Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]Cl)([O-:15])=[O:14]>CN(C)C=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]([CH3:12])[S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CNC(=O)Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1SCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN(Sc1ccccc1[N+](=O)[O-])C(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
N-4-chlorophenyl-N'-methyl urea (4.1 g) was dissolved in a mixture of dimethylformamide (20 ml) and pyridine (5 ml) and then 2-nitrophenylthiochloride (4.17 g) was added to and dissolved in the solution. After allowing the solution to stand overnight, it was poured into 200 ml of ice-water. The initial product was an oily product which solidified after a while. The solid product was separated by filtration, washed with water and dried. Recrystallization from a mixture of ethyl acetate and n-hexane gave 4.3 g of the object compound. (m.p.: 157°-158° C.)
Reaction SMILES: O/C=C1/C(=O)CCC(C)(C)C/1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[CH:27]=O)=[CH:15][CH:14]=1.[N:29]1([C:35]2[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH2:24][CH2:23][C:22]([CH3:25])([CH3:26])[CH2:21][C:20]=2[CH2:27][N:32]2[CH2:31][CH2:30][N:29]([C:35]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:44][CH:45]=3)[CH2:34][CH2:33]2)=[CH:17][CH:18]=1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CC1(C)CCC(=O)/C(=C/O)C1
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(C)(C)C3)CC2)cc1

Procedure:
Scheme 1 shows three synthetic routes used to prepare the aldehyde intermediate (2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde) (4) from (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone (1A). The aldehyde intermediate (4) can then be reacted with ethyl 4-(piperazin-1-yl)benzoate (4A) to provide ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate, which is hydrolyzed to provide 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid (6).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[C:12]1([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.CC(C)=O>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:1][C:22]([NH:21][S:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:20])=[O:19])=[O:23])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: Cc1cc(N(C)C)nc(N)n1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cc(N(C)C)nc(NC(=O)NS(=O)(=O)c2ccccc2)n1
Reaction time: 4 h

Procedure:
To a suspension of 15.2 g of 2-amino-4-dimethylamino-6-methylpyrimidine in 400 ml of methylene chloride at ambient temperature was added slowly 18.3 g of benzenesulfonylisocyanate. After stirring for four hours the mixture was stripped in-vacuo and the white semisolid residue triturated with ethyl ether and isolated by filtration. The solid was then slurried in hot acetone, cooled and refiltered to yield the solid named above which decomposed at 180°-182°.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[O:16])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH:40]3[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]3)[CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:35]3[CH:36]=[N:37][N:38]([CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[CH:39]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[O:16])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)Oc2ccc(F)cc2F)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(C4CCNCC4)c3)cc2N(C(=O)Oc2ccc(F)cc2F)C[C@@H]1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A 1.5 mL reaction vial was charged with 2,4-difluorophenyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.02 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylate (0.2 M solution in 1,4-dioxane, 225 μL, 0.03 mmol), and 1,4-dioxane (100 μL). Potassium carbonate (1 M solution in water, 60 μL, 0.06 mmol) was then added, and the reaction mixture was purged with nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.02 M solution in 1,2-dichloroethane, 150 μL, 0.003 mmol) was then added, the reaction was purged with nitrogen and heated to 80° C. on a heater shaker overnight. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The aqueous layer was separated and extracted with ethyl acetate (1 mL) and the combined organic layers were concentrated under a stream of nitrogen. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated. The residue was taken up in 1,2-dichloroethane (200 μL) and trifluoroacetic acid (100 μL was added. The reactions stirred at room temperature for 2 h. The reaction was concentrated, and diluted with ethyl acetate (0.5 mL) and saturated aqueous sodium bicarbonate solution (0.5 mL). The aqueous layer was separated and extracted with ethyl acetate (1 mL), and the combined organic layers were concentrated under a stream of nitrogen and vacuum. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford 2,4-difluorophenyl (S)-4-acetyl-3-methyl-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 496 [M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:37]1([O:43]C(Cl)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>ClCCl.C(#N)C>[F:29][C:26]([F:27])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]4[NH:30][C:37](=[O:43])[O:1][N:2]=4)=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH2:13]3)=[CH:21][CH:22]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N=C(NO)c1ccc(N2CCCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2ccc(N3CCCc4cc(-c5ccc(C(F)(F)F)cc5)ccc43)cc2)no1
Temperature: 25 °C

Procedure:
355 mg crude N-Hydroxy-4-[6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-benzamidine were dissolved in 4 ml dichloromethane. 73 μl pyridine and 113 μl phenylchloroformate were added and the mixture stirred at room temperature for ten minutes. The mixture was diluted by the addition of 4 ml acetonitrile and 558 μl 1,8-diazabicyclo[5.4.0]undec-7-ene were added. The mixture was stirred at room temperature for 15 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 209 mg 3-{4-[6-(4-Trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:10]([C@@H:11]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[C:7]([OH:16])[CH:6]=1.[CH3:17]O>>[CH3:17][O:13][C:12](=[O:14])[CH:11]([NH2:15])[C:10]1[CH:9]=[CH:8][C:7]([OH:16])=[CH:6][CH:5]=1
Reactant: CO
Reactant: N[C@@H](C(=O)O)c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 50 mL of methanol cooled to 0° C. was dropwise added 3.75 mL of thionyl chloride followed by 5.0 g (0.030 mmol) of D-4-hydroxyphenylglycine. The reaction was heated to reflux for 5 h then stirred overnight at room temperature. The resulting mixture was concentrated in vacuo and the residue was diluted with ether. The resulting solid was collected by filtration and dried in vacuo to provide 5.9 g of amino-(4-hydroxy-phenyl)-acetic acid methyl ester as a white solid. Electrospray Mass Spec 182.2 (M+H)+
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:11]1)=[O:5].[CH3:35][O-:36].[Na+]>CO>[CH3:35][O:36][C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:11][N:12]([CH:14]2[CH2:15][CH2:16][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)[CH2:13]1)=[O:5]
Reactant: C[O-]
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1F)NC1CN(C2CCC(c3ccccc3)CC2)C1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
2-Fluoro-N-{[1-(4-phenyl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide (as prepared in Example 66, 50 mg, 0.11 mmol) was treated with NaOMe (0.5 M in MeOH, 600 μL, 0.30 mmol) in MeOH (1 mL) at room temperature overnight. The solvent was removed and the residue was purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][C@@:4]1([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[C:6]#N.C([OH:20])C.[OH-].[Na+].Cl>ClCCl>[C:8]1([C@@:4]23[CH2:5][C@@H:3]2[CH2:2][O:1][C:6]3=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: N#C[C@]1(c2cccc3ccccc23)CC1CO
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1OC[C@H]2C[C@@]12c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
(1R)-2-Hydroxymethyl-1(1-naphthyl)-cyclopropanecarbonitrile (1a 10 g, 44.6 mmol), ethanol (20 mL) and 25N sodium hydroxide solution (10 mL) were heated under reflux for 18 hours. The reaction is monitored by TLC (dichloromethane (100%)). The reaction mixture was cooled to room temperature and ice cold water (12 mL) was added to the reaction mixture followed by concentrated hydrochloric acid drop wise to adjust the pH of the reaction mass to 1-2 and stirred for overnight. The aqueous layer was extracted with dichloromethane (200 mL). The organic layer was washed with 3% sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 5 g (50%) of product. 1H NMR δ(300 MHz,CDCl3): 0.78-0.81 (1H,m), 1.45-1.48 (1H,m,), 1.68-1.72 (1H,m,) 2.45-2.51 (1H,m), 4.37-4.40 (1H,d, J=9 Hz), 4.65-4.69 (1H,dd, J=9,3 Hz), 7.34-7.52 (4H,m), 7.76-7.91 (3H,m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+].C(OCC)(=O)C>Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1nc(Cl)ccc1N
Temperature: 25 °C

Procedure:
6-Chloro-N-methyl-3-nitropyridin-2-amine (28-1, 10.5 g, 56 mmol) and tin(II) chloride dihydrate (50.5 g, 224 mmol) were suspended in concentrated HCl (80 mL) and refluxed overnight. The solution was cooled to room temperature and then added very slowly to a NaOH/ethyl acetate solution at −78° C., until the solution had a slightly basic pH. The suspension was washed with sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated to produce 6-chloro-N2-methylpyridine-2,3-diamine (28-2) as a black solid. HRMS (M+H)+: observed=158.0471, calculated=158.0480.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[CH:5]=[C:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][C:32]2[C:35]([C:38](O)=[O:39])=[N:36][NH:37][C:31]=2[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:21][C:3]([F:2])([F:20])[C:4]1[CH:5]=[C:6]([CH:14]2[CH2:19][CH2:18][N:17]([C:38]([C:35]3[C:32]4[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:30][C:31]=4[NH:37][N:36]=3)=[O:39])[CH2:16][CH2:15]2)[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)O)n[nH]c2C1
Reactant: FC(F)(F)c1cc(C2CCNCC2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)n[nH]c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(3,5-bis(trifluoromethyl)phenyl)piperidine hydrochloride (20, 100 mg, 0.31 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (96 mg, 0.36 mmol), and diisopropylethylamine (0.16 mL, 0.90 mmol) in DMF (5.6 mL) was added EDCI (69 mg, 0.36 mmol) and HOBt (49 mg, 0.36 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with a saturated brine solution (4×30 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% CH3OH in CH2Cl2 with 0.1% NH4OH in CH2Cl2) to provide tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (51) as a white film (76 mg, 45%): 1H NMR (300 MHz, DMSO-d6) δ 13.13-12.77 (m, 1H), 8.02-7.98 (m, 2H), 7.96-7.91 (m, 1H), 4.91-4.59 (m, 2H), 4.53-4.41 (m, 2H), 3.60-3.46 (m, 2H), 3.21-3.03 (m, 2H), 2.85-2.69 (m, 1H), 2.63-2.54 (m, 2H, overlaps with solvent), 1.97-1.78 (m, 2H), 1.77-1.58 (m, 2H), 1.42 (s, 9H); ESI MS m/z 547 [M+H]+.
Reaction SMILES: O[Li].O.[CH:4](=[C:6]1[CH2:10][CH:9]([C:11]([O:13]CC)=[O:12])[CH:8]([C:16]([O:18]CC)=[O:17])[CH2:7]1)[CH3:5]>O.C1COCC1>[CH:4](=[C:6]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH:8]([C:16]([OH:18])=[O:17])[CH2:7]1)[CH3:5]
Reactant: CC=C1CC(C(=O)OCC)C(C(=O)OCC)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC=C1CC(C(=O)O)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of LiOH.H2O (5.1 g, 120 mmol) in 130 ml of water is added dropwise at 0° C. to a solution of the compound from Example VIII (13.1 g, 54.5 mmol) in 70 ml of THF. The solution is stirred at room temperature for 20 h, the THF is stripped off in vacuo and the residue is extracted once with 40 ml of ether. The aqueous phase is brought to pH 2 with 10% strength hydrochloric acid and extracted three times with 200 ml of ethyl acetate each time. The combined ethyl acetate phases are dried over Na2SO4 and the solvent is stripped off in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[N+:14]([O-])=O.[H][H]>CO.[Pd]>[NH2:14][C:3]1[CH:4]=[C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1ccc(NC(=O)C2CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)C2CC2)cc1N
Yield: 94.8 %

Procedure:
N-(4-Methyl-3-nitrophenyl)cyclopropanecarboxamide (409 mg) was hydrogenated over 10% Pd/C (50% wet, 80 mg) at atmospheric pressure of hydrogen in MeOH (20 mL) for 5 hr. The catalyst was removed by filtration through Celite® pad and the filtrate was evaporated in vacuo to give N-(3-amino-4-methylphenyl)cyclopropanecarboxamide (335 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.Br[CH2:22][CH2:23][OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[N:16]([CH2:22][CH2:23][OH:24])[S:17]([CH3:20])(=[O:19])=[O:18])[C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3]1
Reactant: OCCBr
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(OCC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(N(CCO)S(C)(=O)=O)c(OCC2CC2)c1
Temperature: 110 °C
Yield: 66.6 %

Procedure:
A mixture of methyl 3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoate (1 g, 3.34 mmol), 2-bromoethanol (0.835 g, 6.68 mmol), and K2CO3 (0.923 g, 6.68 mmol) in CH3CN (12 ml) was heated at 110° C. under microwave irradiation for 12 hours. After cooling the solvent was evaporated and the residue was dissolved in EtOAc and filtered; the solvent was evaporated and the residue was purified by flash chromatography (eluent: EtOAc/petroleum ether 1/1) to give methyl 3-(cyclopropylmethoxy)-4-(N-(2-hydroxyethyl)methylsulfonamido)benzoate as a light brown oil (0.764 g, 2.225 mmol, 66.6% yield, /ESI+ 365.9 [MNa]+).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]([C:13](OCC)=[O:14])[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:13][OH:14])[CH2:8][OH:9])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Oc1ccc(F)cc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC(CO)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
Dissolve diethyl 2-(4-fluorophenoxy)propanedioate (360 mg, 1.33 mmol) in THF (10 mL); slowly add lithium aluminum hydride (1.0 M in THF; 3.6 mL, 3.6 mmol); and stir at ambient temperature for 30 minutes. Quench reaction via the addition of H2O (1 mL) and extract with EtOAc. Dry the organic phase over Na2SO4. Filter and concentrate the filtrate under reduced pressure. Purify the resulting material via silica gel flash column chromatography (12 g), using a gradient of 10%-50% of EtOAc in petroleum ether. Concentrate the desired fractions under reduced pressure to give the title compound as a colorless oil (195 mg, 78.6%). 1H NMR (300 MHz, CDCl3) δ 7.0 (m, 4H), 4.3 (m, 1H), 3.9 (m, 4H), 2.4 (bs, 2H).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:36]([O:38][CH:39]([O:46][CH2:47][CH3:48])[C:40]#[C:41][C:42]([O:44][CH3:45])=[O:43])[CH3:37]>C1COCC1.O>[CH2:47]([O:46][CH:39]([O:38][CH2:36][CH3:37])/[C:40](/[O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1)=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])[CH3:48]
Reactant: CCOC(C#CC(=O)OC)OCC
Reactant: CCCCCCCCc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(O/C(=C\C(=O)OC)C(OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a solution of 2.06 g (10 mmol) of 4-octylphenol in 50 mL of THF was added 0.85 g (15 mmol) of powdered KOH and 3.98 g (15 mmol) of 18-crown-6. The solution was heated to 50° C. for 15 minutes, whereupon 2.8 g (15 mmol) of methyl 4,4-diethoxy-2-butynoate was added. The mixture was stirred for 30 minutes, then allowed to cool to room temperature. The solution was then poured into water, and extracted 3 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude oil was subjected to column chromatography on SiO2. Elution with 20% ethyl acetate-hexane yielded 2.1 g (54%) of an oil, used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:7][C:2]=1[CH3:1])(=[O:10])[CH3:11]
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(C)=O)c(C)c1
Reaction time: 48 h

Procedure:
A mixture of 4-hydroxy-2-methylacetophenone (4.8 g), anhydrous potassium carbonate (5.3 g) and methyl bromoacetate (3.55 ml) in anhydrous acetone (100 ml) was stirred for 2 days. The mixture, after filtration and evaporation of the solvent, gave methyl 4-acetyl-3-methylphenoxyacetate, 6.6 g, as a crystalline solid: m.p. 49°-50° C.; NMR (d6DMSO) δ 7.84 (1H, d), 6.83 (2H, m), 4.87 (2H, s), 3.71 (3H, s), 2.50 (3H, s), 2.45 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[C:15]([O:17][CH3:18])=[O:16])([O-])=O.C(O)C.C(OCC)(=O)C>[Pt].C(Cl)Cl>[NH2:1][C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1C(=O)OC
Agent: [Pt]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c(N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A mixture of dimethyl 3-nitro-4-hydroxyphthalate (28.9 g, 0.113 mol), ethanol and 5% platinum on carbon (2.80 g, 50% aqueous) is shaken on a Parr hydrogenator under hydrogen for 1.75 hours at room temperature. The reaction mixture is filtered through diatomaceous earth and the filtrate is concentrated in vacuo to give a pale green solid residue. Chromatography (silica gel, ethyl acetate:methylene chloride eluent) affords the title product as a pale yellow solid, 3.69 g, mp 112°-113° C., identified by NMR and IR spectral analyses.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[C:11]([O:15][C:16]([NH:18][C@@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:11]([O:15][C:16]([NH:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=2)[CH2:20]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)c2cccc(O)c2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Hydroxybenzoic acid (500 mg, 3.62 mmol), (R)-3-(tert-butoxycarbonylamino)pyrrolidine (708 mg, 3.80 mmol), EDC (729 mg, 3.80 mmol), 1-hydroxybenzotriazole hydrate (514 mg, 3.80 mmol), and N,N-diisopropylethylamine (631 mL, 3.62 mmol) were combined in DMF (20 mL) and the mixture was stirred at ambient temperature for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (25 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted further with CH2Cl2 (2×25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with CH2Cl2—3% MeOH—0.3% NH4OH to yield the titled product as a white foam.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([C:6]1([CH2:15][CH:16]=C)[C:13](=[O:14])[N-:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH3:5].[Na+].[O:19]=[O+][O-]>CO>[CH3:5][CH:4]([C:6]1([CH2:15][CH:16]=[O:19])[C:7](=[O:8])[NH:9][C:10](=[O:11])[NH:12][C:13]1=[O:14])[CH2:3][CH2:2][CH3:1]
Reactant: O=[O+][O-]
Reactant: C=CCC1(C(C)CCC)C(=O)[N-]C(=O)NC1=O
Agent: [Na+]
Solvent: CO
Product: CCCC(C)C1(CC=O)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium secobarbital (5.30 g, 22.2 mmol) in methanol was passed a stream of ozone until the solution turned a blue color. After excess ozone was removed by passing nitrogen through the reaction dimethyl sulfide (14 mL) was added. The reaction was stirred at room temperature overnight before solvents were removed on a rotovap. The aldehyde was then purified on silica prep plates using ethyl acetate:hexanes (1:1).