Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH3:12][O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH2:16]>>[CH3:19][CH:18]([CH3:20])[CH2:17][C@@H:15]([NH:16][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=1)[C:14]([O:13][CH3:12])=[O:21]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CSc1ccc(C(=O)O)cc1
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(SC)cc1

Procedure:
Prepared in a similar manner to example 4 using 4-(methylthio)benzoic acid and D Leucine methyl ester. MS (M+H, 296).
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: ClCCCCBr
Reactant: CCC1C(=O)Nc2c(C)cccc21
Product: CCC1(CCCCCl)C(=O)Nc2c(C)cccc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-7-methyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[Cl:6][C:7]1[CH:16]=[C:15]([SH:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>>[Cl:6][C:7]1[CH:16]=[C:15]([S:17][CH2:4][C:2]([OH:5])([CH3:3])[CH3:1])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC1(C)CO1
Reactant: COC(=O)c1ccc(S)cc1Cl
Product: COC(=O)c1ccc(SCC(C)(C)O)cc1Cl

Procedure:
8 g of methyl 4-amino-2-chlorobenzoate was dissolved in 16 mL of MeOH, 8 mL of H2O and 8 mL of concentrated hydrochloric acid and was then cooled to 0° C. A solution of 3.9 g of sodium nitrite in 15 mL of H2O was added dropwise over 30 min. The reaction was stirred at 0° C. for an additional 1 h. The cold diazonating mixture was added to a solution of 13.8 g of potassium ethyl xanthate in 10 mL of H2O at 50˜60° C. The reaction was heated to 65° C. for 2 h and monitored by TLC until complete. The mixture was cooled to 25° C. and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purified by silica gel chromatography (0-10% ethyl acetate/hexane) to afford methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate. A solution of 2.6 g of sodium hydroxide in 20 mL of H2O was added to 5.9 g of methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate in 40 mL of EtOH The reaction mixture was heated to 70° C. for 1 h. Upon completion, the mixture was cooled to 25° C., and then acidified to pH 3 by the addition of 10 N HCl. The solid was filtered and washed with H2O to give 2-chloro-4-mercaptobenzonic acid. 3.8 g of 2-chloro-4-mercaptobenzonic acid in 40 mL of 5% sulfuric acid-methanol was refluxed under nitrogen atmosphere for 3 h. After concentration of the reaction mixture, 10 mL of H2O was added and the resulting mixture was made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield methyl 2-chloro-4-mercaptobenzoate. 80 mg of isobutylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate. 190 mg of methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate was hydrolyzed via Procedure M to give 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid. 160 mg of 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid was reacted via procedure R to give 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-methylpropylsulfonyl)benzamide. MS (Q1) 479.1 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[O:23]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[O:29])[CH2:24]1.C(Cl)CCl>CN(C=O)C>[O:23]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[CH:32][CH:31]=2)=[O:29])[CH2:24]1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Reactant: Nc1ccc(C(=O)N2CCOC2)cc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C(=O)N2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (44 mg, 0.14 mmol) and 4-(oxazolidin-3-ylcarbonyl)phenylamine (25 mg, 0.13 mmol) in DMF (3 mL), EDC (75 mg, 0.39 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (20 mg). MS 493.2 and 495.2 (M+H, Cl pattern).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([Sn:7](Cl)([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6]>>[CH3:6][CH2:5][CH2:4][CH2:3][Sn:7]([O:1][Sn:7]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH3:6])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [OH-]
Agent: [Na+]
Product: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A four-necked flask was provided with a stirrer, a thermometer and a reflux condenser. Then, 385 g of 20% aqueous sodium hydroxide solution was introduced into the flask and heated to 50° C. 200 g of tri-n-butyltin chloride containing 4.8% di-n-butyltin dichloride was dropwise added thereto over a period of 30 minutes, and then, reaction was allowed to proceed at that temperature for an hour. The resulting reaction mixture was permitted to stand, whereby it split into a turbid organic phase and an aqueous phase, respectively having specific gravities of 1.15 and 1.2. However, the diameters of the thus-formed di-n-butyltin oxide particles were so small as to cause the interface to be in an indistinct emulsified state and, hence, separation of the two phases was difficult. The organic phase was a mixture of bis(tri-n-butyltin) oxide and di-n-butyltin oxide particles having an average particle diameter of 2 μm. Vacuum filtration was tried on this organic phase but the two oxides could not be separated. Hence, 5 g of acid clay was added to the organic phase as a filter aid, which was then filtered. 100 g of water was added to the resulting filtate for washing, and the resulting organic phase was taken out and then dehydrated under reduced pressure, thereby obtaining 167 g of bis(tri-n-butyltin) oxide. Hydrochloric acid titration revealed that its purity was 96.3%, and its yield based on the starting material was 92%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[N:4]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28](Cl)=[N:27][C:26]([Cl:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]>CN1CCCC1=O>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[N:4]=2)=[N:27][C:26]([Cl:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: OCc1cccc(CO)n1
Solvent: CN1CCCC1=O
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cccc(CO)n1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using 2,6-bis(hydroxymethyl)pyridine (0.11 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.11 g) in N-methylpyrrolidinone (2 mL). Yield 0.043 g.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[S:32][C:31]3[C:26](=[N:27][CH:28]=[CH:29][C:30]=3Cl)[CH:25]=2)=[O:23])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[S:32][C:31]3[C:26](=[N:27][CH:28]=[CH:29][C:30]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:25]=2)=[O:23])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(NCCCN1CCOCC1)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCCN5CCOCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (3-morpholin-4-yl-propyl)-amide by a procedure analogous to Example 1C. MS: 450 (MH+); HPLC Rf: 3.48 min.; HPLC purity 96%.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C1COCC1.CCOC(C)=O.O>[C:26]([O:25][C:23](=[O:24])[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.8 %

Procedure:
To a suspension of tert-butyl piperazine-1-carboxylate (3.0 g, 16.1 mmol) and triethylamine (4.5 mL, 32.2 mmol) in THF (80 mL) was added tert-butyl 2-bromoacetate (2.4 mL, 16.1 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (200 mL) and H2O (100 mL). The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to afford the sub-title compound (4.2 g, 87%).
Reaction SMILES: [CH3:1][N:2](C)CCCN=C=NCC.[C:12]1([O:22][CH2:23][C:24]([OH:26])=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.ON1C2C=CC=CC=2N=N1.CN>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[CH3:1][NH:2][C:24](=[O:26])[CH2:23][O:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)COc1cccc2ccccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)COc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (14.2 g, 74.2 mmol) was added to a solution of (1-naphthyloxy)acetic acid (15.0 g, 74.2 mmol) and 1-hydroxybenzotriazole (10.0 g, 74.2 mmol) in DCM (100 ml) and N,N-dimethylformamide (100 ml). The reaction mixture was stirred for 30 min at this temperature. A 8.0 M solution of methylamine (185 ml, 1.4 mol) was added. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (300 ml) and washed with a 10% aqueous solution of sodium hydrogen sulphate (2×300 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (400 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using ethyl acetate/heptane as eluent, to give 17.44 g of N-methyl-2-(1-naphthyloxy)acetamide.
Reaction SMILES: Br[C:2]1([O:10][CH2:11][CH2:12][OH:13])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.C1CCN2C(=NCCC2)CC1.CCOC(C)=O.O>CS(C)=O>[CH:2]1([O:10][CH2:11][CH2:12][OH:13])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3]1
Reactant: OCCOC1(Br)C=CCCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: OCCOC1C#CCCCCC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
Compound 9 (3.76 g, 15.1 mmol) was dissolved in DMSO M, 30 Ml) and heated to 60° C. DBU (4.51 ml, 30.2 mmol, 2.0 eq) was added, the resulting solution was stirred for 15 min and more DBU (18.0 ml, 121 mmol, 8.0 eq) was added. The mixture was stirred at 60° C. overnight and then cooled to RT. EtOAc (100 ml) and water (100 ml) were added. After acidification to pH 1 with concentrated HCl, the aqueous phase was extracted with EtOAc (3×50 ml). The combined organic layers were washed with 1 M HCl/saturated NaCl solution (100 ml each), dried over Na2SO4 and evaporated under reduced pressure. FC (cHex/EtOAc 9:1) afforded compound 10 (1.89 g, 11.2 mmol, 74%) as a light yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=3)=[CH:13][C:4]1=2)[CH3:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
4,4-Diethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one was prepared, from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-nitrophenyl boronic acid according to the procedure of Example 4, as an off-white solid: mp 193-194° C.; 1H-NMR (CDCl3) d 9.19 (s, 1H, D2O exchangeable), 8.38 (t, 1H, J=1.9 Hz), 8.20 (m, 1H), 7.83 (m, 1H), 7.61 (t, 1H, J=8.0 Hz), 7.50 (dd, 1H, J=8.2, 2.0 Hz), 7.23 (d, 1H, J=1.7 Hz), 6.99 (d, 1H, J=8.3 Hz), 2.09 (q, 4H, J=7.4 Hz), 0.96 (t, 6H, J=8.3 Hz); MS (EI) m/z 325 ([M−H]−, 100%). Anal. Calcd. For C18H18N2O4.0.3H2O: C, 65.17; H, 5.65; N, 8.44. Found: C, 65.31; H, 5.60; N, 8.10.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:23](O)=[O:24])[C:13]3=[O:30])[CH2:5]1)([CH3:3])[CH3:2].CN(C=O)C.S(Cl)(Cl)=O.[NH2:40][C:41]1[CH:45]=[CH:44][O:43][N:42]=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:23]([NH:40][C:41]2[CH:45]=[CH:44][O:43][N:42]=2)=[O:24])[C:13]3=[O:30])[CH2:5]1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(O[C@H]3CCN(C(C)C)C3)cc2c1=O
Reactant: Nc1ccon1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(O[C@H]3CCN(C(C)C)C3)cc2c1=O

Procedure:
To a stirred slurry of 3-[6-{[(3S)-1-isopropylpyrrolidin-3-yl]oxy}-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.29 g) and DMF (0.05 ml) in methylene chloride (15 ml) at 0° C. was added thionyl chloride (0.15 ml). The resultant solution was stirred at room temperature for 21 hour. To this mixture was added 3-aminoisoxazole (0.316 ml) and the resultant solution was stirred for 18 hours. The reaction mixture was evaporated and the residue was dissolved in methanol and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution. The fraction containing the product was further purified by column chromatography on an ion exchange column (isolute NH2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) eluting with MeOH. After evaporation and the residue was dissolved in ethyl acetate and triturated with ether, the resultant solid was removed by filtration and iso-hexane was added to the filtrate and the resulting solid was filtered and dried to give 3-[6-{[(3S)-1-isopropylpyrrolidin-3-yl]oxy}-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide as light tan solid (114 mg); NMR Spectrum: (DMSOd6) 1.02 (m, 6H), 1.76 (m, 1H), 2.18 (s, 3H), 2.27 (m, 1H), 2.40 (m, 2H), 2.85 (m, 3H), 5.01 (m, 1H), 7.04 (m, 1H), 7.49 (m, 2H), 7.60 (d, 1H), 7.72 (d, 1H), 8.07 (m, 2H), 8.21 (s, 1H), 11.45 (s, 1H); Mass Spectrum: M+H+ 474.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.C(OCC)(=O)C>[Br:12][CH2:13][CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc(OCCBr)cc1
Yield: 21.4 %

Procedure:
A suspension of 5.0 g of 4-hydroxybenzotrifluoride, 17.4 g of 1,2-dibromoethane and 2.6 g potassium carbonate in acetone (100 ml) was heated under reflux for 3 days. The reaction solution was diluted with water and ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated ammonium chloride (×2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 1.78 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:20]=[N+:21]=[N-:22])(C)C.Cl>C1(C)C=CC=CC=1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]3[N:22]=[N:21][NH:20][N:2]=3)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a solution of 2-cyano-4'-methylbiphenyl (390 g, 2.02 moles) in toluene (2.3 L) was added trimethyltin azide (525 g, 2.55 moles) at r.t. The mixture was refluxed for 24 h, cooled to r.t., filtered, washed with toluene and sucked dry in a funnel. The precipitate was resuspended in toluene (3.5 L) and THF (250 mL) was added. Anhydrous HCl was bubbled in at a moderate rate at r.t. to give a clear solution (45 min). Addition of HCl gas was continued for another 20 min. with stirring whereupon a white precipitate formed. The reaction mixture was stirred over night. The solid product was filtered, washed with toluene followed with ether and then dried under vacuum. This produced 250 g (53% yield of the tetrazole. m.p. 152°-154° C.; 1H-NMR (CDCl3): 2.40 (s, 3H), 7.19 (dd, 1H), 7.55 (m, 2H), 8.25 (dd, 1H).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[OH-].[K+]>C(O)CCC>[CH2:1]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[C:1]([OH:12])=[O:11])[CH2:2][CH2:10][CH3:9]
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCc1cccc(C(=O)O)c1C(=O)O
Temperature: 90 °C

Procedure:
148.2 g of anhydrous phthalic acid and 1.05 times the molar equivalent 77.8 g of n-butyl alcohol were added to a 500 ml glass round-bottomed flask equipped with stirring blades, thermometer and Dimroth condenser, heated while slowly stirring, and after the generated heat at about 90° C. wore off, raised to a temperature of 130° C., which was maintained for 2 hours. The mixture was subsequently cooled to 60° C. The acid value (number of mg of KOH necessary to neutralize 1 g of a sample) of the reaction solution was 253.8. Since the acid value for the case where the reaction is 100% complete is 248.4, the reaction rate was computed to be 98%.
Reaction SMILES: C1([Bi](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([O:26]C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)CCCCCCC/C=C\CCCCCCCC.C(N)CCCCCCC/C=C\CCCCCCCC.[Se].C(P(CCCCCCCC)CCCCCCCC)CCCCCCC.C([P:106](=[O:123])([CH2:115][CH2:116][CH2:117][CH2:118][CH2:119][CH2:120][CH2:121][CH3:122])[CH2:107][CH2:108][CH2:109][CH2:110][CH2:111][CH2:112][CH2:113][CH3:114])CCCCCCC>C=CCCCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.CO.C(#N)C.CN1CCCC1=O>[CH2:115]([P:106]([CH2:107][CH2:108][CH2:109][CH2:110][CH2:111][CH2:112][CH2:113][CH3:114])(=[O:123])[OH:26])[CH2:116][CH2:117][CH2:118][CH2:119][CH2:120][CH2:121][CH3:122]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCCCCCCCP(=O)(CCCCCCCC)CCCCCCCC
Agent: C=CCCCCCCCCCCCCCCCC
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCCN
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCP(=O)(O)CCCCCCCC

Procedure:
Materials. 1-methyl-2-pyrrolidinone (99.5%, Aldrich), 1-octadecene (90%, Aldrich), acetonitrile (99.9%, Fisher Chemical), triphenylbismuth (99%, Strem), CdO (99.5%, Aldrich), diphenyl ether (99%, Aldrich), methanol (ACS grade, VWR), oleic acid (90%, Aldrich), oleylamine (70% Aldrich), selenium (99.99%, Strem), trioctylphosphine (90%, Aldrich), trioctylphosphine oxide (99%, Strem), toluene (ACS grade, VWR). 0.2M Se-ODE was prepared by dissolving selenium powder in 1-octadecene at 200° C. for 2 hr under inert atmosphere according to the procedure by Bullen et al.[42]; trioctylphosphine oxide (TOPO) was recrystallized from acetonitrile prior to use; di-n-octylphosphinic acid (DOPA) was synthesized according to the procedure reported by Wang et al.[1]; a stock suspension of 2 mM triphenylbismuth (BiPh3) in 1-octadecene was prepared in advance.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:21])[CH2:16][CH:15]([NH:17][CH3:18])[CH2:14][C:13]([CH3:20])([CH3:19])[NH:12]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(C)=CC=CC=1>[Cl:3][C:2]1[N:1]=[C:8]([N:17]([CH3:18])[CH:15]2[CH2:14][C:13]([CH3:20])([CH3:19])[NH:12][C:11]([CH3:21])([CH3:10])[CH2:16]2)[N:7]=[C:5]([N:17]([CH:15]2[CH2:14][C:13]([CH3:20])([CH3:19])[NH:12][C:11]([CH3:21])([CH3:10])[CH2:16]2)[CH3:18])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CN(c1nc(Cl)nc(N(C)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h

Procedure:
18.4 g of cyanuric chloride and 34.0 g of 2,2,6,6-tetramethyl-4-(methylamino)piperidine were dissolved in 250 ml of xylene, and the solution was stirred at a temperature of 90°-110° C. for 3 hours. 30 ml of a saturated aqueous solution of potassium carbonate were then added and the resulting mixture was heated under reflux for 5 hours. At the end of this time, the reaction mixture was poured into water and extracted with benzene. The extract was dried over anhydrous potassium carbonate and then the benzene was distilled off. The residue was recrystallized from ethyl acetate, giving the title compound in the form of crystals melting at 179°-180° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CN1[C@@H]2CC3=CC=C(O)C4[O:34][C@H]5C(CC[C@@H]2[C@]5(C=43)CC1)=O.C1C2C[C@H]3N(CC[C@@]45[C@H]3C=C[C@H](O)[C@@H]4OC(C=25)=C(O)C=1)C>>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:34])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314

Procedure:
To a 150 mL beaker was charged 10.0 g oxycodone hydrochloride and 100 mL water. Concentrated ammonium hydroxide (2.6 grams) was then added to bring the pH to approximately 9. The product was collected by vacuum filtration, washed with cold water and dried for about 5 hours under vacuum to provide 8.3 g (93% yield) of a white solid consistent in structure with oxycodone free base. This procedure was used to prepare hydrocodone, hydromorphone and morphine free base as needed.