Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[S:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([OH:23])(=[S:22])[CH3:21]>C(Cl)(Cl)Cl>[C:20]([S:22][CH:14]([CH2:13][C:11](=[S:12])[C:10]1[CH:18]=[CH:19][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1)[C:15]([OH:17])=[O:16])(=[O:23])[CH3:21]
Reactant: CC(O)=S
Reactant: O=C(O)C=CC(=S)c1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)SC(CC(=S)c1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2.84 g of 3-(4-phenylthiobenzoyl)acrylic acid in 30 ml of chloroform was added 0.8 ml of thioacetic acid, and the resulting mixture was stirred for 5 hours at room temperature. The chloroform was removed from the mixture by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) and then recrystallized from a mixture of hexane and ethyl acetate to give 3.24 g of 2-acetylthio-3-(4-phenylthiobenzoyl)propionic acid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[C:10]([Cu])#[N:11]>CN(C=O)C.CCOC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]#[N:11])=[N:3][CH:4]=1)=[O:7]
Reactant: N#C[Cu]
Reactant: O=Cc1ccc(Br)nc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)cn1
Temperature: 120 °C
Yield: 57.4 %

Procedure:
A mixture of 6-bromonicotinaldehyde (11.2 g, 60 mmol) and CuCN (8.06 g, 90 mmol) in DMF (100 mL) was heated at 120° C. for 3 h under N2. The mixture was cooled to rt and diluted with EtOAc and filtered through a pad of celite. The organic layer was washed with water and brine and then dried (MgSO4) and concentrated. The product 5-formylpicolinonitrile (4.55 g) was obtained by silica gel chromatography (elution with 0-20% EtOAc/Hex).
Reaction SMILES: Cl.[NH2:2][OH:3].CCN(CC)CC.[C:11]([C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([CH3:14])([CH3:13])[CH3:12]>CC#N>[C:11]([C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[N:2][OH:3])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1cccc(C=NO)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.7 %

Procedure:
To a stirred solution of hydroxylamine hydrochloride (437 mg, 6.3 mmol) in CH3CN at 0° C. was added Et3N and 3-tert-butyl-2-hydroxybenzaldehyde (1.02 g, 5.7 mmol). The reaction mixture was warmed up to room temperature and stirred for 24 h. The solvent was removed and the residue was dissolved in EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to provide 3-tert-butyl-2-hydroxybenzaldehyde oxime (1.01 g, 92%) as a pale yellow solid.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:20])[CH3:4].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1>>[ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:7]1([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[OH:20])[CH3:4]
Reactant: COc1cccc(Br)c1
Reactant: Cc1ccc(CC2CCC(=O)C(CN(C)C)C2)cc1
Agent: Cl
Product: COc1cccc(C2(O)CCC(Cc3ccc(C)cc3)CC2CN(C)C)c1
Yield: 39 %

Procedure:
The base of compound (42) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 7:1 ether/methanol via a silica gel column and was taken up in ether. After adding trimethylchlorosilane/water, compound (44) was obtained in a yield of 39% theoretical.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH:4]=[C:5]([C:11]([CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:32][O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37]>CC(O)C>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH:4]1[C:35]([C:34]([O:33][CH3:32])=[O:39])=[C:36]([CH3:37])[NH:38][C:11]([CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[C:19](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]2=[O:27])=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COC(=O)/C=C(/C)N
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)O
Product: CCOC(=O)C1=C(COCCN2C(=O)c3ccccc3C2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 15 °C
Reaction time: 20 h

Procedure:
350 g of crude ethyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy) acetoacetate from Example 1 was dissolved in 540 ml of 2-propanol at 80° C. 50 g of methyl-3-aminocrotonate was added and the mixture was heated at the same temperature for 16 hours. The mixture was evaporated to dryness. The residue was dissolved in 540 ml of glacial acetic acid at 80° C. The mixture was cooled to 15° C. and stirred at the same temperature for 20 hours. The formed solid was filtered off and washed with 280 ml of glacial acetic acid. The solid was suspended in 225 ml of methanol and agitated for 30 minutes. The solid was filtered off, washed with 75 ml of methanol and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[H-].[Na+].Cl[CH2:21][C:22]([NH2:24])=[O:23].O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:21][C:22]([NH2:24])=[O:23])=[CH:9][CH:8]=1
Reactant: NC(=O)CCl
Reactant: OCc1ccc(OCc2cccc(F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)COCc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 1 h
Yield: 5.1 %

Procedure:
A solution of 500 mg of [4-(3-fluoro-benzyloxy)-phenyl]-methanol [Example 25b)] in 10 ml of tetrahydrofurane was treated at room temperature with 57 mg of sodium hydride (55% dispersion in oil) and stirred for 1 h. Thereafter, 183 mg of chloroacetamide were added and the mixture was heated to reflux for 48 h. For the working-up, the cooled mixture was treated with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a gradient of dichloromethane to a 4:1-mixture-mixture of dichloromethane and methanol as the eluent. After crystallisation from ether, there were obtained 29 mg (5% of theory) of 2-[4-(3-fluoro-benzyloxy)-benzyloxy]-acetamide as a white solid; MS: m/e=307 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:15](Cl)(=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[C:9]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(Cl)ccc2o1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCCCc1oc2ccc(Cl)cc2c1C(=O)c1ccc(OC)cc1

Procedure:
2-n-Butyl-5-chlorobenzofuran (9.5 g., 0.046 mol.) was acylated with 8 g. (0.047 mol.) of anisoyl chloride as described in the procedure of Example 10 to give 2-n-butyl-5-chloro-3-(4'-methoxybenzoyl)benzofuran. Demethylation followed by reaction of the 2-n-butyl-5-chloro-3-(4'-hydroxybenzoyl)benzofuran with epichlorohydrin and subsequent opening of the epoxy compound formed with isopropylamine was carried out as described in the procedures of Examples 9 and 7 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Aminobenzophenone (75 g.) is heated with hexadecyl bromide (200 g.) in dry hexamethylphosphoramide (300 ml.) containing anhydrous potassium carbonate (90 g.) for 16 hours at 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water (20 ml.). The solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloromethane provides the product of the Example.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[N:23]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:21][C:19]=3[N:20]=2)[C:11]([Cl:28])=[CH:10][C:9]=1[F:29])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:7][C:8]1[C:9]([F:29])=[CH:10][C:11]([Cl:28])=[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[N:23]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:21][C:19]=3[N:20]=2)[CH:13]=1
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)OC(C)(C)C)c(F)cc3Cl)nc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(N)c(F)cc3Cl)nc2s1
Yield: 74 %

Procedure:
A solution of the above-mentioned crude product of tert-butyl(5-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl]amino}-4-chloro-2-fluorophenyl)carbamate and anisole (1 mL) in trifluoroacetic acid (15 mL) was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (1:1, 50 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (297 mg, 74%) as a yellow solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])=[CH:6][C:5]=1[F:21])=[N+:2]=[N-:3].[C:22]([O:26][CH3:27])(=[O:25])[C:23]#[CH:24]>C1C=CC=CC=1>[F:21][C:5]1[CH:6]=[C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:8]=[CH:9][C:4]=1[N:1]1[CH:24]=[C:23]([C:22]([O:26][CH3:27])=[O:25])[N:3]=[N:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N=[N+]=[N-])c(F)c2)C(=O)O1
Reactant: C#CC(=O)OC
Solvent: c1ccccc1
Product: COC(=O)c1cn(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)nn1
Yield: 68.6 %

Procedure:
A solution 1.0 g (3.4 mmol) of the azide of Example 17 in 50 mL benzene was treated with 573 mg (6.8 mmol) of methyl propiolate followed by warming at reflux for 24 h. The mixture was cooled and the product isolated by filtration of the reaction mixture. These procedures afforded 880 mg of the title compound as a white solid. High Resolution Mass Spectrum (EI): calcd for C16H16FN5O5 : 377.1135. found: 377.1131.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCCC1CCCCCC1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCCCC1CCCCCC1)C(=O)OCC

Procedure:
23.7 g of 7-cycloheptyl-2-methyleneheptanoic acid ethyl ester, in the form of a colourless oil, purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 35 g of 5-cycloheptylpentylmalonic acid ethyl ester, 3,8 g of paraformaldehyde, 35 ml of pyridine and 1 g of piperidine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22]O)[N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:10]1([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22][O:1][C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[CH:5]=[O:6])[N:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cccc(O)c1
Reactant: OCCc1coc(-c2ccccc2)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1cccc(OCCc2coc(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.00 g (81.89 mmoles) of 3-hydroxybenzaldehyde, 15.49 g (81.89 mmoles) of 2-(2-phenyl-4-oxazolyl)ethanol, and 21.48 g (81.89 mmoles) of triphenylphosphine were dried under vacuum and combined with 200 mL THF under N2. The mixture was treated with 16.12 mL (81.89 mmoles) of diisopropylazodicarboxylate added dropwise over 0.25 hr resulting in a mild exotherm. After stirring for 24 hr at ambient temperature, the crude reaction mixture was concentrated under reduced pressure to a viscous amber oil. The oil was diluted in 300 mL EtOAc, washed with 2.5 N NaOH (3×200 mL), H2O (2×300), and brine 300 mL. The combined organics were dried over MgSO4 and concentrated under reduced pressure again to a viscous amber oil. The reaction mixture was separated using silica gel column chromatography (6:1 Hex:EtOAc) from which the product was recovered and then recrystallized from iprOH to afford 15.10 g (63.10%.) of white crystalline solid, m.p. 51-53° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH:14]=O.CCN(CC)CC.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH2:14][NH:26][CH:23]1[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: CC(=O)NCCc1ccc(Cl)c(C=O)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A mixture of N-[2-(4-chloro-3-formyl-phenyl)-ethyl]-acetamide (50.1 mg, 0.222 mmol), Et3N (0.046 mL, 0.332 mmol) and cyclopropylamine (0.023 mL, 0.332 mmol) in MeOH (0.50 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (21.0 mg, 0.554 mmol) was added in portions. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times, and the combined org. extracts were washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC(CH2Cl2/MeOH 95:5) yielded the title compound (35 mg, 59%). LC-MS: tR=0.59 min; ES+: 267.17.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)=[O:11].[CH2:23](O)[CH:24]([CH3:26])[CH3:25].O>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([O:21][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(C(=O)O)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reactant: CC(C)CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COC(=O)C(C)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
3.38 g of 2-[4-(2,3-dichlorophenylcarbamoyl)-phenyl]propionic acid was dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the solution with ice water, 2.43 g of N,N'-carbonyldiimidazole was added thereto, and the mixture was stirred for 30 minutes. Thereafter, 0.74 g of isobutyl alcohol was added thereto. The mixture was returned to room temperature and stirred for 5 hours. After completion of the reaction, the reaction solution was poured into 300 ml of water, and the resulting crystals were collected by filtration, washed with water and dried, and then recrystallized from toluene-hexane to obtain 3.15 g of desired isobutyl 2-[4-(2,3-dichloropheylcarbamoyl)-phenyl]-propionate. The yield was 80%, and the melting point of this compound was from 70° to 72° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:13]=1)[CH:9]=O.[NH2:27][C:28]1[C:33]([NH2:34])=[CH:32][C:31]([Br:35])=[CH:30][N:29]=1>>[Br:35][C:31]1[CH:32]=[C:33]2[NH:34][C:9]([C:8]3[CH:11]=[C:12]([O:14][CH2:15][C:16]4[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:13]=[C:6]([O:5][CH2:4][C:3]4[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=4[F:1])[CH:7]=3)=[N:27][C:28]2=[N:29][CH:30]=1
Reactant: Cc1cccnc1COc1cc(C=O)cc(OCc2ccccc2F)c1
Reactant: Nc1cc(Br)cnc1N
Product: Cc1cccnc1COc1cc(OCc2ccccc2F)cc(-c2nc3ncc(Br)cc3[nH]2)c1

Procedure:
The final product (217) was obtained using the procedure described for Example 191 except that 3-(2-fluorobenzyloxy)-5-((3-methylpyridin-2-yl)methoxy)benzaldehyde (217c) and 2,3-diamino-5-bromopyridine were used. 1H NMR (400 MHz, 90% DMSO-d6; 10% CDCl3) δ ppm 8.46 (br s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.78 (m, 1H), 7.52 (s, 1H), 7.48 (m, 1H), 7.45 (m, 2H), 7.40 (m, 2H), 7.16 (t, 1H, J=8.2 Hz), 7.08 (t, 1H, J=8.2 Hz), 6.79 (s, 1H), 5.32 (s, 2H), 5.19 (s, 2H), 2.31 (s, 3H). Calc'd for C26H20BrFN4O2; m/z (M+2H+)=521; found 521.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH2:13][CH:14](O)[CH2:15][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:25])CC>ClCCl.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[CH2:13][CH:14]([F:25])[CH2:15][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: N#Cc1nn(Cc2ccccc2)c2c1CC(O)C2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nn(Cc2ccccc2)c2c1CC(F)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.1 %

Procedure:
To a solution of 1-benzyl-5-hydroxy-1,4,5,6-tetrahydrocyclo-penta[c]pyrazole-3-carbonitrile (see Example 9.7, 30 mg, 0.125 mmol) in anhydrous dichloromethane (0.9 mL) was added DAST (33 μL, 0.25 mmol) under a nitrogen atmosphere. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vacuo. The residue was purified by PTLC (SiO2) using 30% ethyl acetate-hexanes to give the desired compound (16 mg).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].O>S(=O)(=O)(O)O>[F:1][C:2]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CCCN1C(=O)COc2cc(F)ccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 20.0 grams (0.096 mole) of 7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one in 100 ml of concentrated sulfuric acid was cooled to -10°C. A mixture of 10 ml of nitric acid (70% nitric acid by weight in water) and 10 ml of concentrated sulfuric acid was added dropwise during a 20 minute period. After complete addition the mixture was stirred at -5° C. for 10 minutes. The reaction mixture was poured into water which was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave a tacky solid. This solid was triturated witha mixture of diethyl ether, petroleum ether, and ethyl acetate (1:1:1) to yield, after filtration, 7.2 grams of 7-fluoro-6-nitro-4-propyl-2H-1,4-benzoxazin-3(4H)-one.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[CH:32]1([C:21]2[N:20]=[C:19]([C:17](=[N:16][C:15]3[C:11]([C:9]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])=[O:8])=[N:12][N:13]([CH3:35])[CH:14]=3)[OH:18])[C:24]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[N:28][CH:27]=3)=[CH:23][CH:22]=2)[CH2:34][CH2:33]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CC1CCCN1
Product: CC1CCCN1C(=O)c1nn(C)cc1N=C(O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 19 %

Procedure:
According to the general method described above (step 5), reaction of 2-methylpyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (19%) as sticky yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[CH2:18]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 8 h

Procedure:
2-Bromo-4-nitrophenol (10 g), potassium carbonate (12.7 g) and benzyl bromide were dissolved in dimethylformamide and the mixture was stirred overnight. The mixture was diluted with water (1 L) and extracted with ethyl acetate (3×50 ml). The organic laver was washed with water, brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (95:5) to give the title compound as a pale vellow solid, (11.8 g, 77%). 1H NMR (250 MHz, CDCl3) δ 8.49 (1H, d, J=2.7 Hz), 8.17 (1H, dd, J=9.1, 2.7 Hz), 7.45 (5H, m), 7.00 (1H, d, J=9.1 Hz), and 5.28 (2H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19]>>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)=[O:19]
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Cn1ccnc1
Agent: [Li]CCCC
Product: Cn1ccnc1C(=O)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flask was placed 1.0 g (12.2 mmol) 1-methylimidazole. Then, 5.1 ml (12.8 mmol) n-butyllithium was added dropwise and the mixture was stirred for 30 minutes. Then, 2.7 g (12.2 mmol) 3-trifluoromethoxybenzoyl chloride was added dropwise. The contents were mixed for 2 hours at -78° C., then allowed to warm to room temperature for an additional 2 hours. The mixture was quenched with water. The product was extracted with ether, dried and purified by flash chromatography (5-10% ethyl acetate/hexanes, silica gel) and was identified as the desired product by spectroscopic analyses.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1/[CH:11]=[CH:21]/[CH:22]=[O:23]
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: Cn1c(/C=C/C=O)nc2ccccc21

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 1-methyl-1H-benzimidazole-2-carboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 187 (M+H)+.