Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-:8].[NH4+:9].[OH-].[Na+]>O>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:8])=[O:5].[NH4+:9].[NH4+:9]
Reactant: O=C1C=CC(=O)O1
Reactant: [OH-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 9.8 g (0.1 mole) maleic anhydride was dissolved in 20 ml water at 50°-60° C. and stirred for 30 minutes while allowing the mixture to cool to 25° C. To this colorless solution at 25° C. was added 26 g of 30% aqueous solution of ammonium hydroxide (0.22 mol NH3) to give a colorless solution. This solution was boiled to dryness over a period of 30 minutes at approximately 100°-120° C. and 10-20 Torr, to give a white crystalline solid. The solid was tumbled under nitrogen at 100 Torr, at 240°-250° C. for 1.5 hours to give a water insoluble, red-brown brittle glasslike solid weighing 9.4 g. This solid was dissolved in 40 g of an aqueous solution containing 3.8 g of sodium hydroxide to form a clear red-brown solution, pH 7.0, containing 25% solids.
Reaction SMILES: [H-].[Na+].[S:3]1[CH2:8][CH2:7][CH2:6][S:5][CH:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].I[CH3:17].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:17][C:4]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[S:5][CH2:6][CH2:7][CH2:8][S:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)C1SCCCS1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1(C)SCCCS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (2.08 g, 52 mmol) was suspended in anhydrous toluene (75 mL). In a different flask, tert-butyl 1,3-dithiane-2-carboxylate (10 g, 45.4 mmol) and iodomethane (3.0 mL, 47.7 mmol) were dissolved in N,N-dimethylformamide (35 mL), and the solution was added dropwise to the first flask at room temperature. After the dropwise addition, the mixture was stirred at room temperature for further 2 hours. The progress of the reaction was then stopped by adding a saturated aqueous solution of ammonium chloride. The mixture was extracted with a mixture (1:1 v/v, 200 mL) of n-hexane and ethyl acetate. The separated organic layer was washed twice with water, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain quantitatively the target compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[C:8](=[O:14])[NH:9][C:10]1=[O:13])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccsc1-c1c[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccsc1-c1cn(CCCO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a suspension of 5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep26, 110 mg, 0.52 mmol) in dry DMF (10 mL), 60% NaH (31 mg, 0.78 mmol) was added. The mixture was then heated at 100° C. for 1 hour. (3-bromo-propoxy)-tert-butyl-dimethyl-silane (180 μl, 0.7 mmol) was then added at room temperature and the reaction was stirred overnight. The solvent was evaporated and the crude was partitioned between NaHCO3 and Et2O. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (2-8) to give the title compound as a white solid (73 mg, 37% yield).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]([C:20]2[CH:21]=[N:22][N:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH:24]=2)=[O:19])[CH:7]=[N:8][C:9]=1[C:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH:11]=1.[OH-].[Na+].[CH3:37]O>>[OH:16][CH:13]1[CH2:14][CH2:15][C:10]([C:9]2[N:8]=[CH:7][C:6]([NH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=4)[C:24]=3[CH3:37])=[O:19])=[CH:5][C:4]=2[CH3:3])=[CH:11][CH2:12]1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2)cnc1C1=CCC(=O)CC1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2C)cnc1C1=CCC(O)CC1
Reaction time: 0.5 h

Procedure:
Sodium borohydride (19 mg) was added to a solution of N-[5-methyl-6-(4-oxocyclohex-1-en-1-yl)pyridin-3-yl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (114 mg) in methanol (15 ml) under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. After the reaction, 1N aqueous solution of sodium hydroxide was added and the organic solvent was evaporated. The precipitated solid was washed with water, filtered and dried at 60° C. under current of air to give the titled compound (110 mg) as a white solid.
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3]C1.P(Cl)(Cl)(Cl)(Cl)Cl.O.[CH:15]([Cl:18])(Cl)[Cl:16]>>[Cl:16][C:15]1([Cl:18])[CH2:3][CH2:4][CH2:5][NH:6][C:1]1=[O:7]
Reactant: O=C1CCCCN1
Reactant: ClC(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=C1NCCCC1(Cl)Cl
Yield: 85 %

Procedure:
Part A. δ-Valerolactam (22.22 g, 222.89 mmol) was stirred in CHCl3 (500 mL) at 0° C. PCl5 (140.0 g, 68.29 mmol) was added portionwise. The resulting slurry was stirred at reflux for 3 h until the solution became clear. The mixture was cooled in an ice bath and H2O was added carefully until the PCl5 was quenched completely. The two layers were separated. The organic layer was washed with H2O (3×) and brine (2×), dried over MgSO4, filtered, and concentrated to dryness to give 3,3-dichloro-2-piperidinone (31.63 g, yield: 85%). This solid (16.50 g, 98.80 mmol) was dissolved in DMF (20 mL), and Li2CO3 (21.93 g, 296.40 mmol, 3.0 eq) was added. The mixture was stirred at 120° C. for 1 day. The solvent was further concentrated, and 1N HCl was added to acidify the mixture. It was then extracted with CHCl3 (6×). The organic layers were washed with H2O, brine, dried over MgSO4, and concentrated to dryness to give almost pure 3-chloro-5,6-dihydro-2(1H)-pyridinone (11.13 g, 87%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[O-]Cl.[Na+].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH:19]=[N:20][OH:21])=[CH:17][C:16]=1[CH3:24]>O.C1COCC1.CCOC(C)=O>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[CH:3]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[O:21][N:20]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: C#CC(=O)OCC
Reactant: COCOc1ccc(C=NO)cc1C
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(OCOC)c(C)c2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Ethyl propiolate (0.60 mL, 5.88 mmol) and 6% W/V NaOCl solution in water (10.8 mL) were added to a solution of 4-(methoxymethoxy)-3-methylbenzaldehyde oxime (570 mg, 2.92 mmol) in THF (12 mL). The reaction mixture was stirred at 25° C. for 2 h then was diluted with EtOAc. The resulting solution was successively washed with aqueous 10% Na2S2O3 solution, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure to yield the title compound (745 mg, 88% yield) as a yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]([C:6]2[N:7]=[C:8]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: NCc1ccc(Cl)cc1
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(Cl)cc2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4-chlorobenzylamine (71 mg, 0.5 mmol). The title product was obtained as an off-white solid (32.3 mg, 80% yield). 1HNMR (500 MHz, CDCl3) δ: 12.25 (1H, s), 7.80 (1H, br s), 7.52–7.46 (1H, m), 7.81 (2H, d, J=8.55 Hz), 7.25 (2H, d, J=8.24 Hz), 7.05 (2H, dd, J=8.54, 7.32 Hz), 4.55 (2H, d, J=6.10 Hz), 3.41 (3H, s). HRMS (ESI) calcd for C19H15ClF2N3O3 (M+H): 406.0770; found: 406.0775.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:31][C:32]([CH3:38])([CH2:36]O)[C:33]([OH:35])=[O:34].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][C:32]([CH3:38])([CH2:36][O:14][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:33]([OH:35])=[O:34]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)O
Reaction time: 2 h

Procedure:
N-Boc-L-valine (10.8 g, 50 mmole), 4-dimethylaminopyridine (610 mg, 5 mmole) and DCC (6.18 g, 30 mmole) were dissolved in methylene chloride (100 ml). After stirring for 2 hour the mixture was filtered. To the filtrate were added 2,2-dimethyl-3-hydroxy-propionic acid (3.54 g, 30 mmole) and pyridine (10 ml). After 18 hr, the reaction mixture was filtered, and the filtrate was poured into sodium hydrogen carbonate aqueous solution, the organic phase was then washed with citric acid aqueous solution and water succesively. After evaporation the product was isolated with silica gel column chromatography to yield 4.4 g. This compound can be activated and esterified directly to a drug or further modified as described below.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH3:18]O>[OH-].[Pd+2].[OH-]>[OH:17][C:11]1([C:14]([O:16][CH3:18])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C(O)C1(O)CCN(Cc2ccccc2)CC1
Reactant: CO
Agent: [Pd+2]
Agent: [OH-]
Product: COC(=O)C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 1-benzyl-4-hydroxypiperidine-4-carboxylic acid (1.2 g, 5.1 mmol) in MeOH (15 mL) was added palladium hydroxide and the resulting mixture was stirred at rt for 6 h under H2 atmosphere. After completion (by TLC), the mixture was passed through celite and the filtrate evaporated under reduced pressure. The crude (1 g) residue was carried forward to the next step without further purification. MS: 160.18 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:8]([NH:10][C@H:11]2[C@H:18]3[C@H:14]([CH2:15][N:16]([C:19](=[O:33])[C@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CCOCC>[NH2:25][C@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]([N:16]1[CH2:17][C@H:18]2[C@H:11]([NH:10][C:8](=[O:9])[CH:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:12][CH2:13][C@H:14]2[CH2:15]1)=[O:33]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H]2CC[C@@H](NC(=O)C(C3CCCCC3)C3CCCCC3)[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)C[C@@H](N)C(=O)N1C[C@@H]2CC[C@@H](NC(=O)C(C3CCCCC3)C3CCCCC3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl(R)-1-((3aS,4R,6aR)-4-(2,2-dicyclohexylacetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-ylcarbamate (185 mg, 0.339 mmol) from Step A, and 2 N HCl in ether (2.5 mL, 5.00 mmol) were combined in ether (1 mL). The reaction mixture was stirred at room temperature overnight. The solids were collected and dried to give N-((3aS,4R,6aR)-2-((R)-2-amino-4-methylpentanoyl)octahydrocyclopenta[c]pyrrol-4-yl)-2,2-dicyclohexylacetamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.34-8.24 (m, 1H), 4.92 (br s, 2H), 4.46-4.31 (m, 1H), 4.07 (d, J=9.2, 0.5H), 3.91-3.81 (m, 1.5H), 3.77 (dd, J=8.8, 12.1, 1H), 3.72-3.64 (m, 0.5H), 3.59-3.53 (m, 0.5H), 3.45 (dd, J=5.2, 12.2, 0.5H), 3.32 (d, J=6.5, 0.5H), 2.82-2.69 (m, 1H), 2.63 (dd, J=8.4, 14.5, 0.5H), 2.54 (dd, J=8.0, 16.4, 0.5H), 2.21-2.06 (m, 2H), 2.02 (q, J=7.6, 1H), 1.99-1.55 (m, 15H), 1.50-1.38 (m, 3H), 1.37-1.12 (m, 9H), 1.09 (d, J=6.5, 3H), 1.01 (d, J=6.6, 2H), 0.96 (d, J=6.4, 1H), 0.91 (d, J=6.6, 1H). MS (ESI+) m/z 466 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([OH:31])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([O:31][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: CCCCO
Product: CCCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and butan-1-ol (74 μl; 0.773 mmol), example 44 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][PH:8](=[O:13])[O:9]C(C)C)[CH2:3]1.CCOC(/[N:19]=N/C(OCC)=O)=O.N=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C1COCC1.O>[NH2:19][C@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][PH:8](=[O:13])[OH:9])[CH2:3]1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CC(C)O[PH](=O)C[C@H]1CC[C@@H](O)C1
Agent: [N-]=[N+]=N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](C[PH](=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.4 %

Procedure:
To a stirred solution of (±)-cis-isopropyl (3-hydroxycyclopentanyl)methylphosphinate (6) (1.6 g, 7.8 mmol), DEAD (2.5 cm3, 17.05 mmol) and HN3 (8.2 cm3 of a 1.9 M solution in benzene) in anhydrous THF (70 cm3) under an atmosphere of N2 at 0° C. was added triphenylphosphine (8.15 g, 31.2 mmol) in small portions over a period of 1 h. The reaction mixture was allowed to warm to room temperature and stirring continued for 12 h. The reaction mixture was then heated to 50° C. for 3 h after which time water (2 cm3) was added and heating continued for a further 2 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between aqueous HCl (1 M, 30 cm3) and DCM (30 cm3). The organic layer was separated and further extracted with aqueous HCl (2×30 cm3). The combined aqueous fractions were washed with DCM (2×30 cm3) and concentrated in vacuo. The crude amino ester hydrochloride salt was hydrolysed by refluxing in aqueous HCl (6M) for 30 h after which time the reaction mixture was cooled to room temperature and the aqueous HCl removed under reduced pressure. The crude product was purified by ion exchange chromatography (Dowex 50, H+), eluting first with water until the eluate was colourless and pH 7. On further elution with aqueous pyridine (1M), ninhydrin positive fractions were collected and the solvent removed in vacuo giving an off white foam. Recrystallisation from ethanol/acetone followed by drying gave the desired product (7) (0.68 g, 43%): 1H NMR (300 MHz, D2O) δ 1.17 (3H, d, J=12.3 Hz, PCH3), 1.52-2.06 (7H, m, C(1)—H, C(2)—H, C(2)-—H′, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′), 3.73 (1H, m, C(3)—H), 13C NMR (75.46 MHz, D2O) δ 13.16 (PCH3, d, JPC=91.6 Hz), 25.10 (C(5)), 31.31 (C(2)) 30.50 (C(4), d, 3JPC=11.4 Hz), 37.34 (C(1), d, JPC=98.2 Hz), 52.40 (C(3), d, 3JPC=9.7 Hz), 31P NMR (121 MHz, D2O) δ 45.9, MS (CI, CH4) m/z 164 (38%) (MH+), 147 (30), 105 (100), (ESI) 164.0821 (MH+-C6H15NO2P requires 164.0840).
Reaction SMILES: [CH2:1]([C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1[CH2:12][C:13]([OH:15])=O)[CH:2]=[CH2:3].C(N=C=N[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])C)C.ON1C2N=CC=CC=2N=N1.N1CCCC1.CCN(CC)CC>CN(C=O)C.O>[CH2:1]([C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:10])([CH3:11])[C:5]=1[CH2:12][C:13]([N:24]1[CH2:23][CH2:22][CH2:21][CH2:26]1)=[O:15])[CH:2]=[CH2:3]
Reactant: C=CCC1=C(CC(=O)O)C(C)(C)CCC1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCC1=C(CC(=O)N2CCCC2)C(C)(C)CCC1
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of 2-(2-allyl-6,6-dimethyl-cyclohexen-1-yl)acetic acid (80 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (103 mg, 0.54 mmol) and 1-hydroxy-7-azabenzotriazole (73 mg, 0.54 mmol) in DMF (2 mL) was added the pyrrolidine (55 mg, 0.77 mmol) followed by Et3N (117 mg, 1.15 mmol). The solution was stirred under Ar for 18 h. Water was added (20 mL) and the solution was extracted with ether (3*20 mL). The combined organic layers were washed with water (3*30 mL) and brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (4-1 to 3/1) to give the title compound as colourless oil (82 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 5.75 (1H, ddt, J=16.7, 10.5, 6.1, 6.1 Hz), 4.93 (2H, m, J=19.1, 1.8 Hz), 4.93 (0H, dd, J=8.1, 1.8 Hz), 3.44 (4H, td, J=6.8, 4.0 Hz), 2.93 (2H, s), 2.64 (2H, d, J=5.9 Hz), 1.89-2.02 (4H, m), 1.82 (2H, quin, J=6.6 Hz), 1.58 (2H, d, J=11.7 Hz), 1.43-1.50 (2H, m) 0.90-0.99 (6H, s) ppm.
Reaction SMILES: C([CH:8]([NH:12][C:13]([NH:15][OH:16])=[O:14])[C:9]([O-:11])=[O:10])C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:16][NH:15][C:13](=[O:14])[NH:12][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(NO)NC(Cc1ccccc1)C(=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)CNC(=O)NO

Procedure:
5 g of palladium on activated charcoal are added to a solution of 22.4 g (0.1 mole) of benzyl-3-hydroxy-ureido-acetate in 300 ml of methanol. Hydrogen is introduced with shaking. After about 20 minutes the hydrogen uptake is finished. The catalyst is filtered off with suction and the filtrate is evaporated in a vacuum. The solid residue of crude 3-hydroxy-ureido-acetic acid is recrystallized from dioxane.
Reaction SMILES: [Cl:1][C:2]([Cl:25])([Cl:24])[CH2:3][O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.B.C1COCC1>C1COCC1>[Cl:25][C:2]([Cl:1])([Cl:24])[CH2:3][O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: B
Solvent: C1CCOC1
Product: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CSc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of 2-(4-Carboxy-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (80 mg, 0.191 mmol) in THF (1 mL) at 0° C. was added dropwise BH3-THF (0.4 mL, 1.0M solution in THF). The reaction was stirred at 0° C. for 0.5 h after the addition was complete, thereafter the cooling bath was removed and the reaction was stirred for 2 h at rt. The reaction was quenched at 0° C. by careful addition of THF/H2O, 80/20 followed by dropwise addition of 2M HCl. The mixture was stirred for an additional 10 minutes and thereafter diluted with water. THF was removed and the water phase was extracted with DCM and the combined organic phase was dried through a phase separator and concentrated to give the titled compound (70 mg, 91%) as an oil; 1H NMR (400 MHz, CDCl3): δ 4.53 (s, 2H), 4.64 (s, 2H), 4.94 (s, 2H), 7.19-7.30 (m, 5H), 7.30-7.36 (m, 1H), 7.37-7.44 (m, 1H), 8.06 (d, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:16][CH3:17])[CH:10]([CH3:15])[CH2:11][N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.I>>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:16][CH3:17])[CH:10]([CH3:15])[CH2:11][N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CCC(c1cccc(OC)c1)C(C)CN(C)C
Agent: I
Product: CCC(c1cccc(O)c1)C(C)CN(C)C
Temperature: 25 °C

Procedure:
The steps are: add 3-(3-methoxy-phenyl)-N,N,2-trimethyl pentylamine into a reaction flask, add hydroiodic acid, and perform heating and reflux for 5 hours; detect the reaction process by TLC; after that, cool the resultant to the room temperature, pour it to an alkaline solution to make the pH become 9, perform extraction by ethyl acetate and rinse by water; recycle the solvent by drying and decompression to obtain a light yellow liquid, 3-(3-hydroxy-phenyl)-N,N,2-trimethyl pentylamine; and separate the mother solution by a separator, form the salt by the acidification of hydrochloric acid to obtain tapentadol hydrochloride. HPLC: 99.56%, ee %>99.5%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:20]([F:29])[CH:19]=2)=[O:15])=[CH:10][CH:9]=[C:8]([C:30]([F:33])([F:32])[F:31])[N:7]=1)[CH2:2][CH2:3][CH3:4].CO>[Pd]>[CH2:1]([O:5][C:6]1[C:11]([CH2:12][CH2:13][C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[C:20]([F:29])[CH:19]=2)=[O:15])=[CH:10][CH:9]=[C:8]([C:30]([F:32])([F:33])[F:31])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(C(F)(F)F)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CCCCOc1nc(C(F)(F)F)ccc1CCC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.1 %

Procedure:
To a suspension of 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (19.3 mg, 0.039 mmol) in 5% Pd/C (6 mg) was added CH3OH (1.0 ml). The mixture was purged three times with hydrogen gas (50 psi) and shaken for 40 min at room temperature. The reaction mixture was filtered over celite pad and concentrated under reduced pressure. The crude residue was chromatographed to yield the 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-propionamide (19 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][CH:4]=1.C[Li].CN([CH:18]=[O:19])C>C1COCC1.C(NC(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(OC)cc1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCOc1ccc(OC)c(C=O)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a mixture of 2-methoxy-5-(methoxymethoxy)benzene (30 g, 0.178 mol, 1 eq.) and diisopropylamine (507 uL, 3.6 mmol, 0.02 eq.) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol, 1.8 eq.) at −40° C. Upon the completion of addition, the mixture was warmed to 0° C., continued to stir at 0° C. for 3 h, cooled back down to −40° C. and added DMF (24.7 mL, 0.32 mol, 1.8 eq.) slowly. The mixture was then stirred at −40° C. for 1 h, quenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL), warmed to rt, and added water (200 mL). The pH of the mixture was adjusted to pH 8-9 with solid K2CO3. The aqueous layer was extracted with EtOAc (300 mL) twice. The combined organic layers were dried over Na2SO4 and concentrated to give 2-methoxy-5-(methoxymethoxy)benzaldehyde (33.5 g, 95.7%) as a brown solid, which was used for next step without further purification. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H). LRMS (M+H+) m/z 198.1