Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH2:40]Cl)[CH2:35][CH2:34]2)=[CH:24][CH:23]=1>C(O)(C)(C)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][O:14][CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:35][CH2:34]2)=[CH:24][CH:23]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(C(OCCCN2CCN(CCCl)CC2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Fc1ccc(C(OCCCN2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)c2ccccc2)cc1

Procedure:
10.1 g of benzhydrol are refluxed with 6.2 g of potassium tertiary butoxide in 100 ml of anhydrous tertiary butanol under argon gas for 30 minutes, then 19.6 g of 1-[3-[(4-fluorophenyl)-phenylmethoxy]propyl]-4-(2-chloroethyl)piperazine dissolved in 40 ml of anhydrous tertiary butanol are dropwise added. The mixture is boiled for one additional hour, then evaporated to about 40 ml under reduced pressure and after adding water it is extracted with benzene. The organic phase is dried over anhydrous magnesium sulfate and, after evaporating benzene under reduced pressure, the residue is fractionally distilled. The aimed compound boils at 247°-250° C./0.01 Hgmm.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[NH:3]1.[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:25][NH:24][C:23]=1[CH:35]=O>C(O)C>[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:28])=[CH:25][NH:24][C:23]=1/[CH:35]=[C:10]1\[C:2](=[O:1])[NH:3][C:4]2[C:9]\1=[C:8]([C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=O
Reactant: O=C(O)Cc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: CCO
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(CC(=O)O)c3)c21
Yield: 53.2 %

Procedure:
[3-(2-Oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid (80.1 mg, 0.3 mmol) was condensed with 3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (66.7 mg, 0.3 mmol) in ethanol to give 75.3 mg of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([NH:29][C@H:30]([C:35](O)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])(OCC1C=CC=CC=1)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]([C:35](=[O:36])[C@H:30]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH2:29])[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Yield: 34.3 %

Procedure:
By reacting 7 g of N-(indan-2-yl)glycine tert-butyl ester with 8.5 g of N-(carbobenzoxy)-L-leucine and treating the reaction mixture as in Reference Example 5, there is obtained 3.5 g of L-leucyl-N-(indan-2-yl)glycine tert-butyl ester as colorless amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[C:14]([O:15][CH2:16][CH2:17][O:18]C2CCCCO2)=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:25]([O-])=O.O.O.[Sn](Cl)Cl>C(O)C.Cl>[NH2:25][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:15][CH2:16][CH2:17][OH:18])[C:7]=1[O:6][C:5]1[CH:28]=[CH:29][CH:30]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:11]#[N:12]
Reactant: COc1cccc(Oc2c(OCCOC3CCCCO3)cc(C#N)cc2[N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1cccc(Oc2c(N)cc(C#N)cc2OCCO)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.0 g of 4-(3-methoxy-phenoxy)-3-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzonitrile were dissolved in ethanol (60 ml), a solution of tin dichloride dihydrate (4.5 g) in 37% HCl (12 ml) was added dropwise thereto at room temperature and the mixture was subsequently stirred at room temperature for 12 hours. The mixture was poured on to ice-water, adjusted to pH 7 and the product was extracted with ethyl acetate. After usual processing of the organic phase there was obtained 3-amino-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzonitrile as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[N:23]1[CH:32]=[C:26]2[C:27]([NH2:31])=[N:28][CH:29]=[CH:30][C:25]2=[N:24]1>C(Cl)Cl>[CH3:14][O:13][C:11](=[O:12])[NH:31][C:27]1[C:26]2=[CH:32][N:23]([C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])[N:24]=[C:25]2[CH:30]=[CH:29][N:28]=1
Reactant: Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Temperature: 25 °C
Yield: 49.4 %

Procedure:
DIPEA (51 μL, 0.3 mmol) and then methyl chloroformate (19 μL, 0.25 mmol) were added to a solution of 2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-ylamine (60 mg, 0.21 mmol) in DCM (2 mL). The reaction was stirred at room temperature until completion as determined by TLC. The mixture was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (40-50% ethyl acetate in cyclohexane) to afford the title compound as a white solid (35 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.54 (d, J=0.9 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.86 (d, J=1.4 Hz, 1H), 7.84 (d, J=0.6 Hz, 1H), 7.80-7.78 (m, 1H), 7.72 (dd, J=7.3, 0.9 Hz, 1H), 3.97 (s, 3H). LCMS (Method B): RT=2.71 min, m/z: 337 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[S:26])[CH:20]=[CH:21][C:22]=1[Cl:23].C1(C)C=CC=CC=1>CCOCC>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: S=C(Nc1ccc(Cl)c(Cl)c1)Nc1ncccc1OCc1ccccc1

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (2.14 g, 0.011 mol), 3,4-dichlorophenyl isothiocyanate (2.62 g, 0.013 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 3.64 g (84%), m.p. 144°-146 ° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>N1C=CC=CC=1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3][C:2]([F:11])([F:12])[F:1])(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2OC(F)(F)F)cc1
Temperature: 85 °C
Yield: 76.6 %

Procedure:
To a pre-cooled solution of 2-(trifluoromethoxy)aniline (1.8 g, 10.16 mmol) in pyridine (20 ml) was added 4-nitrobenzene-1-sulfonyl chloride (2.252 g, 10.16 mmol) in 5-10 mL of pyridine at 0° C. slowly. The reaction mixture was stirred and heated to 85° C. for 3 h, then cooled down to 45° C. and stirred at the same temperature over weekend. The solvent was removed under reduced pressure. The residue was diluted with methylene chloride and washed with 1N HCl (×2), water (×2), and brine. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2.82 g of title product.
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH2:38])([CH3:37])[CH3:36])=[CH:30][C:29]=1[CH3:39].Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:38][C:35]([CH3:36])([CH3:37])[CH2:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([CH3:39])[CH:30]=2)[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Reactant: Cc1cc(CC(C)(C)N)ccc1F
Agent: Cl
Product: Cc1cc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)ccc1F

Procedure:
1.10 g (3.1 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.50 g (2.8 mmol) of 2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamine are reacted and worked up analogously to the method for Example 8(d). White solid. Yield: 0.75 g (47%, hydrochloride); melting point 228° C.-230° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([C:39]([C:41]2[N:42]=[CH:43][N:44]3[CH:48]=[C:47]([Sn](CCCC)(CCCC)CCCC)[S:46][C:45]=23)=[O:40])[CH2:35][CH2:34]1)=[N+:28]=[N-:29]>>[N:27]([CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([C:39]([C:41]2[N:42]=[CH:43][N:44]3[CH:48]=[C:47]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[O:13])[S:46][C:45]=23)=[O:40])[CH2:35][CH2:34]1)=[N+:28]=[N-:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)C3CCN(CCCN=[N+]=[N-])CC3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)C5CCN(CCCN=[N+]=[N-])CC5)c4s3)[C@H](C)[C@H]12
Yield: 71.6 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-[1-(3-azidopropyl)piperidin-4-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (862 mg) was prepared in the same manner as in step a) of Example 1, except that 658 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.16 g of 7-[1-(3-azidopropyl)piperidin-4-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.Cl>[OH-].[Na+].O.O1CCOCC1>[C:29]([CH2:28][CH2:27][C:26]([N:18]1[CH2:17][CH2:16][N:15]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:21])[CH2:20][CH2:19]1)=[O:32])([OH:31])=[O:30]
Reactant: O=C1CCC(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)N1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Reaction time: 12 h
Yield: 55.7 %

Procedure:
3.5 g (0.01 mol) of 1-cyclopropyl-6,8-difluoro7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are dissolved in a mixture of 0.4 g of sodium hydroxide in 20 ml of water, and a solution of 1 g of succinic anhydride in 10 ml of dioxane, and a solution of 0.4 g of sodium hydroxide in 10 ml of water, are simultaneously added dropwise at 20° C. After standing for 12 hours, the mixture is adjusted to pH 5 with 2N hydrochloric acid, and the precipitate is filtered off under suction, washed with water, heated with methanol, filtered off under suction and dried. 2.5 g of 7-[4-(3-carboxypropionyl)-piperazin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid having a decomposition temperature of 217°-219° C. are obtained. The following compounds are obtained analogously to Example 21:
Reaction SMILES: [CH3:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:6]1[O:5][C:4](=[O:7])[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(c2ccccc2)C(=O)OC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1=C(c2ccccc2)C(=O)OC1Br

Procedure:
2,5-Dihydro-4-methyl-2-oxo-3-phenylfuran, (U.S. Pat. No. 3,622,569), (355 g) in carbon tetrachloride (50 mls) and N-bromosuccinimide (3.85 g) were heated under reflux in the presence of 2,2'-azobisisobutyronitrile (AIBN) (cat.quantity) and a 150W lamp. After 1 h a pale yellow solution was formed accompanied by the presence of succinimide. T.l.c. analysis showed a mixture of products. After filtration, and removal of solvent, the residue was purified by flash chroma-tography on silica gel eluting with 10% ethyl acetate/hexane. The title compound was obtained as a viscous yellow oil, (3.53 g, 68%), (Found; M+, 251.9802. C11H9O2Br requires M, 251.9786); νmax 1780(s) and 1650(w)cm-1 ; δH (CDCl3) 2.28 (3H,s), 6.80 (1H,s) and 7.45 (5H,m).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][OH:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][S:36]([CH3:35])(=[O:38])=[O:37])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CO)nn23)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COS(C)(=O)=O)nn23)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 106.5 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.50 g, 1.054 mmol) in DCM (6 ml) cooled to 0° C. were added DMAP (0.013 g, 0.105 mmol) and TEA (0.294 ml, 2.107 mmol) followed by methanesulfonyl chloride (0.098 ml, 1.264 mmol) and the resulting solution was stirred at 0° C. After 45 min, the reaction was diluted with DCM and quenched with sat'd aq NaHCO3. The organic phase was washed with water, dried and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.62 g, 1.122 mmol, 106% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 6.15-5.97 (m, 1H), 5.98-5.81 (m, 1H), 5.55-5.38 (m, 3H), 5.29-5.20 (m, 1H), 4.32-4.11 (m, 2H), 4.02 (d, J=4.9 Hz, 2H), 3.06 (s, 3H), 2.63 (s, 3H), 1.93 (br. s., 4H), 1.35 (s, 3H), 1.29-1.19 (m, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[CH3:12][O:13]C1C(N)=CC=CC=1>[O-2].[V+5].[O-2].[O-2].[O-2].[O-2].[V+5]>[CH:12]([NH:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:2][CH3:1])=[O:13]
Reactant: COc1ccccc1N
Reactant: COc1ccccc1[N+](=O)[O-]
Agent: [V+5]
Agent: [O-2]
Product: COc1ccccc1NC=O
Yield: 24.8 %

Procedure:
The procedure of Example 4 was repeated using o-nitroanisole (4 mmol, 0.55 g) as starting material and vanadium(v) oxide (2.3 mg) instead of sodium molybdate dihydrate. After 2.5 h at 90-95° C. a yield of 24.8% of o-formoanisidide was obtained. o-Anisidine (62.8%) was found to be the main product.
Reaction SMILES: [CH3:1][CH2:2][C:3]([N:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4].[CH2:26]([C:30](O)([C:35]([OH:37])=O)[CH2:31][C:32]([OH:34])=O)[C:27]([OH:29])=O.[C:39]([O-])(=O)[CH2:40]CCCCCCCCCCCCCCCC.[Mg+2].C([O-])(=[O:78])CCCCCCCCCCCCCCCCC>>[CH2:12]=[CH:17][CH2:16][N:15]1[C@@H:18]2[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([OH:78])=[C:32]4[O:34][C@H:26]5[C:27]([CH2:39][CH2:40][C@:35]2([OH:37])[C@:30]5([C:31]=34)[CH2:13][CH2:14]1)=[O:29].[CH3:1][CH2:2][C:3]([N:5]([CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CCC(=O)N(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Agent: [Mg+2]
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5

Procedure:
Fentanyl citrate, croscarmellose sodium and silicified microcrystalline cellulose, and then magnesium stearate, were all added and admixed under the same conditions as those described in Examples 1 and 2 above. The mixture was compressed as described in Example 2.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>O>[N+:15]([C:12]1[CH:13]=[CH:14][C:7]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:17])=[O:16]
Reactant: Oc1ccccc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a dimethylformamide solution (30 ml) containing 2-chloro-5-nitrobenzonitrile (10 g) and phenol (5.7 g) was added sodium hydride (60% content, 2.63 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether to give 5-nitro-2-phenoxybenzonitrile (10.8 g), melting point: 126° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2OC(=O)[S:12][N:11]=2)=[CH:6][CH:5]=1.[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:19]>CCCCCCCCCCCC>[CH2:23]([O:22][C:20]([C:18]1[S:12][N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:1])[F:17])=[CH:9][CH:8]=2)[N:19]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C#N
Reactant: O=c1oc(-c2ccc(OC(F)(F)F)cc2)ns1
Solvent: CCCCCCCCCCCC
Product: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)ns1
Temperature: 150 °C
Yield: 12.3 %

Procedure:
To a solution of 5-(4-trifluoromethoxyphenyl)-[1,3,4]oxathiazol-2-one (0.74 g, 2.81 mmol) in n-dodecane (0.50 ml) was added ethyl cyanoformate (1.10 ml, 11.24 mmol). The resulting reaction mixture was refluxed for 24 h at 150° C. After the completion of the reaction (TLC monitoring), added ice-cold water and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 2% EtOAc-Hexane) to get the product (0.11 g, 12%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:27])[CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].Cl.[NH2:31]O.Cl>C(O)C.O>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:27][N:31]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
To 92 mg (0.26 mmol) methyl 4-[3-(4-pentyloxyphenyl)-3-oxopropanoyl]benzoate in 10 mL ethanol was added 146 mg (3.63 mmol) sodium hydroxide and 500 mg (7.25 mmol) hydroxylamine hydrochloride in 2 mL water. The solution was refluxed for 7 h. After cooling to room temperature, 1 M hydrochloric acid was added and the precipitate formed was filtered off and washed with water. Upon drying, the product was obtained as a white solid (22 mg, 0.06 mmol, 23%). 1H NMR (D6-acetone, 500 MHz): δ=8.18 (d, 2H, J=8.6 Hz), 8.06 (d, 2H, J=8.5 Hz), 7.89 (d, 2H, J=8.6 Hz), 7.30 (s, 1H), 7.11 (d, 2H, J=8.6 Hz), 4.08 (t, 2H, J=7.3 Hz), 1.82 (m, 2H), 1.47 (m, 4H), 0.93 (t, 3H, J=7.3 Hz). HPLC: 4.641 min.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][N:4]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].[BrH:14]>>[BrH:14].[BrH:14].[NH2:10][CH2:11][CH2:12][S:13][CH2:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][N:4]=1
Reactant: NCCS
Reactant: Cn1cnnc1CO
Agent: Br
Agent: Cl
Product: Cn1cnnc1CSCCN

Procedure:
Reaction of 3-hydroxymethyl-4-methyl-1,2,4-triazole with cysteamine hydrochloride and hydrobromic acid by the procedure of Example 1 gives 3[(2-aminoethyl)thiomethyl]-4-methyl-1,2,4-triazole dihydrobromide, m.p. 175°-177°.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([CH2:14][C@@H:15]([O:36][C:37]([N:39]2[CH2:44][CH2:43][CH:42]([N:45]3[CH2:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[NH:47][C:46]3=[O:56])[CH2:41][CH2:40]2)=[O:38])[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[O:17])=[CH:6][C:5]=1[Cl:57]>O.C1COCC1>[NH2:3][C:4]1[C:9]([C:10]([F:12])([F:11])[F:13])=[CH:8][C:7]([CH2:14][C@@H:15]([O:36][C:37]([N:39]2[CH2:40][CH2:41][CH:42]([N:45]3[CH2:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[NH:47][C:46]3=[O:56])[CH2:43][CH2:44]2)=[O:38])[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]3)[CH2:22][CH2:23]2)=[O:17])=[CH:6][C:5]=1[Cl:57]
Reactant: CCOC(=O)C1(C)CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 2.00 mg (0.08 mmol) LiOH in 1 mL water was added to 40 mg (0.05 m mol) ethyl 1′-{(R)-3-(4-amino-3-chloro-5-trifluoromethyl -phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-4-methyl-1,4′-bipiperidinyl-4-carboxylate in 0.8 mL THF and the reaction mixture was stirred for 1 h at RT and for 8 h at 50° C. This was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:19]([N:21]1[C:25]([NH2:26])=[CH:24][CH:23]=[N:22]1)[CH3:20]>O1CCCC1>[CH2:19]([N:21]1[C:25]([NH:26][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[CH:24][CH:23]=[N:22]1)[CH3:20]
Reactant: CCn1nccc1N
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CCn1nccc1NC=C1C(=O)Nc2ccccc21

Procedure:
The named compound is prepared by substituting 2-ethyl-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1632 gms. 2-ethyl-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).