Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(Br)c(C(F)(F)F)c1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-3-(trifluoromethyl)benzoic acid 46-2 (1.35 g, 5 mmol) in THF (10 mL) was added 1M BH3.THF in THF (20 mL) slowly at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The reaction was quenched with water at 0° C. All the solvents were evaporated and the residue was redissolved in ethyl acetate (100 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and then concentrated. The crude product was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to give (4-bromo-3-(trifluoromethyl)phenyl)methanol 46-3 as white solid. MS m/z 237.1 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3COCC[Si](C)(C)C)[CH3:21])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:42][CH2:43][N:44]([CH3:46])[CH3:45].COC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3COCC[Si](C)(C)C)C)C=CC=1.Cl.OC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1>CO>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Agent: COc1cccc(-n2c(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)nc3cccc(C)c3c2=O)c1
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Agent: Cl
Solvent: CO
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(OCCN(C)C)c3)c(=O)c12

Procedure:
Compound 126 (300 mg, 0.54 mmol) was treated with 2-chloro ethyl dimethylamine hydrochloride salt, at 90° C. for 17 hrs, using the procedure described above for compound 127. The resulting compound was then treated with 4N HCl, in MeOH, using the procedure described for compound 121 (step D). Compound 129 was obtained. m/z=485 (M+H). The structure of compound 129 is shown below.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([O:19][C:20](=[O:25])[NH:21][CH2:22][CH2:23][NH2:24])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:24][CH2:23][CH2:22][NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:25])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Yield: 76.2 %

Procedure:
4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-benzoic acid methyl ester (650.0 mg) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (542.0 mg) and (2-amino-ethyl)-carbamic acid tert-butyl ester (500.0 mg) in DMF (3.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6](S(C)(=O)=O)=[N:5][N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][N:27]=[C:26]([CH:29]([OH:31])[CH3:30])[N:25]=2)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][N:27]=[C:26]([CH:29]([O:31][C:6]3[N:2]([CH3:1])[C:3]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[N:4][N:5]=3)[CH3:30])[N:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Reactant: CC(O)c1noc(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(Oc1nnc(-c2ccncc2)n1C)c1noc(-c2cccc(Cl)c2)n1
Temperature: 30 °C
Reaction time: 72 h
Yield: 15.5 %

Procedure:
1.45 g (6.08 mmol) 4-[4-Methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine, 1.73 g (7.70 mmol) 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethanol and 4.03 g (12.3 mmol) cesium carbonate were dissolved under Ar-atmosphere in DMF (25 mL) and stirred at 30° C. for 3 d. After filtration and evaporation to dryness the crude was purified on 4mm silica chromatotron plate (DCM/MeOH=100/0 to 90/10). Further purification on 2 mm silica chromatotron plate (Hep/EA/MeOH=15/15/1) gave 0.36 g (15%) of the title compound. 1H NMR: 8.75 (br s, 2 H), 8.12 (s, 1 H), 8.00 (d, 1 H), 7.64 (d, 2 H), 7.56 (d, 1 H), 7.46 (t, 1 H), 6.39 (q, 1 H), 3.63 (s, 3 H), 1.94 (d, 3 H).
Reaction SMILES: [F:1][C:2](F)(F)[C:3]([C:8]([F:11])([F:10])[F:9])=[C:4](F)[O:5][CH3:6].C(O)(=O)C.[CH:18]([NH2:20])=[NH:19].[OH-].[Na+]>O.ClCCl>[F:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[C:4]([O:5][CH3:6])[N:20]=[CH:18][N:19]=1
Reactant: N=CN
Reactant: COC(F)=C(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1ncnc(F)c1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a rapidly stirred mixture of 1,1,1,3-tetrafluoro-2-(trifluoromethyl)-4-oxapent-2-ene (N-1) (10.0 g, 47.15 mmol) and formamidine acetate (7.37 g, 70.73 mmol) in a mixture of water (50 mL) and dichloromethane (50 mL) at 0° C., a solution of sodium hydroxide (7.54 g, 189 mmol) in water (40 mL) is added dropwise and the resulting mixture is stirred for 30 min after complete addition. The dichloromethane layer is separated, washed with 1M aqueous HCl solution and water, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford 4-fluoro-6-methoxy-5-(trifluoromethyl)pyrimidine (N-2) as a yellow solid. The product is used directly in the next step without further purification.
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1.O>[CH3:13][C:10]1[CH:9]=[C:4]2[C:3]([CH2:8][O:7][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(C)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)C(=O)OC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.9 %

Procedure:
A heterogeneous, colorless solution of methyl 2-(bromomethyl)-5-methylbenzoate and regioisomer (27.2 mmol) and calcium carbonate (16.33 g, 163 mmol) in 1,4-dioxane (194 mL) and water (194 mL) was refluxed. After 5 hr, the reaction was cooled to room temperature. The insolubles were filtered, and the filtrate was concentrated in vacuo. The residue was extracted with CH2Cl2 (2×200 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give an oil which was purified by flash chromatography using an ISCO 220 g column eluting with 10-50% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (1.205 g, 8.13 mmol, 29.9% yield) as a white solid.
Reaction SMILES: C(N1C2=NC=C(C(O)=O)[C:11]([N:12](C)[CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=C2C=N1)C.[C:23]([NH:26][NH:27][C:28]([C:30]1[C:31](NC2CCCC2)=[C:32]2[CH:38]=[N:37][N:36]([CH2:39][CH3:40])[C:33]2=[N:34][CH:35]=1)=[O:29])(=[O:25])[CH3:24]>>[C:23]([NH:26][NH:27][C:28]([C:30]1[CH:31]=[C:32]2[C:38]([N:12]([CH3:11])[CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:37][N:36]([CH2:39][CH3:40])[C:33]2=[N:34][CH:35]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)NNC(C)=O)cnc21
Reactant: CCn1ncc2c(N(C)C3CCOCC3)c(C(=O)O)cnc21
Product: CCn1nc(N(C)C2CCOCC2)c2cc(C(=O)NNC(C)=O)cnc21

Procedure:
Intermediate 53 was prepared from Intermediate 52 using an analogous method to that for Intermediate 4. LCMS showed MH+=361; TRET=1.91 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CCN2CCCCC2)cc1
Solvent: CCO
Product: Nc1ccc(CCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 86 h
Yield: 100.3 %

Procedure:
In ethanol (100 ml) was dissolved 1-[2—(4-nitro-phenyl)ethyl]piperidine (24.8g), and to the mixture was added dried 10% palladium on carbon (1.24 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 86 hours. The palladium was filtered off, and the filtrate was concentrated to give 1-[2—(4-aminophenyl)ethyl]-piperidine (21.7 g) as pale brown oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[CH2:5][C@H:4]1[OH:17].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>O.C1C=CC=CC=1>[C:18]([NH:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[CH2:5][C@H:4]1[OH:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(OC)c2c1C[C@@H](N)[C@H](O)C2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](NC(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of 74.8 g of trans-3-amino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol, hydrochloride in 2 liters of water is cooled in an ice bath and a solution of 40 g of benzoyl chloride in 300 ml of benzene is added. While stirring vigorously a solution of 23 g of sodium hydroxide in 100 ml of water is added dropwise at 0°-5° C over a period of 30 minutes. Semi-solid material begins adhering to the sides of the flask almost immediately. The mixture is stirred at 0°-5° C for an additional 2 hours. The solid is removed by filtration, washed with a small amount of water, then washed with chloroform and dried in vacuo over phosphorous pentoxide to give 78.5 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[F:33][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:18]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14][C@@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1CN[C@H](CCOc2ccc(F)cc2CCc2ccc(F)c(F)c2)C1
Reaction time: 1 h
Yield: 77 %

Procedure:
83 mg of (2R,4R)-1-t-butoxycarbonyl-2-[2-{2-[2-(3,4-difluorophenyl)ethyl]-4-fluorophenoxy}ethyl]-4-hydroxypyrrolidine [prepared as described in Example 7(b)] were dissolved in 2 ml of dioxane, and then 2 ml of a 4N solution of hydrogen chloride in dioxane were added to the resulting solution. The resulting mixture was then allowed to stand at room temperature for 1 hour. At the end of this time, the crystals which precipitated were collected by filtration, and dried in vacuo, to give 55 mg (yield 77%) of the title compound as colorless crystals, melting at 170°-171° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C:13]1[C:14]([F:40])=[CH:15][C:16]([F:39])=[C:17]([N:19]2[C:28]3[C:23](=[C:24]([CH3:32])[C:25]([F:31])=[C:26](F)[C:27]=3[Cl:29])[C:22](=[O:33])[C:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:20]2)[CH:18]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>CN(C)C=O>[N:1]([C:26]1[C:27]([Cl:29])=[C:28]2[C:23]([C:22](=[O:33])[C:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:20][N:19]2[C:17]2[CH:18]=[C:13]([NH:12][C:10]([O:9][C:5]([CH3:7])([CH3:8])[CH3:6])=[O:11])[C:14]([F:40])=[CH:15][C:16]=2[F:39])=[C:24]([CH3:32])[C:25]=1[F:31])=[N+:2]=[N-:3]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)c(C)c2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N=[N+]=[N-])c(F)c(C)c2c1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
Sodium azide (500 mg) was added to a solution of ethyl 1-(5-tert-butoxycarbonylamino-2 4-difluorophenyl)-8-chloro-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (2 g) in N,N-dimethylformamide (20 ml), and the mixture was heated and stirred at 70° C. for 4 hours. After water and ethyl acetate were added to the reaction mixture, and an organic layer was collected and dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to column chromatography on silica gel to conduct elution with chloroform, thereby obtaining the title compound (1.75 g) as a brown oil.
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]=[C:13]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:12]=2)C=CC=CC=1>[Pd].C(OCC)(=O)C>[CH2:18]([O:17][C:15]1[CH:16]=[C:11]([NH2:10])[CH:12]=[C:13]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:14]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCOc1cc(NC(=O)OCc2ccccc2)cc(OCCCCCCCCCC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOc1cc(N)cc(OCCCCCCCCCC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
A mixture of 34 g (0.063 mol) of 3,5-bis(decyloxy)phenylcarbamic acid phenylmethyl ester and 4.0 g of 10% palladium on charcoal in 650 ml of ethyl acetate was shaken under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to yield 25 g (98% yield, mp 48°-50°) of 3,5-bis(decyloxy)benzenamine.
Reaction SMILES: [C:1]([C:3](=[N:7][OH:8])[C:4]([NH2:6])=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:15][CH2:16]Br.O>CS(C)=O.CN(C)C=O>[C:1]([C:3](=[N:7][O:8][CH2:16][F:15])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: FCBr
Reactant: N#CC(=NO)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: N#CC(=NOCF)C(N)=O
Temperature: 25 °C
Yield: 49.7 %

Procedure:
2-Cyano-2-hydroxyiminoacetamide (22.6 g) was dissovled in dimethyl sulfoxide (100 ml), and then potassium carbonate (55.2 g) was added thereto with stirring at room temperature, and the solution was further stirred for additional 20 minutes. Fluorobromomethane (27 g) dissolved in dimethylformamide (20 ml) was then added to the solution, and the solution was stirred for 20 hours at room temperature and the allowed to cool. The reaction solution was added to iced water (1 liter), and extracted twice with ethyl acetate (150 ml). The organic layer was washed twice with a saturated brine, and dried with addition of anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was washed with ethyl ether, and dried to obtain the objective product (14.4 g).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[C:14]([CH3:16])[C:13]2[CH:12]=[C:11]3[O:17][C:18]([CH3:23])([CH3:22])[C@@H:19]4[O:21][C@@H:20]4[C:10]3=[CH:9][C:8]=2[N:7]=1)(=O)C.Cl([O-])(=O)(=O)=O.[Li+].[C:30]1([CH2:36][CH2:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[OH:4][CH2:5][C:6]1[CH:15]=[C:14]([CH3:16])[C:13]2[CH:12]=[C:11]3[O:17][C:18]([CH3:22])([CH3:23])[C@H:19]([OH:21])[C@@H:20]([NH:38][CH2:37][CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:10]3=[CH:9][C:8]=2[N:7]=1
Reactant: NCCc1ccccc1
Reactant: CC(=O)OCc1cc(C)c2cc3c(cc2n1)[C@H]1O[C@H]1C(C)(C)O3
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(CO)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3NCCc1ccccc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
To a solution of (3R*,4R*)-(3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinolin-7-yl)-methyl acetate (403 mg, 1.29 mmol) in 1,4-dioxane (1 mL), lithium perchlorate (137 mg, 1.29 mmol) and phenylethylamine (0.195 mL, 1.55 mmol) were added at room temperature and the resulting mixture was stirred at 70° C. for 1.5 hour. Upon the completion of the reaction, sodium hydrogencarbonate aqueous solution was added to the reaction solution, and it was extracted with ethyl acetate. The resulting organic phase was washed with sodium hydrogencarbonate aqueous solution and then with sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by medium pressure column chromatography (hexane/ethyl acetate=1/1) and the aimed product was obtained (yield: 32%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C@H:3]([OH:11])[C:4]([O:6]C(C)(C)C)=[O:5].[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[NH2:1][C@@H:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C@H:3]([OH:11])[C:4]([OH:6])=[O:5]
Reactant: CCCC[C@H](N)[C@H](O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](N)[C@H](O)C(=O)O

Procedure:
0.26 g of tert-butyl 3(S)-amino-2(S)-hydroxyheptanoate was treated with 2 ml of trifluoroacetic acid for 30 minutes. The trifluoroacetic acid was evaporated and the residue was evaporated twice with toluene. Trituration with diethyl ether gave 0.155 g of 3(S)-amino-2(S)-hydroxyheptanoic acid trifluoroacetate as a white solid, MS: m/e 162 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[C:11]([CH:13](O)[CH3:14])[CH:10]=[C:9]([C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][CH3:19])[C:8]=1[OH:22])([CH3:6])[CH2:3][CH2:4][CH3:5].Cl>CCCCCC>[CH3:21][C:16]([C:9]1[CH:10]=[C:11]([CH:13]=[CH2:14])[CH:12]=[C:7]([C:2]([CH3:1])([CH3:6])[CH2:3][CH2:4][CH3:5])[C:8]=1[OH:22])([CH3:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(C)(C)c1cc(C(C)O)cc(C(C)(C)CCC)c1O
Agent: Cl
Solvent: CCCCCC
Product: C=Cc1cc(C(C)(C)CCC)c(O)c(C(C)(C)CCC)c1

Procedure:
A solution of 91.8 grams of 2,6-bis(1,1-dimethylbutyl)-4-(α-hydroxyethyl)phenol in 400 milliliters of hexane was stirred vigorously with 400 milliliters of concentrated HCl for 1 hour. The hexane layer was separated and the hexane was removed by distillation under aspirator vacuum. The residual 2,6-bis(1,1-dimethylbutyl)-4-(α-chloroethyl) phenol was dissolved in 150 milliliters of pyridine and the solution was heated under reflux for 1 hour. Pyridine was removed by distillation under aspirator vacuum. The residue was washed with water, then dried in a vacuum oven. The product, a viscous yellow liquid, weighed 26 grams.
Reaction SMILES: [CH2:1]([N:5]([C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[CH2:9][S:10][C:11]1[NH:12][C:13]2[C:14]([N:19]=1)=[N:15][CH:16]=[CH:17][CH:18]=2)[CH3:6])[CH:2]([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:5]([C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[CH2:9][S:10]([C:11]1[NH:12][C:13]2[C:14]([N:19]=1)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:32])[CH3:6])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CN(C)c1ccccc1CSc1nc2ncccc2[nH]1
Solvent: ClC(Cl)Cl
Product: CC(C)CN(C)c1ccccc1CS(=O)c1nc2ncccc2[nH]1

Procedure:
2-Mercaptoimidazo[4,5-b]pyridine and 2-(N-isobutyl-N-methylamino)benzyl chloride hydrochloride were reacted in an aqueous ethanol solution in the presence of sodium hydroxide to obtain 2-[2-(N-isobutyl-N-methylamino)benzylthio]imidazo[4,5-b]pyridine in the same manner as in Example 1-(2). The obtained 2-[2-(N-isobutyl-N-methylamino)benzylthio]imidazo[4,5-b]pyridine was oxidized by m-chloroperbenzoic acid in chloroform in the same manner as in Example 9-(3) to give 2-[2-(N-isobutyl-N-methylamino)benzylsulfinyl]imidazo[4,5-b]pyridine as a pale yellow crystalline product. m.p.: 116°-118° C. (decompn.)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=O)[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.C([O-])(=O)C.[Na+].[NH2:39][OH:40]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:39]/[OH:40])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(/C=N/O)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (11B, 100 mg, 0.220 mmol), sodium acetate (54.2 mg, 0.661 mmol), and hydroxylamine (21.8 mg, 0.331 mmol) were taken up in Ethanol (2.2 ml). The reaction was allowed to stir at 70° C. for 1 hour. Room temperature was attained and the reaction mixture was concentrated in vacuo. The mixture was partitioned between EtOAc and saturated NaHCO3. The combined orgniac layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give (E)-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde oxime. The products were carried forward without purification. MS: [M+H]+ m/z 469.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[CH:27][CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1Cl

Procedure:
The title compound was prepared from rac-[(3-chloro-4-methyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 4) and (4-bromo-phenoxy)-tert-butyl-dimethyl-silane in analogy to Example 1a): MS (ISP): 374.3 ((M−Si(CH3)2C(CH3)3)+H)+ (100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl>CN(C=O)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(Nc1ccc(O)cc1O)C(F)(F)F
Reactant: CCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(NC(=O)C(F)(F)F)c(O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.5 %

Procedure:
To a solution of N-(2,4-dihydroxy phenyl)-2,2,2-trifluoro-acetamide (0.44 g; 2 mmol) in DMF (4 mL) was added K2CO3 and 1-bromooctane (0.37 mL; 2.1 mmol). The slurry was stirred for 2 days at room temperature, poured onto 0.1 M HCl (aq.; 50 mL) and then extracted with diethylether (30 mL). The organic phase was dried (MgSO4), filtered and the eluate evaporated to leave 550 mg of black solid which was purified by chromatography (SiO2; PE80-100° C./EtOAc=4:1) to leave 100 mg (15%) of a pure white solid. Mp. 114-116° C.; MS (GC-MS; Cl): 334 (MH+).