Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3CC(C[CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([C:28]([OH:30])=[O:29])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])C2.[CH2:31](O)[CH3:32]>>[CH:2]1([NH:11][C:12]([N:14]2[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20]3)[CH2:18][CH2:19]2)=[O:13])[CH2:1][CH2:10][CH2:5][CH2:4][CH2:3]1
Reactant: CCO
Reactant: O=C(O)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Product: CCOC(=O)C1CC2(CCN(C(=O)NC3CCCCC3)CC2)c2ccccc21

Procedure:
A procedure analogous to that described Example 4 was followed using 1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]3-carboxylic acid and ethanol. 1H NMR (CD3OD) δ=1.29 (t, 3H), 1.54 (m, 1H), 1.64 (m, 2H), 1.86 (m, 9H), 1.96 (m, 5H), 2.43 (m, 2H), 3.04 (m, 2H), 3.86 (s, 1H), 4.06 (m, 2H), 4.15 (m, 1H), 4.20 (m, 1H), 7.20 (m, 3H), 7.34 (m, 1H); LC-MS (4 min) tR=2.12 min, m/z=437.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[S:38])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:4]3([CH3:3])[O:8][C:7]4=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]4[CH2:5]3)[CH2:21][CH2:20]2)=[S:38])=[CH:32][CH:31]=1
Reactant: CC1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(CN2CCN(C(=S)Nc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 322 (196 mg, 0.73 mmol) was suspended in methylene chloride (10 ml), then neutralized with triethylamine (0.27 ml, 1.94 mmol). To the solution, 4-chlorophenyl isothiocyanate (140 mg, 0.83 mmol) was added followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carbothioic acid (4-chlorophenyl)amide (128 mg, yield 40%) as a light brown powder.
Reaction SMILES: C([O:4][CH2:5][C:6](=O)[CH2:7][S:8][C:9]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([OH:24])[C:16]2[C:11](=[C:12]([F:27])[C:13]([F:26])=[C:14]([F:25])[CH:15]=2)[N:10]=1)(=O)C.S(=O)(=O)(O)O>O>[F:25][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([F:27])[C:13]=1[F:26])[N:10]1[C:6]([CH2:5][OH:4])=[CH:7][S:8][C:9]1=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2=[O:24]
Reactant: CCOC(=O)c1c(SCC(=O)COC(C)=O)nc2c(F)c(F)c(F)cc2c1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1c(=O)c2cc(F)c(F)c(F)c2n2c(CO)csc12
Temperature: 25 °C
Reaction time: 26 h
Yield: 78.5 %

Procedure:
Ethyl 2-(3-acetoxy-2-oxopropylthio)-6,7,8-trifluoro-4-hydroxyquinoline-3-carboxylate (3.54 g) was added to concd. sulfuric acid (35 ml) and the mixture was stirred at room temperature for 2 hours and 15 minutes. Thereto water (29 ml) was added gradually with ice-cooling and the mixture was stirred at room temperature for 26 hours, followed by addition of ice-water (400 ml). After precipitated crystal was filtered and washed with water, the resultant was recrystallized from a mixed solvent of chloroform - ethanol to give the title compound (2.38 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:1][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCCC(=O)N(C)OC
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCCCC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Methyl magnesium bromide (3M in ether, 3 eq.) was added dropwise to a stirred mixture of N-methoxy-N-methylhept-6-enamide 58 in THF (0.1 M) cooled at 0° C. After sting for 1 h at 0° C., the mixture was poured into sat. aq. NH4Cl and diluted with EtOAc. The aqueous layer was further extracted with EtOAc, the combined organic layers were washed with brine and dried (Na2SO4). Evaporation of the solvent at 30 mbar afforded the title compound (96%) as a colorless oil. 1H NMR (400 MHz, CDCl3, 300 K) δ 5.81 (ddt, J 17.1, 10.3, 6.7, 1H), 5.02 (dd, J 17.1, 1.5, 1H), 4.97 (d, J 10.3, 1H), 2.46-2.43 (m, 2H), 2.15 (s, 3H), 2.10-2.05 (m, 2H), 1.65-1.57 (m, 2H), 1.45-1.37 (m, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:20]1([C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([N:20]5[CH2:21][CH2:22][CH2:23][CH2:24]5)[CH:26]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OB(O)c1cccc(N2CCCC2)c1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCCC5)c4)nc23)CCCCC1
Yield: 62.1 %

Procedure:
A microwave tube was charged with (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone (95 mg, 0.29 mmol), 3-pyrrolidino phenylboronic acid (62 mg, 0.32 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(ll) (19 mg, 0.02 mmol), and freshly grounded K2CO3 (102 mg, 0.74 mmol). Dioxane (3 ml) and water (0.7 ml) were added, and the reaction mixture was microwaved at 150° C. for 30 minutes. The reaction mixture was partitioned between EtOAc/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a dark brown solid. The residue was purified by silica gel chromatography using 10-50% EtOAc in hexanes as eluant to provide 70 mg (61%) of (1-methyl-cyclohexyl)-[2-(3-pyrrolidin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a yellow solid. MP 243-245.4° C., M+H=389.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[N:7]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: COc1ccc(CCNc2ccnc(Cl)n2)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1ccc(CNc2nccc(NCCc3ccc(OC)c(OC)c3)n2)cc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
In a sealed flask, a mixture of 7 (744 mg, 2.53 mmol), methyl 4-(aminomethyl)benzoate (628 mg, 3.80 mmol) and i-Pr2NEt (882 μl, 5.07 mmol) in isopropanol (50 mL) was heated to 120-125° C. for 7 days (during this period of time an excess of methyl 4-(aminomethyl)benzoate was added to the reaction mixture). The reaction mixture was allowed to cool to the room temperature, concentrated and purified by flash chromatography on silica gel (MeOH/CH2Cl2, 5/95→10/90 plus several drops of NH4OH) to afford the title compound 8 (671 mg, 1.59 mmol, 63% yield) as an orange sticky solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl>C(O)C>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(F)ccc1O)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(F)ccc1O)C2
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
To a mixture of 7-(5-fluoro-2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.75 g) and aminoguanidine hydrochloride (0.333 g) were added ethanol (8 ml) and concentrated hydrochloric acid (0. 5 ml), and the mixture was stirred at 110° C. (bath temperature) for 2.5 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(5-fluoro-2-hydroxyphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 169) (1 g) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:7]([C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)=[O:8])[CH:10]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1cc(Br)ccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)ccc2F)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzoyl chloride (27.0 g, 114 mmol) and anisole (12.9 g, 13.0 mL, 119 mmol) in dichloromethane (150 mL) at 0° C. was added aluminum trichloride (16.2 g, 119 mmol) portionwise so that the internal temperature remained below 10° C. After stirring for 4 hours at 0° C., the solution was poured over crushed ice and the resulting mixture was stirred. After 30 minutes, the organic phase was removed and the aqueous phase was extracted two times with dichloromethane. The combined organic phases were washed once with aqueous 1M hydrochloric acid solution, once with aqueous 1M sodium hydroxide solution, and once with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized from ethanol to afford (5-bromo-2-fluoro-phenyl)-(4-methoxy-phenyl)-methanone (22.5 g, 64%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][O:16]/[CH:17]=[CH:18]/[C:19](Cl)=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])/[CH:18]=[CH:17]/[O:16][CH3:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CO/C=C/C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO/C=C/C(=O)Nc1ccc(Br)cc1
Yield: 95.6 %

Procedure:
Combined 4-bromoaniline (285 mg, 1.659 mmol), CH2Cl2 (2.0 ml) and pyridine (0.25 ml, 3.09 mmol) and slowly added (E)-3-methoxyacryloyl chloride (200 mg, 1.659 mmol) and stirred at room temperature for 2 h. The resulting yellow solid was filtered off and washed with water. The solid was dried under vacuum to give the title compound (406 mg, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([C:14](=[O:15])[NH:13][CH2:12][CH:11]2[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([C:14](=[O:15])[N:13]([CH3:26])[CH2:12][CH:11]2[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCC2c1cccnc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1CC(c2cccnc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a cooled (−60° C.) solution of 1-oxo-4-pyridin-3-yl-2,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester (diastereomer 1) (343 mg, 1.03 mmol) in THF (7 ml) was added dropwise 1M LHMDS in THF (1.34 ml, 1.34 mmol). After stirring for 1 h at −60° C., iodomethane (0.084 ml, 1.34 mmol) in THF (1 ml) was added. The cooling bath was removed and the reaction mixture was allowed to warm to RT and stirred for 3 h. A further portion of 1M LHMDS in THF (0.75 ml, 0.75 mmol) was added to the cooled (−60° C.) reaction mixture. After 30 minutes, iodomethane (0.042 ml, 0.67 mmol) in THF (0.5 ml) was added, the cooling bath was removed and the reaction mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with NH4Cl saturated solution (5 ml) and extracted with EtOAc (2×25 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-5% MeOH in DCM afforded the title compound as a yellow oil.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([CH2:16][CH3:17])=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[N:11]2)=O.[CH:19]1([NH:22][C:23]([NH2:25])=[NH:24])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:19]1([NH:22][C:23]2[N:25]=[C:5]([C:7]3[C:8]([CH2:16][CH3:17])=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[N:11]4)[CH:4]=[CH:3][N:24]=2)[CH2:21][CH2:20]1
Reactant: N=C(N)NC1CC1
Reactant: CCc1nn2ncccc2c1C(=O)/C=C/N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nn2ncccc2c1-c1ccnc(NC2CC2)n1
Temperature: 135 °C
Yield: 360 %

Procedure:
To a solution (2E)-3-(dimethylamino)-1-(2-ethylpyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one (75 mg, 0.31 mmol) in DMF (2.0 mL) was added N-cyclopropylguanidine.0.5H2SO4 (181 mg, 0.92 mmol) and potassium carbonate (212 mg, 1.54 mmol). The reaction was heated at an oil bath temperature of 135° C. for about 18 hours. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in chloroform and filtered. The filtrate was concentrated in vacuo then disolved in CH2Cl2 and triturated with diethylether and hexanes to give the title compound as an orange solid (32 mg, 360% o). 1H-NMR (300 MHz, CDCl3) δ 8.96 (d, 1H, J=8.7 Hz), 8.38 (d, 1H, J=5.4 Hz), 8.34 (dd, 1H, J=4.4, 1.9 Hz), 7.14 (dd, 1H, J=9.0, 4.5 Hz), 6.92 (d, 1H, J=5.4 Hz), 5.47 (s, 1H), 3.23 (q, 2H, J=7.5 Hz), 2.88 (m, 1H), 1.50 (t, 3H, J=7.5 Hz), 0.91 (m, 2H), 0.67 (m, 2H); MS (ESI) (M+H)+ 281.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=O)[N:22]=3)[CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:32])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([Cl:32])=[O:29])[N:22]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C(=O)O)n3)c2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C(=O)Cl)n3)c2)cc1

Procedure:
To 1 g of 4′-(4-methoxyphenyl)-2,2′:6′2″-terpyridine-6-carboxylic acid is added a solution of 1 mL of thionyl chloride in 25 mL of methylene chloride. The reaction mixture is heated gently for 1 hour, and the solvent and excess thionyl chloride are removed under reduced pressure. The crude product is triturated with anhydrous heptane and isolated by filtration under nitrogen.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.[CH3:34][NH:35]C(=O)CN.CN1CCOCC1>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][C:16]([NH:35][CH3:34])=[O:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: CNC(=O)CN
Reactant: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Solvent: CN1CCOCC1
Product: CNC(=O)CNC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Yield: 33 %

Procedure:
The title compound was prepared by a procedure similar to the one described for (±)3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide using glycine methyl amide HCl (1.77 g, 14.25 mmol) as the amine and with an addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (1.55 g, 33%) as white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.97 (dd, 1H, J=1.6 Hz), 7.73 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.57 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.98 (s, 2H), 2.74 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H); ES-HRMS m/z 491.1262 (M+H C23H22ClF2N4O4 requires 491.1292). Both (+) and (−) atropomers will be resolved and characterized.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([S:28][C:25]3[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=3)=[C:3]([N+:18]([O-:20])=[O:19])[CH:4]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(S)cc1
Reactant: COc1ccc(COc2ccc(Cl)c([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of the product of Example 10C (0.812 g, 2.76 mmol), 4-hydroxythiophenol (0.419, 3.32 mmol) and cesium carbonate (2.16 g, 6.64 mmol) in N,N-dimethylformamide (5 mL) was heated to 100° C. for 16 hours. After cooling to room temperature the mixture was poured into ice water (20 mL) and the resultant solution acidified with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3×10 mL), the combined extracts dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.06 g, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=C)=[CH:7][CH:6]=1.[OH:13]C1C=CC(C=O)=CC=1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:13])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C=Cc1ccc(OCCO)cc1
Product: O=Cc1ccc(OCCO)cc1

Procedure:
Ueno et al. (U.S. Pat. No. 6,340,759) also describe a two-step procedure for preparing p-(2-hydroxyethoxy)styrene starting with p-hydroxybenzaldehyde. In the first step, p-(2-hydroxyethoxy)benzaldehyde is formed by reacting p-hydroxybenzaldehyde, sodium hydride, and (2-bromoethoxy)-tert-butyldimethylsilane. In the second step, p-(2-hydroxyethoxy)styrene is formed by reacting the isolated p-(2-hydroxyethoxy)benzaldehyde with (ethyl)triphenylphosphonium bromide in the presence of sodium hydride.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4](=[O:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[OH:10][C:4]1[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1[nH]c(=O)cc(O)c1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1nc(O)c([N+](=O)[O-])c(O)c1C

Procedure:
The above nitration process was essentially repeated using 23.612 g 4-hydroxy-5,6-dimethyl-2(1H)-pyridone, 460 ml acetic acid, 12.2 ml nitric acid, and cooling the mixture in an ice bath after refluxing and prior to filtration. Combined product was used in the next step.
Reaction SMILES: [N:1]1([C:5]2[N:9](COCC[Si](C)(C)C)[C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[O-]CC.[Na+]>CN(C=O)C.O>[N:1]1([C:5]2[NH:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c(N2CCC2)nc2ccccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(N3CCC3)nc2c1
Temperature: 150 °C
Yield: 98.8 %

Procedure:
Into a sealed vessel was placed crude 2-(azetidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H benzo[d]imidazole (0.55 g) and sodium ethoxide (1.2 g) in DMF (14 mL). The reacted was heated for 30 mins at 150° C. in an oil bath. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to give 310 mg of 2-(azetidin-1-yl)-1H-benzo[d]imidazole as yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([N:15]([CH3:14])[O:16][CH2:17][C:18]([OH:20])=[O:19])=[S:12])([CH3:3])[CH3:2]
Reactant: CNOCC(=O)O
Reactant: CC(C)c1ccccc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1NC(=S)N(C)OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A mixture of 2-isopropylphenyl-isothiocyanate (17.7 g), N-methyl aminooxy acetic acid hydrochloride (14.2 g), triethylamine (20 g) and chloroform (300 mL) was stirred at ambient temperature for two hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with 2N HCl (2×200 mL) then with water (100 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (21 g) of [[[[(2-isopropylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil. 1H-NMR (DMSO-d6; 300 Mhz) δ13.0 (br s, 1H), 10.15 (s, 1H), 7.42-7.05 (m, 4H), 4.63 (s, 2H), 3.58 (s, 3H), 3.08 (m, 1H), and 1.15 ppm (d, 6H). The acid (20 g) was dissolved in benzene (200 mL). Phosphorus pentachloride (14.7 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (700 mL) and washed with sodium bicarbonate saturated solution (3×400 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (10-50% methylene chloride in hexane). The title compound (12.8 g) was obtained as a solid, m.p. 98-101° C. Mass spectrum (El, M.+) m/z 264. 1H-NMR (CDCl3; 400 MHz) δ7.37 (m, 2H), 7.22 (t, 1H), 7.06 (d, 1H), 5.12 (q, 2H), 3.69 (s, 3H), 2.69 (m, 1H), 1.15 (d, 3H), and 1.04 ppm (d, 3H).
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11](OC)=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>O1CCCC1>[SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: COC(=O)c1nc2nc(C)cc(S)n2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(S)n2nc(CO)nc2n1
Reaction time: 0.17 h

Procedure:
2.24 g of methyl 7-mercapto-5-methyl-s-triazolo[1,5-a]-pyrimidine-2-carboxylate were suspended in 350 ml of tetrahydrofuran and treated at 2° within 15 minutes with 40 ml of a 1M diisobutylaluminium hydride/hexane solution. The reaction mixture was stirred at 2° for 10 minutes and subsequently treated with ice. The reaction mixture was concentrated extensively, the residue was taken up in 30 ml of water, and the solution was acidified to pH 1.2 with concentrated hydrochloric acid. The solid was collected by filtration and dried in a high vacuum. There was obtained 7-mercapto-5-methyl-s-tria-zolo[1,5-a]pyrimidine-2-methanol of melting point 233° (dec.).
Reaction SMILES: C(OC[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[C:8]=1[S:16]([CH3:19])(=[O:18])=[O:17])C.FC(F)(F)C(O)=O>ClCCl>[CH3:19][S:16]([C:8]1[C:9]2[O:15][CH2:14][O:13][C:10]=2[CH:11]=[CH:12][C:7]=1[CH2:6][OH:5])(=[O:17])=[O:18]
Reactant: CCOCOCc1ccc2c(c1S(C)(=O)=O)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1c(CO)ccc2c1OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
571 mg of 1-[(ethoxymethoxy)methyl)-2-(methylsulfonyl)-3,4-methylenedioxybenzene was dissolved in 2 ml of dichloromethane, 2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), to give 308 mg of the title compound as a colorless oil.