Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].C1(C)C(C)=CC=CC=1.CO.O.[OH-].[Ca+2:17].[OH-]>>[B:1]([O-:4])([O-:3])[O-:2].[Ca+2:17].[B:1]([O-:4])([O-:3])[O-:2].[Ca+2:17].[Ca+2:17]
Reactant: OB(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CO
Product: [O-]B([O-])[O-]
Temperature: 60 °C

Procedure:
Two hundred (200) grams of a neutral calcium alkylsalicylate (calcium content; 2.0 wt. %) (A), which had been diluted to an extent of effective concentration of 50% by weight with a lubricating oil fraction, 26 g of calcium hydroxide (B), 43.4 g (2.0 moles per mole of calcium hydroxide) of orthoboric acid (C) and 400 g of xylene (F) were put in a 1000-ml four-necked flask fitted with a condenser and heated to 60° C. while agitating. To this mixture were added 120 g of methanol (D) and 20 g of water (E), and the resulting mixture was heated up to a refluxing temperature (66° C.) under agitation and reacted for 4 hours. The reaction mixture was further heated to 140° C. for 1.5 hours to distill out the methanol, water and xylene. Finally the reaction product was diluted twofold with hexane and filtered to remove any residual solids present, and the hexane was distilled out to obtain a desired calcium borate overbased alkylsalicylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][CH:10]2[CH2:23][O:24][S:26]([CH3:25])(=[O:28])=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(COS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To tert-butyl (6RS,7RS)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (896 mg) were added triethylamine (0.50 mL) and methanesulfonyl chloride (0.26 mL) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with 1 N hydrochloric acid, distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.07 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 5-acetyl-2-chlorobenzenesulphonamide (4.7 g) in glacial acetic acid (100 ml) was treated with bromine (3.2 g) in glacial acetic acid (20 ml), added dropwise with vigorous stirring at 50°. After an initial induction period of 5 minutes the colour of bromine was discharged. The addition took 30 minutes. The resulting solution was stirred for 15 minutes before removing the acetic acid under reduced pressure. The resulting white solid was dissolved in acetone (30 ml), diluted with benzene (250 ml) and the solution concentrated until the volume of solution was 150 ml. On cooling white crystals were deposited, 4.1 g, m.p. 168-172°.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].N1C=CC=CC=1.[Br:19][C:20]([CH3:25])([CH3:24])[C:21](Br)=[O:22]>O1CCCC1>[Br:19][C:20]([CH3:25])([CH3:24])[C:21]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])=[O:22]
Reactant: C=CCCCCCCCCCO
Reactant: CC(C)(Br)C(=O)Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCCCCCCCCCOC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A similar synthetic scheme was conducted as followed.x To a solution of 4.257 g (25 mmol) of co-undecylenyl alcohol in 25 mL of dry tetrahydrofuran was added 2.1 mL of pyridine (26.5 mmol) by dropwise addition of 3.10 mL of 2-bromoisobutyryl bromide (25 mmol). The mixture was stirred at ambient temperature for 8 hours. The remaining THF was removed under reduced pressure followed by dilution with hexane (50 mL). The mixture was washed with 2 M HCl solution and twice with water (50 ml). The organic phase was dried over sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure yielding a colorless oil (89%). 1H NMR (500 MHz, CDCl3) δ: 1.22-1.45 (br m, 12H); 1.62-1.75 (m, 2H); 1.94 (s 6H); 2.05 (q, 2H, J) 6 Hz); 4.17 (t, 2H, J=9 Hz); 4.9-5.05 (m, 2H); 5.72-5.9 (m, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:23])[N:7]([CH:14]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[C:15]([OH:17])=[O:16])[C:8]2=[O:13])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:23])[N:7]([CH:14]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[C:15]([OH:17])=[O:16])[C:8]2=[O:13]
Reactant: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc(N)c2C1=O
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid (1.75 g, 5.45 mmol) and 10% Pd/C (0.2 g) in methanol (52 mL) is hydrogenated at 50 psi of hydrogen for 2 hours. The mixture is filtered through celite and the celite pad is washed with methanol (30 mL). The filtrate is concentrated in vacuo and the residue is slurried with ethyl acetate (20 mL) for 30 min. The resulting slurry is filtered and the solid is washed with ethyl acetate (10 mL) and dried (60° C., <1 mmHg) to give 2-(4-amino-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid (1.39 g, 88%) as a yellow solid; mp 165-167° C.; 1H NMR (DMSO-d6) δ13.08 (b, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.02-6.97 (dd, J=4.1 and 5.5 Hz, 1H), 6.73 (s, 1H), 6.51 (s, 2H), 4.68-4.62 (dd, J=4.5 and 10.5 Hz, 1H), 2.50-1.99 (m, 4H); 13C NMR (DMSO-d6) δ173.07, 170.75, 168.88, 167.63, 146.66, 135.36, 132.03, 121.58. 110.87, 108.63, 50.74, 31.34, 24.03; Anal. Calcd. For C13H13N3O5: C, 53.60; H, 4.50; N, 14.43. Found: C, 53.71; H, 4.40; N, 14.31.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[Na].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH3:22])CCl>C(O)C>[CH3:13][C:14]1[CH:15]=[C:16]([CH2:3][CH2:2][C:1]([OH:9])=[O:8])[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(CCl)cc1C
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(CCC(=O)O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 70.0 ml of diethyl malonate dissolved in 400 ml of dry ethanol was added 10.0 g of metallic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0° C; and 66.5 g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred at a room temperature for another 1 hour, heated at the boiling temperature for 4 hours and concentrated under a reduced pressure. The residue was dissolved in ethyl ether and the solution was washed with water. After further concentration under a reduced pressure, the organic phase was combined with 500 ml of water and 170 g of KOH; and this mixture was heated at the boiling temperature for 24 hours. The mixture was concentrated under a reduced pressure to about one half volume; then 200 ml of 98% sulfuric acid was added slowly thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300 ml of ethyl acetate. The organic solvent was distilled off under a reduced pressure and the residue was recrystallized from boiling hexane to obtain 42.1 g of the title compound as a white solid(yield: 55%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]#[CH:16])[CH:6]=1)=[O:4].[CH:19]1[C:24]([I:25])=[CH:23][CH:22]=[C:21](I)[CH:20]=1>CN(C=O)C.[Cu]I>[F:18][C:2]([F:1])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]#[C:16][C:21]2[CH:20]=[CH:19][C:24]([I:25])=[CH:23][CH:22]=2)[CH:6]=1)=[O:4]
Reactant: Ic1ccc(I)cc1
Reactant: C#CCn1cc(C(=O)C(F)(F)F)c2ccccc21
Agent: [Cu]I
Solvent: CN(C)C=O
Product: O=C(c1cn(CC#Cc2ccc(I)cc2)c2ccccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of product of Step B (0.25 g, 1 mmol), 1,4 di-idobenzene (0.4 g, 1.2 mmol) Cl2Pd(PPh3)2 (0.06 g) and catalytic amount of CuI in a mixture of DMF:DIPEA (10 ml: 0.5 ml) at room temperature was degassed under reduced pressure and saturated with N2. This was stirred overnight at room temperature, quenched with NaHCO3 solution and diluted to 50 ml with EtOAc. The organic layer was separated and washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.28 g, 51%), as light yellow solid. 1H-NMR (CDCl3) 8.43-8.40 (b, 1H); 8.12 (b, 1H); 7.66 (t, 2H, J=8.36 Hz); 7.55-7.51 (m, 1H); 7.44-7.38 (m, 2H); 7.14 (d, 2H, J=8.30 Hz); 5.16 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:27]C(=O)OC(C)(C)C)([CH2:7][C:8]#[C:9][C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:11]=2)[C:3]1=[O:35].S(=O)(=O)(O)O>O1CCOCC1.C(#N)C>[NH2:27][C@@:4]1([CH2:7][C:8]#[C:9][C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:11]=2)[CH2:5][CH2:6][N:2]([CH3:1])[C:3]1=[O:35]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(N)CCN(C)C2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 7) (99.5 g, 203.68 mmol) in 1,4-dioxane (750 mL) cooled with an ice/water bath to an internal temperature of 15° C. was added conc. sulphuric acid (75 mL, 1407 mmol) dropwise maintaining internal temperature below 20° C. over approximately 35 minutes. After complete addition, the reaction mixture was stirred at room temperature over 30 minutes. The reaction was poured into a beaker and washed in with ethyl acetate (400 mL) and a little water. The mixture was cooled to 15° C. and a solution of sodium carbonate (160 g in 1200 mL water) was added over 5 minutes. The mixture was filtered over a pad of celite and the remaining solids washed with ethyl acetate (400 mL). The filtrate phases were separated and the aqueous phase was extracted with ethyl acetate (2×400 mL). The combined organics were washed with brine (500 mL), dried over magnesium sulphate, filtered and evaporated to yield a foaming amber oil. This was twice dissolved in acetonitrile (100 mL) and evaporated and the resulting yellow foam dried under vacuum to give the title material (D8) in good purity by NMR, consistent spectroscopically with that produced by Method 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[Cl:17].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)(O)[O-].[Na+]>CC(=O)CC>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:18][C:3]1[C:2]([Cl:1])=[C:16]([Cl:17])[C:6]2[S:7][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][C:5]=2[CH:4]=1)[CH3:25]
Reactant: Oc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Yield: 71.3 %

Procedure:
A mixture of 5.1 g of 6,7-dichloro-5-hydroxy-2-phenylbenzo[b]thiophene. 3.5 g of ethyl bromoacetate and 5 g of sodium bicarbonate in 100 ml of 2-butanone containing 10 ml of dimethylformaide is stirred at 85°-90° for 16 hours. The mixture is concentrated at reduced pressure to remove the sovents and the residue is triturated with 50 g of ice-water. After 30 minutes the solid is filtered and air dried. Recrystallization from ether-hexane gives 4.7 g of ethyl[(6,7-dichloro-2-phenylbenzo[b]thien-5-yl)oxy]acetate as fine needles, mp 116.5°-117°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[C:12]([Cu])#[N:13]>CN(C=O)C.CCOC(C)=O>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([C:12]#[N:13])=[CH:3][C:4]=2[O:8]1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(=O)oc2c1
Temperature: 175 °C
Reaction time: 6 h

Procedure:
To a solution of 6-bromo benzoxazolinone (2 g, 9.4 mmol) in DMF (20 mL) was added CuCN (16.79 g, 188 mmol), and the reaction was stirred at 175° C. for 6 h. The reaction progress was monitored by TLC (100% EtOAc). The reaction was diluted with EtOAc (10 mL) and filtered through Celite® brand filter agent. The organic layer was concentrated and purified by column chromatography (silica gel, 0-50% EtOAc in hexanes) to give the title compound. MS (ESI pos. ion) m/z: 158.9 (MH−).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:10]([OH:14])[C:11]#[C:12][CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.CC1C(C(=O)C#CC)C(C)(C)CCC=1>CO>[CH3:1][C:2]1[CH:3]([C:10](=[O:14])/[CH:11]=[CH:12]\[CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: CC#CC(O)C1C(C)=CCCC1(C)C
Agent: CC#CC(=O)C1C(C)=CCCC1(C)C
Solvent: CO
Product: C/C=C\C(=O)C1C(C)=CCCC1(C)C

Procedure:
The acetylenic carbinol which was obtained as described above under paragraph (b) was oxidized as described for its isomer in Example 18, paragraph (c). Thus, 1.38 g. of carbinol gave 0.9 g. (66%) of 2,6,6-trimethyl-1-tetrolyl-2-cyclohexene, b.p. 100°-105°/0.7 Torr. NMR spectrum (CCl4): 0.96 (6 H, d badly resolved), 1.52 (3 H, m), 2.0 (3 H, s), 5.57 (1 H, m), 2.66 (1 H, m) ppm (δ).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2F)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][CH3:32])(=[O:30])[CH2:28][SH:29].C1COCC1.[H-].[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([OH:26])[CH:28]([C:27]([O:31][CH3:32])=[O:30])[S:29][C:16]3[C:17]([C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=[CH:20][C:15]2=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1Sc2c(C(F)(F)F)cccc2C1(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 1.67 h
Yield: 56 %

Procedure:
To a room temperature solution of 4-(2-fluoro-3-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.00 g, 24.0 mmol), methyl thioglycolate (2.40 mL, 26.8 mmol), and anhydrous THF (200 mL) under nitrogen was added NaH (1.15 g of a 60% oil dispersion, 28.7 mmol) in one portion. After the gas evolution ceased, the reaction was stirred at 55° C. After 100 min, the reaction was cooled to room temperature and diluted with ethyl acetate (500 mL). The mixture was washed with water (300 mL) and brine (300 mL) successively, dried over magnesium sulfate, filtered, and the solvent removed to afford a sticky white solid. Trituration with 20% ethyl acetatetheptane afforded 6.20 g (56%) of the desired product as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].CCO>[Pd].CCOC(C)=O>[NH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(F)c1
Yield: 94.8 %

Procedure:
Methyl 3-fluoro-4-nitrobenzoate (5.18 g, 26.0 mmol) in a 1:1 mixture (50 mL) of EtOH and AcOEt with 10% Pd/C (0.52 g) was hydrogenated on a Parr hydrogenation apparatus at 40 psi. Pd/C was removed by filtration through a pad of Celite® 545. The filtrate was concentrated under vacuum. The residue was diluted with AcOEt, washed with brine, and dried over anhydrous MgSO4. Evaporation of solvent under vacuum gave the title compound (4.17 g, 95% yield) as a pale solid.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[C:1]1([N:11]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: c1cc2c(c(N3CCNCC3)c1)CCCC2
Reaction time: 48 h

Procedure:
5,6,7,8-Tetrahydronaphthalen-1-ylamine (1.4 ml, 15 mmol) is brought to the reflux point of 1-butanol (50 ml) in the presence of bis(2-chloroethyl)amine hydrochloride (2.68 g, 15 mmol) and sodium carbonate (800 mg, 7.5 mmol). After 48 h, the reaction mixture is concentrated and impregnated onto silica and then purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane/methanol/aqueous ammonia.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1)=[O:16].IC>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([CH3:1])[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1)=[O:16]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCC(C(=O)O)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
N,N-Diisopropylamine (1.18 mL, 8.35 mmol) was added dropwise to a 2M solution of “butyllithium (4.18 mL, 8.4 mmol) at −78° C. under nitrogen. After 15 min at this temperature the solution was raised to and held at 0° C. for 15 min prior to re-cooling to −78° C. and treatment with a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (0.62 g, 3.34 mmol) in THF (8 mL). After 30 min., iodomethane (0.31 mL, 5 mmol) was added dropwise and the mixture was allowed to warm to rt over 2 hr. The mixture was cooled to at 0° C., quenched with 2 N HCl (10 mL) then was extracted with EtOAc (2×10 mL), washed with brine (3×15 mL), and dried over anhydrous magnesium sulfate. Concentration of the combined organic extracts afforded a yellow solid. NMR (CDCl3) consistent with crude, desired product.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br-].[K+].C(N(CC)CC)C.Cl>CN1CCCC1=O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: FC(F)CCl
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: FC(F)CNCc1ccccc1
Yield: 94 %

Procedure:
An amount of 10 g (92 mmol) of 2,2-difluoro-1-chloroethane, 5 g (46 mmol) of benzylamine, 1 g of potassium bromide and 5.2 g (51 mmol) of triethylamine are heated in 20.6 g of N-methylpyrrolidone in an autoclave at an internal temperature of 120° C. for 6 hours. Subsequently, 100 g of 1N hydrochloric acid are added and the solvent is removed under vacuum. The residue is taken up in 30 ml of dichloromethane and adjusted to pH 8 with solid sodium hydrogencarbonate. The phases are subsequently separated and the aqueous phase is again extracted with 20 ml of dichloromethane. The organic phase is distilled. An amount of 7.4 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 94%, based on benzylamine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1>CC#N>[CH2:17]([N:1]([C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:9])[CH2:4][CH2:3]1)[CH2:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To an 80° C. heated mixture of trans-4-Aminocyclohexanecarboxylic acid (8 g, 55.97 mmol) and K2C03 (23.4 g) in 112 mL of CH3CN, was added dropwise a solution of BnBr (23.3 mL, 195.5 mmol) in 70 mL of CH3CN by addition funnel. Reaction stirred overnight at 80° C. The reaction was cooled to room temperature and filtered. Precipitate did not form in filtrate like it did with the cis-somer so the filtrate was concentrated to an oil and carried on to next step (23.01 g, 99% yield).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11]O>S(=O)(=O)(O)O>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)cc1
Reaction time: 15 h

Procedure:
A solution of 4-iodobenzoic acid (5.0 g in a mixture of 50 mL methanol and 2.2 mL of conc. sulfuric acid) was heated to reflux on an oil bath. After 15 hours, the mixture was concentrated to half-volume in vacuo then poured into saturated sodium bicarbonate. This mixture was extracted with diethyl ether and the organic portion washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 95:5) gave the title compound (5.12 g).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].C[O-].[Na+].C(O)(=O)C>CO>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3=[CH:1][CH:2]=[C:3]([OH:4])[C:5]4[O:9][C@H:8]5[C:10]([CH2:12][CH2:13][C@@H:14]2[C@:7]5([C:6]=43)[CH2:21][CH2:20]1)=[O:11]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 7 °C

Procedure:
A 100 mL Schlenk tube was charged with methanol (50 mL), morphine free base (5.0 g, 17.52 mmol) and sodium methoxide (47.4 mg, 0.876 mmol). The mixture was stirred and heated to reflux under nitrogen for 15 min then treated with the solution of the catalyst added by a pipette. The resulting brown solution was stirred and heated to reflux under nitrogen for 1 hour, cooled to 7° C. in an ice bath, treated with acetic acid (0.05 mL, 0.876 mmol), stirred for another 30 min and filtered. The filtered solid was washed with isopropanol (3×8 mL) and dried in an oven at 95° C. to give hydromorphone free base as a white solid. The yield was 4.12 g, 82.4%.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5]O.N1C=CC=CC=1.S(Cl)([Cl:22])=O>CCOCC>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][Cl:22]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Br)c(OC)c(CO)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1cc(Br)c(OC)c(CCl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
To a solution of 8.18 gm (33.11 mmol) of 3-bromo-2,5-dimethoxybenzyl alcohol and 0.8 ml pyridine in 100 ml ether was added dropwise a solution of 8.5 ml (116 mmol) thionyl chloride in 20 ml ether. After stirring at ambient temperature for 20 hours, the reaction mixture was poured onto ice. The ether extract was washed with brine, dried (NaSO4), filtered and concentrated in vacuo to give 7.59 gm of a colorless oil. A portion, 3.9 gm, was purified by silica gel chromatography using 3:7 CH2 Cl2 :hexane to yield 3.62 gm of a white solid.