Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.C(N(CC)CC)C.[CH3:18][C:19]1(C)[O:26]C(=O)CC(=O)[O:20]1.[OH-].[Na+]>CN(C=O)C.C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:18][C:19]([OH:26])=[O:20])=[C:4]([OH:10])[CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(O)CCc1ccc(Cl)cc1O

Procedure:
The subtitle compound was prepared by using the product from step i). (3.48 g) was added to a solution of triethylamine (10 ml) and formic acid (7 ml) in DMF (30 ml) after 20 minutes. Meldrum's acid (3.22 g) was added and the mixture heated to 100 C for 4 hours. The solution was basified with 2M NaOH, extracted with ether (discarded). The aqueous layer was acidified with 2M HCl, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. The residue was purified by chromatography on silica eluting with diethyl ether/isohexane 1:5, yield 0.40 g.
Reaction SMILES: [CH:1]1([N:7]=[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([O:19][CH3:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][C:21](=[O:23])[CH3:22])=[C:10]([O:19][CH3:20])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1=CC(=NC2CCCCC2)c2ccccc2C1=O
Reactant: CC(=O)OC(C)=O
Product: COc1cc(NC2CCCCC2)c2ccccc2c1OC(C)=O

Procedure:
A suspension of 4-cyclohexylimino-1-oxo-2-methoxy-1,4-dihydronaphthalene in acetic anhydride is hydrogenated according to the procedure in Example 1 to obtain 4-cyclohexylamino-1-acetoxy-2-methoxynaphthalene, m.p. 134°-136° C.
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([N:12]=[C:13]=[O:14])=[N:9][N:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([NH:17][CH2:18][CH:19]=[O:20])[CH3:16]>C1C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH:19]=[O:20])[C:13]([NH:12][C:10]1[S:11][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][N:9]=1)=[O:14])[CH3:16]
Reactant: CCCCCCc1nnc(N=C=O)s1
Reactant: CCNCC=O
Solvent: c1ccccc1
Product: CCCCCCc1nnc(NC(=O)N(CC)CC=O)s1

Procedure:
A mixture of 5-hexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-ethylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-hexyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1>>[CH3:21][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:31][CH:32]=4)=[O:20])=[CH:17][C:11]=3[N:10]=2)=[CH:7][CH:8]=1
Reactant: NNC(=O)c1ccc(N)cc1
Reactant: CN(C)c1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Product: CN(C)c1ccc(-c2nc3cc(C(=O)Nc4ccc(C(=O)NN)cc4)ccc3[nH]2)cc1

Procedure:
Compound 275 was prepared according to the procedure similar to that described in Scheme V from 2-(4-dimethylaminophenyl)benzimidazole-5-carboxylic acid and 4-aminobenzhydrazide. [M+H]+ calcd for C23H22N6O2: 415.18; found: 414.91.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18]([C:20]3[C:21]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:19])[CH:14]=2)[CH2:9]1)(C)(C)C>C(O)=O>[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18]([C:20]3[C:21]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=4)=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:19])[CH:14]=2)[CH2:9]1
Reactant: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(NC(=O)OC(C)(C)C)C3)c1-c1ccc(C(F)(F)F)cc1
Solvent: O=CO
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(N)C3)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of {5-[(6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carbonyl)-amino]-indan-2-yl}-carbamic acid tert-butyl ester (5.19 g, 10.5 mmol) in formic acid (40 mL) is heated to 40° C. with stirring. After 3 h, the reaction mixture is cooled to room temperature and stirring is continued for 16 h. The reaction mixture is concentrated under reduced pressure and the resulting oil dissolved in ethyl acetate. The organic layer is washed with 8% NaHCO3 solution until the aqueous layer remains basic at which point a precipitate forms in the organic layer. The precipitate is collected by filtration to give N-(2-aminoindan-5-yl)-6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxamide.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=1.[C:18]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>C1COCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:14][C:15]([C:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)([OH:20])[CH3:19])=[CH:16][N:17]=2)=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccncc1
Reactant: Fc1ccc(-c2ncco2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80336.6 %

Procedure:
To a stirred solution of DIPA (0.13 mL, 0.00092 mmol) in THF (7 mL) at −78° C. was added n-BuLi (0.76 mL, 0.001226 mmol). The mixture was allowed to stir at 0° C. for 30 min, was again cooled to −78° C., and then a solution of 2-(4-fluorophenyl)oxazole (0.1 g, 0.000613 mmol) in THF (2 mL) was added dropwise during 30 min. 4-Acetyl pyridine (0.07 mL, 0.000674 mmol) in THF (2 mL) was then added, the reaction mixture was stirred for an additional 1 hour at −78° C., quenched with saturated ammonium chloride (2 mL), diluted with water (10 mL), and extracted with ethyl acetate (20 mL). The organic layer was dried with sodium sulfate, filtered and the solvent was concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel chromatography (200-400 mesh, 2% of methanol in dichloromethane) to give 1-(2-(4-fluorophenyl)oxazol-5-yl)-1-(pyridin-4-yl)ethanol (0.14 g, 82%) as white solid in 98.5% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.53 (d, 2H), 7.95-7.91 (m, 2H), 7.45 (d, 2H), 7.32 (t, 2H), 7.14 (d, 1H), 6.38 (s, 1H), 1.81 (s, 3H); LC-MS m/z calculated for [M+H]+ 285.10. found 285.1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH:29]=[O:30].O>CCCCCC.O1CCCC1>[Br:25][C:26]1[CH:27]=[C:28]([CH:29]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[OH:30])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CC(C)[Si](C#Cc1ccc(Br)cc1)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2)cc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
14.8 mL of a 1.6 M solution of n-butyllithium in hexane are added dropwise under argon to a solution of 8.0 g 1-bromo-4-triisopropylsilylethynyl-benzene in 80 mL dry tetrahydrofuran chilled to −78° C. The solution is stirred for 1 h at −70° C. Then 5.1 g 3-bromo-4-methoxy-benzaldehyde dissolved in 20 mL tetrahydrofuran are added dropwise over 15 min. The resulting solution is left in the cooling bath to warm to ambient temperature overnight. Then water is added and the mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is purified over silica gel (cyclohexane/ethyl acetate 9:1->1:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[C:12]1([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)(=O)C.O>[C:12]1([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[O:24][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: Oc1cccc(C2=CCCCC2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
1.34 g (9.72 mmol) of potassium carbonate was added to a DMF (10 mL) solution comprising 564 mg (3.24 mmol) of 3-(cyclohex-1-en-1-yl)phenol and 541 mg (3.82 mmol) of ethyl bromoacetate. The mixture was heated while stirring at 80° C. for 3 hours, and then cooled to room temperature. Water and ethyl acetate were added thereto, and extraction was performed. The organic layer was then separated, washed with water 3 times, and washed with saturated saline once. The organic layer was dried over sodium sulfate, and filtered. Thereafter, the filtrate was condensed, followed by drying under reduced pressure, thereby giving 777 mg of ethyl [3-(cyclohex-1-en-1-yl)phenoxy]acetate (yield: 92%).
Reaction SMILES: [CH3:1][S:2]([C:5]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[ClH:23].O1CCOCC1>O1CCOCC1>[ClH:23].[CH3:1][S:2]([C:5]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C1(S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(S(C)(=O)=O)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 1-tert-butyl 4-ethyl 4-(methylsulfonyl)piperidine-1,4-dicarboxylate (0.20 g, 0.60 mmol) in 1,4-dioxane (5.0 mL) was added HCl-dioxane (4.0 M, 1.0 mL) solution and the resulting mixture stirred at rt for 30 min. After completion of reaction (by TLC), solvent was evaporated to obtain a brownish solid material (0.20 g) that was carried forward to the next step without further purification. MS: 236.11 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[C:13](=O)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]C(C)([O-])C.[K+]>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C:13](=[CH2:17])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by combining (3aR,6aS)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (100 mg, 0.464 mmol) [prepared as described by Santora, V. J., et. al. Bioorganic & Medicinal Chemistry Letters 2008, 18(4), 1490-1494] in 2 mL of tetrahydrofuran with methyltriphenylphosphonium bromide (249 mg, 0.697 mmol) and potassium tert-butoxide (78 mg, 0.697 mmol). The reaction was stirred at room temperature overnight, concentrated, and the crude material was purified by silica gel chromatography using 1-100% ethyl acetate/hexanes to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.47-7.41 (m, 2H), 7.40-7.33 (m, 2H), 7.31-7.25 (m, 1H), 4.93-4.89 (m, 1H), 4.80-4.76 (m, 1H), 3.55 (d, J=13.1, 1H), 3.47 (d, J=13.1, 1H), 2.96-2.87 (m, 1H), 2.63-2.41 (m, 5H), 2.33 (dd, J=8.9, 3.9, 1H), 2.17 (dddt, J=14.9, 7.4, 5.8, 1.6, 1H), 1.68 (ddd, J=16.0, 12.4, 8.1, 1H), 1.51-1.39 (m, 1H); MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25]C(=O)C)[C@@H:18]([CH3:29])[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.C[O-].[Na+]>CO>[S:7]([CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:6]1[O:17][C@H:18]([CH3:29])[C@@H:19]([OH:25])[C@H:20]([OH:21])[C@@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SCC=Cc2ccccc2)O[C@H](C)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1O[C@H](SCC=Cc2ccccc2)[C@@H](O)[C@@H](O)[C@@H]1O

Procedure:
Compound 21 is deacetylated with sodium methoxide in methanol to give 22 in near quantitative yield: [α]D27 +354° (C 1.0, chloroform); MS:m/e 296 (M.+), 278 (M.+ --H2O), 147 (M.+ --SCH2CH=CHC6H5).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9](=O)[CH:10]=[C:11]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([F:25])[CH:16]=2)SC)[CH:5]=[CH:4][N:3]=1.[NH:27]([CH2:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[NH2:28]>CC(O)(C)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[N:27]([CH2:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[N:28]=[C:11]([NH:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([F:25])[CH:16]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)CCNN
Reactant: CSC(=CC(=O)c1ccnc(Cl)c1C)Nc1cc(F)cc(C(F)(F)F)c1
Solvent: CC(C)(C)O
Product: Cc1c(-c2cc(Nc3cc(F)cc(C(F)(F)F)c3)nn2CCC(=O)N(C)C)ccnc1Cl
Temperature: 150 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
D6 (prepared according to Description 6) (1.0 g; 2.48 mmol) was added to a mixture of 3-hydrazinyl-N,N-dimethylpropanamide (0.65 g; 4.95 mmol) in t-BuOH (20 ml) and the reaction mixture stirred at 150° C. for 16 h. The solvent was then evaporated in vacuo and the residue purified by flash chromatography over silica gel (Biotage flash purification system: gradient acetone/heptane from 20/80 to 50/50). The solvent was then evaporated in vacuo and two fractions were collected. The desired fraction yielded 0.40 g of E1 (34.3%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:19][N:18]=1.CC(O)CC.C1C2C(=CC=CC=2)C=NN=1>CCCCCC>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:19][N:18]=2)=[CH:9][N:10]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: Nc1cnc(Oc2ccccc2Br)nc1
Agent: c1ccc2cnncc2c1
Solvent: CCCCCC
Solvent: CCC(C)O
Product: Brc1ccccc1Oc1ncc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
2-(2-Bromophenoxy)pyrimidin-5-amine (3.01 g, 11.3 mmol), 1-chloro-4-phenylphthalazine (2.72 g, 11.3 mmol), and butan-2-ol (56.6 ml, 11.3 mmol) were placed in a sealed tube. The reaction vessel was sealed and mixture heated to 120° C. After 1.5 h, LCMS showed mainly product as [M+H]+=470 and a small amount of bromo starting material. 200 mg of phthalazine was added. After another 3.5 h, the reaction was cooled to RT. Hexane was added to allow a yellow solids to precipitate. The yellow solids were filtered and recrystallized with DCM and hexanes. The resulting dark brown solids were dried under vacuum overnight, affording the product, N-(2-(2-bromophenoxy)pyrimidin-5-yl)-4-phenylphthalazin-1-amine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:33]1[CH:34]=[CH:35][C:36]2[N:41](O)N=N[C:37]=2[CH:38]=1.[I:43][C:44]1C=C(C=CC=1C)N.CCN(C(C)C)C(C)C>CN(C=O)C>[I:43][CH2:44][C:34]1[CH:35]=[C:36]([NH:41][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:8])[CH:37]=[CH:38][CH:33]=1
Reactant: Cc1ccc(N)cc1I
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccoc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(CI)c1)c1ccoc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Furoic acid (2.4 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) were stirred at room temperature for 15 mins. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at room temperature for 16 hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (3:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodomethylphenyl)-3-furamide.
Reaction SMILES: [CH3:1]NCCN(C)C.C([Li])CCC.C1CCCCC1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH:32]=[O:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.IC>C1COCC1>[CH3:1][C:29]1[CH:28]=[C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:34])([F:19])[F:35])=[CH:26][CH:25]=2)[S:31][C:30]=1[CH:32]=[O:33]
Reactant: CNCCN(C)C
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Temperature: -18 °C
Reaction time: 0.25 h

Procedure:
To a solution of trimethylethylenediamine (0.296 mL, 2.28 mmole) in THF at −78° C., is injected 2.0M n-butyllithium in cyclohexane (1.14 mL, 2.28 mmole) dropwise. The mixture is stirred for 15 minutes, then added a solution of 5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (0.530 g, 2.07 mmole) in THF (5 mL) and stirred for another 15 minutes. To the resulting mixture is injected 2.0M n-butyllithium in cyclohexane (1.55 ml, 3.10 mmole) at −78° C. and warmed up to −18° C. for an hour. The reaction is cooled down to −78° C. again, quenched with excess amount of iodomethane (0.644 mL, 10.35 mmole) and allowed to warm up to room temperature, then poured into well stirred ice-water (30 mL). The aqueous solution is then extracted with ethyl acetate (2×30 mL). The combined organic solution is washed with brine (3×30 mL), dried over Na2SO4 and concentrated. The crude product is purified on a silica gel column, gradient eluting with 0-20% ethyl acetate in hexane and concentrated to provide the titled compound as yellow crystalline.
Reaction SMILES: [Cl:1]C(OC1C=CC=CC=1)=O.[NH2:11][C:12]1[N:17]=[C:16]([O:18][CH:19]([F:21])[F:20])[CH:15]=[C:14]([CH3:22])[N:13]=1>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[ClH:1].[NH2:11][C:12]1[N:17]=[C:16]([O:18][CH:19]([F:21])[F:20])[CH:15]=[C:14]([CH3:22])[N:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cc1cc(OC(F)F)nc(N)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 24 h

Procedure:
3.9 g (0.025 mol) of phenyl chloroformate and 0.05 g of 4-dimethylamino-pyridine are added in succession to a solution of 9.0 g (0.05 mol) of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine in 30 ml of absolute tetrahydrofuran. The solution is stirred at 20°-25° C. for 24 hours and the reaction mixture is then diluted with 250 ml of ethyl acetate and the precipitate is separated off. 3.1 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine hydrochloride of melting point 204°-205° C. (decomposition) are thus obtained. To remove the residual starting material, the filtrate is eluted over a column containing the ion exchanger I® (MERCK), and the eluate is dried over sodium sulfate and evaporated. 4.0 g of 2-phenoxycarbonylamino-4-difluoromethoxy-6-methyl-pyrimidine are obtained as the crude product in the form of a viscous oil. After crystallisation, the product has a melting point of 56°-58° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15]C)=[N:5][C:6]([CH3:14])=[C:7]([C:9]2[O:13][N:12]=[CH:11][N:10]=2)[CH:8]=1)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[O:13][N:12]=[CH:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2ncno2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(-c2ncno2)c(C)[nH]c1=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 71.3 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-(1,2,4-oxadiazol-5-yl)pyridine (36 mg, 0.164 mmol) and sodium iodide (74 mg, 0.493 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (3 mL) followed by chlorotrimethylsilane (62 μL, 0.494 mmol) drop-wise. The reaction mixture is stirred at 60° C. under nitrogen for 12 hr. The reaction mixture is allowed to cool and then quenched with water (0.5 mL). After stirring for 30 min the mixture is diluted with water and extracted with five portions of dichloromethane. The combined dichloromethane layer is dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (49:1, increasing to 19:1). Fractions containing the product are combined, the solvent evaporated and the residue triturated with heptane to give 3-ethyl-6-methyl-5-(1,2,4-oxadiazol-5-yl)-1H-pyridin-2-one (24 mg, 71% yield) as a white solid. LC/MS: RT: 2.37 min, MS: m/e=206 (M+H); 1H NMR (CDCl3, δ, ppm): 12.56 (1H, s), 8.44 (1H, s), 7.96 (1H, s), 2.82 (3H, s), 2.62 (2H, q), 1.26 (3H, t).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[C:47](=O)([O:55]C1C=CC([N+]([O-])=O)=CC=1)[O:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:19]=[C:1]([O:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:47](=[O:55])[O:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN(C)CCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)OCCCN(C)C
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
Compound 73 (160 mg, 0.252 mmol) obtained in Example 73 was dissolved in chloroform (2.5 mL), and heat-stirred at 110° C. for 30 minutes with a microwave reactor after adding 3-(dimethylamino)propyl 4-nitrophenyl carbonate hydrochloride (115 mg, 0.379 mmol) synthesized according to the method described in Journal of American Chemical Society (J. Am. Chem. Soc.), 1981, Vol. 103, p. 4194-4199, and triethylamine (0.141 mL, 1.01 mmol). 3-(Dimethylamino)propyl 4-nitrophenyl carbonate hydrochloride (38.4 mg, 0.126 mmol) was added to the reaction mixture, and heat-stirred at 110° C. for 30 minutes with a microwave reactor. After being diluted with chloroform, the reaction mixture was washed with a 1 mol/L sodium hydroxide aqueous solution three times and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to give compound 116 (42.6 mg, 22.1%).