Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([O:24][C:25]2[C:30]3[N:31]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[S:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[N:21]=[CH:20][N:19]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=[CH:10][C:9]=1[C:18]1[N:19]=[CH:20][N:21]=[C:22]([O:24][C:25]2[C:30]3[N:31]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[S:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[CH:23]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)OC(C)(C)C)ncn3)cccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reaction time: 16 h

Procedure:
To {2-[6-(2-acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester, (Example 150) (0.35 g, 0.60 mmol) was added 4 M HCl in dioxane (25 mL). The mixture was stirred for 16 h and then was concentrated in vacuum. The residue was dissolved in ethyl acetate (40 mL) and washed with saturated NaHCO3 (2×70 mL), dried over Na2SO4 and concentrated in vacuum. Purification by silica gel chromatography (2:1, EtOAc:hexanes) afforded the title compound as thick yellow oil. Mp: 160–161° C. MS (ESI, pos. ion) m/z: 446 (M+1). Anal. Calcd for C20H14F3N5O2S.0.4H2O: C, 53.07; H, 3.30; F, 15.47; N, 12.59. Found: C, 53.12; H, 3.27; F, 15.19; N, 12.70.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([C:12]([O:14]C)=[O:13])=[C:4]2[N:3]=1>[OH-].[Na+]>[SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cnn2c(C)cc(S)nc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(S)nc2c(C(=O)O)cnn12

Procedure:
7.20 g of methyl 5-mercapto-7-methylpyrazolo[1,5-a]-pyrimidine-3-carboxylate were heated to 100° in 2N sodium hydroxide solution until almost all had dissolved. The solution was cooled, filtered and the filtrate was adjusted to pH 2. The product was filtered off under suction, washed with water and acetone and dried. There was obtained 5-mercapto-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid of m.p. 225° (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:14])=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1.Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:14][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]4)=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: CCCc1c(O)ccc2c(C)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2)CC[C@H]3CC(=O)OCC)ccc2c(C)noc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To a mixture of 3-methyl-7-propyl-1,2-benzisoxazol-6-ol (269 mg, 1.01 mmol) (Example 67) and ethyl [(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (331 mg, 1.01 mmol) (Example 45) in DMF (8 mL, containing 1 vol % water) was added Cs2CO3 (661 mg, 2.03 mmol). The mixture was stirred for 16 h at rt, and then the reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc and filtered through a small plug of silica to give 204 mg (39%) of the title compound as a white solid that was used in the next step without further purification.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][C:15](=[O:25])[CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:13])[CH:8]=[CH:9][CH:10]=1)([O-])=O>CO.[Ni]>[ClH:1].[NH2:2][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][C:15](=[O:25])[CH2:16][NH:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(Cc1cccc([N+](=O)[O-])c1)NC(=O)CNCc1ccccc1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: CC(Cc1cccc(N)c1)NC(=O)CNCc1ccccc1

Procedure:
7.5 gm of chloroacetyl chloride were added dropwise to a mixture of 18 gm of 1-(3'-nitro-phenyl)-2-amino-propane, 14 gm of potassium carbonate and 150 ml of acetonitrile, whereby the temperature of the mixture rose to 45° C., and the resulting mixture was refluxed for two hours. Thereafter, the reaction mixture was allowed to cool, and then it was diluted with ice water, whereupon 1-(3'-nitro-phenyl)-2-(chloroacetyl-amino)-propane (m.p. 118°-120° C., recrystallized from ethyl acetate/petroleum ether) crystallized out. 17 gm of this compound were added to a mixture of 14 gm of benzylamine and 200 ml of acetonitrile, and the mixtute was refluxed for two hours. Thereafter, the benzylamine hydrochloride which had precipitated out was removed by suction filtration, the filtrate was acidified with ethereal hydrochloric acid, and the crystalline precipitate formed thereby was recrystallized from 1 N hydrochloric acid, yielding 11.5 gm of 1-(3'-nitro-phenyl)-2-(benzylaminoacetyl-amino)-propane hydrochloride, m.p. 167°-170° C. This hydrochloride was hdyrogenated in methanol in the presence of Raney nickel at atmospheric pressure and room temperature, yielding 1-(3'-aminophenyl)-2-(benzylaminoacetyl-amino)-propane hydrochloride which was dissolved in ethanol, and the solution was admixed with the calculated amount of ethereal hydrochloric acid, yielding the dihydrochloride of the formula ##STR26## which had a melting point of of 234°-236° C. (decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([OH:16])[C:7]=2[CH:17]=1)#[N:2].S(OC)(O[CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([O:16][CH3:22])[C:7]=2[CH:17]=1)#[N:2]
Reactant: CCOC(=O)c1oc2ccc(C#N)cc2c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2ccc(C#N)cc2c1OC
Yield: 90.9 %

Procedure:
Ethyl 5-cyano-3-hydroxy-2-benzofurancarboxylate (200 mg, 0.866 mmol), dimethyl sulfate (131 mg, 1.04 mmol) and potassium carbonate (132 mg, 0.953 mmol) were added to acetone (140 ml), and the mixture was refluxed under heating for 1.5 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and water (200 ml) was added to the residue, which was followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 193 mg of ethyl 5-cyano-3-methoxy-2-benzofurancarboxylate (91%). The obtained compound (170 mg, 0.694 mmol) was dissolved in methanol (5 ml) and potassium hydroxide (160 mg, 2.86 mmol) was added, which was followed by refluxing under heating for 45 minutes. Low boiling matters were distilled away from the reaction mixture under reduced pressure and 1N hydrochloric acid was added to the residue to adjust the pH to 2-3. The resulting precipitate was collected by filtration to give 123 mg of 5-cyano-3-methoxy-2-benzofurancarboxylic acid as a colorless solid (82%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13]
Reactant: CC(C)N1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 130 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.35 g, 7.8 mmol), 1-isopropyl-piperazine (2.0 g, 15.6 mmol) and anhydrous potassium carbonate (1.18 g, 8.6 mmol) in N,N-dimethylacetamide (2.5 ml) was stirred at 130° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured onto cold water and stirred vigorously for 3 h. The resulting brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting brown solid was slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 5-(4-Isopropyl-piperazin-1-yl)-2-nitro-phenylamine (1.1 g, 53%) and used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:21]([O-:23])=[O:22])=[N:14][C:15]([N:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)[N:4]=1.[K+].[CH2:25]([O:27][C:28]([O:30][CH:31](Cl)[CH3:32])=[O:29])[CH3:26].O>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:21]([O:23][CH:25]([O:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26])=[O:22])=[N:14][C:15]([N:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=2)[N:6]=1
Reactant: COc1cc(OC)nc(Oc2ccc(N(C)C)nc2C(=O)[O-])n1
Reactant: CCOC(=O)OC(C)Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1nc(N(C)C)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.0 g (5.6 mmol) of potassium 3-(4,6-dimethoxypyrimidin-2-yl)oxy-6-dimethylaminopicolinate and 0.8 g (5.7 mmol) of 1-(ethoxycarbonyloxy) ethylchloride were suspended in 5 ml of dimethylformamide, and were stirred at room temperature for 6 hours. The reaction mixture was poured into water, and was extracted with ethyl acetate twice. The organic layer was then washed with water and dried, and the solvent was distilled off to obtain a viscous product which was then column-purified to obtain an aimed compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3](O)=[O:4].C([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[O:21])[CH2:15][CH2:14]1)(=O)C(C)C>>[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=2)=[O:21])[CH2:15][CH2:14]1)=[O:4]
Reactant: CC(C)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: CCC(C)C(=O)O
Product: CCC(C)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 88 %

Procedure:
2-Methylbutyric acid (50 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (80 mg, 0.215 mmol, 88% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.77 (d, J=8.4 Hz, 1H), 7.57 (s, 4H), 6.37 (s, 1H), 4.22 (m, 1H), 3.88 (d, J=13.2 Hz, 1H), 3.71 (m, 1H), 3.17 (t, J=12.8 Hz, 1H), 2.84 (m, 2H), 1.85 (m, 2H), 1.54 (m, 1H), 1.29 (m, 3H), 0.97 (s, 3H), 0.81 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:17])[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([O:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:9])[CH3:8])=[O:3].C([O-])(O)=[O:20].[Na+]>O>[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([O:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:9])[CH3:8])(=[O:3])[C:1]([OH:17])=[O:20]
Reactant: CC(CC(C)(C)OOC(C)(C)C)OC(=O)C(=O)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)C(=O)O
Temperature: 25 °C

Procedure:
A 50 mL Erlenmeyer flask equipped with a magnetic stirrer and a thermometerwas charged with 50 g of water and 2.8 g (10 mmoles) of 3-t-butylperoxy-1,3-dimethylbutyl chlorooxalate and the resulting mixture was stirred at room temperature. No reaction appeared to be occurring, therefore, 2.1 g (23 mmoles) of NaHCO3 was added. Gas evolution occurred and the organic liquid dissolved in the aqueous phase at room temperature. The pH of the solution was about 9. The aqueous solution was washed twice with 30 mL portions of MTBE in order to remove neutral impurities. Then the aqueous solution was acidified with 20 g (27 mmoles) of aqueous 5% HCl solution and a yellow organic liquid formed. The resulting mixture was extracted twice with 30 mL portions of MTBE. The MTBE extracts were combined, washed once with 50 mL of water, dried over 5% by weight of anhydrous MgSO4, and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 2.2 g (85% of theory, uncorrected) of a clear yellow liquid. An IR spectrum of the product showed an acid OH band at about 3200 cm-1, a very strong carbonyl band at 1740 cm-1 and a peroxide (--OO--) band at about 875 cm-1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccn2)CC1

Procedure:
Amine preparation: A mixture of 1-BOC-4-piperidone (496 mg), 2-aminopyridine (234 mg), sodium triacetoxyborohydride (580 mg) and acetic acid (0.14 mL) was stirred together in dry 1,2-dichloroethane (10 mL) at room temperature. After 24 h the reaction was quenched with saturated NaHCO3 solution and extracted with DCM, dried (Na2SO4), filtered and concentrated in vacuo to give 4-(pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. (135 mg) after flash chromatography. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH3:34])([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1)[CH2:9][C:8]2=[O:35])(=[O:3])[CH3:2].[H][H]>CO.C1C=CC=CC=1.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])[O:11][C:10]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)([CH3:34])[CH2:9][C:8]2=[O:35])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2=O

Procedure:
12.3 g of 6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman-4-one (prepared as described in Preparation 19) were dissolved in a mixture of 200 ml of methanol and 20 ml of benzene, and then catalytically reduced for 6 hours at room temperature, in the presence of 2.4 g of 10% w/w palladium-on-carbon, under 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[S:6][C:7]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=2[N:9]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[Br:21][CH2:2][CH2:3][CH2:4][C:5]1[S:6][C:7]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=2[N:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc2nc(CCCO)sc2c(OC)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1cc2nc(CCCBr)sc2c(OC)c1OC
Reaction time: 1 h

Procedure:
2-(3-Hydroxypropyl)-5,6,7-trimethoxybenzothiazole (388 mg) was dissolved in dichloromethane (5 mL), carbon tetrabromide (590 mg) and triphenylphosphine (431 mg) were added to the solution at room temperature, and the mixture was vigorously stirred for 1 hour. Water was added to conduct extraction with dichloromethane, and the resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[C:4](Cl)[N:3]=1.[I-].[Na+].[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:23][C:21]1[NH:20][N:19]=[C:18]([NH:17][C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=2)[CH:22]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CCOC(=O)Cc1cc(Cl)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1cc(Nc2cc(C)[nH]n2)nc(Cl)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of ethyl 2-(2,6-dichloropyrimidin-4-yl)acetate (1.0 g, 4.25 mmol), sodium iodide (0.637 g, 4.25 mmol), 3-amino-5-methylpyrazole (0.413 g, 4.25 mmol), and N,N-diisopropylethylamine (0.96 ml, 5.53 mmol) was heated at 90° C. until reaction was complete (˜3 h). Reaction mixture was then cooled to room temperature, diluted with ethyl acetate (100 ml), washed with sat. sodium hydrogen carbonate solution (1×30 ml), water (3×30 ml), brine (30 ml), dried (MgSO4), filtered and evaporated in vacuo to leave an orange oil. Crude product was purified by flash chromatography (SiO2, 60-100% EtOAc/Petrol) to give title compound as a red sticky oil (0.520 g, 41%). 1H NMR (CDCl3) 1.29 (3H, t), 2.41 (3H, s), 3.52 (2H, s), 4.23 (2H, q), 5.20-4.60 (2H, very broad signal); ES+296.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4](F)[N:3]=1.[CH3:10][O-:11].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: C[O-]
Reactant: Fc1cc(I)cc(F)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(I)cc(F)n1
Temperature: 25 °C

Procedure:
To a solution of 2,6-difluoro-4-iodopyridine (7.37 g, 30.6 mmol) in tetrahydrofuran (200 ml) cooled to 0° C. was added a 0.5 M solution of sodium methoxide (61.2 ml, 30.6 mm) in methyl alcohol. After 4 h the reaction mixture was warmed to ambient temperature. LRMS indicated incomplete conversion to product and additional 0.5 M sodium methoxide solution in methyl alcohol (6.12 ml, 3.06 mmol) was added. After 1 hour the reaction mixture was quenched with water (50 ml), partially concentrated, diluted with ethyl ether, washed with water and brine, then dried over magnesium sulfate, filtered, and concentrated to afford 2-fluoro-4-iodo-6-methoxypyridine as a yellow oil which was used without further purification. 1H NMR (600 MHz, DMSO-d6) δ 7.19 (s, 1H); 7.16 (d, 1H); 3.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH:13]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
4-Chlorobenzaldehyde (1x, 1.00 g, 7.1 mmol) and acetone (19, 0.26 ml, 3.5 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10.0 mmol) and water (10 ml) was added and the mixture stirred for 3 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 0.75 g (70%) of yellow crystals: mp 187-189° C. [expected mp 191-193° C.]; 1H NMR: δ 7.00 (d, 2H, J=15.9 Hz), 7.37 (d, 4H, J=8.5 Hz), 7.52 (d, 4H, J=8.5 Hz), 7.66 (d, 2H, J=15.9 Hz); 13C NMR: δ 125.7, 129.2, 129.5, 133.2, 136.4, 141.9, 188.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:29]2[O:20][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: N#CCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3noc(-c4cccc(F)c4)c3c2)cc1

Procedure:
The title compound, light yellow solid (74 mg, 56%), MS (ISP) m/z=374.1 [(M+H)+], mp 176° C., was prepared in accordance with the general method of example 1 from 1-(4-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate C) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)[C:6]=2[CH:20]=1.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23]>>[NH2:19][C:15]1[N:14]=[C:13]([N:7]2[C:6]3[CH:20]=[C:2]([C:25]#[C:24][C:22]([CH3:23])([OH:26])[CH3:21])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][CH3:12])[CH:18]=[CH:17][N:16]=1
Reactant: C#CC(C)(C)O
Reactant: CCOc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Product: CCOc1nc2ccc(C#CC(C)(C)O)cc2n1-c1ccnc(N)n1

Procedure:
The title compound was prepared by the procedure described in Step 2 of Example 142-b by reacting 4-(6-bromo-2-ethoxy-1,3-benzodiazol-1-yl)pyrimidin-2-amine with 2-methyl-3-butyn-2-ol; 1H NMR (500 MHz, MeOD) delta 1.54 (3H, t, J=7.09 Hz), 1.58 (6H, s), 4.68 (2H, q, J=7.09 Hz), 7.11 (1H, d, J=5.67 Hz), 7.25-7.32 (1H, m), 7.39 (1H, d, J=8.20 Hz), 8.29 (1H, s), 8.31-8.43 (1H, m); LC-MS: m/z=+338.5 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=2[N+:20]([O-])=O)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO.C1COCC1.[Ni]>[NH2:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)=[O:11]
Reactant: COc1cccc(C(=O)c2ccc(C(C)C)cc2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2ccc(C(C)C)cc2)c1N

Procedure:
A solution of 6.8 g (22 mmol) (4-isopropyl-phenyl)-(3-methoxy-2-nitro-phenyl)-methanone in 90 ml methanol and 40 ml THF is hydrogenated at normal pressure and rt during 20 h in the presence of 2 g Raney nickel. After filtration and evaporation of the solvent the residue is taken up in ether and (4-isopropyl-phenyl)-(3-methoxy-2-nitro-phenyl)-methanone precipitates by the addition of saturated etheric hydrochloric acid as its hydrochloride.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:23]=[CH:22][C:11]([CH:12]([OH:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>N1C=CC=CC=1>[C:24]([O:21][CH:12]([C:11]1[CH:22]=[CH:23][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: C=C(C)C(=O)Cl
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OC(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 1 L round-bottom flask equipped with magnetic stirrer and nitrogen inlet was added 700 ml anhydrous THF containing BHT as inhibitor, 98 g anhydrous pyridine, and 51.6 g (211 mmol) of 4,4′-dimethoxybenzhydrol. The reaction mixture was cooled to −10° C. and 26.5 g (254 mmol) methacryloyl chloride was added dropwise over 10 minutes. The reaction mixture was stirred at −10-0° C. for 1 hour and then stirred at ambient temperature for 20 hours. The solid was filtered and the filtrate was extracted using Et2O/water. The organic layer was washed with 1 N NaHCO3, 1 N HCl, brine, and water and then dried with MgSO4, filtered, and concentrated under reduced pressure to give the desired crude product which was recrystallized from cold ether/hexanes at −20° C.