Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=1.[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[O:21])=[CH:18][N:17]=1.C(OC(=O)C)(=O)C>>[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[CH:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[CH3:14])[N:3]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:18][N:17]=1
Reactant: O=Cc1ccc(C(=O)c2ccc(Cl)nc2)cc1
Reactant: Cc1cccc2nc(C)n(C)c(=O)c12
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(Cl)nc4)cc3)n(C)c(=O)c12
Temperature: 140 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (1.1 g) and 4-(6-chloronicotinoyl)benzaldehyde (1.5 g) was added acetic anhydride (2 ml) and the mixture was stirred at 140° C for 2 hours. This reaction mixture was concentrated and the residue was washed with toluene-diethyl ether and dried to provide 1.4 g of yellow powder.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=1.[I-].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: Fc1ccc(CCCl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(O)c1ccc(NCCc2ccc(F)cc2)cc1

Procedure:
A mixture of 15.8 g. of 1-(2-chloroethyl)-4-fluorobenzene, 33 g. of ethyl p-aminobenzoate, 16.6 g. of potassium iodide and 100 ml. of hexamethylphosphoramide is heated at 95° C. for 15 hours. The mixture is poured into water and extracted with ether. The ether extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. To the oil is added 200 ml. of ethanol-water (9:1) and 21 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with water, cooled and filtered to give gray crystals. Recrystallization from ethanol gives light gray crystals, m.p. 161°-163° C.
Reaction SMILES: Cl[C:2]([CH2:7][C:8]([F:33])([F:32])[CH2:9][C@H:10]([C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19]([CH2:20][C@@H:21]([OH:31])[CH2:22][CH2:23]2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)[CH3:11])([CH2:5][OH:6])[CH2:3][OH:4].[H-].[Na+]>C(COC)OC>[O:4]1[CH2:3][C:2]1([CH2:7][C:8]([F:33])([F:32])[CH2:9][C@H:10]([C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19]([CH2:20][C@@H:21]([OH:31])[CH2:22][CH2:23]2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)[CH3:11])[CH2:5][OH:6]
Reactant: C[C@H](CC(F)(F)CC(Cl)(CO)CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@H](CC(F)(F)CC1(CO)CO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 38.7 %

Procedure:
The chlorodiol (11) (183 mg, 0.32 mmol) was treated with sodium hydride (18 mg, 0.75 mmol) in dimethoxyethane (18 ml) at room temperature for 6 days. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (100 g). Elution with dichoromethane provided the epoxyalcohol (12) (56 mg, 32%), glass. 1H-NMr δ: 2.92 (2H, m, 26-H2), 3.67-4.16 (3H, m, 3-H and 27-H2). MS m/z: 434 (M+ -THP OH), 416, 404, and the recovery of chlorodiol 11 (92 mg, 50%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.[CH3:18][NH2:19]>>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([NH:19][CH3:18])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: CN
Reactant: O=C1CCCCN1c1ccc(F)c([N+](=O)[O-])c1
Product: CNc1ccc(N2CCCCC2=O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 7b from 4-(2-oxo-piperidin-1-yl)-2-nitro-fluorobenzene and aqueous methylamine solution.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([NH:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=2[Cl:35])=[N:19][CH:20]=[N:21]3)[CH2:10][CH2:9]1)=O)(C)(C)C.C=O>C(O)=O>[Cl:35][C:28]1[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=1[NH:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)[N:21]=[CH:20][N:19]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cccc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c23)c1
Agent: C=O
Solvent: O=CO
Product: COc1ccc(Cl)c(Nc2ncnc3cccc(OCC4CCN(C)CC4)c23)c1
Temperature: 100 °C

Procedure:
A mixture of 5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-(2-chloro-5-methoxyanilino)quinazoline (0.2 g), a concentrated aqueous formaldehyde solution (37%, 0.4 ml) and formic acid (4 ml) was stirred and heated to 100° C. for 2.5 hours. The mixture was cooled to ambient temperature and evaporated. The residue was triturated under diethyl ether and the resultant solid was isolated and dried under vacuum. There was thus obtained 4-(2-chloro-5-methoxyanilino)-5-(N-methylpiperidin-4-ylmethoxy)quinazoline, as a formic acid salt (0.09 g); NMR Spectrum: (CDCl3) 1.8–2.0 (m, 2H), 2.05–2.15 (m, 2H), 2.35 (m, 1H), 2.6 (t, 2H), 3.55 (d, 2H), 3.93 (s, 3H), 4.21 (d, 2H), 6.68 (m, 1H), 6.95 (d, 1H), 7.31 (d, 1H), 7.54 (d, 1H), 7.7 (m, 1H), 8.35 (br s, 1H), 8.39 (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 413.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].[CH2:19]=[O:20]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:19][OH:20])[C:7]=1[CH2:13][CH3:14]
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: C=O
Solvent: CCO
Solvent: O
Product: CCc1nn(CO)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
A solution of the pyrazole of Example 11 (283 mg, 1.00 mmol) in water (1 ml) and ethanol (0.5 ml) was treated with 37% w/w aqueous formaldehyde solution (112 μL, 1.50 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction was then stirred under reflux for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (2:1, by volume) to afford the title compound (231 mg) as a white solid, m.p. 117-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>CCOCC.[Cu]>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2([CH3:9])[CH3:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)=COc1ccc(Cl)cc1
Agent: [Cu]
Solvent: CCOCC
Product: CCOC(=O)C1C(Oc2ccc(Cl)cc2)C1(C)C

Procedure:
A mixture of 3-(4-chlorophenoxy)-2-methyl-2-propene (4.5 g, 0.032 mol) and 0.158 g of copper powder is heated at 110° for 30 min; then 2.78 g ethyl diazoacetate (0.025 mol) is added dropwise, keeping the temperature at 110°. After the addition is complete (approximately 30 min), the mixture is stirred at 110° until nitrogen evolution is complete. The mixture is cooled, diluted with ether, filtered and concentrated. Distillation of the residue yields ethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[S:30])=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(C(=S)Nc2ccc([N+](=O)[O-])cc2)cc1
Yield: 129.3 %

Procedure:
A mixture of 4-methoxy-4′-nitrothiobenzaniline 3 (1.0 g, 3.7 mmol) and Lawesson's reagent (0.89 g, 2.2 mmol, 0.6 equiv.) in chlorobenzene (15 mL) was heated to reflux for 4 hrs. The solvent was evaporated and the residue was purified with flush column (hexane:ethyl acetate=4:1) to give 820 mg (77.4%) of the product 4 as orange color solid.
Reaction SMILES: O[C:2]1([C:12]#[C:13][C:14]([CH3:18])=[CH:15][CH2:16][OH:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH:4]=[C:3]1[CH3:11].[OH-].[Na+]>C(O)CC.O.[Zn]>[OH:17][CH2:16][CH2:15][C:14]([CH3:18])=[C:13]=[CH:12][CH:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH:4]=[C:3]1[CH3:11]
Reactant: CC(C#CC1(O)C(C)=CC(=O)CC1(C)C)=CCO
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCCO
Solvent: O
Product: CC(=C=CC1C(C)=CC(=O)CC1(C)C)CCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.6 %

Procedure:
10 g (40 mmol) of 4-hydroxy-4-(5-hydroxy-3-methyl-3-penten-1-ynyl)-3,5,5-trimethyl-2-cyclohexen-1-one (prepared in accordance with Example 1) were dissolved in 200 ml of n-propanol/water (1:1, v/v) under argon in a 500 ml multi-necked flask provided with stirrer, thermometer, dropping funnel and gasification headpiece and treated with 20.9 g (0.32 g-atoms) of zinc powder. Thereupon, 120 ml (0.12 mol) of 1N sodium hydroxide solution were added dropwise thereto in 5 minutes at room temperature while stirring and the mixture was stirred for a further 1 hour. The resulting mixture was then worked-up in a manner analogous to that described in Example 1 and there were obtained 9.2 g of crude product. The purification on silica gel in a manner analogous to that described in Example 1 gave 6.9 g (74.3%) of 4-(5-hydroxy-3-methyl-1,2-pentadienyl)-3,5,5-trimethyl-2-cyclohexen-1-one in the form of an oil. The structure of this compound was characterized unequivocally by microanalysis, NMR, IR and MS spectra.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH:19]1([S:24](Cl)(=[O:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:24]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:26])=[O:25])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CCCC1
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)C1CCCC1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with cyclopentanesulfonyl chloride to obtain the desired product 1H NMR (300 MHz, CDCl3): δ 7.42 (dd, J=2.1 & 10.5 Hz, 1H), 7.36 (ddd, J=2.4, 4.8, & 9.3 Hz, 1H), 7.25 (m, 2H), 7.10 (dd, J=9.6 & 17.7 Hz, 1H), 6.67 (br s, D2O exchangeable, 1H), 6.20 (dt, J=1.5, 8.4 & 17.4 Hz, 1H), 3.53 (p, 1H), 1.80 (m, 8H); m/z=495 [M−1]−.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]([OH:15])[CH2:13][CH3:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13][CH3:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)c1ccn(-c2ccccc2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
1-(1-Phenyl-1H-pyrazol-3-yl)-propan-1-ol (631 mg, 3.12 mmol) was dissolved in CH2Cl2 (16 mL) and Dess-Martin periodinane (1.6 g, 3.8 mmol) was added in one portion. After 40 minutes, TLC (2:1 hexanes:EtOAc) indicated a mixture of starting material and product. Additional Dess-Martin periodinane (800 mg, 1.88 mmol) was added and the mixture was stirred at ambient temperature. After 30 minutes, TLC indicated no further conversion to product. The reaction mixture was diluted with CH2Cl2 and washed with aqueous Na2S2O3 (1×) and saturated NaHCO3 (2×). The CH2Cl2 layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (2:1 hexanes:EtOAc) to provide the title compound as a colorless solid (487 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, 1H, J=2.4 Hz), 7.73 (d, 2H, J=8.8 Hz), 7.48 (t, 2H, J=7.2 Hz), 7.35 (t, 1H, J=7.6 Hz), 6.96 (d, 1H, J=2.8 Hz), 3.13 (q, 2H, J=7.2 Hz), 1.24 (t, 3H, J=7.2 Hz). MS (ES) m/z 201.0 (M+H+).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]2>CCOCC.C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:1])=[O:20])=[CH:14][CH:13]=[CH:12]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cccc2cc(O)ccc12
Reaction time: 1.5 h
Yield: 56 %

Procedure:
A solution of (trimethylsilyl)diazomethane (4.0 mL of a 2.0 M solution in Et2O, 8.0 mmol) was added slowly to a solution of 6-hydroxy-1-naphthoic acid (commercially available from TCI, 1.50 g, 8.0 mmol) in THF (40 mL) at 0° C. After 1.5 h at 0° C., the reaction mixture was concentrated in vacuo and absorbed onto silica. The resulting residue was purified on 80 g silica gel (100% hexanes→100% EtOAc, gradient) to afford 910 mg (56%) of methyl 6-hydroxy-1-naphthoate.
Reaction SMILES: [S:1]1CS[C:2]1=[C:5]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=O.[NH2:22][NH2:23]>C1COCC1>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:2]([SH:1])[NH:22][N:23]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(C(=O)C(=C2SCS2)c2ccncc2)c1
Reactant: NN
Solvent: C1CCOC1
Product: COc1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
2-[1,3]Dithietan-2-ylidene-1-(3-methoxy-phenyl)-2-pyridin-4-yl-ethanone (1.18 g, 3.17 mmol) was suspended into a 1 M solution of hydrazine in THF and heated to 70° C. for two hours. The suspension was then concentrated under reduced pressure, taken up with a small volume of ethanol and diluted with THF (10 mL) and stirred for 5 minutes. The solid was filtered, washed with THF and dried at 50° C. for 2 hours. 1.26 g of 5-(3-methoxy-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol were obtained as an orange solid and used in the following step without further purification.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[F:12][CH:13]([F:31])[N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:15]1=[O:30].[H-].[Na+]>CN(C=O)C.CO>[F:31][CH:13]([F:12])[N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[N:3]=3)=[CH:25][CH:24]=2)[C:15]1=[O:30]
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-n3c(=O)n(C(F)F)c4cccnc43)cc2)nc2ccccc21
Temperature: 180 °C
Yield: 46.7 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (70 mg) was added to a solution of 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (122 mg) and NaH (25.2 mg) in DMF (3 mL) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-(difluoromethyl)-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (80 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([O:16][CH3:22])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)s1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(Cl)s1
Yield: 86 %

Procedure:
To a solution of 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionic acid (2.20 g) in methanol (50 ml) was added conc. sulfuric acid (1 ml) and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated, iced water was poured on the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals (3.80 g, yield 86%) of methyl 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionate were obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from diethyl ether-isopropyl ether to give a colorless prism. melting point: 34–35° C.
Reaction SMILES: [Na:1].[N:2]1[C:10]([NH2:11])=[C:9]2[C:5]([N:6](C([C@@H]([C@H](CO)OCP(O)(O)=O)O)=O)[CH:7]=[N:8]2)=[N:4][CH:3]=1.N1C(N)=C2C(N([C:35]([CH2:37][C@H:38]([CH2:51][OH:52])[O:39][CH2:40][P:41]([O:47]C(C)C)([O:43]C(C)C)=[O:42])=[O:36])C=N2)=NC=1>>[Na:1].[N:2]1([C:35]([CH2:37][C@H:38]([CH2:51][OH:52])[O:39][CH2:40][P:41]([OH:43])([OH:47])=[O:42])=[O:36])[C:10]([NH2:11])=[C:9]2[C:5](=[N:6][CH:7]=[N:8]2)[N:4]=[CH:3]1
Reactant: CC(C)OP(=O)(CO[C@@H](CO)CC(=O)n1cnc2c(N)ncnc21)OC(C)C
Reactant: Nc1ncnc2c1ncn2C(=O)[C@H](O)[C@H](CO)OCP(=O)(O)O
Agent: [Na]
Product: Nc1c2ncnc-2ncn1C(=O)C[C@H](CO)OCP(=O)(O)O
Yield: 43 %

Procedure:
This compound was prepared as described for 3a, using 19 (70 mg, 0.23 mmol) as a starting material. Compound 3e (38 mg, 0.11 mmol) was obtained as a colorless solid, in 43% yield, which was characterized as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=4[N:23]3[CH3:26])=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 626.8 %

Procedure:
4-(Benzyloxy)pyridin-2(1H)-one (580 mg, 0.28 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (850 mg, 0.23 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (700 mg, 62%) as a green solid: 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J=8.2 Hz, 1H), 7.44-7.39 (m, 4H), 7.38-7.35 (m, 1H), 7.31-7.28 (m, 2H), 7.01 (dd, J=8.3, 1.8 Hz, 1H), 6.09 (d, J=2.6 Hz, 1H), 6.04 (dd, J=7.6, 2.6 Hz, 1H), 5.05 (s, 2H), 4.64 (br m, 2H), 3.74 (br m, 2H), 3.62 (s, 3H), 2.79 (br m, 2H), 1.47 (s, 9H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.CO>CC(N(C)C)=O>[C:4]1(=[O:6])[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(N2C(=O)C=CC2=O)cc1
Yield: 65 %

Procedure:
In dimethylacetamide, 98 g of maleic anhydride was reacted with 135 g of p-aminoacetophenone at 140° C. for 4 hours. After the reaction, methyl alcohol was added to the reaction solution to precipitate a solid. The precipitate was recovered by filtration and dried in vacuo to obtain 139 g (a yield of 65%) of p-maleimidoacetophenone.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[C:6]([C:7]#[N:8])=[CH:16][N:17]([CH3:18])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)Nc1ccccc1Br
Product: CN(C)C=C(C#N)C(=O)Nc1ccccc1Br

Procedure:
As for Example 1, 2'-bromo-2-cyanoacetanilide, white crystals, m.p. 140°-141° C. (prepared as described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2'-bromo-2-cyano-3-dimethylaminoacrylanilide as off-white prisms, m.p. 91°-93° C.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=[O:2].[NH3:11]>O1CCCC1>[C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(=[O:2])[NH2:11]
Reactant: O=C(O)Cn1nnnc1S
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)Cn1nnnc1S
Reaction time: 2.5 h

Procedure:
1-Carboxymethyltetrazole-5-thiol and 1,1-carbonyl-diimidazole were reacted as described in Example 4. To the reaction mixture was added tetrahydrofuran saturated with dry ammonia gas. The resulting suspension was stirred for 2.5 hours and the solid which formed was collected by filtration, washed with tetrahydrofuran and dissolved in methanol. Amberlite IR-120 ion-exchange resin (50 g.) was added and the suspension was stirred for 15 minutes. The resin was then removed and washed with absolute methanol. The methanol solution was concentrated to give 1- carbamoylmethyltetrazole-5-thiol, m.p. 200° (dec.).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:17]2[N:13]([N:14]=[C:15]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:16]2[O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.O[Li].O>C1COCC1.O>[Cl:33][C:27]1[C:26]([CH3:34])=[C:25]([C:15]2[C@@H:16]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C@@H:17]3[C@H:10]([OH:9])[CH2:11][CH2:12][N:13]3[N:14]=2)[CH:30]=[CH:29][C:28]=1[C:31]#[N:32]
Reactant: Cc1c(C2=NN3CC[C@@H](OC(=O)c4ccccc4)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C2=NN3CC[C@@H](O)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of (3S,3aS,4R)-2-(3-chloro-4-cyano-2-methylphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-4-yl benzoate (100 mg, 0.208 mmol) in THF (2 mL) at 0° C. was added a solution of LiOH.H2O (25 mg, 0.586 mmol) in water (1 mL) and the reaction mixture was stirred at room temperature for overnight. Once the starting material had disappeared (monitored by TLC), reaction mixture was extracted with ethyl acetate. Organic layer was washed with water and brine then dried over Na2SO4 and concentrated to get the crude product which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.CO.C[C:12](C)([O-:14])C.[K+]>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:14][CH3:12])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,5-dibromopyridine (6.95 g, 29 mmol) in N,N-dimethylformamide (5 ml) was added methanol (3.56 ml) and 1M potassium tert-butoxide (32.3 ml) and the resulting mixture was stirred at room temperature for 18 hours. The resulting slurry was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ether and hexane to afford the 5-Bromo-2-methoxypyridine compound as an oil.