Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1cc(F)cc(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+]
Product: COc1cc(F)cc(-c2cccc(Cl)c2)c1
Temperature: 25 °C
Yield: 101.8 %

Procedure:
A RBF was charged with 1-bromo-3-fluoro-5-methoxybenzene (2.104 g, 10.26 mmol), (3-chlorophenyl)boronic acid (1.765 g, 11.29 mmol), potassium carbonate (4.25 g, 30.8 mmol), and Pd(Ph3P)4 (0.593 g, 0.513 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (25.7 ml) and water (8.55 ml) were added. A reflux condenser was attached, and the flask was lowered into a 90° C. heating bath for 45 min. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 25-g silica gel column, 0-5% EtOAc/Heptane) to give 3′-chloro-3-fluoro-5-methoxy-1,1′-biphenyl (2.47 g, 10.44 mmol, 102% yield) as a clear oil containing about 10 wt % impurities.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C1C(=O)N([Br:26])C(=O)C1.CCOC(C)=O.C(Cl)Cl>CN(C=O)C>[Br:26][C:7]1[N:8]([CH:11]([CH3:12])[CH3:13])[C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]=1[CH3:14]
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)cn2C(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (2.5 g, 9.41 mmol) in DMF (25 mL) was added NBS (1.7 g, 9.55 mmol). The reaction was stirred for 18 h then evaporated to dryness under vacuum. The reaction was purified by silica gel chromatography (Analogix, SF40-80 g, 0 to 5% EtOAc in hexanes) then (Analogix, SF25-60 g, 25% CH2Cl2 in hexanes) to give the product methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (1.79 g, 5.19 mmol, 55.2% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ=7.98 (d, J=1.8 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 5.05 (dt, J=6.7, 13.4 Hz, 1H), 3.89 (s, 3H), 2.22 (s, 3H), 1.57 (d, J=7.1 Hz, 6H). MS(ES)+ m/e 344.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:12]#[C:13][Si](C)(C)C)[C:5]([NH:8]C(=O)C)=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:13][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Nc1ncc(Br)nc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Brc1cnc2[nH]ccc2n1
Yield: 41.5 %

Procedure:
A solution of N-(5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-yl)acetamide [Intermediate AR] (2.6 g, 8.4 mmol) and tetrabutylammonium fluoride [1 M in THF] (18 mL, 18 mmol) in anhydrous THF (26 mL) was heated at 75° C. for 20 h, after which it was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, and evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 30% EtOAc in hexanes to give the title compound as a tan solid (0.69 g, 42%). 1H NMR (CDCl3, 300 MHz): δ 8.88 (bs, 1H), 8.34 (s, 1H), 7.62 (t, J=3.3 Hz, 1H), 6.71 (dd, J=3.6 Hz, 3.9 Hz, 1H). HPLC retention time: 1.73 minutes. MS ESI (m/z): 198.2, 200.2 (M+H)+, calc. 197.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18]CC)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]4)=[N:9][C:10]=2[CH:15]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)O)ccc3c1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)O)ccc3c1)n2C1CCCCC1

Procedure:
A solution of 90 mg (0.2 mmol) of Compound 402a and 1 mL 2 N aq. NaOH in 4 mL MeOH was heated overnight at 55° C. The solvent was evaporated, the residue was dissolved in H2O and neutralized. The precipitate was filtered, washed with H2O and dried. The product was purified by HPLC to yield 34 mg.
Reaction SMILES: Cl.[NH2:2][OH:3].[N:4]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18](=[O:25])[C:17](=O)[CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1>C(O)C.O>[N:4]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18](=[O:25])[C:17](=[N:2][OH:3])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NO
Reactant: O=C1C=C(c2ccc(N3CCCC3)cc2)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1C(=NO)C=C(c2ccc(N3CCCC3)cc2)c2ccccc21
Yield: 84 %

Procedure:
A solution of hydroxylamine hydrochloride (0.08 mol) in anhydrous ethanol (50 cm3) was added dropwise to a stirred solution of 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone (0.02 mol) in warm anhydrous ethanol (250 cm3). The mixture was refluxed until thin layer chromatography indicated that no 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone remained. The mixture was cooled in ice, diluted with water and the brown precipitate was collected by vacuum filtration and washed with water and air dried. Yield=84%, m.p.=278-300° C. (decomp.).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[O-]CC.[Na+].CN([CH:14]=[C:15]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O)C>C(O)C>[CH3:35][S:34][C:30]1[N:29]=[C:28]([C:15]2[CH:14]=[C:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:16]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:33]=[CH:32][N:31]=1
Reactant: N#CCC(N)=O
Reactant: CSc1nccc(C(=CN(C)C)C(=O)c2cccc(C(F)(F)F)c2)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CSc1nccc(-c2cc(C#N)c(=O)[nH]c2-c2cccc(C(F)(F)F)c2)n1
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a mixture of cyanoacetamide (1.42 gm, 0.0169 mole) in ethanol (20 mL) was added a solution of sodium ethoxide (6.3 mL, 21 wt % solution, 0.0169 mole) in ethanol. The mixture was stirred for 5 minutes and dimethylamino-2-(2-methylsulfanylpyrimidin-4-yl)-1-(3-trifluoromethylphenyl)-prop-2-en-1-one (5.88 gm, 0.0160 mole) in ethanol (40 mL) added. The reaction was stirred for 18 hrs at room temperature and then concentrated to an oil. The oil was dissolved in ethyl acetate (50 mL) and water (50 mL) and the pH adjusted to 5.0 with a 10% solution of sodium hydrogen sulfate. The ethyl acetate layer was removed, dried over sodium sulfate, and concentrated to an oil. The oil was chromatographed on silica eluting with 5% acetone/dichloromethane to give 4.0 gm (68%) of the title compound as an oil.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[Cl:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[C:20]([OH:22])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[C:20]([N:3]([O:4][CH3:5])[CH3:2])=[O:22]
Reactant: Cn1ncc(C(=O)O)c1Cl
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cnn(C)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.6 %

Procedure:
To a stirred suspension of N,O-dimethylhydroxyamine hydrochloride (0.668 g, 6.85 mmol) and triethylamine (2.60 mL, 18.7 mmol) in DMF (6 mL) was added 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (1.00 g, 6.23 mmol, purchased from Nissan Chemical) and HBTU (2.60 g, 6.85 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-toluene (1:1, 200 mL), washed with water (200 mL), saturated aqueous sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a column of silica gel, using ethyl acetate-hexane (1:1) as eluent to give the title compound (1.39 g, quant.) as white solid. 1H NMR (270 MHz, CDCl3) δ ppm 3.34 (3H, s), 3.67 (3H, s), 3.88 (3H, s), 7.93 (1H, s). MS (ESI): m/z 204 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]1=[O:13].[I:17]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:17])[C:7]1=[O:13]
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C(O)C(Cl)Cl
Solvent: CC#N
Product: O=c1c(I)c(O)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1.1 g, 5 mmol) in acetonitrile (15 mL) was added N-iodosuccinimide (1.1 g, 5.5 mmol) along with a ca. amount of dichloroacetic acid (0.1 mL). The reaction mixture stirred at room temperature for 1 hour under nitrogen. The mixture was chilled in an ice bath and filtered cold with fresh MeCl2. The beige solid was dried to afford the desired iodinated intermediate (1.21 g, 69%). ES-LRMS m/z 346.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[N:9]([O-])=[O:10].[Na+].C(O)(=O)C>O>[OH:10][N:9]=[C:5]([C:6]#[N:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C#N)=NO

Procedure:
Ethylcyanoacetate (11.3 g, 100 mmol) is added to a solution of sodium nitrite (8.3 g, 120 mmol) in distilled water (50 ml) and acetic acid (8.0 ml=8.4 g, 140 mmol) is added to the stirred mixture. The ester disappears and soon yellow crystals of the sodium derivative start to separate. Next day the crystals are collected and then dissolved in 2N HCl (50 ml). The product is extracted with ether (four times, 50 ml each time) and the extracts dried over anhydrous Na2SO4. Removal of the solvent by evaporation in vacuo leaves a crystalline residue, ethyl 2-hydroxyimino-2-cyanoacetate, melting at 133° C. (12.4 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[C:27]#[N:28])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: N#Cc1ccccc1O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4C#N)ncnc32)CC1

Procedure:
4-[4-(2-Cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-hydroxybenzonitrile (available from Alfa Aesar, Ward Hill, Mass., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.98-2.08 (m, 4H), 2.98-3.08 (m, 2H), 4.08-4.11 (m, 2H), 5.01-5.06 (m, 1H), 7.55-7.59 (m, 1H), 7.63-7.65 (m, 1H), 7.85-7.90 (m, 1H), 8.02-8.04 (m, 1H), 8.47 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=421.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3C2CCCCO2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[CH3:6][NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ncnc3c2ncn3C2CCCCO2)CC1
Agent: Cl
Solvent: CCO
Product: CNC1CCN(c2ncnc3[nH]cnc23)CC1
Yield: 40 %

Procedure:
A solution of methyl-{1-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (83 mg, 0.2 mmol), ethanol (4 ml) and 1M aqueous HCl solution (1 ml) was stirred overnight at room temperature. The solvents were then evaporated in vacuo and the crude product was purified with a flash NH2 column (2 g, 15 ml) eluting with methanol to afford the required compound (18 mg, 0.08 mmol, 39%) LC-MS (LCT) Rt 1.27 [M+H]+] 233.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccc(Cl)cc2)oc2ccccc12
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 2-(4-chlorophenyl)-3-(4-hydroxyphenylsulfonyl)benzofuran with 3-diethylaminopropyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[7-(2-Butynyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (50 mg) and potassium carbonate (20 mg) were dissolved in N,N-dimethylformamide (1.5 ml) and methyl bromoacetate (14 μl) was added to the solution while cooling on ice. After the mixture was stirred at room temperature overnight, the mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After the organic layer was concentrated by distillation, the residue was purified by silica gel column chromatography to give 26 mg of the title compound from the elution fraction of hexane-ethyl acetate (1:1).
Reaction SMILES: C(O)(=O)C.[C:5]1([C:11]2([CH2:21][C:22]([NH2:24])=[NH:23])[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:25]([O:29][C:30](=[O:45])/[C:31](/O)=[C:32](\[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)/[C:33](O)=[O:34])([CH3:28])([CH3:27])[CH3:26].C[O-].[Na+].CCCCCC>CO.C(OCC)(=O)C>[C:25]([O:29][C:30]([C:31]1[C:32]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:33]([OH:34])[N:24]=[C:22]([CH2:21][C:11]2([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:12][CH2:13][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:19][CH2:20]2)[N:23]=1)=[O:45])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Reactant: N=C(N)CC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCC3(CC2)OCCO3)nc(O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A mixture of 2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetamidine acetic acid salt (268) (500 mg, 1.5 mmol) and 2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (553 mg, 1.8 mmol) in methanol (15 mL) were cooled to 0° C., followed by the addition of NaOMe (25% in methanol) (1 mL, 4.5 mmol) and the reaction mixture was stirred at room temperature for 16 h while silica thin layer chromatography was performed (ethyl acetate:hexane=7:3, Rf=0.6). The reaction mixture was diluted with ethyl acetate (40 ml) and washed with brine (2×20 mL). the reaction mixture was subsequently dried and concentrated in vacuo to get a crude mixture which was purified by normal silica gel (100-200 mesh) column chromatography using an eluent gradient (30-50% ethyl acetate in hexane) to obtain pure 5-benzyloxy-6-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (269) (590 mg, 74.09%) as a brown sticky mass.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Ic1ccccn1
Product: c1ccc(-n2ccc3ccccc32)nc1

Procedure:
Prepared by Procedure C and Scheme O using 2-iodopyridine and 1H-indole: ESMS m/e: 195.0 (M+H)+.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)([O-:7])=[O:6].[N+:13]([O-])([OH:15])=[O:14]>O>[N+:13]([N:11]1[CH:12]=[C:8]([N+:5]([O-:7])=[O:6])[N:9]=[CH:10]1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Reaction time: 1 h

Procedure:
430 mL of acetic acid and 188 g of 4-nitroimidazole were charged into a 2 L-volume reactor and stirred. While stirring the mixture, 100% nitric acid(137 mL) was slowly added dropwise to the mixture at the reaction temperature of 35° C. Anhydrous acetic acid(318 mL) was added dropwise thereto at 25° C. over 1 hour. After stirring the reaction mixture at 25° C. for 2 days, 1,4-dinitroimidazole was synthesized. Then, the resultant was poured in 2 L cold water, and extracted three times with 500 mL of methyl chloride for each time. The obtained methylene chloride solution was dried over MgSO4 so as to completely remove the water therefrom, resulting in methylene chloride extract solution containing 1,4-dinitroimidazole. The structure of the obtained 1,4-dinitroimidazole was as same as that of the comparative example.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=O)[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:4]1)[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([N:3]1[C:8](=[S:29])[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:4]1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1nc(-c2ccccn2)c2cccnc2c1=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCn1nc(-c2ccccn2)c2cccnc2c1=S
Temperature: 25 °C

Procedure:
A mixture of 7-ethyl-5-(pyridin-2-yl)pyrido[2,3-d]pyridazin-8(7H)-one RL-8 (90 mg, 0.36 mmol), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (145 mg, 0.36 mmol), and toluene (8 mL) was heated to 115° C. for 3.5 h. After cooling to ambient temperature, the reaction mixture was diluted with 20 mL of ethyl acetate and washed with a 1:1 solution of saturated brine/1 N NaOH. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by normal phase flash chromatography eluting with 0-10% methanol in dichloromethane over 22 minutes. Like fractions containing the desired product were pooled, concentrated under reduced pressure, and dried overnight at 60° C. under vacuum to give 7-ethyl-5-(pyridin-2-yl)pyrido[2,3-d]pyridazine-8(7H)-thione RL-9 (52 mg, 0.20 mmol). 1H NMR (400 MHz, DMSO-d6) δ 9.17 (dd, J=4.3, 1.7 Hz, 1H), 8.98 (dd, J=8.3, 1.7 Hz, 1H), 8.77 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 8.08-7.97 (m, 2H), 7.91 (dd, J=8.3, 4.3 Hz, 1H), 7.59 (ddd, J=7.3, 4.8, 1.5 Hz, 1H), 4.86 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:37][CH:38]([CH3:40])[CH3:39])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:37][CH:38]([CH3:40])[CH3:39])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCCCOc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCCC(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
To a solution of ethyl 5-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}pentanoate (1.6 g, 2.9 mmol) in tetrahydrofuran (10 ml)-ethanol (10 ml) was added 2N aqueous sodium hydroxide solution (3 ml), and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was acidified with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under-reduced pressure and the residue was crystallized from diisopropyl ether to give 5-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}pentanoic acid (1.3 g, yield 87%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O[C@:13]([CH3:28])([CH2:26][CH3:27])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=O>>[CH2:26]([C@@:13]1([CH3:28])[O:10][C:9](=[O:11])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:14]1[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=1)[CH3:27]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CC[C@@](C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Product: CC[C@@]1(C)OC(=O)C(c2ccc(F)cc2)=C1c1ccc(S(C)(=O)=O)cc1

Procedure:
Using the procedures described in Example 1, Step 4 and Step 5, replacing phenylacetic acid with p-fluorophenylacetic acid and replacing 2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-butanone with (2R)-2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]butan-1-one from Step 4, the title compound was obtained as a white solid.