydride (1.44 g.), and a solution of 1-chlorocarbonyl-4methylpiperazine (24.4 g.) in anhydrous tetrahydrofuran (200 cc.) is then added, at 5°C. The reaction mixture is stirred for 4 hours at 5°C. After evaporating the solvent under reduced pressure (20 mm.Hg), the residue is dissolved in diethyl ether (450 cc.). The ether solution is rapidly extracted twice with an ice-cold normal aqueous solution of methanesulphonic acid (total 500 cc.). The combined aqueous extracts are rendered alkaline by adding 10N sodium hydroxide solution (100 cc.). The oil which separates out is extracted with methylene chloride (250 cc.) and then with diethyl ether (300 cc.). The combined organic extracts are washed five times with distilled water (total 250 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.1 g.) and evaporated. The crystals obtained (18.0 g.; m.p. 170°C.) are dissolved in boiling ethanol (225 cc.). After filtering the boiling solution and then cooling it for three hours at 2°C., the crystals which have appeared are filtered off, washed three times with ice-cold ethanol (total 45 cc.) and dried under reduced pressure (20 mm.Hg). 6-(5-Chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (15.6 g.), melting at 180°C., is thus obtained.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)C(C)C)(C)C.[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:36]([N:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([CH2:20][N:17]2[CH2:18][CH2:19][N:14]([C:12]([NH:11][C:6]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=3)=[O:13])[CH2:15][CH2:16]2)[CH2:22]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)-1-[(3R)-piperidin-3-ylmethyl]piperazine-4-carboxamide dihydrochloride (800 mg) in dichloromethane (25 mL) was added N,N-di-iso-propylethylamine (0.94 mL) under argon. The mixture was stirred at room temperature for 5 minutes before benzaldehyde (0.22 mL) and sodium triacetoxyborohydride (573 mg) were added. The reaction mixture was stirred at room temperature under argon for 4 hours. The reaction was quenched with water and then partitioned between dichloromethane and water. The organic extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (550 mg, 66%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].S(Cl)(Cl)=O.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1>O>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[C:21]1[S:22][C:23]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:24][CH:25]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccc2ncnc(-c3cccs3)c2c1
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 60 °C

Procedure:
0.18 mL chlorosulfonic acid and 0.19 mL thionyl chloride were added to 0.1 g of 6-bromo-4-(2-thienyl)quinazoline (compound in Production Example 96) under ice-cooling in a stream of nitrogen, and the mixture was heated for 13 hours at 60° C., then neutralized by adding water and a sodium bicarbonate solution and extracted with dichloromethane. 5-(6-Bromoquinazolin-4-yl)-thiophen-2-sulfonyl chloride obtained by drying the organic layer over anhydrous sodium sulfate was dissolved in 3 mL tetrahydrofuran, then 0.3 mL morpholine was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was removed, and the positional isomers were separated and purified by silica gel column chromatography (ethyl acetate/hexane) to give 57 mg of the title compound (colorless crystals).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[S:5][C:4]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)=[N:3]1.[H-].[Li+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:3]1[C:2](=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[S:5][C:4]1=[N:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: CCOC(=O)c1ccc(N=c2sc3ncccc3c(=O)n2Cc2ccccc2)cc1

Procedure:
The reaction procedure of Example 11 was followed except that 1.31 g of ethyl 4-[(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]benzoate, 36 mg of lithium hydride and 0.48 ml of benzyl bromide were used. As a result, 1.28 g of ethyl 4-[(3-benzyl-4-oxo-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-2-ylidene)amino]benzoate was obtained as a low polarity substance, and 20 mg of ethyl 4-[N-benzyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]benzoate was obtained as a high polarity substance.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][CH2:10][CH2:11]Br.[F:13][C:14]1[C:15]([O:28][CH3:29])=[C:16]([CH:24]=[CH:25][C:26]=1[F:27])[NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20]>CN(C)C=O>[F:13][C:14]1[C:15]([O:28][CH3:29])=[C:16]([CH:24]=[CH:25][C:26]=1[F:27])[N:17]([CH2:11][CH2:10][F:9])[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20]
Reactant: FCCBr
Reactant: COc1c(NC(=O)C(F)(F)F)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(N(CCF)C(=O)C(F)(F)F)ccc(F)c1F
Temperature: 65 °C
Reaction time: 5 h
Yield: 19.1 %

Procedure:
2.44 g (0.018 mole) of potassium carbonate, a catalytic amount of potassium iodide and 1.80 g (0.014 mole) of 2-fluoroethyl bromide were added to a solution of 3.00 g (0.012 mole) of 3,4-difluoro-2-methoxy-N-(trifluoroacetyl)aniline (XI) [prepared as described in Step (C1) above] dissolved in 50 ml of dimethylformamide. The mixture was then stirred at 65° C. for 5 hours. At the end of this time, the solvent was distilled off from the mixture under reduced pressure. The residue was extracted with ethyl acetate and purified by column chromatography through silica gel eluted with toluene, to give 0.69 g of 3,4-difluoro-N-(2-fluoroethyl)-2-methoxy-N-(trifluoroacetyl)aniline (XII, R9' =2-fluoroethyl) as a colorless oil.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4([C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)=[O:29])[CH2:27][CH2:26]4)=[O:24])=[C:18]([F:38])[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)=[O:29])[CH2:27][CH2:26]3)=[O:24])=[C:18]([F:38])[CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Yield: 42.3 %

Procedure:
A mixture of N-(4-(2-(4-methoxybenzylamino)pyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (160 mg, 0.29 mmol) in CH2Cl2 (0.2 mL) was treated with trifluoroacetic acid (0.4 mL, 5.26 mmol) and the resultant mixture was stirred overnight at RT. The reaction mixture was concentrated to dryness and the residue was purified by reverse-phase silica gel chromatography (25-95% acetonitrile in water, 0.1% TFA). The desired fractions were partitioned between saturated aqueous NaHCO3 and EtOAc. The organics were washed with saturated aqueous NaHCO3, water, and brine and were dried over Na2SO4 and concentrated in vacuo to provide N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (52 mg, 39% yield). MS (ESI) m/z: 425.1 (M+H+).
Reaction SMILES: Cl.Cl.[OH:3][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[C:15]2=[O:21])[CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[F:34])[CH:26]=[CH:27][C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:27]/[C:28]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]3[CH2:7][CH2:8][C@H:9]([CH3:10])[C@H:4]([OH:3])[CH2:5]3)[C:15](=[O:21])[CH:16]2[CH3:20])=[O:29])[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: O=C(O)C=Cc1ccc(F)c(Cl)c1
Reactant: CC1NCCN(CCCN2CC[C@H](C)[C@H](O)C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CC[C@H](C)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 41; 0.03 mg, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3-chloro-4-fluorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=452.2 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[C:15](=[O:17])=[O:16]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[N:9]=[C:8]1[C:15]([OH:17])=[O:16]
Reactant: c1cnc2ccoc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1nc2ccccc2o1
Reaction time: 0.5 h

Procedure:
Furopyridine (8, 0.71 g, 5.96 mmol) is treated with n-butyl lithium (2.5M in hexane, 2.86 ml, 7.15 mmol) in anhydrous THF (30 ml) at −78° C. After 30 minutes, dry carbon dioxide is passed through the reaction mixture and the temperature is allowed to rise gradually to room temperature in 3 hours. The mixture is concentrated to dryness. The residue is dissolved in water (˜10 ml) and extracted with ethyl acetate. The aqueous layer is acidified to pH˜3 with 1N HCl and kept in the refrigerator over night. The resulting precipitates are filtered and dried to give azabenzofuran carboxylic acid as a white powder (9)
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:34]=1)=O.[OH-].[Na+].O>C(O)C>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:34]=1
Reactant: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C(F)(F)F)cn3c2)c1)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 107.8 %

Procedure:
To a solution of N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide (400 mg, 0.787 mmol) produced in Example A1(vi) in ethanol (4.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at room temperature for 12 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), fractions containing the object product was concentrated under reduced pressure, and the residue was washed with ethyl acetate/diisopropyl ether (1:4) to give the title compound (350 mg, quantitative) as a colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=O.C(OCC)C>CC(C)=O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:7]=[C:2]3[N:1]([CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3]3)=[CH:13][CH:14]=1
Reactant: Cc1ccccn1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cc1ccc(-c2cc3ccccn3c2)cc1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 74.2 %

Procedure:
To a stirred solution of 2-picoline (5.12 g) in acetone (10 ml) was added 2-bromo-4'-methylacetophenone (10.4 g) in one portion and the mixture was heated at 80° C. for one hour. After addition of diethyl ether, the crystalline product was collected and washed with diethyl ether. After drying in air for several hours, this product was suspended in water (100 ml) and a solution of sodium bicarbonate (21 g) in water (100 ml) was added dropwise to the suspension. The mixture was stirred at ambient temperature for 45 minutes and refluxed for half an hour. The mixture was diluted with methylene chloride and washed with aqueous saturated sodium chloride. The organic layer was separated, dried over potassium carbonate and filtered. The solvent was removed in vacuo and the resulting solid was recrystallized from benzene to give 2-(4-methylphenyl)indolizine (7.51 g).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])CCC.[C:36](=[O:38])=[O:37]>C1COCC1.O>[F:1][C:2]1[C:10]2[O:9][C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:36]([OH:38])=[O:37]
Reactant: O=C=O
Reactant: Fc1cccc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1F)OC(c1ccccc1)(c1ccccc1)O2
Temperature: -78 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
4-Fluoro-2,2-diphenyl-benzo[1,3]dioxole (5.8 g, 20 mmol) were dissolved in THF (40 ml). The reaction was cooled to −78° C. under argon. TMEDA (2.9 ml, 20 mmol) was added followed by n-butyl lithium (12.5 ml, 1.6 N in hexane) dropwise. The reaction was stirred at −78° C. for 2 hours. Carbon dioxide (20 g) was added at that temperature. The reaction was allowed to warm to 0° C. and poured into water (80 ml). The reaction was extracted twice with ethyl acetate. The aqueous layer was neutralized with 1N aqueous HCl solution, extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated and the residue suspended in n-hexane, stirred for 10 minutes and the product was filtered off to yield the acid as a white solid (4.0 g, 60%). m.p.: 189-191° C.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:6][N:5]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH2:4][CH2:3][N:2]([CH3:1])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNCCN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN(C)c1ccc([N+](=O)[O-])cc1)c1ccncc1
Reaction time: 0.5 h

Procedure:
A mixture of the product of part (i) (0.83 g), 4-fluoronitrobenzene (0.71 g) and sodium bicarbonate (1.0 g) in N,N-dimethylformamide (20 ml) was heated at 100° with stirring for 0.5 hour and then evaporated. The residue was stirred with water (2 ml) and the insoluble material was filtered off, washed with water and dried. The solid was chromatographed on silica gel. Elution with ethyl acetate/methanol (10:1) gave, after combination and evaporation of appropriate fractions, pure product (0.60 g), m.p. 126°-127° (from ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10]([N:19]3[CH2:25][C:24]4[CH:26]=[C:27]([O:30]C)[CH:28]=[CH:29][C:23]=4[S:22](=[O:33])(=[O:32])[CH2:21][CH2:20]3)[CH:9]=2)[CH2:5][O:4][CH2:3]1.[OH-].[K+]>CS(C)=O>[NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10]([N:19]3[CH2:25][C:24]4[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:23]=4[S:22](=[O:32])(=[O:33])[CH2:21][CH2:20]3)[CH:9]=2)[CH2:3][O:4][CH2:5]1
Reactant: COc1ccc2c(c1)CN(c1cc(NCC3(N)COC3)c3cc(C)ccc3n1)CCS2(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccc(O)cc4C3)cc(NCC3(N)COC3)c2c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
A mixture of N-[(3-aminooxetan-3-yl)methyl]-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (20 mg, 0.044 mmol, prepared in analogy to Example 1-5), potassium hydroxide (24 mg, 0.44 mmol) in dimethylsulfoxide (2 mL) was heated with stirring in a sealed 5 mL of microwave process via for 20 minutes at 100° C. under microwave irradiation. The resulting mixture was purified by preparative HPLC to afford 6 mg of the product (yield was 30%). MS obsd. (ESI+) [(M+H)+] 455, 1HNMR (400 MHz, CD3OD) δ ppm 7.77 (d, J=8.59 Hz, 1 H), 7.67 (s, 1 H), 7.45 (d, J=8.59 Hz, 1 H), 7.31 (dd, J=8.46, 1.64 Hz, 1 H), 7.18 (d, J=2.53 Hz, 1 H), 6.72 (dd, J=8.59, 2.27 Hz, 1 H), 6.19 (s, 1 H), 5.03 (s, 2 H), 4.68 (d, J=6.57 Hz, 2 H), 4.61 (d, J=6.57 Hz, 2 H), 3.66 (s, 2 H), 3.50 (brs, 2 H), 3.30 (m, 2 H), 2.43 (s, 3 H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]([F:15])([F:14])[C:9](OCC)=[O:10]>C(#N)C>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:9](=[O:10])[C:8]([F:15])([F:14])[F:7]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CNCCCN
Solvent: CC#N
Product: CNCCCNC(=O)C(F)(F)F
Temperature: 85 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
N-Methyl-1,3-diaminopropane (50 g, 0.56 mol) was dissolved in 200 mL acetonitrile followed by addition of ethyl trifluoroacetate (154 ml, 1.28 mol). The reaction mixture was stirred overnight at 85° C. The solvent was then removed in vacuo to yield the depicted product as a brown oil (101 g, 98.5%).