Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(C1[O:20][CH2:19]1)Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(#N)C>[O:1]1[C:7]2[CH:6]=[CH:5][C:4]([C:8]3[C:12]4[S:13][CH:14]=[CH:15][C:11]=4[O:10][N:9]=3)=[C:3]([O:20][CH3:19])[C:2]1=2
Reactant: Oc1cccc(-c2noc3ccsc23)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1c(-c2noc3ccsc23)ccc2c1O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
A mixture of 28 g of 3-(3-hydroxyphenyl)thieno[2,3-d]isoxazole, 23 g of epibromohydrin and 30 g of milled potassium carbonate in 40 ml of dimethylformamide and 40 ml of acetonitrile was stirred under nitrogen at 90°-100° C. until completion of reaction. The reaction was complete after 4 hours and allowed to cool to room temperature. Quenching with water (400 ml), extracting with 50/50 ether/ethyl acetate soluiton (3×400 ml), and washing with water (2×400 ml) were conducted. The organics were dried over anhydrous magnesium sulfate and the solvents were evaporated to give an oil. The oil was purified by HPLC (4:1 hexane/ethyl acetate) to yield 23.3 g of a solid with a melting point of 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19](I)[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].[C:25]([C:27]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]1)#[CH:26]>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][C:25]([C:27]5([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]5)=[CH:26][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1Cl
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Temperature: 45 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of the product of Step C (0.1 g; 0.22 mmol) and tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (0.056 g; 0.22 mmol) in a mixture of DMF and DIPEA (3 ml:0.3 ml) was degassed with N2 and Cl2Pd(PPh3)4 (0.025 g) was added, followed by catalytic amount of CuI. The mixture was stirred overnight at 45° C. under N2, diluted to 20 ml with saturated NH4Cl and extracted with EtOAc (40 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.11 g, 78%), as pale paste. 1H-NMR (CDCl3) 8.34 (d, 1H, J=1.29 Hz); 8.24 (d, 1H, J=2.13 Hz); 8.08 (t, 1H, J=1.56 Hz); 8.05 (t, 1H, J=1.56 Hz); 7.53 (d, 1H, J=8.67 Hz); 7.03 (d, 1H, J=8.67 Hz); 6.75 (s, 1H); 4.26-4.19 (m, 4H); 4.06 (t, 2H, J=5.49 Hz); 1.94-1.87 (m, 2H); 1.41 (s, 9H); 1.36 (s, 6H); 1.1 (t, 3H, J=7.44 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12.C([O-])(=[O:14])C.[Na+]>C(O)(=O)C>[CH3:11][C:9]1[NH:8][C:4]2[N:5]=[CH:6][CH:7]=[C:2]([OH:14])[C:3]=2[CH:10]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cc2c(Cl)ccnc2[nH]1
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2c(O)ccnc2[nH]1
Yield: 84.4 %

Procedure:
A mixure of 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine (120 mg, 0.72 mmol) and sodium acetate (150 mg, 1.83 mmol) in acetic acid (1.5 mL) was microwaved at 200° C. for 40 minutes. The mixture was purified by preparative HPLC and the appropriate fractions were concentrated in vacuo and lyophilized to afford the title compound (90 mg, 47%). 1H NMR (CD3OD) δ 8.09 (d, 1H, J=5.5 Hz), 6.80 (d, 1H, J=5.5 Hz), 6.49 (s, 1H), 2.46 (s, 3H); MS(ESI+) m/z 149 (M+H)+.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH2:8]([SH:11])[CH2:9][CH3:10].[NH2:12][C:13]1[N:21]=[C:20](Cl)[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cl-].[Na+].O>[NH2:12][C:13]1[N:21]=[C:20]([S:11][CH2:8][CH2:9][CH3:10])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CCCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 110 °C
Yield: 88.8 %

Procedure:
To DMF suspension (50 ml) containing sodium hydride (917 mg, 23 mmol, 60% in mineral oil) were added propanethiol (5.0 ml, 55 mmol) and 6-amino-9-benzyl-2-chloropurine (500 mg, 1.9 mmol) in order. The mixture was stirred under heating at 110° C. for 2.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (505 mg, yield 87%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]=1[CH2:10]Br)=[O:4].[OH2:27]>CN(C=O)C>[OH:27][CH2:10][C:9]1[C:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=2)=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[S:6][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: O
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(SC)cc2)c1CBr
Solvent: CN(C)C=O
Product: CSc1ccc(-c2c(-c3ccc(F)cc3)sc(C(=O)O)c2CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 249 mg of the product of Step 2 in 5 mL of DMF was added 237 mg of n-Bu4NOAc. The reaction mixture was stirred at r.t. for 15 min. Water (20 mL) was added and the product was extracted with 50 mL of EtOAc. The extract was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in 4 mL of THF and 2 mL of MeOH and treated with 1 ml of 1N LiOH. After 12 h, the reaction mixture was treated with 0.2 ml of HOAc and 10 mL of brine. The product was extracted with 40 mL of EtOAc. The extract was dried over MgSO4 and concentrated in vacuo to provide 120 mg of title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[C:8](Br)=[N:7][CH:6]=1)[CH3:2].[CH2:14](B(O)O)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:11][C:9]1[C:8]([CH2:14][CH3:15])=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:13]
Reactant: CCB(O)O
Reactant: CCOC(=O)c1cnc(Br)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(CC)c(Br)c1
Temperature: 110 °C
Yield: 38 %

Procedure:
Method-2: A solution of ethyl-5,6-dibromonicotinate (6.0 g, 19.4 mmol, 1.0 eq; prepared by following the procedure described in WO2011024004), ethylboronic acid (1.72 g, 23.3 mmol, 1.2 eq) and potassium carbonate (8.0 g, 58.3 mmol, 3.0 eq) in 1,4-dioxane (10 mL) in a oven dried sealed tube was subjected to three cycles of evacuation-backfilling with argon, and then tetrakis(triphenylphosphine)palladium(0) (2.24 g, 1.94 mmol, 0.1 eq) was added. The sealed tube was sealed and the mixture was stirred and heated in an oil bath to 110° C. After three days of stirring at the same temperature, the reaction was cooled to RT and filtered through Celite®. The filtrate was evaporated and the resultant residue was purified by flash column chromatography (silica gel, ethyl acetate-hexane system as eluent) to afford 1.90 g (38%) of the desired product as a white solid. 1HNMR (400 MHz, CDCl3) δ 9.06 (d, J=1.5 Hz, 1H), 8.40 (d, J=1.5 Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 3.05 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H); GC-MS (m/z) 257, 259 [M+, Br79,81].
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH:35]=O)=[O:31])=[N:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:3])[CH3:2].[C:40]([CH2:42]P(=O)(OCC)OCC)#[N:41].CC(C)([O-])C.[K+]>C1COCC1>[CH:1]([C:4]1[C:5]([C:30]([C:32]2[CH:33]=[C:34]([CH:35]=[CH:42][C:40]#[N:41])[CH:37]=[CH:38][CH:39]=2)=[O:31])=[N:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:3])[CH3:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c(C(C)C)c(C(=O)c3cccc(C=O)c3)n2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c(C(C)C)c(C(=O)c3cccc(C=CC#N)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a stirred mixture of 3-[5-isopropyl-2,6-bis-(4-methoxy-benzyloxy)-pyrimidine-4-carbonyl]-benzaldehyde (1.73 g, 3.22 mmol) and diethyl cyanomethylphosphonate (0.52 ml, 3.22 mmol) in anhydrous THF (10 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (397 mg, 3.54 mmol). After 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then partitioned between ether and water. The ether layer was taken, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow syrup. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (2:7)) to afford 1.46 g (81%) of a pale yellow syrup. 1H NMR (200 MHz, CDCl3) δ 1.19 (6H, d, J=7.0 Hz), 2.86 (1H, m), 3.82 (3H, s), 3.85 (3H, s), 5.31 (2H, s), 5.46 (2H, s), 5.93 (1H, d J=16.8 Hz), 6.81-6.97 (4H, m), 7.28-7.93 (8H, m).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (193.6 mg, 0.56 mmol, 1.00 equiv) in methanol (15 mL). A solution of sodium hydroxide (111.6 mg, 2.79 mmol, 5.00 equiv) in water (1.5 mL) was added. The resulting solution was stirred overnight at 50° C. in an oil bath and concentrated to dryness. The residue was diluted by 10 mL of water and adjusted to PH=3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration. This resulted in 130 mg (69%) of (S)-3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].S1[C:10]2[CH:11]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:13]=[CH:14][C:9]=2NC1.Cl[C:33]1C=CC=C(C(OO)=O)C=1>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[O:3]=[S:2]1(=[O:5])[C:1]2[CH:13]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:11]=[CH:10][C:9]=2[CH2:14][CH2:33]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)SCN2
Agent: CS(=O)(=O)O
Product: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)S(=O)(=O)CC2

Procedure:
The product from Example 54 is treated with two equivalents of m-chloroperbenzoic acid to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C>[CH2:14]([O:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([C:1]2[NH:18][N:17]=[N:16][N:2]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1cc(C#N)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-cyano-5-ethoxybenzoate (182 mg, 0.89 mmol), sodium azide (173 mg, 2.66 mmol), triethylamine hydrochloride (366 mg, 2.66 mmol) and DMF (4.4 mL) was stirred in a nitrogen atmosphere at 100° C. for 12 hours. After left cooled, aqueous 5 N sodium hydroxide solution (0.53 mL, 2.66 mmol) was added to the reaction mixture, and washed with chloroform. The aqueous layer was made to have a pH of 2 with 5 N hydrochloric acid, and extracted with chloroform. The organic layer was dried with sodium sulfate, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to obtain the title compound as a colorless solid.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[C:10](O)(=[O:13])[CH2:11][OH:12].C(N(CC)CC)C>O1CCCC1>[C:1]([S:4][CH2:5][CH2:6][C:7]([O:9][C:11](=[O:12])[CH2:10][OH:13])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(O)CO
Reactant: CC(=O)SCCC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(=O)OC(=O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(Acetylthio)propanoic acid (2.96 g) and 1,1'-carboxyldiimidazole (3.24 g) are dissolved in 20 ml of dry tetrahydrofuran with stirring at room temperature. After twenty minutes, a solution of glycolic acid (1.52 g) and 2.80 ml of triethylamine in 15 ml of dry tetrahydrofuran are added. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the crude residue taken up into ethyl acetate, washed with 1N hydrochloric acid and three times with water, dried over magnesium sulfate and the O-(3-acetylthiopropanoyl)glycolic acid is concentrated to dryness in vacuo, yield 3.9 g. This is dissolved in ether and dicyclohexylamine is added. The dicyclohexylamine salt precipitates, yield 2.85 g.; m.p. 150-157° . The salt is converted to the free acid by adding to ethyl acetate and adding 10% potassium bisulfate solution, yield 1.5 g.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C:13]([CH3:33])([CH3:32])[CH2:14][O:15][S:16]([CH2:19][CH2:20][CH2:21][S:22]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:24])=[O:23])(=[O:18])=[O:17])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](Cl)(=O)[C:35](Cl)=O.CN(C)C=O>ClCCl>[CH2:1]([O:8][C@H:9]([C:13]([CH3:33])([CH3:32])[CH2:14][O:15][S:16]([CH2:19][CH2:20][CH2:21][S:22]([O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:23])=[O:24])(=[O:17])=[O:18])[C:10]([O:12][CH2:34][CH3:35])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(COS(=O)(=O)CCCS(=O)(=O)Oc1ccccc1)[C@@H](OCc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCS(=O)(=O)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred 0° C. solution of (2R)-2-benzyloxy-3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfonyloxy)butanoic acid (Example 8(a), Step 3) (0.8 g) in dichloromethane (10 mL), was added oxalyl chloride (0.28 mL) followed by a drop of N,N-dimethylformamide. The reaction mixture was stirred for 1 hour and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (10 mL), to which was added ethanol (2 mL). The reaction mixture was stirred overnight at room temperature. The volatiles were removed, and the residual material was purified by silica gel chromatography (hexanes/ethyl acetate 70:30) to afford ethyl (2R)-2-benzyloxy-3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfonyloxy)butanoate (0.70 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14]([CH:15]=[O:16])=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ncncc2CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1ccc(-c2ncncc2C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of [4-(4-methoxyphenyl)pyrimidin-5-yl]methanol (8.6 g), manganese dioxide (48 g) and tetrahydrofuran (300 mL) was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (5.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:5].ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)CCl>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N+:15]([O-:30])=[CH:14][CH:13]=[CH:12]2)=[O:5]
Reactant: O=C(Nc1cccc2cccnc12)c1c(Cl)cccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(Nc1cccc2ccc[n+]([O-])c12)c1c(Cl)cccc1Cl
Yield: 45.7 %

Procedure:
A solution of 8-(2,6-dichlorobenzoylamino)quinoline (100 mg) and m-chloroperbenzoic acid (71 mg) in ethylene chloride was stirred for 1 hour at 40° C. To the mixture was added 5% sodium thiosulfate solution, and the mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from dichloromethane-methanol to give 8-(2,6-dichlorobenzoylamino)quinoline 1-oxide (48 mg).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C(OC(C)C)(C)C.C(N(CC)CC)C.Cl[C:21]([C:23]([F:34])([F:33])[CH:24]([O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:25][CH3:26])=[O:22]>>[CH2:1]([O:5][C:21]([C:23]([F:33])([F:34])[CH:24]([O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:25][CH3:26])=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)Cl
Reactant: CCCCO
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OCCCC
Temperature: 0 °C
Yield: 91.1 %

Procedure:
Into a 1 L glass flask with a dropping funnel, 62.8 g (0.847 mol, 1.2 eq) of n-butanol, 510 g of diisopropyl ether, 100 g (0.988 mol, 1.4 eq) of triethylamine and 1 g of antioxidant “Nonflex MBP” (manufactured by Seiko Chemical Co., Ltd.) were added. The resulting solution was cooled to 0° C. and stirred, followed by dropping thereto 170 g (purity: 99%, 0.706 mol) of methacrylic acid 1-chlorocarbonyl-1,1-difluoro-2-butyl ester. The thus-obtained reaction solution was stirred for 1 hour at room temperature. The completion of the reaction was confirmed by 19F NMR. The reaction-completed solution was separated into an organic layer and an aqueous layer by the addition of 500 mL of water. The organic layer was dehydrated with magnesium sulfate, filtrated, and then, concentrated under a reduced pressure. The concentration residue was subjected to distillation under a reduced pressure. With this, 179 g of methacrylic acid 1-(n-butoxycarbonyl)-1,1-difluoro-2-butyl ester was obtained as a colorless transparent liquid (yield: 91%, purity: 99%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[CH:10][N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH2:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:23].O>CS(C)=O.Cl>[CH2:25]([N:24]([CH2:22][CH3:23])[C:2]1[C:3]2[C:11]([CH3:12])=[CH:10][N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Cc1cc(C)c(-n2cc(C)c3c(Cl)nc(C)nc32)c(C)c1
Reactant: CCCCNCC
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CCCCN(CC)c1nc(C)nc2c1c(C)cn2-c1c(C)cc(C)cc1C
Yield: 81.2 %

Procedure:
A mixture of 4-chloro-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine (1.000 g, 3.36 mmol) and N-ethylbutylamine (3.400 g, 33.60 mmol) in 5 ml of dimethylsulfoxide was heated to reflux for 1.5 hours. The mixture was cooled and treated with water and a few drops of 2 N HCl to pH 6.5 and extracted with ethyl acetate. The organic layer was separated, washed with dilute sodium bicarbonate, brine, and dried over sodium sulfate anhydrous and concentrated to dryness. The residue was purified through silica gel column chromatography to give 995 mg (81% yield) of the title compound as an oil. 1H NMR (CDCl3) δ 6 0.90 (t, 3H), 1.23(t, 3H), 1.35(m, 2H), 1.60-1.70(m, 2H), 1.92(s, 6H), 2.30(s, 3H), 2.40(s, 3H), 2.46(s, 3H), 3.58(t, 2H), 3.66(q, 2H), 6.55(s, 1H), 6.95(s, 2H) ppm. The corresponding hydrogen chloride salt was prepared as a white crystals after recrystallization from ethyl acetate. 1H NMR (D2O) δ 0.90(t, 3H), 1.34(m, 5H), 1.75(m, 2H), 1.90(s, 6H), 2.37(s, 3H), 2.48(s, 3H), 2.55(s, 3H), 3.80-3.94(m, 4H), 7.09(s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>ClCCl.CC(C)=O>[CH2:26]([O:25][C:23](=[O:24])[C:22](=[CH:21][NH:1][C:2]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(OCc2ccccc2)c(=O)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ccc(OCc2ccccc2)c(=O)cc1)C(=O)OCC
Temperature: 140 °C

Procedure:
A mixture of 5-amino-2-benzyloxy-2,4,6-cycloheptatrien-1-one (10 g), described in example 1b, and diethyl ethoxymethylenemalonate (100 ml) was heated at 140° C. for 1.5 hr. The cooled reaction mixture was subjected to chromatography on silica gel using dichloromethane-acetone (9:1) as the eluant. The pure fractions were pooled to give 2-[(4-benzyloxy-5-oxo-1,3,6-cycloheptatrien-1-yl)aminomethylene]propanedioic acid diethyl ester (V; R7 =OCH2C6H5 and R8 =C2H5); nmr (CDCl3) δ1.3 (m 6H), 4.2 (m, 4H), 5.2 (s, 2H), 7.2 (m, 2H), 7.2 (m, 9H), 8.25 (d, 1H), 10.9 (d, 1H); ir (CHCl3) 3490, 3240, 1700, 1690, 1570; uv λmax (MeOH) 279 nm (ε10,410), 224 (27,380).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:19][NH:18][C:17](=O)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:28]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([Cl:28])[N:18]=[N:19][C:20]=2[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1n[nH]c(=O)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A suspension of 5-(4-benzyloxy-phenyl)-6-butyl-2H-pyridazin-3-one (5.4 g, 14.73 mmol) in POCl3 (8 mL) was stirred at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and to the residue was added ice (50 g). The mixture was stirred for 1 h. This was extracted with DCM (3×50 mL), the combined organic layer was dried, filtered and concentrated under reduced pressure. The resultant residue was purified by flash silica gel column chromatography eluting with in 10% ethyl acetate in hexanes to provide 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine.
Reaction SMILES: C(OC(CO[N:8]=[C:9]([C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)[C:10]([O:12][CH3:13])=[O:11])=O)C.[H][H]>C(O)C.[Pd]>[NH2:8][CH:9]([C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(=O)CON=C(C(=O)OC)c1ccn(C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(N)c1ccn(C)n1

Procedure:
2.61 g (9.69 mmol) methyl ethoxycarbonyl-methoxyimino-(1-methyl-pyrazol-3-yl)-acetate are hydrogenated in 60 ml of ethanol with 1.1 g 5% palladium charcoal for 16 h at 50° C. under 3.4 bars pressure in a hydrogen atmosphere. Then the mixture is suction filtered and the filtrate is evaporated down completely i. vac.