Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[C:10](C)([C:20](O)=O)[CH2:9]2)=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([CH2:13][N:12]3[CH2:8][CH2:9][CH2:10][CH2:11]3)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:5][CH:6]=1.[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[C@@H:10]([CH3:20])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)N1C(=O)C(C)(C(=O)O)CC1Cc1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(CN2CCCC2)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
63 mg (3R/S, 5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid (R1=Piv; R10=OH; R11=Me) [65:35. ratio of C3 isomers] is added to 25 ml toluene. The resulting mixture is heated to reflux and stirred for 16 h. The mixture is then cooled to room temperature and washed successively with 10 ml aqueous sodium hydrogen carbonate, brine and water. The organic phase is dried (MgSO4) and concentrated in vacuo to afford (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (2-a, R1=pivaloyl) and (3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (2-b, R1=pivaloyl) as a 55:45 diastereomer mixture, respectively, according to the 1H NMR spectrum.
Reaction SMILES: [NH2:1][C@H:2]([CH:21]([CH3:23])[CH3:22])[C:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([CH3:20])([CH3:19])[CH2:6]1)=[O:4].C(N(CC)CC)C.C(Cl)Cl.[C:34](Cl)(=[O:42])[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOC(C)=O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C@@:8]2([OH:11])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:34](=[O:42])[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:21]([CH3:23])[CH3:22])[CH2:6][C:7]2([CH3:19])[CH3:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)Oc1ccccc1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reaction time: 1 h
Yield: 59.8 %

Procedure:
(R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one (500 mg, 1.33 mmol), triethylamine (0.371 mL, 2.66 mmol) and methylene chloride (10 mL) were mixed at 0° C. under nitrogen then a methylene chloride solution of phenyl carbonochloridate (209 mg, 1.33 mmol) was added dropwise via an addition funnel. The reaction was stirred for 1 hour, diluted with EtOAc, and washed consecutively with 1N HCl and sat'd sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (3:1 to 1:1 hexanes/EtOAc) to obtain phenyl (R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (365 mg, 0.795 mmol, 59% yield) as a white glass. MS found: (M+H)+=459.32.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+]>O1CCCC1>[C:12]([O:14][C:7](=[O:9])[CH2:8][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])([CH3:15])([CH3:13])[CH3:11]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(CC(=O)O)CC(=O)OC(C)(C)C
Yield: 25.9 %

Procedure:
3,3-Dimethylglutaric anhydride (455 mg, 3.2 mmol) in tetrahydrofuran (THF, 5 mL) was treated with sublimed potassium t-butoxide (395 mg, 3.5 mmol). After 30 min the solution was concentrated, poured into saturated NaHCO3 solution and washed with ether. The aqueous phase was acidified to pH 4 with 0.5M H3PO4 and extracted with chloroform which was dried over Na2SO4 and evaporated to afford 179 mg (26%) of the desired product as an oil. NMR (300 MHz, CDCl3, ppm), 1.13 (s, 6H), 1.47 (s, 9H), 2.33 (s, 2H), 2.45 (s, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8](COC)[C:7]=2[CH:19]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:19]=1
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: ClCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 0 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
Into 250 ml of a solution of 26.9 g of 8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in methylene chloride was dropped 50 ml of trifluoroacetic acid at 0° C. After reacting at room temperature for 12 hours, the reaction mixture was cooled to 0° C. and neutralized by adding an aqueous solution of sodium hydrogencarbonate. The crystals thus precipitated were taken up by filtration and washed successively with water and diethyl ether to thereby give 19.1 g of the title compound as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[C:3]([OH:11])=[C:4]([CH:5]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(Br)c1O
Reactant: CC(C)(C)NO
Product: CC(C)(C)[N+]([O-])=Cc1cc(Br)cc(Br)c1O

Procedure:
The title compound was prepared according to the procedure described in Example 13 using 3,5-dibromo-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 68.7% yield as a yellow crystalline solid, m.p. 111.3° C. (Rf=0.54 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant).
Reaction SMILES: [CH2:1](N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1.C([N:22](CC)CC)C>ClCCl>[CH2:1]([C:12]1[C:13]([N+:17]([O-:19])=[O:18])=[CH:14][NH:15][C:10]([Cl:9])([NH2:22])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCN(CC)CC
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: NC1(Cl)N=C(Cc2ccccc2)C([N+](=O)[O-])=CN1
Reaction time: 1 h

Procedure:
2.7 ml of benzylamine is added to a solution of 5.0 g of the 2,4-dichloro-5-nitropyrimidine (Reference Example 1) in 75 ml of dichloromethane at 5° C., and the solution is stirred for 1 hour. 3.6 ml of triethylamine is added to the solution at 5t, stirred for 10 minutes, washed with 150 ml of saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 6.6 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>>[ClH:1].[C:12]1([C:4]2[CH:3]=[C:2]([NH:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCC(O)CO
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Product: Cl
Product: OCC(O)CNc1cc(-c2ccccc2)nc2ccccc12

Procedure:
The title compound, m.p. 225-227° C., and MS: m/e=295.3 (M+H+), was prepared from 4-chloro-2-phenyl-quinolin and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][S:27]([OH:30])(=[O:29])=[O:28].C(O)C.C([BH3-])#N.[Na+]>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][S:27]([OH:30])(=[O:29])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: NCCS(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCS(=O)(=O)O)ccc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of 6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.1662 g, 0.5354 mmol) and Taurine (0.06700 g, 0.5354 mmol) in anhydrous Ethanol (4.00 mL, 68.5 mmol) was refluxed for 2 hours. The mixture was cooled to room temperature and Sodium cyanoborohydride (0.04037 g, 0.6425 mmol) was added. The mixture was then refluxed overnight. The reaction mixture was cooled to room temperature and washed with Sat. aqueous citric acid (4 mL). The mixture was then concentrated to dryness under reduced pressure. The resulting solid was suspended in water and filtered. The residue was washed with water, air-dried and purified by prep HPLC to give the title compound. ESI-MS(M+H+): 420.34; 1H NMR (400 MHz, DMSO-d6) Shift 8.68 (br. s., 1H), 7.84 (br. s., 1H), 7.73-7.81 (m, 2H), 7.45 (dd, J=1.76, 8.53 Hz, 1H), 7.32-7.35 (m, 1H), 7.12 (dd, J=2.51, 8.78 Hz, 1H), 4.29-4.38 (m, 1H), 4.24 (br. s., 2H), 3.13 (d, J=13.80 Hz, 2H), 2.76 (d, J=13.55 Hz, 2H), 2.10-2.18 (m, 2H), 1.72-1.80 (m, 2H), 1.23-1.36 (m, 2H), 1.09-1.22 (m, 2H), 0.96-1.06 (m, 1H), 0.81 (s, 9H).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[C:8]([CH:11]([CH3:14])[C:12]#[N:13])[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1ccc(C(C)C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(C)C#N)cc1Br
Reaction time: 0.5 h

Procedure:
Bromine (21.4 ml) is added dropwise over a period of 1 hour to a stirred solution of 4-methoxyphenylpropionitrile (67.5 g) and sodium acetate (68.4 g) in glacial acetic acid (40 ml). The reaction mixture is stirred for an additional 30 minutes and partitioned between water and ether. The ether layer is washed with sodium carbonate solution, 10% aqueous NaOH, saturated salt, dried over Na2SO4 and filtered. The filtrate is evaporated in vacuo yielding the desired product, B.P. 155°-158° C. (4 mm).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1>C(N)C(C)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[S:20]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:9]2[N:10]=[CH:11][S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:10][CH2:9][CH:13]([CH3:14])[CH3:18])[N:7]=2)[CH:14]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Nc1cccc(-c2ncsc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Solvent: CC(C)CN
Product: CC(C)CNc1nccc(-c2scnc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)n1
Temperature: 35 °C
Yield: 130 %

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.1 g, 0.2 mmol) was taken up in 2 mL isobutylamine and heated to 35° C. overnight. The solvent was removed in vacuo and the residue taken up in EtOAc and washed with 2 mL of 0.1 N HCl (aq). The organic layer was dried over Na2SO4 and evaporated to afford the title compound (65 mg, 0.130 mmol), 60.2% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (s, 1H), 9.15 (s, 1H), 7.98 (d, J=5.1 Hz, 1H), 7.60-7.69 (m, 1H), 7.37 (t, J=5.9 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.26 (s, 1H), 7.15-7.24 (m, 4H), 5.93-6.05 (m, 1H), 2.95-3.06 (m, 2H), 0.82 (d, J=6.6 Hz, 6H). MS (ESI): 501 [M+H]+.
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.Cl>C1COCC1.C(OCC)(=O)C>[OH:18][C:19]1([C:6]2[NH:5][CH:9]=[CH:8][N:7]=2)[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1
Reactant: CCOC(OCC)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ncc[nH]2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A mixture of imidazole (25.6 g, 0.4 mol), triethyl orthoformate (236.8 g, 1.6 mol) and p-toluenesulfonic acid (2 g) was heated at 130° C. overnight with no condenser so ethanol can boil off. The excess orthoformate was removed by rotary evaporation and the residue was purified by vacuum distillation to give 1-(diethoxymethyl)-1H-imidazole (46.7 g). To a solution of the resulting protected imidazole (46.7 g) in anhydrous THF (350 mL) under N2 cooled at −40° C., was added n-butyllithium (2.5 M in hexane, 110 mL) at such a rate that the temperature did not rise above −35° C. After complete addition, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (18.25 g, 91.5 mmol) in anhydrous THF (70 mL) under N2 was added dropwise over 10 minutes keeping the temperature below −40° C. The reaction was stirred at 40° C. for 2 hours then 350 mL of 0.1 N HCl added and stirred for 15 minutes, ethyl acetate (350 mL) added and stirred for 5 minutes. The organic layer was separated and aqueous extracted with ethyl acetate (350 mL). The combined organic layers were washed with saturated NaHCO3, brine, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 10% methanol in ethyl acetate with 0.5% ammonia hydroxide to give tert-butyl 4-hydroxy-4-(1H-imidazol-2-yl)piperidine-1-carboxylate (10.5 g).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][CH:5]([CH2:17][CH2:18][CH2:19][CH:20]([O:26]C(=O)C)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].OO.[OH2:32].C(O)(=[O:35])C>CCOCC>[CH:3]([S:4]([CH:5]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:35])=[O:32])=[CH2:2]
Reactant: O
Reactant: CC(=O)O
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCCl)OC(C)=O
Agent: OO
Solvent: CCOCC
Product: C=CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(O)CCCCC
Reaction time: 20 h

Procedure:
A solution of ethyl 8-(2-chloroethylthio)-12-acetoxyheptadecanoate (45.1 g., 0.1 mole) and 30% aqueous hydrogen peroxide (50 ml.) in acetic acid (225 ml.) is allowed to stand 20 hours at 25° C. The solution is diluted with 600 ml. of water. The oily product is taken up in ether, washed with dilute sodium bicarbonate solution and four portions of water and dried over sodium sulfate. Evaporation of the ether in vacuo leaves the title compound as a light yellow viscous oil.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[O-]CC.[Na+].CCO.[S:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[O:10]=[C:4]([CH:20]1[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH2:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCSc2ccccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)C1CSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A solution of diethyloxalate (30.9 mL; 228.34 mmol; 1.5 eq.) in toluene (250 mL) is added dropwise at 0° C. to a solution of sodium ethoxide 21% w/w in EtOH (9.87 g; 182.67 mmol; 2 eq.). A solution of thiochroman-4-one (25 g; 152.23 mmol; 1 eq.) in toluene (250 mL) is added dropwise at 0° C. and the reaction mixture is allowed to warm up to rt. After overnight stirring, the solvent is removed and DCM (200 mL) and water (200 ml) are added. The aqueous phase is washed with DCM then acidified to pH=1-2 with 5N HCl (˜50 mL). The product is extracted with EtOAc (2×200 mL). The organic phases are combined, dried over MgSO4 and the solvent evaporated to afford 39.4 g (98%) of the title compound as an orange oil. MS (ESI+): 265.9.
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].[CH:23]([OH:32])([C:29]([OH:31])=[O:30])[CH:24]([OH:28])[C:25]([OH:27])=[O:26].C([OH:35])C>O>[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].[C@H:23]([OH:32])([C:29]([OH:31])=[O:30])[C@@H:24]([OH:28])[C:25]([OH:27])=[O:26].[OH2:35]
Reactant: CCO
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
A sample of 149.4 g of hydrocodone bitartrate containing 2.1 wt % of ethanol was placed in a crystallisation dish. The sample was placed in a vacuum oven along with a crystallisation dish containing water (ca 200 ml). A vacuum was applied (16665 pascals (approximately 10 mm to 1 mm Hg)) and the sample was dried at 60° C. for 24 hours to afford 151.7 g of ethanol-free (as defined below) product. The water content measured by Karl Fisher titration was 9.66% which indicated that the final product was a hemi-pentahydrate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:14]1[CH2:19][CH:18]=[C:17]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.O>CS(C)=O>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][N:14]3[CH2:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[N:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH:21]=4)[CH2:18][CH2:19]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=C(c2c[nH]c3ncccc23)CCNC1
Reactant: ClCCOc1cccc2[nH]ccc12
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C1=C(c2c[nH]c3ncccc23)CCN(CCOc2cccc3[nH]ccc23)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 10.2 %

Procedure:
A solution of 2-(1H-indol-4-yloxy)ethylchloride (0.5 g, 26 mmol), 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (0.61 g, 31 mmol) and triethylamine (0.71 ml, 52 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 4 hours at 80° C. The mixture was poured into water and extracted with ethyl acetate (3×100 ml). The organic layer was washed with water (3×100 ml), sodium bicarbonate and dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) afforded 0.95 g (97%) of product as a green oil.
Reaction SMILES: O(Cl)Cl.[Zr:4].[Sn].O(Cl)Cl.[Zr].O(Cl)Cl.[Sn].[P:14](=[O:18])([OH:17])([OH:16])[OH:15]>[Ti].O(Cl)Cl.[Ti]>[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Zr+4:4].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Zr+4:4].[Zr+4:4]
Reactant: [Zr]
Reactant: O=P(O)(O)O
Agent: [Ti]
Agent: ClOCl
Agent: [Sn]
Product: O=P([O-])([O-])[O-]
Product: [Zr+4]

Procedure:
That is, an oxychloride having a tetravalent metal such as zirconium, titanium or tin as a constituent element, for example, zirconium oxychloride, titanium oxychloride or tin oxychloride is added to a concentrated aqueous phosphoric acid solution, and after refluxing under heating for 24 hours, the precipitate is subjected to filtration, washing with water, drying and grinding to obtain a phosphate such as zirconium phosphate [Zr(HPO4)2.H2O]. This phosphate is immersed in an aqueous solution which contains an antimicrobial metal at a suitable concentration, thereby to obtain the phsophate of the present invention.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.S(Cl)(Cl)=O.[CH2:19](O)[CH2:20][CH3:21]>>[OH:1][C:2]1[C:11]([C:12]([O:14][CH2:19][CH2:20][CH3:21])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CCCO
Reactant: O=C(O)c1cc2ccccc2cc1O
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)c1cc2ccccc2cc1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
2-Hydroxy-naphthalene-3-carboxylic acid (2 g) was dissolved in 1-propanol (10 ml) to prepare a solution. The solution was brought to 0° C., and thionyl chloride (1.16 ml) was gradually added dropwise. The mixture was stirred at 120° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give propyl 2-hydroxy-3-naphthoate (2.15 g, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:40][C:39]([F:41])([F:42])[C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:38][CH:37]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(F)(F)F)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 14.5 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.2 g, 0.43 mmol) was reacted with 4-aminobenzotrifluoride (Alfa) (0.14 g, 0.86 mmol), HATU (0.29 g, 0.77 mmol) and iPr2NEt (0.15 mL, 0.86 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-trifluoromethyl-phenyl)-amide as a white solid (38 mg, 15%).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[O:35]([CH2:42][C:43](Cl)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][C:43](=[O:44])[CH2:42][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)COc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
To a cooled (0° C.) mixture of 1.5 g (3.8 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.7 ml (19 mmol) of triethylamine in 15 ml of CH2Cl2 was added 1.58 g (11.4 mol) of phenoxyacetyl chloride. The mixture was stirred at room temperature overnight and filtered. The filtrate was washed with H2O, 2 N citric acid, and brine and dried with Na2SO4. The solvent was removed to give 2.4 g of crude methyl 2-{(4-methoxybenzenesulfonyl)-[2-(phenoxyacetylamino)benzyl]amino}acrylate as an oil. Anal. for C26H26N2O7S: Calc'd: C,61.2; H,5.1; N,5.5; Found: C,62.6; H,5.1; N,4.0; Mass spectrum (ES) 511 (M+H).