Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C:9]1[N:14]=[CH:13][C:12]([N:15]([CH3:35])[C:16](=[O:34])[C:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)([CH3:19])[CH3:18])=[C:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[CH:10]=1)C1C=CC=CC=1.Cl>C(O)C.CO.[Pd]>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([N:15]([CH3:35])[C:16](=[O:34])[C:17]([C:20]2[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)([CH3:19])[CH3:18])=[C:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[CH:10]=1
Reactant: Cc1ccccc1-c1cc(NCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 81 %

Procedure:
A solution of 750 mg (1.28 mmol) N-(6-benzylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 25 ml of a 5 N solution of hydrochloric acid in ethanol was evaporated to dryness and the residue was dissolved in 30 ml methanol and hydrogenated in the presence of 60 mg 10% palladium on activated charcoal (room temperature, 10 bar) for 20 h. After filtration of the catalyst and evaporation of the solvent the residue was dissolved in 30 ml ethyl acetate, washed twice with saturated aqueous sodium hydrogencarbonate solution and dried (magnesium sulfate). Evaporation of the solution afforded 514 mg (81%) of the title compound as light brown crystals.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15].C(N(CC)CC)C.CO>C(C(C)=O)C(C)C.O.O1CCCC1>[C:13]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)Cl
Solvent: CO
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
Into a reaction vessel were charged 116.41 g of tetrahydrofuran and 16.63 g (0.1 mol) of 2-methyl-2-adamantanol, and 21.56 g (0.2 mol) of methacryloyl chloride was poured thereto at -10° C. under stirring. To the mixture, 25.56 g (0.25 mol) of triethylamine was added dropwise and the resulting mixture was left as it was for 15 minutes. The mixture was heated up to 69° C., the refluxing temperature, and stirring was continued for 11 hours while maintaining the refluxing state to react the mixture. After cooling, 6.41 g (0.2 mol) of methanol was added dropwise at -10° C. to deactivate the unreacted methacryloyl chloride. Then, the mixture was diluted with 116.41 g of methy isobutyl ketone. To the mixture, 68.87 g of water was added to wash it and thereafter the mixture was separated into layers. To the organic layer was added 112 g of a saturated aqueous sodium chloride solution. The resulting mixture was neutralized, under ice cooling, with a 5% aqueous sulfuric acid solution so as to adjust pH to from 7 to 8 and thereafter the mixture was separated into layers. The organic layer after separation was concentrated at a bath temperature of 40° C. to yield 23.62 g of brown crude 2-methyl-2-adamantyl methacrylate.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9](=[O:10])[CH:8]=[CH:7][O:6][C:5]=1[CH3:11].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.O>[CH2:12]([O:3][C:4]1[C:9](=[O:10])[CH:8]=[CH:7][O:6][C:5]=1[CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: Cc1occc(=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1occc(=O)c1OCc1ccccc1
Yield: 76.8 %

Procedure:
A solution of sodium hydroxide (126 g, 1.1 mol) in 1000 ml of methanol in water (9:1 v/v) was added to 3-hydroxy-2-methyl-4-pyrone (126.12 g, 1 mol). Benzyl chloride (126.59 ml, 1.1 mol) was then added slowly and the mixture was refluxed for 10 hours with rapid stirring. The resultant solution was cooled, the methanol removed by rotary evaporation and the aqueous solution was extracted with dichloromethane (3×250 ml). The combined dichloromethane extracts were washed with 5% sodium hydroxide and then with water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The resultant solid was recrystallised from diethylether to yield the title compound in 76.8% yield as colourless needles, m.p. 53°-55° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.[CH3:19][S:20]C.O>CCOCC>[CH3:19][S:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: CSC
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2cccc(SC)c2C1
Reaction time: 1 h

Procedure:
A solution of 5,6,7 or 8-bromo-2-(di-n-propylamino)tetralin (1.4 g; 4.5 mmol) in dry ether (20 ml) was cooled to -78° C. under nitrogen atmosphere. S-BuLi (7 ml, 10 mmol) was added and the mixture was stirred for 1 hr. Methylsulphide (0.31 g; 5 mmol) was added and the mixture was stirred for 3 hr. When the temperature reached -10° C., water was added. Workup afforded the product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:23]=[CH:24][CH3:25])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:6]>CCO.[Pd]>[CH3:1][C:2]1[C:3]([CH2:23][CH2:24][CH3:25])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:6]
Reactant: CC=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Yield: 58.4 %

Procedure:
To a solution of 2-[3-methyl-2-(1-propenyl)-benzoylamino]-indan-2-carboxylic acid (143) (220 mg, 0.65 mmol) in absolute EtOH (10 mL) is added the catalyst, Pd—C (5 wt. % Pd, 55 mg, 2.6% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 50 psi, room temperature, overnight. The catalyst is removed by the filtration through a pre-column (10 g silica gel) and washed with EtOH. The combined solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (144) as white solid (128 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(Cl)cc([N+](=O)[O-])c2=O)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
To a stirred solution of 5-chloro-3-nitropyridin-2-ol (12 g, 68.8 mmol) in DMF (80 ml) was added in several portions NaH (3.30 g, 83 mmol) at 0° C. The reaction mixture was stirred in the ice-bath for 2 hours. Then 4-methoxybenzyl chloride (11.19 ml, 83 mmol) was added and the reaction mixture was heated at 80° C. for 1 hour. The reaction mixture was quenched with aqueous saturated NaHCO3 solution and extracted twice with EtOAc. The organic layers were washed with brine, combined, dried over sodium sulphate, filtered and evaporated. The crude material was taken up in n-heptane/AcOEt 10:1 and the suspension was kept in the sonic bath for 10 minutes. After filtration the filtrate was washed with n-heptane and dried in vacuum to obtain 11.84 g (40.2 mmol, 58.4% yield) of the title compound as a greenish solid. LCMS: (M+H)=295; tR=0.94 min (LC-MS 4). 1H-NMR (d6-DMSO, 400 MHz) 8.72 (d, 1H) 8.56 (d, 1H) 7.36 (d, 2H) 6.94 (d, 2H) 5.13 (s, 2H) 3.74 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: O=S(=O)(Nc1ccccc1)c1cccc(CO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Yield: 82.5 %

Procedure:
Reaction of 3-Hydroxymethyl-N-phenyl-benzenesulfonamide (crude from previous step, 1.36 mmol), MnO2 (1.40 g, 13.60 mmol) in CH2Cl2 (10 mL) at 40° C. under N2 overnight gave the title compound (293 mg, 82%) as a white solid.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45]>C1COCC1.C(Cl)Cl.O>[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CC(=O)N(C)C)CC3)ccc1-2
Reaction time: 65 h
Yield: 43.3 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 375 TFA salt (386 mg, 0.76 mmol) in THF (5 mL) was added potassium carbonate (210 mg, 1.52 mmol) followed by 2-chloro-N,N-dimethylacetamide (102 mg, 0.84 mmol). The reaction mixture was stirred for 65 hours before being diluted with DCM and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (SiO2, gradient 0-3% methanol in DCM) then freeze-dried from methanol and water to give 509 as a white solid (158 mg, 43%). LCMS: RT=3.33 min, [M+H]+=481. 1H NMR δ (ppm) (DMSO-d6): 8.27 (1H, d, J=8.20 Hz), 8.09 (1H, d, J=0.59 Hz), 7.09 (1H, dd, J=8.25, 1.83 Hz), 6.93 (1H, d, J=1.77 Hz), 5.83-5.81 (1H, m), 4.35 (2H, t, J=5.02 Hz), 3.41 (2H, t, J=5.05 Hz), 3.15 (2H, s), 3.05 (3H, s), 2.93 (2H, d, J=10.95 Hz), 2.82 (3H, s), 2.48-2.44 (1H, m), 2.16-2.13 (2H, m), 1.81-1.70 (2H, m), 1.66-1.64 (2H, m), 1.54 (6H, d, J=6.59 Hz)
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:14][CH:15]([CH2:27][CH3:28])[CH2:16][CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[H-].[Na+].O>CN(C)C=O>[C:4]([C:3]1[C:2]([O:14][CH:15]([CH2:27][CH3:28])[CH2:16][CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[N:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][CH:6]=1)#[N:5]
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1nc(C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
2-Chloro-6-(trifluoromethyl)nicotinonitrile (207 mg) and 1,1-dimethylethyl (3-hydroxypentyl)methylcarbamate (217 mg) were dissolved in dimethylformamide (10 ml) under nitrogen at room temperature. To the resulting solution was added sodium hydride (60% in oil) (80 mg). The solution was then allowed to stir at room temperature under nitrogen for 24 h. The mixture was then poured into water and extracted with diethyl ether three times. The combined organic fractions were washed with brine and then dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography (silica, 25% ethyl acetate/isohexane as eluent) to give 175 mg (45%) of the subtitle compound as an oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH3:4].CN1CCOCC1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH3:4])(=[O:28])=[O:27]
Reactant: C[C@@H](CO)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H](COS(C)(=O)=O)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
To a solution of (S)—N-(1-hydroxypropan-2-yl)-2-nitrobenzenesulfonamide (6.20 kg, 23.8 mol) in methylene chloride (32 L) was added 4-methylmorpholine (3.13 kg, 30.9 mol) at an internal temperature of 10° C. or below. The resulting reaction mixture was cooled to 0° C., and added a solution of methanesulfonyl chloride (3.27 kg, 28.5 mol) in methylene chloride (2 L) at an internal temperature of −5° C. to 0° C. Subsequently, the reaction mixture was stirred at room temperature for 20 hours. After confirming the disappearance of the starting materials by TLC, purified water was added to the reaction mixture. The resulting organic layer was partitioned, washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure to give the target product as a yellow solid (7.30 kg, yield 90.70).
Reaction SMILES: [O:1]=[O+][O-].[C:4]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([F:16])[C@@H:13]([O:17][CH2:18][CH:19]=C)[C@H:12]1[C:21](=[O:32])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[F:31])=[O:10])([CH3:7])([CH3:6])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:4]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([F:16])[C@@H:13]([O:17][CH2:18][CH:19]=[O:1])[C@H:12]1[C:21](=[O:32])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[F:31])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: C=CCO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](OCC=O)[C@H]1C(=O)NCc1cccc(Cl)c1F

Procedure:
Ozone was bubbled through a solution of (2S,3S,4S)-3-allyloxy-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (59 mg, 0.137 mmol) in CH2Cl2 (20 mL) at −78° C. When the solution turned blue, ozone addition was stopped and nitrogen was passed through the solution until the blue color was discharged. Triphenylphosphine (35.9 mg, 0.137 mmol) was added to the ozonide solution at −78° C. and the reaction mixture was allowed to slowly reach RT. The reaction mixture was concentrated and the material thus obtained used without further purification in the next step. MS (UPLC): 433.4/435.4 [M+H]+, 477.4/579.5 [M+HCOO]−.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)O[C:29](=[O:30])C=2C=1.C=O.[OH-].[Na+]>CC(C)=O.O>[OH:1][C@H:2]1[C@H:7]([NH:8][C:9]2[CH2:13][CH2:12][C:11](=[O:14])[C:10]=2[CH2:29][OH:30])[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=CC(=O)CC2)[C@@H]1O
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=C(CO)C(=O)CC2)[C@@H]1O
Reaction time: 5 h

Procedure:
2,98 of the title compound of example 5 are dissolved in 150 ml of acetone and a drop of a phenolphtalein-solution and the solution is mixed with 2,5 ml of a 37% formaldehyde solution three times every hour. The pH-value of the solution is kept between 8 and 9 by controlled addition of 0,1 aq. sodium hydroxide-solution. After stirring during 5 hours the reaction solution is diluted with water and the organic components are extracted with dichloromethane. Usual work up yields white crystalls of the title compound having a m.p. of 218°-220° C. (from dichloromethane/ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][Cl:15])[C:3]=1[N+:16]([O-:18])=[O:17].CI.[C:21](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:21])=[O:7])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][Cl:15])[C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1NCCCCl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1NCCCCl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
A mixture of 4-chloro-2-[(3-chloropropyl)amino]-3-nitrobenzoic acid (150 mg, 0.512 mmol), methyl iodide (0.0319 mL, 0.512 mmol) and potassium carbonate (70.8 mg, 0.512 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at room temperature for 12 h. After addition of ethyl acetate, the resultant mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on NH silica gel eluting with a 5% ethyl acetate/n-hexane mixture to afford a yellow oil (141 mg, 0.459 mmol, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20]O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:20])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: CO
Reactant: O=C(O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1

Procedure:
A solution of 2,2',4'-trifluoro-4-biphenylyl acetic acid (10 g.) in anhydrous methanol (100 ml.) and concentrated sulphuric acid (5 ml.) was refluxed overnight. Excess solvent was distilled and the residue was poured onto ice-water and extracted with ether. The extracts were washed with dilute aqueous sodium bicarbonate and then dried, evaporated and distilled to give a yellow oil, b.p. 142°-146°/0.5 mm., which solidified on cooling. This was crystallized from 62-68 petroleum ether to give methyl 2,2',4'-trifluoro-4-biphenylylacetate, m.p. 74°-77° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][OH:9])[CH2:4][CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[CH3:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30]>>[C:29]([O:31][C:5]1([N:8]=[O:9])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27]
Reactant: CC(C)(C)C(=O)O
Reactant: CN1CCC(=NO)CC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CN1CCC(N=O)(OC(=O)C(C)(C)C)CC1

Procedure:
1-Methyl-4-nitrosopiperidin-4-yl pivalate was prepared from 1-methyl piperidin-4-one oxime, lead tetraacetate and trimethylacetic acid using conditions of General Method 3. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.86-3.00 (2H, m), 2.37 (3H, s), 2.21-2.35 (4H, m), 1.82-1.94 (2H, m), 1.32 (9H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:20]([OH:24])(=[O:23])[CH:21]=[CH2:22].C=CC1C=CN=CC=1.Cl>>[C:20]([O:24][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)(=[O:23])[CH:21]=[CH2:22]
Reactant: C=CC(=O)O
Reactant: C1=COCC1
Agent: C=Cc1ccncc1
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)OC1CCCO1
Temperature: 25 °C

Procedure:
To a 100 mL 3-neck round bottom flask equipped with a stir bar, condenser, and addition funnel was added 39 mL of dihydrofuran (FW 70.09, d=0.927), and 0.18 g of phenothiazine. Acrylic acid (19 mL, FW 72.06, d=1.05) was added dropwise slowly with stirring. A mild exotherm (55° C.) occurred. After cooling to room temperature, 0.415 g of poly(4-vinylpyridine hydrochloride) was added and the reaction was stirred overnight. The acid catalyst was then filtered off and 0.2 g each of calcium hydride and potassium carbonate was added to the filtrate. After removal of excess dihydrofuran on a rotovap, 10 mg of DPPH (2,2-diphenyl-1-picrylhydrazyl hydrate) was added and the slurry was vacuum distilled at 200 mtorr at 26° C. to give 26.0 g of 2-tetrahydrofuranyl acrylate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1)=[O:3])[CH3:19]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-carboxyphenylboronic acid (15 g, 0.09 mol), 99% ethanol (150 mL) and concentrated sulphuric acid (0.5 mL) was heated to reflux for two days. The volume was reduced to approximately 20 mL. The residue was triturated with petroleum ether to give 13.4 g of the desired material.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]([OH:8])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (0.5 g, 1.84 mmole) in THF (20 mL) at 0° C., is added a solution of benzyl magnesium chloride in tetrahedronfuran (2.0M, 1.0 mL, 2 mmole) dropwise. The reaction is stirred for 5 minutes and then warmed up to room temperature for 2 hrs. The reaction is quenched with NH4Cl(aq), partitioned between ethyl ether and water. Extracted the aqueous layer with ethyl ether. The combined organic is washed with brine, dried over Na2SO4, filtered and concentrated. Column chromatography on silica gel gave the title compound.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:17]([O:18]C(=O)C(C)(C)C)[C@H:16]([F:25])[C@@H:15]([CH2:26][O:27]C(=O)C(C)(C)C)[O:14][C@H:5]1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:2]=[N-:3].C[O-].[Na+]>CO>[N:1]([C@H:4]1[C@@H:17]([OH:18])[C@H:16]([F:25])[C@@H:15]([CH2:26][OH:27])[O:14][C@H:5]1[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@@H](N=[N+]=[N-])[C@@H](OC(=O)C(C)(C)C)[C@@H]1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1[C@H](OCc2ccccc2)O[C@H](CO)[C@@H](F)[C@@H]1O
Temperature: 40 °C
Reaction time: 4.5 h

Procedure:
Compound (22) (180 mg, 0.387 mmol) was dissolved in methanol (8 ml), sodium methoxide (922 mg, 9.67 mmols) was added to the solution, and the mixture was reacted with stirring at 40° C. TLC revealed 4.5 hours later that the reaction mixture collected into a spot, and the mixture was neutralized with a cation-exchange resin IR-120(+), followed by filtration and concentration. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), giving Compound (23) (in an amount of 105.3 mg, 91.6% in yield).
Reaction SMILES: OC1CCCCC1=O.[CH:9](S)([SH:11])[CH3:10].[C:13]1(C)[CH:18]=[CH:17][C:16]([S:19](O)(=O)=O)=[CH:15][CH:14]=1>>[S:19]1[C:16]2[CH2:17][CH2:18][CH2:13][CH2:14][C:15]=2[S:11][CH2:9][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(S)S
Agent: O=C1CCCCC1O
Product: C1CCC2=C(C1)SCCS2
Yield: 75.1 %

Procedure:
The method of Example 4 was used, using 2-hydroxycyclohexanone (10 g), ethane dithiol (8.3 g) and p-toluenesulphonic acid to give 5,6,7,8-tetrahydro-1,4-benzodithian as a brownish oil (not distilled), yield 75.1%. NMR (CDCl3) 3.14 δ, 1.5-2.3 δ (two overlapping complex multiplets).