Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:1][C:2]2[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][C:5]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[N:20]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)c1nc(N2CCCC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N2CCCC2)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 0 °C
Yield: 84 %

Procedure:
1.55 g (7 mmol) of methyl 3-hydroxy-6-(1-pyrrolidinyl)picolinate, 1.83 g (8.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.96 g (7 mmol) of potassium carbonate were added to 50 ml of DMF and reacted at 100° C. for 3 hours. After completion of the reaction, the reaction product was poured into ice water, extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off, and the residue was crystallized from diisopropyl ether to obtain the desired product.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:28])=[C:13]([C:23](OCC)=[O:24])[C:14](=[O:22])[N:15]2[CH2:18][CH:19]2[CH2:21][CH2:20]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:33])[CH2:32][CH2:31][CH2:30]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:28])=[C:13]([C:23]([NH:33][CH:29]3[CH2:32][CH2:31][CH2:30]3)=[O:24])[C:14](=[O:22])[N:15]2[CH2:18][CH:19]2[CH2:21][CH2:20]2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(CC2CC2)c1=O
Reactant: NC1CCC1
Product: O=C(NC1CCC1)c1c(O)c2ncc(Cc3ccccc3)cc2n(CC2CC2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-1-(cyclopropylmethyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 5 and was obtained as an off-white solid: 1H NMR (CDCl3) δ 10.34 (1H, br d, J=7 Hz), 8.59 (1H, s), 7.46 (1H, s), 7.35 (2H, t, J=7 Hz), 7.28 (1H, t, J=7 Hz), 7.21 (2H, d, J=7 Hz), 4.53 (1H, m), 4.17 (2H, s), 4.08 (2H, d, J=7 Hz), 2.42 (2H, m), 2.09 (2H, m), 1.80 (2H, m), 1.01 (1H, m), 0.50 (2H, m), 0.40 (2H, m); HRMS calcd for C24H25N3O3+H+: 404.1974. Found: 404.1971.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([C@H:21]([N:23]2[CH2:28][CH2:27][O:26][C@@H:25]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C@@H:36]4[CH2:40][CH2:39][O:38][CH2:37]4)=[CH:31][CH:30]=3)[CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C=O>ClC(Cl)C>[CH3:1][N:35]([C:32]1[CH:33]=[CH:34][C:29]([C@@H:25]2[O:26][CH2:27][CH2:28][N:23]([C@@H:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:22])[CH2:24]2)=[CH:30][CH:31]=1)[C@@H:36]1[CH2:40][CH2:39][O:38][CH2:37]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N[C@@H]3CCOC3)cc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N(C)[C@@H]3CCOC3)cc2)C1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Sodium triacetoxyborohydride (2.4 g, 11.3 mmol) was added to a solution of 4-((1R)-1-phenylethyl)-(2S)-2-(4-(N-((3R)-tetrahydrofuran-3yl)amino)phenyl)-morpholine (1.3 g, 3.69 mmol) and formalin (35%, 1.6 g, 18.6 mmol) in dichloroethane (50 mL) at room temperature. After stirring for 2 hours, the resulting suspension was partitioned between ethyl acetate and 1 N sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish (2S)-2-(4-(N-methyl-N-((3R)-tetrahydrofuran-3-yl)amino)phenyl)-4-((1R)-1-phenylethyl)morpholine (1.35 g, 100%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:8][CH:9]=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:12][CH:13]([Cl:18])[C:14]([F:17])([F:16])[F:15].O1CCCC1.CC(C)([O-])C.[Na+]>CN(C)C=O>[Cl:12][C:13]([Cl:18])([C:14]([F:17])([F:16])[F:15])[CH:9]([OH:10])[CH2:8][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: FC(F)(F)C(Cl)Cl
Reactant: COC(=O)CC(C)(C)CC=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(C)CC(O)C(Cl)(Cl)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To an agitated mixture of methyl 3,3-dimethyl-5-oxopentanoate (1.0 g), 1,1-dichloro-2,2,2-trifluoroethane (1.06 g) and dry tetrahydrofuran (10 cm3), maintained at -78° C., was added, over a period of 5 minutes, sodium t-butoxide (1.66 cm3 of a 42% w/w solution in dimethylformamide) after which the mixture continued to be agitated at -78° C. for a further 60 minutes. The reaction was quenched with saturated ammonium chloride at low temperature and the mixture allowed to warm to the ambient temperature. After addition of water (20 cm3) and separation of the organic phase, the aqueous phase was extracted with di-isopropyl ether (3×30 cm3) and the extracts combined with the organic phase, which was washed with brine (2×10 cm3) and dried over anhydrous magnesium sulphate. After removal of the volatile components by evaporation under reduced pressure the residual oil was purified by column chromatography (silica gel column eluted with a 9:1 mixture (by volume) of hexane and ethyl acetate) to give methyl 6,6-dichloro-3,3-dimethyl-5-hydroxy-7,7,7-trifluoroheptanoate as a colourless oil (yield 56%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[N:12][CH:11]=[CH:10]3)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[CH:13]1[C:14]2[C:9](=[CH:8][C:7]([C:4]3[O:3][C:2]([NH:17][C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)=[N:6][CH:5]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: Clc1ncc(-c2ccc3cnccc3c2)o1
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc4cnccc4c3)o2)c1
Temperature: 80 °C
Yield: 36.5 %

Procedure:
A mixture of 2-chloro-5-(isoquinolin-6-yl)oxazole 14 (0.15 g, 0.652 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.121 g, 0.649 mmol) in 2-propanol (20 mL) was heated to 80° C. for 12 h with stirring. Additional one more equivalent of N-(3-aminophenyl)methanesulfonamide 6 (0.121 g, 0.649 mmol) was added to reaction mixture and heated to 80° C. for further 12 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(isoquinolin-6-yl)oxazol-2-yl)amino)phenyl)methane sulfonamide 59 (0.09 g, 38% yield) as pale yellow solid. MS (ES) m/z 381 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)(O[C:14]([CH3:18])([CH3:17])[C:15]#[CH:16])OC.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:17][C:14]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:18])[C:15]#[CH:16]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)OC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 23 h

Procedure:
To a solution of 4-cyanophenol (3.0 g, 25.18 mmol) and methyl 1,1-dimethyl-2-propynyl carbonate (3.93 g, 27.64 mmol) in anhydrous acetonitrile (24 mL) at 0° C. under argon was added DBU (5.0 mL, 33.43 mmol). After the solution had cooled to ~0° C., cupric chloride dihydrate (14.6 mg, 0.086 mmol) was added. After stirring at ~0° C. for 23 hours, the mixture was concentrated at reduced pressure. The residue was partitioned between 1N HCl (44 mL) and toluene (200 mL). The organic fraction was washed with 1N HCl (2×40 mL), 1N NaOH (2×40 mL), 1N NaHCO3, and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (4.05 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[N:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([Cl:32])=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(N)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 81.5 %

Procedure:
To a solution of tert-butyl {5-[2-(3-aminophenyl)ethyl]pyridin-3-yl}carbamate (0.50 g, 1.6 mmol) and 2,4,5-trichloropyrimidine (0.30 g, 1.6 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (0.43 g, 3.11 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc once. The combined organic layers were washed with water and brine then dried (Na2SO4), filtered, and concentrated. The crude mixture was purified by silica gel column chromatography to give the desired product as a white powder (0.60 g, 82%). LCMS for C22H24Cl2N5O2 (M+H)+: m/z=460.1, 462.1.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([Br:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[Br:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:13])[N:18]([OH:19])[C:11](=[O:12])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1O
Yield: 82.6 %

Procedure:
4-Bromo-1,8-naphthalic anhydride (1.6 g, 5.8 mmol) and hydroxylamine hydrochloride (0.8 g, 11.5 mmol) were reacted in pyridine (30 mL) following the procedure of Example 1 to give 1.4 g of the title compound, mp 248-251 ° C.;
Reaction SMILES: COC(=O)[NH:4][C:5]1[O:6][C:7]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[C:8]=2[N:9]=1.[OH-].[Na+]>O1CCOCC1.C(O)CO>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[C:7]3[O:6][C:5]([NH2:4])=[N:9][C:8]=3[C:10]([O:21][CH3:22])=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(-c3ccc(F)cc3)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Temperature: 100 °C
Yield: 41.6 %

Procedure:
To a stirred solution of 2.80 g (8.85 mmol) [7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl]-carbamic acid methyl ester in 100 ml dioxane and 30 ml ethylene glycol was added 100 ml of a 5 N aq. sodium hydroxide solution, and the mixture was heated at 100° C. for 16 h. After cooling to room temperature the mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Trituration in ether afforded 0.95 g (42%) 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine as an off-white solid. ES-MS m/e (%): 259 (M+H+, 100).
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:25][NH2:26])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>CO.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11](/[C:14](=[N:26]/[NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)/[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: NNC(=O)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: O
Product: C/C(=N\NC(=O)c1cccnc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (215 mg, 0.93 mmol) was suspended in methanol (3 ml) and water (1 ml). Nicotinic acid hydrazide (137 mg, 1.0 mmol, 1.1 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with water to yield the product, one apparent isomer, as a white solid: 311 mg (95%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)(=[O:22])=[O:21]
Reactant: OCCCCC1CCCOC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCC1CCCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(tetrahydro-2H-pyran-3-yl)-1-butanol (1.20 g) in dry dichloromethane (30.3 ml), cooled to 0° C., was added triethylamine (2.43 ml) and methanesulphonyl chloride (0.77 ml) to give a yellow solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (25 ml). The organic layer was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to afford a yellow oil (1.80 g). The product was purified by silica chromatography using a gradient elution of 0-40% ethyl acetate/cyclohexane to afford the title compound as a yellow oil (1.58 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=3)=[CH:14][CH:13]=2)=[O:30])=[CH:32][CH:33]=1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Reactant: NCc1ccc(-c2ccnc(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)cc1)c1ccc(-c2cnccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)methanamine 28-3 (16 mg, 0.063 mmol), 4-(pyrazin-2-yl)benzoic acid 18-3 (13 mg, 0.065 mmol), and HATU (26 mg, 0.068 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield 4-(pyrazin-2-yl)-N-(4-(2-(trifluoromethyl)pyridin-4-yl)benzyl)benzamide 28 as a solid. MS m/z 435.0 (M+1).
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([CH2:15][CH:16]=[CH2:17])[C:11]([O:13][CH3:14])=[O:12].C>O1CCOCC1>[N:9]([CH:10]([CH2:15][CH:16]=[CH2:17])[C:11]([O:13][CH3:14])=[O:12])=[C:2]=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(N)C(=O)OC
Solvent: C1COCCO1
Product: C=CCC(N=C=O)C(=O)OC

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of methyl 2-amino-4-pentenoate, prepared as described by D. Ferroud, J. P.Genet, and R. Kiolle in Tetrahedron Letters, 1986, 27, 23-26, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give methyl 2-isocyanato-4-pentenoate.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[N:10]=1.OO>O>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[N+:10]=1[O-:4]
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1cccc(Cl)n1
Agent: OO
Solvent: O
Product: [O-][n+]1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 87.7 %

Procedure:
After the reaction solution of trifluoroacetic acid (485 mL, 6.3 mol), 2,6-dichloropyridine (48 g, 324 mmol) and 35% hydrogen peroxide (85.0 mL, 971 mmol) was stirred for 6.5 h under the condition of reflux, it was cooled to room temperature. The reaction solution was poured into beaker contained 2.4 L water, and cooled overnight at 0° C. The solid (unreacted 2,6-dichloropyridine) was removed through a suction filtration. The filtrate was concentrated, to which 500 mL chloroform was added, and potassium carbonate was added until no gas was produced. It was filtrated. The filtrate was concentrated under vacuum to afford 46.6 g light yellow solid, 87.6%.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Br.Br.[CH:22]12[CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][NH:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:22]12[CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][N:23]2[C:10]1[C:11]([F:13])=[C:12]2[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1NC2CNC1C2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CC3CN4)c(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 0.54 g (2.0 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.57 g (2.2 mmol) of 2,5-diazabicyclo(2.2.1)heptane dihydrobromide [P. S. Portoghese and A. A. Mikhail, J. Org. Chem., 31, 1059 (1966)], 0.90 ml (6.0 mmol) of 1,8-diazabicyclo(5.4.0)undec-7ene, and 20 ml of acetonitrile was heated under reflux for one hour and stirred at room temperature for two hours. The reaction mixture was filtered and the solid was washed with ethanol to give 0.60 g of the title compound, mp 275° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@H:18]3[CH2:22][CH2:21][N:20]([S:31](=[O:33])(=[O:32])[N:30]([CH3:35])[CH3:29])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCNC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(S(=O)(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-pyrrolidin-3-yloxy]quinazoline hydrochloride (0.21 g, 0.49 mmole; prepared as described in Example 30-preparation of starting materials) was dissolved in a mixture of methylene chloride (4 ml), pyridine (1 ml) and di-isopropylethyl amine (0.17 ml) under a nitrogen atmosphere. Dimethylsulfamoyl chloride (0.08 ml, 0.75 mmole) was added to the stirred solution. After stirring overnight at ambient temperature, the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia)(98/2). The fractions containing the expected product were evaporated under vacuum and the residual gum was triturated with diethylether and evaporated to give the title product as a dry foam (0.13 g; 53%); 1H NMR Spectrum: (DMSO d6) 2.16-2.21 (m, 1H); 2.25-2.38 (m, 1H); 2.76 (s, 6H); 3.41-3.50 (m, 3H); 3.71 (dd, 1H); 3.93 (m, 3H); 5.18 (m, 1H); 7.15-7.35 (m, 2H); 7.44-7.55 (m, 2H); 7.78 (s, 1H); 8.37 (s, 1H); 9.59 (s, 1H); Mass Spectrum: (M+H) 496.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[C:4]([CH2:13][CH3:14])[CH:3]=1.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].O>CN(C=O)C.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>[CH2:17]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[C:4]([CH2:13][CH3:14])[CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCOCOc1ccc(Br)cc1CC
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1ccc(OCOCC)c(CC)c1
Temperature: 120 °C

Procedure:
15 g (58 mmol) of 4-bromo-1-ethoxymethoxy-2-ethylbenzene are dissolved in 150 ml of DMF. 26.9 ml (87 mmol) of allyltributyltin are added, and then the mixture is degassed with a nitrogen stream. 1.2 g (1.8 mmol) of dichlorobis (triphenylphosphino)palladium are added, and the medium is heated at 120° C. for 10 hours. The reaction medium is poured into water, and then extracted with ethyl acetate. The residue obtained after drying and concentration is purified by chromatography on a silica column (eluent heptane, and then heptane 95/ethyl acetate 5). A yellow oil is obtained (m=13.6 g, y=100%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:32]=[CH:31][C:11]([CH2:12][O:13][C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:26][C:25](=[O:27])[NH:24][S:23]3(=[O:29])=[O:28])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14](=[O:30])[C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]3[CH2:26][C:25](=[O:27])[NH:24][S:23]3(=[O:28])=[O:29])=[CH:19][CH:20]=2)=[CH:31][CH:32]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(COC(=O)c2ccc(CN3CC(=O)NS3(=O)=O)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(Cc2ccc(C(=O)OCc3ccc(C(=O)O)cc3)cc2)S(=O)(=O)N1
Reaction time: 2 h

Procedure:
The title C compound, 4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4-t-butoxycarbonyl-benzyl ester (119 mg, 0.19 mmol) is dissolved in CH2Cl2 (5 mL) and then added TFA (5 mL, 64.9 mmol). This is stirred for 2 h and then concentrated under reduced pressure. The residue is suspended in MeCN:water (6:4) (12 mL), centrifuged, decanted and filtered through a 0.1 micron Acrodisc filter. The resulting mixture is loaded onto a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in 6 aliquots and eluted at 30 mL/min with a gradient of 90:10 (water containing 0.1% TFA: MeCN) at 0 min to 10:90 at 5 min. Then held at 10:90 until 7 min. Fractions containing product are combined and concentrated by lyophilization to yield 4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4-carboxy-benzyl ester as a white amorphous solid: [M−1]−=403.