Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[OH:3][CH:4]([CH:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:15])[CH2:5][C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].S(=O)(=O)(O)O>C(O)C>[OH:13][CH:6]([CH2:5][CH:4]([OH:3])[CH:14]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:15])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CC(=O)CC(O)C(C)Oc1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(O)CC(O)C(C)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 37 %

Procedure:
To 2.5 g (0.006 mole) sodium borohydride in 30 ml of absolute ethanol was added dropwise 30 ml of an absolute ethanol solution containing 3.5 g 80.0135 mole) of the ethyl 5-hydroxy-3-oxo-6-phenoxyheptanoate obtained in step (a). After completion of the addition, cooling was immediately stopped and the mixture was allowed to warm to room temperature and was stirred for about 40 minutes. To the reaction mixture were then added about 300 ml of ice-water and the mixture was then acidified by the addition of 2 N sulphuric acid. After saturating the solution with sodium chloride, it was extracted three times, each time with 50 ml of ethyl acetate. The combined extracts were dried over anhydrous sodium sulphate and then the solvent was evaporated off, to give 1.3 g (yield 37%) of ethyl 3,5-dihydroxy-6-phenoxyheptanoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1F.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(Br)c(N2CCNCC2)c1
Temperature: 100 °C
Yield: 30.9 %

Procedure:
A mixture of 2 g (8 mmol) 1-Bromo-2-fluoro-4-trifluoromethyl-benzene and 2.13 g (25 mmol) piperazine in 2 ml N,N-dimethylacetamide was heated to 100° C. for 2 h and subsequently all volatiles were removed under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/methanol/1% NH3 aq. to yield 0.765 g (37%) of the title compound as colourless oil.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]1[CH2:16][CH2:15][CH2:14][O:13][C:11]1=[O:12]>>[OH:8][CH:1]([C:10]1([CH3:9])[CH2:16][CH2:15][CH2:14][O:13][C:11]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC1CCCOC1=O
Product: CC1(C(O)c2ccccc2)CCCOC1=O

Procedure:
Benzaldehyde is reacted with 2-methyl-δ-valerolactone to produce 2-(1-hydroxy-1-phenylmethyl)-2-methyl-δ-valerolactone.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Product: O=C(O)c1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1
Yield: 100 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-(chloromethyl)benzoic acid instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 100%) was obtained as colorless crystals.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:22])=[O:23])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(/C=C/c3ccc(Cl)cc3)c2c1
Yield: 65.8 %

Procedure:
N-{3-[(E)-2-(4-Chlorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 631 mg of trans-2-(4-chlorophenyl)vinylboronic acid, 28 ml of dimethylformamide, 3.25 ml of a saturated aqueous sodium hydrogencarbonate solution and 48 mg of tetrakis(triphenylphosphine)-palladium[0]. 556 mg of N-{3-[(E)-2-(4-chlorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a pale yellow solid melting at 247° C. (analysis C22H18ClN3O4S2 % calculated C, 54.15; H, 3.72; Cl, 7.27; N, 8.61; O, 13.11; S, 13.14. % found C, 54.32; H, 4.40; Cl, 5.65; N, 7.83; S, 11.93).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.C([N:28]([CH2:32][CH3:33])[CH:29]([CH3:31])C)(C)C>CN(C=O)C>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:28]3[CH2:29][CH2:31][C:6]4[N:5]=[CH:4][NH:12][C:13](=[O:24])[C:33]=4[CH2:32]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCc4nc[nH]c(=O)c4C3)n2n1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 52 mg, 0.151 mmol), 5,6,7,8-tetrahydropyrido[4,3-c/]pyrimidin-4(3H)-one hydrochloride (78 mg, 0.395 mmol), and N,N-diisopropylethylamine (60 mg, 0.467 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was filtered and the crude material recrystallized from hot methanol, providing the titled compound as a white solid (26.9 mg, 39%). 1H NMR (DMSO-d6) δ: 8.13 (br. s., 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.45 (s, 1H), 6.18 (s, 1H), 5.18 (s, 1H), 4.49 (br. s., 2H), 4.10 (t, J=6.7 Hz, 2H), 2.87 (t, J=6.7 Hz, 2H), 2.40 (s, 3H), 1.45 (s, 6H); ESI-MS: m/z 460.2 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[C:13]([CH3:21])([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH3:14])=[CH:8][CH:7]=1.Br[CH2:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:29][O:28][C:26](=[O:27])[C:25]([CH2:30][S:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[C:13]([CH3:14])([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH3:21])=[CH:8][CH:7]=1)=[CH2:24]
Reactant: CC(C)(C(=O)c1ccc(SCCCS)cc1)N1CCOCC1
Reactant: C=C(CBr)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=C(CSCCCSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3.0 g (8.8 mmol) of 1-[4-(3-mercaptopropylthio)phenyl]-2-methyl-2-morpholin-4-yl-propane-1-one are dissolved in 1.50 ml of methanol. To the solution are successively added 1.89 g (10.6 mmol) of methyl 2-(bromomethyl)acrylate and 1.22 g (8.8 mmol) of potassium carbonate, and the reaction mixture is stirred at room temperature for 10 min. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with water, and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:3) as an eluent, and an oily product is obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:16]=[CH:15][C:12]([NH:13][CH3:14])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[CH2:20][C:21]([N:23]=[C:24]=[S:25])=[O:22].C(=O)(O)[O-].[Na+]>C(COC)OC>[F:1][C:2]([F:17])([F:18])[C:3]([C:9]1[CH:16]=[CH:15][C:12]([N:13]([C:24]2[S:25][CH2:20][C:21](=[O:22])[N:23]=2)[CH3:14])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: CNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C(CCl)N=C=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CN(C1=NC(=O)CS1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To p-(hexafluoro-2-hydroxy-2-propyl)-N-methylaniline (2.73 gm., 0.01 mole) in dimethoxyethane (40 ml), add chloroacetyl isothiocyanate (1.50 gm., 0.011 mole) and stir 1 hr. Pour the reaction mixture onto water and neutralize with sodium bicarbonate. Extract with ether, dry and concentrate. Recrystallize from ether to obtain the product, m.p. 240°-242° C.
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][N:7]=[C:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:5][O:6]/[N:7]=[C:8](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)\[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:36][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][C:27]([O:26][CH3:25])=[O:37])=[CH:35][CH:34]=2)=[CH:13][CH:12]=1
Reactant: CON=C(COc1ccc(C=O)cc1)c1ccccc1
Reactant: COC(=O)CCc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CO/N=C(\COc1ccc(CNc2ccc(CCC(=O)OC)cc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged 5 mL of dichloroethane. To the stirred solvent was added 4-(2-methoxyimino-2-phenyl-ethoxy)-benzaldehyde (0.4 g, 1.5 mmol), 3-(4-amino-phenyl)-propanoic acid methyl ester (0.27 g, 1.5 mmol). RM was cooled to 0° C. and sodium triacetoxyborohydride (0.47 g, 2.25 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was stirred at RT for 2 h. The RM was quenched with NaHCO3 solution (40 mL 10% solution in water) and extracted with ethyl acetate (20 mL×2). The organic layer washed with saturated brine solution (25 mL), dried over anhydrous Na2SO4 and evaporated in vacuum to dryness. The resulting crude compound was purified by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate as eluent to give the product (0.450 g, Yield: 69.4%): MS (ESI, 120 eV): m/z=433.1 (M+H)+.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Br[C:10](Br)([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:18][C:16]([C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Ex-1A: Catechol (2.2 g, 20 mmol) was dissolved in acetone. Diethyl dibromomalonate (7.0 g, 22 mmol) and potassium carbonate (2.76 g) were added, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and water was added to the residue. The residue was extracted with dichloromethane, and the organic phase was washed with brine, dried over magnesium sulfate and evaporated. Chromatography (hexanes/ethyl acetate, 4:1) gave 3.9 g of benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester. 1H-NMR (CDCl3) δ 6.90–6.97 (m, 4H), 4.37 (q, J=7 Hz, 4H), 1.32 (t, J=7 Hz, 6H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[O:19]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=1[NH:51]C(=O)OC(C)(C)C)[Si](C(C)(C)C)(C)C>C1COCC1>[CH3:50][O:49][C:47]1[CH:48]=[C:43]2[C:44](=[CH:45][CH:46]=1)[NH:51][C:41]([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:19])=[CH:42]2
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C#CCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(CCCCCCCCCCCCCCO)cc2c1
Yield: 64.7 %

Procedure:
A mixture of 1M THF solution of TBAF (5.1 mL, 5.11 mmol, 15 eq) and tert-butyl {2-[16-(tert-butyl-dimethylsilanoxy)-hexadecynyl]-4-methoxyp henyl}-carbamate (195 mg, 0.34 mmol, 1 eq) was refluxed for 24 hours. After removing THF, the residue was diluted with 50 mL of water, and extracted three times with AcOEt (50 mL). The extract was washed with aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated. The resulting concentrate was subjected to silica gel flush chromatography (eluate: hexane-AcOEt=70-30) to give white solid of the title compound (79.1 mg, yield 81%).
Reaction SMILES: F[B-](F)(F)F.[N+:6]([C:9]1[CH:10]=[C:11]([N+]#N)[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C([O-])(=O)C.[K+].[C:22]1([O:28][CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:29][O:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1
Reactant: N#[N+]c1cccc([N+](=O)[O-])c1
Reactant: COc1ccccc1
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [K+]
Product: COc1ccccc1-c1cccc([N+](=O)[O-])c1
Reaction time: 12 h

Procedure:
Anisole (400 mL) and 3-nitrobenzenediazonium tetrafluoroborate (54.5 g, 0.23 mol) were placed in a 1-L flask and stirred mechanically. Potassium acetate (49.0 g, 0.5 mol) was added in one portion. The mixture turned red and warmed slightly. Stirring was continued 12 h., then the solution was filtered and the anisole evaporated in vacuo. Column chromatography of the residue (alumina, 0-10% ether/hexane, first yellow band) and recrystallization (95% EtOH) provided pure 2-methoxy-3'-nitrobiphenyl: 18 g (35%); mp 68°-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5]([CH2:10][CH2:11][CH3:12])[CH:4]=1>S(=O)(=O)(O)O.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH2:11][CH3:12])[CH:4]=1
Reactant: CCCc1cc(OC)cc[n+]1[O-]
Agent: O=S(=O)(O)O
Agent: [Zn]
Product: CCCc1cc(OC)ccn1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A solution of 4-methoxy-2-n-propylpyridine-N-oxide (59.3 g, 0.355 mol) in 800 ml of 1 M sulfuric acid was stirred and heated to 70-80° C. Zinc dust (140.0 g, 214 mol) was added in portions over four hours. When the addition was complete, heating was continued for a further eight hours. The resulting precipitate was filtered off and washed with water. The filtrate was made strongly alkaline by addition of a 32% sodium hydroxide solution and extracted with dichloromethane (3×250 ml). The extracts were combined, dried over sodium sulfate, filtered, evaporated and distilled. This gave 46.1 g (86%) of 4-methoxy-2-n-propylpyridine as a colourless oil. B.p. 44-46° C./0.1-0.2 mbar. 1H-NMR (CDCl3, 200 MHz) δ: 0.99 (t, 3H); 1.75 (sext, 2H); 2.72 (t, 2H); 3.81 (s, 3H); 6.10-6.18 (m, 2H); 8.35 (d, 1H).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[N:9][N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[N:6]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].[Br:19]Br>C(O)(=O)C>[Br:19][C:11]1[N:8]2[N:9]=[CH:10][C:5]([C:2]([F:1])([CH3:4])[CH3:3])=[N:6][C:7]2=[N:13][CH:12]=1
Reactant: CC(C)(F)c1cnn2ccnc2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(F)c1cnn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.4 %

Procedure:
To a stirred solution of 3-(1-fluoro-1-methylethyl)imidazo[1,2-b][1,2,4]triazine (0.6208 g, 3.45 mmol) in acetic acid (15 ml) was added sodium acetate (0.4251 g, 5.18 mmol), then, dropwise over 5 min, a solution of bromine (0.195 ml, 3.78 mmol) in acetic acid (2 ml). The solution was stirred at room temperature for 30 min, then partitioned between saturated aqueous NaHCO3 (300 ml) and ethyl acetate (150 ml). The aqueous layer (pH 7) was further extracted with ethyl acetate (2×150 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 25% EtOAc/isohexane) to afford 0.8437 g (95%) of the title compound as a yellow solid: 1H NMR (360 MHz, CDCl3) δ 1.82 (6H, d, J 22.1), 7.99 (1H, s), 8.81 (1H, d, J 1.1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[N:8][C:7]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:12][C:10]2[CH:9]=[N:8][C:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:11]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: Nc1cnc(-c2ccncc2)c(-c2ccco2)n1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1cnc(-c2ccncc2)c(-c2ccco2)n1)c1ccc(F)cc1
Yield: 45 %

Procedure:
Obtained as a solid (50 mg, 45%) from 6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5) and 4-fluorobenzoyl chloride following the procedure of Example 15 (step b).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:21]([O-])([N+]([O-])=O)=[O:22]>>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 67.8 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-ribofuranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(D-ribofuranosyl)urea are thereby obtained as yellow liquid.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([CH3:14])=[C:12](I)[C:11]([F:16])=[C:10]([O:17][CH3:18])[C:9]=1[NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])#[N:7].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>[Cl-].[Na+].O>[C:6]([C:8]1[C:9]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:10]([O:17][CH3:18])[C:11]([F:16])=[C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]=1[CH3:14])#[N:7]
Reactant: OB(O)c1ccccc1
Reactant: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(F)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Under nitrogen atmosphere, tetrakistriphenylphosphine palladium(0) (288 mg, 0.25 mmol) was added to an N,N-dimethylformamide (15 ml) suspension of N-(2-cyano-5-fluoro-4-iodo-6-methoxy-3-methylphenyl)-2,2,2-trifluoroacetamide (I-35) (500 mg, 1.24 mmol), phenylboronic acid (228 mg, 1.87 mmol), potassium phosphate n-hydrate (890 mg, 3.1 mmol), followed by stirring with heating under reflux for 15 hours and a half. After cooling to room temperature, water and saturated brine were added to the reaction liquid, followed by extraction three times with ethyl acetate, the organic layer was washed with saturated ammonium chloride water, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (5:1) was concentrated under reduced pressure to obtain the entitled compound (427 mg, 98%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=3)[S:10][C:3]=12.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Cn1cncc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: Cn1cncc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 190 °C
Yield: 42.6 %

Procedure:
A mixture of the compound 16 (1.52 g, 6.09 mmol), 2-fluoro-4-nitrophenol (3.87 g, 24.6 mmol) and K2CO3 (4.31 g, 31.2 mmol) in Ph2O (20 mL) was heated at 190° C. overnight. DCM (250 mL) was added to the resultant dark-brown mixture, which was then extracted with aqueous 1M HCl. The aqueous layer was collected, washed with DCM and basified with NH4OH. The resultant cloudy mixture was extracted with DCM. The organic phase was combined, filtered; the filtrate was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resultant yellow solid was purified by flash chromatography, eluent EtOAc/MeOH (80:20) to afford title-compound 17 as a yellow solid (0.96 g, 43% yield). MS (m/z): 371.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([C:16]([OH:18])=O)[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([C:16]([Cl:27])=[O:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1c(C(=O)O)nnn1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1c(C(=O)Cl)nnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carboxylic acid (830 mg, 3.13 mmol) in dichloromethane (3 mL) was added DMF (50 μL) followed by oxalyl chloride (546 μL, 6.26 mmol) dropwise. After 5 min, the ice bath was removed and the mixture was stirred at room temperature for 1 h. CH2Cl2 was removed in vacuo to give 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carbonyl chloride as a white solid which was used in the next step without further purification.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:42])[C@@H:10]([NH:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([Cl:40])[C:33]=1[CH3:41])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:40][C:34]1[C:33]([CH3:41])=[C:32]([NH:31][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:42])[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(CO[Si](C)(C)C(C)(C)C)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(CO)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl

Procedure:
To a pre-cooled (−50° C.) solution of 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-((tert-butyldimethylsilyloxy)methyl)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (4.35 g, 6.93 mmol) in THF (600 mL) was added TBAF (13.87 mL, 13.87 mmol, 1 M solution in THF) dropwise over 10 min. Upon complete addition, the reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in EtOAc (100 mL) and washed with H2O (80 mL). The biphasic mixture was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (1×70 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (65% EtOAc in hexanes then EtOAc to provide the title compound as an off-white solid. The resulting solid was diluted with CH2Cl2 (30 mL) and hexanes (70 mL) was added. Upon concentration of the suspension a white solid was provided (2.4 g, 87%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.98 (d, J=8.8 Hz, 2H), 7.57 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 1H), 6.84 (d, J=9 Hz, 1H), 5.69 (d, J=8 Hz, 1H), 5.11-5.05 (m, 1H), 4.74-4.71 (m, 2H), 2.40 (s, 3H) and 1.40 (d, J=7 Hz, 3H).