Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:35][O:36][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[N:14](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]3=[O:34].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:35][O:36][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13]3=[O:34]
Reactant: CN(C)CCOc1ccc2c(c1)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Yield: 106.9 %

Procedure:
A mixture of 6-[2-(dimethylamino)ethoxy]-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.75 g, 1.5 mmol), triethylsilane (1.3 mL, 8.2 mmol) and trifluoroacetic acid (10 mL) was refluxed for 3 h. The mixture was concentrated under vacuum, and the residue was treated with diethyl ether/hexanes to afford 6-[2-(dimethylamino)ethoxy]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.52 g, 99%) as a colorless solid: mp 95-97° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.21 (td, J=7.6, 1.3 Hz, 1H), 7.04 (d, J=6.4 Hz, 1H), 6.97-6.84 (m, 2H), 6.64-6.57 (m, 2H), 6.40 (dd, J=8.3, 2.3 Hz, 1H), 4.79 (d, J=9.3 Hz, 1H), 4.67 (d, J=9.3 Hz, 1H), 4.25 (t, J=4.7 Hz, 2H), 3.45 (t, J=4.7 Hz, 2H), 2.81 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ 178.9, 162.1, 159.5, 142.3, 133.1, 129.2, 124.2, 124.1, 122.8, 122.7, 110.3, 108.2, 97.5, 80.4, 62.9, 57.6, 55.7, 43.2; MS (ES+) m/z 325.2 (M+1).
Reaction SMILES: C[Li].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20](O)=[O:21])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27](OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20](=[O:21])[CH3:27])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccccc1Nc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1Nc1ccc(OCc2ccccc2)cc1
Reaction time: 1.25 h

Procedure:
Methyllithium (280 ml, 1M in ether) was added slowly to a solution of 31.9 g (0.1 mole) of 2-(4-benzyloxyphenylamino)benzoic acid (Example 2, part a) in 300 ml of tetrahydrofuran cooled to 0°-5° C. The reaction mixture was stirred at 0°-5° C. for 75 minutes. Ethyl acetate was then added and the mixture poured into a mixture of ice and saturated ammonium chloride solution. The aqueous suspension was extracted with ether, the ether extracts dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from isopropyl alcohol to give 24 g of 1-[2-(4-benzyloxyphenylamino)phenyl]ethanone.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.Cl.[Br:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CN([CH:24]=[O:25])C>C1COCC1>[Br:14][C:15]1[C:20]([CH:24]=[O:25])=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: Brc1ccncc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cnccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a stirred solution of diisopropylamine (9.02 mL, 63.3 mmol) in THF (75 mL) at −78° C. was added n-butyllithium (1.6 M in hexane) (30 mL, 76 mmol) dropwise under nitrogen atmosphere. After complete addition the solution was stirred for 30 min at −78° C. 4-Bromopyridine HCl (5 g, 31.6 mmol) was added portionwise and the resultant solution stirred at −78° C. for 1 h. DMF (2.94 mL, 38.0 mmol) was then added dropwise at −78° C. to the solution. The reaction mixture was warmed to room temperature slowly and stirred for 12 h. The reaction mixture was quenched with 3 N HCl and stirred for 2 h. The solution was neutralized with saturated sodium bicarbonate solution, extracted with EtOAc (75 mL), dried over sodium sulfate and concentrated under reduced pressure to give 4-bromonicotinaldehyde (3.75 g, 20.16 mmol, 64% yield). The crude product was used without purification in the next step. 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.00 (s, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.62 (d, J=5.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=O)[CH2:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Cl)cc2C1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Clc1ccc2c(c1)C=C(N1CCCC1)CC2

Procedure:
11.0 g of 7-chloro-3,4-dihydro-2(1H)-naphthalenone was boiled at reflux for 2 hours in 200 ml of benzene and 6.0 ml of pyrrolidine in the presence of 0.25 g of p-toluenesulphonic acid. The 1-(7-chloro-3,4-dihydro-2-naphthyl)pyrrolidine obtained was recrystallized from 150 ml of isopropyl ether and exhibits a melting point of 115°-116°.
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][C:5](OC)=[O:6].[BH4-].[Na+].[H][H].Cl>CC(=O)OCC.O.C(O)C>[CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: [H][H]
Reactant: COC(=O)CCC(C)(C)[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CCCO)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Methyl 4-methyl-4-nitropentanoate (15.5 g, 96.1 mmol) was added to a 1 L round bottomed flask, dissolved into denatured ethanol (300 ml) and cooled in an ice bath for 15 min. Sodium borohydride (7.27 g, 2 equiv, 190 mmol) was added in one portion. Hydrogen was liberated and slowly subsided. The reaction was stirred at 0° C. for 1 h then placed into a 70° C. water bath for 3 h. Water (150 ml) was poured into the flask and 6 N HCl (25 mL) was added dropwise to adjust the pH˜3 while cooled in an ice bath. The ethanol was removed under reduced pressure to give a suspension. Water (150 mL) and EA (300 mL) were added to the flask and the mixture poured into a separatory funnel. The layers were separated and the organic layer was washed with brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated on a rotovap to give a pale yellow oil (12.0 g, 85.1%). 1H NMR (CDCl3, 400 MHz): ±1.5 (m, 2H), 1.61 (s, 6H), 1.95-2.05 (m, 2H), 3.65 (t, 2H). LRMS (ESI+) for C6H13NO3 (147.1); Found: 148 (MH+).
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1>>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: CC(C)(C)c1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3ccccc3)CC2)cc1

Procedure:
Also, N-cyclopropyl-N-[1-(4-tert-butylbenzyl)piperidin-4-yl]-benzenesulfonamide was prepared from N-cyclopropyl-N-piperidin-4-yl-benzenesulfonamide and 1-bromomethyl-4-tert-butylbenzene. LC: 100%, MS: m/z=427.2, 428.3 (M+H+). 1H NMR (400 MHz, CDCl3): δ 7.85 (2H, m), 7.56 (1H, m), 7.50 (2H, m), 7.32 (2H, d, J=8.4 Hz), 7.19 (2H, d, J=8.4 Hz), 3.85 (1H, m), 3.44 (2H, s), 2.89 (1H, s), 2.87 (1H, s), 1.97 (5H, m), 1.59 (4H, s), 1.49 (1H, s), 1.47 (1H, s), 1.32 (9H, s), 0.97 (2H, m), 0.75 (2H, m).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=2)[C:12](O)=[O:13])=[CH:6][CH:5]=1.[NH3:33]>>[NH2:33][C:12](=[O:13])[CH:11]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:32])([F:31])[F:1])=[CH:5][CH:6]=1
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1
Reactant: N
Product: NC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 3-[4-(trifluoromethoxy)phenyl]-2-{[4-(3,3,3-trifluoropropoxy)benzoyl]amino}propanoic acid (5.00 g) prepared in Example 70 (70a) and ammonia (16.1 mL, 2 M ethanol solution) to give 4.51 g of the title compound (white powder).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[C:13]([CH3:19])([CH3:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO>[NH2:26][CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][C:13]1([CH3:19])[CH3:18]
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CCC1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CN(C(=O)OCc2ccccc2)CCC1N
Temperature: 5 °C
Yield: 155.9 %

Procedure:
1-Benzyloxycarbonyl-3,3-dimethyl-4-piperidone (290 g, 1.11 mol) was dissolved in methanol (1.5 L) and under stirring addition of ammonium acetate (600 g, 7.80 mol ) was made at 30-35° C. The reaction mixture was stirred for 5 hrs. Sodium cyanoborohydride (35 g, 0.55 mol) was added portion wise to the suspension. over 0.5 hrs by maintaining temperature between 0-10° C. The reaction mixture was stirred for 6-7 hrs. After completion of reaction, solvent was evaporated under reduced pressure and addition of 3.00 L water was made under stirring. The reaction mixture was stirred for 15 minutes. It was extracted with 1.5 L×2 CHCl3. Combined organic extract was evaporated under vacuum. The residue was dissolved in 3 N HCl till pH 1 and was extracted with 500 ml×2 dichloromethane. The aqueous layer was basified with 300 ml aqueous ammonia solution (23-25%) to pH 10-11 and then was extracted with 1.5 L×3 dichloromethane. Combined organic extract was washed with water and was dried over sodium sulfate. Evaporation of organic solvent afforded 225 g (77%) title compound.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([N:18]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])=[C:10]([O:35][CH3:36])[CH:9]=1)(=O)=O.[CH3:37][O:38][C:39](=[O:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16](=[O:17])[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][O:5][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[C:39]([O:38][CH3:37])=[O:47])=[CH:9][C:10]=1[O:35][CH3:36]
Reactant: COC(=O)c1ccccc1O
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOS(C)(=O)=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1OC
Yield: 51 %

Procedure:
2-(4-{2-[(2,4-Difluorobenzyl)(heptyl)amino]-2-oxoethoxy}-3-methoxyphenyl)ethyl methanesulfonate (138 mg, 0.262 mmol) was dissolved in acetonitrile (10 ml). 2-Hydroxybenzoic acid methyl ester (40 mg, 0.262 mmol) was added and then potassium carbonate anhydrous (54 mg, 0.392 mmol) was added. The mixture was heated to reflux overnight and then evaporated to dryness. Water (10 ml) and ethyl acetate (10 ml) were added and the two phases were separated. The organic phase was washed with water and brine, dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, MeOH/DCM (1:99) as eluant gave 78 mg the desired product, yield 45% (two steps).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[C:7]=1[CH3:8])#[N:2].[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:8][C:7]1[N:6]([C:9]2[C:10]([Cl:20])=[CH:11][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:13][C:14]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C#N)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1CBr
Yield: 103.5 %

Procedure:
By the method of Example 5, Step D, 106 g (0.331 mole) of 4-cyano-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole was reacted with 71.1 g (0.40 mole) of N-bromosuccinimide in 2000 mL of carbon tetrachloride, yielding 136.7 g of 5-bromomethyl-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole as red oil, a portion of which later solidified.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:14]([CH3:34])=[C:13]([CH3:35])[N:12]=1.[O-]C1C=CC=CC=1.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:35][C:13]1[C:14]([CH3:34])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCNC(=O)OC(C)(C)C)c1C
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCNC(=O)OC(C)(C)C)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Phenol (5.33 g, 56.63 mmol) was added in small portions over a period of 10 minutes to a chilled (0°) suspension of sodium hydride (2.39 g of 60%, 59.75 mmol) in anhydrous tetrahydrofuran (100 mL). After the addition was complete, the reaction was allowed to stir at 0° for 30 minutes. A solution tert-butyl 2-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethoxy}ethylcarbamate (20.67 g, 53.16 mmol) in tetrahydrofuran (100 mL) was added over a period of 1 hour while maintaining the temperature at 0° C. The ice bath was removed and the reaction mixture was heated to reflux. At 46 and 52 hours additional fresh sodium phenoxide (11.3 mmol) was added. Refluxing was continued for 2 hours after the second addition. The reaction mixture was diluted with ethyl acetate (500 mL); washed sequentially with water (3×100 mL), 1N sodium hydroxide (2×100 mL), and brine; dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (450 g of silica gel eluting with 1/1 hexanes/ethyl acetate) to provide 19.85 g of tert-butyl 2-{2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]ethoxy}ethylcarbamate.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Difluoro-1-nitrobenzene (2.00 g, 12.57 mmol) was dissolved in acetonitrile (20 mL) and DIPEA (2.2 mL, 12.57 mmol) added, followed by the dropwise addition of benzylamine (1.35 g, 12.57 mmol). The reaction mixture was stirred at RT, under an atmosphere of nitrogen overnight. The mixture was concentrated in vacuo to afford the title compound as a yellow oil, which solidified on standing (3.8 g, 100%). The crude material was used without purification in the next step. 1H NMR (CDCl3, 400 MHz): δ 8.55 (1H, s), 8.25 (1H, dd, J=9.46, 6.08 Hz), 7.43-7.29 (5H, m), 6.47 (1H, dd, J=11.35, 2.60 Hz), 6.39 (1H, ddd, J=9.46, 7.28, 2.61 Hz), 4.51 (2H, d, J=5.60 Hz)
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C@@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)(=O)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:6][CH2:7][C@@H:8]2[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COS(=O)(=O)C(F)(F)F)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)S[C@@H]1CO[C@@H](COc2ccc(F)cc2)C1
Yield: 73.7 %

Procedure:
The title compound is prepared by the procedure of Example 23 using 1.49 g of product from Example 22 in 1 ml of methylene chloride, 0.542 g of 4-fluorophenol, 2.5 ml of Hunig's base and 3 ml of methylene chloride to give 0.963 g of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CC(C)=O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])=[CH:9][CH:10]=1)[CH3:32]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.33 g (12.8 mmol) of 4-hydroxy-naphthalen-1-yl-carbamic acid tert-butyl ester was dissolved in 60 ml of acetone and treated at 0° C. subsequently with 4.60 g (1.1 eq.) of cesium carbonate, 0.107 g (0.05 eq.) of KI, and 1.42 ml (1.0 eq.) of ethyl bromoacetate. After vigorous stirring for 1 h at ambient temperature, the solvent was evaporated and the residue redissolved in AcOEt. Washing with water, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=75/25), yielded 4.28 g of the title product as off-white crystals.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([OH:10])=[CH:5][C:4]=1[NH:11][NH:12][CH:13]=[O:14].[OH-].[Na+].CO.[CH3:19][C:20]([CH3:22])=O>O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH2:22][C:20]#[CH:19])=[CH:5][C:4]=1[NH:11][NH:12][CH:13]=[O:14]
Reactant: CC(C)=O
Reactant: O=CNNc1cc(O)c(Cl)cc1Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CCOc1cc(NNC=O)c(Cl)cc1Cl
Temperature: 40 °C

Procedure:
A stirred suspension of formic acid N'-(2,4-dichloro-5-hydroxyphenyl)-hydrazide sodium salt (1.1 g, 5 mmol) in a mixture of 25 ml acetone and 25 ml water is reacted at room temperature with benzene sulfonic acid-(2-propargyl)ester (1.01 g, 5 mmol). Sodium hydroxide solution (0,2 g, 5 mmol in 5 ml water) is added dropwise within 30 minutes so that the pH value lies between 9.5 and 10. The result is reacted with 10 ml methanol to produce a clear solution. This is heated to 40° C. for 30 minutes during which a precipitate forms. The result is stirred over night, the product is filtered off and washed with water. Yield: 0.8 g (61%) pale brown crystals Melting point: 184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[CH:7][CH:8]=1.[C:12]1([CH:19]=[CH:18][C:16](O)=[CH:15][CH:14]=1)[OH:13].B(O)(O)O.S(=O)(=O)(O)O>O>[OH:13][C:12]1[CH:19]=[CH:18][C:16]([O:10][C:9](=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: O
Product: COc1ccc(C(=O)Oc2ccc(O)cc2)cc1

Procedure:
912 g p-methoxybenzoic acid and 660 g hydroquinone are heated under reflux in the presence of 12 g boric acid and ml sulfuric acid (98%) until the elimination of water is over. After cooling, the crystals precipitating are filtered under suction, washed and redried. Yield: 1250 g colorless crystals. Melting point: 162°-165° C. Mp. J. Org. Chem. 37, 1425 (1972) 156° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH2:2][O:1][C:27](=[O:28])[NH:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16]
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CO
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1COC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R,5S)-4-hydroxymethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (108 mg) in pyridine (0.5 ml) was added phenyl isocyanate (0.1 ml) and the mixture was stirred at room temperature for 30 minutes. Water (1 ml) was added and extracted with ether and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the crude product was purified with preparative TLC (hexane:ether=1:1) to give (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-phenylcarbamoyloxymethyl-1,3-dioxane (140 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:26]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:27])[C:13]=1[OH:34])([O-])=O.C1(C)C=CC=CC=1.[OH-].[Na+].Cl>[Zn].O.C(O)(C)C>[OH:34][C:13]1[C:14]([C:26]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:27])=[CH:15][C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC(C)(C)C)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a 5-liter 3-necked flask fitted with a stirrer, thermometer, reflux condenser and nitrogen inlet was charged 400 grams (0.855 mol) of the o-nitroazobenzene intermediate of Example 1 and 1200 ml of toluene. To the resulting solution was added 260 ml of isopropanol and 260 ml of water. A nitrogen atmosphere was imposed and 175 ml of 50.1% aqueous sodium hydroxide was added. A flask containing 170.0 gram (2.6 gram-atoms) of zinc was connected to the reaction flask by Gooch rubber tubing and the zinc dust was added portionwise to the reaction mixture over a 120-minute period. The zinc was added at such a rate to keep the internal temperature at 70° C. After the zinc was all added, an additional 30 ml of 50.1% sodium hydroxide and 20 grams of zinc were added to insure complete reaction. The reaction mixture was heated for 3 hours at 70° C. The mixture was cooled to room temperature by standing overnight and acidified with 500 ml of concentrated hydrochloric acid.