Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]([C:32]1[N:33]=[C:34]([NH:37][C:38](=[O:48])[C@@H:39]([NH2:47])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:35][CH:36]=1)=[O:31].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[CH3:28][O:29][C:30]([C:32]1[N:33]=[C:34]([NH:37][C:38](=[O:48])[C@@H:39]([NH:47][C:10](=[O:11])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@H:21]3[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]3)=[CH:15][CH:14]=2)[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:35][CH:36]=1)=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OC[C@H]3COC(C)(C)O3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
(R)-tert-Butoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid (280 mg, 0.73 mmol), 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (203 mg, 0.66 mmol) (prepared as described in example 10, step 1), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (191 mg, 1.0 mmol) and 1-hydroxybenzotriazole hydrate (135 mg, 1.0 mmol) were combined in dichloromethane (5 mL) and stirred overnight at room temperature. The resulting solution was poured into ethyl acetate and washed with 0.2 M aqueous hydrochloric acid, water, brine and dried over magnesium sulfate. The solvents were removed and the crude was purified by chromatography over silica gel gradient eluted between 40% and 50% v/v ethyl acetate in hexane to give 2-((S)-2-{(R)-2-tert-butoxycarbonylamino-2-[4-((S)-2,2-dimethyl-[1,3]dioxolan4-ylmethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as a foam (170 mg, 38%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH:26]=[O:27])[CH2:22][CH2:21]2)=[C:16]([F:28])[C:15]=1[F:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OCC)(=O)C.N>C1COCC1>[CH2:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:21][CH2:22][C@H:23]([CH2:26][OH:27])[CH2:24][CH2:25]2)=[C:16]([F:28])[C:15]=1[F:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCOc1ccc([C@H]2CC[C@H](C=O)CC2)c(F)c1F
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc([C@H]2CC[C@H](CO)CC2)c(F)c1F
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (1.1 g) was suspended in THF (200 ml). trans-4-(4-Hexyloxy-2,3-difluorophenyl)-cyclohexanecarboaldehyde (s-15) (15.8 g) was added dropwise to the suspension in the temperature range of −20° C. to −10° C., and the stirring was continued in this temperature range for 2 hours. After the completion of the reaction had been confirmed by means of GC analysis, ethyl acetate and then a saturated aqueous solution of ammonia were added to the reaction mixture under ice-cooling and deposits were removed by filtration through Celite. The filtrate was extracted with ethyl acetate. The combined organic phase was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by recrystallization from heptane to give trans-4-(4-hexyloxy-2,3-difluorophenyl)-hydroxymethylcyclohexane (s-16) (4.7 g). The yield based on the compound (s-15) was 29.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[CH3:37])=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CC(C)(C)CCN
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCC(C)(C)C)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3,3-dimethylbutylamine.
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.Br[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(PC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:26]1)#[N:29]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Temperature: 100 °C
Yield: 85.2 %

Procedure:
A mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (0.250 g, 0.518 mmol), methyl 4-bromobenzoate (0.13 g, 0.60 mmol, Aldrich: Cat. #407593), cesium carbonate (0.39 g, 1.2 mmol), palladium acetate (0.014 g, 0.060 mmol), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine (0.070 g, 0.12 mmol) in dry toluene (3 mL) was de-gassed and purged several times with nitrogen, and heated at 100° C. in a sealed tube for 14 hours with stirring. Upon cooling to room temperature the reaction mixture was filtered through a pad of celite. The filtrate was washed with water (1×), brine (1×), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on a silica gel column with ethyl acetate in hexane to afford the desired product (0.240 g, 87%). LCMS (M+H)+: m/z=544.2.
Reaction SMILES: OC(C1C=CC=CC=1)(C1C=CC=CC=1)[C@@H]([O:10][C:11](=[O:39])[CH2:12][C@H:13]([OH:38])[CH:14]=[CH:15][C:16]1[C:17]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[N:18][C:19]([N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])=[N:20][C:21]=1[CH:22]([CH3:24])[CH3:23])C1C=CC=CC=1.[OH-].[Na+].CCCCCC.C(OCC)(=O)C.Cl>O1CCCC1.CO.O.C(Cl)Cl>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:17]2[C:16](/[CH:15]=[CH:14]/[CH:13]([OH:38])[CH2:12][C:11]([OH:39])=[O:10])=[C:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[C:19]([N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[N:18]=2)=[CH:32][CH:33]=1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C=C[C@@H](O)CC(=O)O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/C(O)CC(=O)O
Temperature: 27.5 °C

Procedure:
(3S)-5-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3-hydroxy-4-pentenoic acid (1S)-2-hydroxy-1,2,2-triphenylethyl ester (25 g) was dissolved in a mixture of tetrahydrofuran (75 ml) and methanol (50 ml) at 25-30° C. 1N aqueous sodium hydroxide solution (37 ml) was added dropwise to the above reaction mass over a period of 30 min at 25-30° C. It was stirred at 25-30° C. and monitored the progress of the reaction by TLC (n-Hexane-Ethyl acetate: 7:3 v/v). After completion, the solvent was removed at 45-50° C. under reduced pressure to obtain a residue, which was suspended in water (125 ml). It was subsequently estracted with methylene chloride (2×25 ml) at 25-30° C. Thereafter the resulting aqueous layer was acidified with 1 N aqueous hydrochloric acid (˜18 ml) to pH 3-4 at 25-30° C. The above aqueous layer was extracted with methylene chloride (2×50 ml) at 25-30° C. and the combined methylene chloride layer was washed with aqueous sodium chloride (25% w/v, 60 ml). The crude product was isolated by distilling methylene chloride at 35-40° C. as viscous oil, which was subsequently recrystallised from hexanes to yield the title compound. This compound was used as such for further purification to get better chiral purity.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.[NH2:22][CH2:23][CH:24]([OH:26])[CH3:25]>O1CCOCC1>[OH:26][CH:24]([CH3:25])[CH2:23][NH:22][C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reactant: CC(O)CN
Solvent: C1COCCO1
Product: CC(O)CNc1nnc(C#N)c(N2CCc3ccccc3CC2)n1

Procedure:
In analogy to the procedure as described in example 4 the 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile was reacted with (RS)-1-amino-2-propanol in dioxane at 120° C. overnight to give (RS)-3-(2-hydroxy-propylamino)-5-(1,2,4,5 -tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a white solid; MS: 325 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18]OS(C)(=O)=O)[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CN(C=O)C>[C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18][N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CC(Cn3ccnc3)C2)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A solution of the title compound from Step C (2.3 g, 6.95 mmoles) in DMF (15 mL) was added to a stirred solution of NaH (0.25 g, 10.42 mmoles) and imidazole (0.71 g, 10.44 mmoles) in DMF (10 mL) under nitrogen atmosphere. The mixture was stirred at 60° C. for 16 h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave the title compound (2.1 g, 100%). FABMS (M+1)=304.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OC)c(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OC)c(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (572 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (498 mg, yield: 92%). This was recrystallized from ethanol-hexane. Melting point: 136–137° C.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].CS([O-])(=O)=O.[OH-].[Na+]>C(O)(C)(C)C.C(Cl)(Cl)Cl>[C:1]([C:5]1[C:10]2[CH2:11][CH2:12][O:13][C:9]=2[C:8]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(O)ccc2c1CCO2
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(O)c(C(C)(C)C)c2c1OCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
In a solution of 2.84 g of 4-t-butyl-5-hydroxy-2,3-dihydrobenzofuran [J. Org. Chem. 53, 4135 (1988)] in 10.0 g of t-butyl alcohol and 20 ml of chloroform was added dropwise 10 ml of methane sulfonate under ice-cooling. The mixture was stirred at 0° C. for 15 minutes, then poured into ice water. Then, the mixture was neutralized with a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extracted layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane) to give 1.78 g of 4,7-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran as a white crystal (yield 48%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([CH3:31])[CH:23]=1>>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[NH:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=2[CH3:31])[N:3]=[C:4]([S:19][CH3:20])[N:5]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Product: CSc1nc(Nc2c(F)cccc2F)c(C=O)c(-c2ccc(F)cc2C)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methyl-phenylboronic acid to give the title compound 4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.21 (s, 3H), 2.25 (s, 3H), 6.95 (m, 4H), 7.18 (m, 4H), 9.54 (s, 1H), 10.29 (br s, 1H). LC MS (m/e)=390 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]=[C:16]([C:20]3[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[N:17]=[N:18][CH:19]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[N+:11]([C:7]1[CH:6]=[C:5]([C:14]2[N:15]=[C:16]([C:20]3[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[N:17]=[N:18][CH:19]=2)[CH:4]=[C:3]([OH:2])[C:8]=1[OH:9])([O-:13])=[O:12]
Reactant: COc1cc(-c2cnnc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2cnnc(-c3cccnc3C(F)(F)F)n2)cc(O)c1O
Temperature: -78 °C
Reaction time: 18 h

Procedure:
5-(3,4-dimethoxy-5-nitrophenyl)-3-(2-(trifluoromethyl)pyridin-3-yl)-1,2,4-triazine (1.221 g, 3 mmol) was taken up in dichloromethane (25 mL). The yellowish solution was cooled to −78° C. under argon and boron tribromide (2.55 mL, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and stirred for 18 hours. It was then carefully poured into ice-water (100 mL) and stirred for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P2O5 under vacuum. The solid was recrystallised from dichloromethane-ethanol to give 3-nitro-5-(3-(2-(trifluoromethyl)pyridin-3-yl)-1,2,4-triazin-5-yl)benzene-1,2-diol as a yellow solid, 0.807 g (71%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[C@@H:10]([N:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:36][C:37]([F:45])(S(F)(=O)=O)C(O)=O>C(#N)C>[CH2:1]([O:8][C:9](=[O:28])[C@@H:10]([N:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][O:12][CH:37]([F:45])[F:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@H](CO)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H](COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 40 °C

Procedure:
A solution of (S)-2-dibenzylamino-3-hydroxy-propionic acid benzyl ester (4.9 g, 13.1 mmol) in acetonitrile (50 mL) was treated with anhydrous sodium sulfate (466 mg, 3.28 mmol) and warmed to 40° C. Difluoro(fluorosulfonyl)acetic acid (1.62 mL, 19.7 mmol) was then added over 90 minutes using a syringe pump. After the end of addition, the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:0 to 95:5 to provide (760 mg, 14%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 3.64 (d, J=13.8 Hz, 2H), 3.73 (app t, J=6.5 Hz, 1H), 3.87 (d, J=13.8 Hz, 2H), 4.09 (dd, J=10.3, 6.2 Hz, 1H), 4.22 (dd, J=10.3, 6.9 Hz, 1H), 5.21, 5.32 (ABq, JAB=12.3 Hz, 2H), 6.16 (t, J=74.7 Hz, 1H), 7.21-7.37 (m, 10H), 7.38-7.47 (m, 5H). LCMS (m/z) 426.1 [M+H], Tr=3.76 min.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][C:7]2([CH3:10])[C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:6]2.O>C(O)C>[OH:3][CH:4]1[CH2:9][CH2:8][C:7]2([CH3:10])[C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:6]2
Reactant: CCOC(=O)C12CC1(C)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C12CC1(C)CCC2O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
0.4 g (0.01 mol) of sodium borohydride is added at room temperature to 1.8 g (0.01 mol) of ethyl 2-keto-5-methyl-bicyclo[3.1.0]hexane-1-carboxylate, dissolved in 20 ml of ethanol, and the mixture is then subsequently stirred at room temperature for about 12 hours. The reaction mixture is poured into water. The residue is extracted with diethyl ether, concentration is effected, and the crude product is chromatographed on silica gel with hexane/ethyl acetate as eluent. 1.5 g (82% of theory ) of ethyl 2-hydroxy-5-methyl-bicyclo[3.1.0]hexane-1-carboxylate are obtained in the form of an oil.
Reaction SMILES: C1C(C(OO)=[O:8])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:29]([CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:30]=[CH2:31]>C(Cl)(Cl)Cl>[CH2:29]([CH:32]=[CH:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]2[O:8][CH:39]2[CH:40]=1)[CH2:30][CH3:31]
Reactant: O=C(OO)c1ccccc1
Reactant: C=CCCCCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCC=CCC1=CC2OC2C=C1
Reaction time: 144 h
Yield: 76 %

Procedure:
To perbenzoic acid in chloroform prepared from 65.5 g of benzoylperoxide was added 1.45 g of p-allylpropylbenzene and the mixture was allowed to stand at 5° C for 6 days. After the completion of the reaction, the mixture was washed with 2% sodium hydroxide solution, water, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 12.1 g (yield 76%) of p-n-propylallylbenzene oxide as colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([S:10]([Cl:13])(=[O:12])=[O:11])=[C:8]([C:14](Cl)=[O:15])[S:7][C:6]=2[CH:17]=1.[CH3:18][OH:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([S:10]([Cl:13])(=[O:12])=[O:11])=[C:8]([C:14]([O:19][CH3:18])=[O:15])[S:7][C:6]=2[CH:17]=1
Reactant: O=C(Cl)c1sc2cc(Cl)ccc2c1S(=O)(=O)Cl
Reactant: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc2cc(Cl)ccc2c1S(=O)(=O)Cl

Procedure:
Prepared analogous to Example 1(c) from 6-chloro-2-chlorocarbonyl-benzo-[b]-thiophene-3-sulfonic acid chloride and methanol in the presence of chloroform.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:11]([O:13]CC)=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[OH-].[K+]>C(O)C>[S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:11]([OH:13])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C(=O)OCC)=C1SCS1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C(=O)O)=C1SCS1

Procedure:
Diethyl 2-(1,3-dithietan-2-ylidene)malonate was treated with a solution of potassium hydroxide in ethanol. The resultant solid was isolated and purified by the same method as in Example 1 to afford the titled compound as a white solid. (51%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH3:11])[C:3]1=[O:12].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]([CH3:11])[C:3](=[O:12])[N:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:19]
Reactant: O=C(Cl)CCCCCl
Reactant: Cn1c(=O)n(C)c2ccccc21
Product: Cn1c(=O)n(C)c2cc(C(=O)CCCCCl)ccc21
Yield: 70.7 %

Procedure:
Using 1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one (3.00 g) and 5-chlorovaleryl chloride (5.74 g) according to the same method as that of Reference Example 1, the title compound (3.67 g) was obtained as colorless crystals.
Reaction SMILES: Cl[CH:2]([O:10][CH2:11][CH3:12])[CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:13]([O-:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].C(Cl)Cl>CN(C)C=O.CCOCC>[C:13]([O:21][CH:2]([O:10][CH2:11][CH3:12])[CH:3]([O:4][CH2:5][CH3:6])[O:7][CH2:8][CH3:9])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CCOC(Cl)C(OCC)OCC
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(OCC)C(OCC)OC(=O)c1ccccc1
Reaction time: 21 h
Yield: 83 %

Procedure:
A mixture of 178 mg (0.905 mmole) of 1-chloro-1,2,2-triethoxyethane (produced in accordance with Example IV) and 206 mg (1.43 mmoles) of sodium benzoate in 3.00 mL of N,N-dimethylformamide, spectrophotometric-grade, commercially available from Aldrich Chemical Co., Milwaukee, Wis., was stirred, while being protected from exposure to atmospheric moisture, at room temperature for 21 hours. The mixture was diluted with 20 mL of 3:1 (volume/volume) ether:methylene chloride; and the organic layer was washed five times with 25 mL portions of I0% aqueous sodium chloride to ensure removal of dimethylformamide. The washed organic layer was subsequently dried over anhydrous sodium sulfate and filtered. Removal of the volatile organic material under reduced pressure afforded 212 mg (83% yield) of the title compound, the identity and purity of which were ascertained by proton NMR analysis [two doublets (J=5.5 Hz), one at δ4.63 (CH3CH2OCHOCH2CH3), the other at δ6.07 (CHOC(=O)C6H5)]. The title compound was subsequently saponified by use of potassium carbonate (2 equivalents) in 4:1 (volume/volume) methanol:water at 0° C. for 5 hours to afford glyoxal mono(diethyl acetal) and the corresponding hydrate (CH3CH2O)2CHCH(OH)2 and hemiacetal ##STR10## in high yield. Heating the latter mixture in toluene as described in Example XVIII affords glyoxal mono(diethyl acetal) as methanol and water are distilled out of the mixture.