Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[CH3:16][C:17]([CH3:31])([CH3:30])[CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19][CH:20]=O>[Na].C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([CH3:16])([CH3:30])[CH3:31])[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)NC(CC=O)C(C)(C)C
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCN1C[C@@H]2COCCN2c2nc(Cl)ncc21)C(C)(C)C

Procedure:
The title compound was prepared in a manner similar to PREPARATION x63 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 115 mg, 0.507 mmol), tert-butyl 4,4-dimethyl-1-oxopentan-3-ylcarbamate (116 mg, 0.507 mmol), titanium(IV) chloride in CH2Cl2 (1M, 0.761 mL, 0.761 mmol) and sodium triacetoxyhydroborate (237 mg, 1.116 mmol) in CH2Cl2 (5 mL) (53 mg, 24%). ESI-MS m/z [M+H]+ calc'd for C21H34ClN5O3, 440.24; found 440.4.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:5]/[CH:4]=[C:2](\[CH3:3])/[C:1]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C(\C)C(=O)OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C(C)=C/CBr

Procedure:
To a solution of methyl tiglate (2.00 g, 17.5 mmol) in CCl4 (8.76 mL) was added NBS (3.43 g, 19.3 mmol) and benzoyl peroxide (212 mg, 0.876 mmol). The reaction was heated to reflux for 3 hours, cooled and filtered through Celite using DCM to wash the filtrate. The reaction was concentrated in vacuo and then purified by silica chromatography using 1-15% EtOAc/hexane. The product was collected and concentrated in vacuo to afford the desired product as a colorless oil that was taken on to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([Br:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH2:19][CH2:20][CH2:21][Cl:22])=[C:6]([Br:10])[CH:5]=2)=[CH:12][CH:13]=1
Reactant: COc1cc(O)c(Br)cc1-c1ccc(F)cc1
Reactant: ClCCCBr
Product: COc1cc(OCCCCl)c(Br)cc1-c1ccc(F)cc1
Yield: 84 %

Procedure:
The title intermediate was prepared from 4-(2-methoxy-4-hydroxy-5-bromophenyl)fluorobenzene and 3-bromopropyl chloride in 84% yield by the procedure of Preparation 36. NMR
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([C@@H:7]1[C:13]2[CH:14]=[CH:15][CH2:16][CH2:17][C:12]=2[CH2:11][CH:10]([NH2:18])[N:9]([CH3:19])[C:8]1=[O:20])=[O:6])[CH3:4].C([NH:28][CH:29]([CH2:33][C:34]([F:37])([F:36])[F:35])[C:30](O)=[O:31])(OC(C)(C)C)=O>>[NH2:28][CH:29]([CH2:33][C:34]([F:37])([F:36])[F:35])[C:30]([NH:2][C@H:3]([C:5]([C@@H:7]1[C:13]2[CH:14]=[CH:15][CH2:16][CH2:17][C:12]=2[CH2:11][CH:10]([NH2:18])[N:9]([CH3:19])[C:8]1=[O:20])=[O:6])[CH3:4])=[O:31]
Reactant: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(=O)O
Reactant: C[C@H](N)C(=O)[C@H]1C(=O)N(C)C(N)CC2=C1C=CCC2
Agent: Cl
Product: C[C@H](NC(=O)C(N)CC(F)(F)F)C(=O)[C@H]1C(=O)N(C)C(N)CC2=C1C=CCC2

Procedure:
Following General Procedure D above using 1-(S)-[L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one hydrochloride (Example 7-30, below) and 2-(N-Boc-amino)-4,4,4-trifluorobutyric acid (Oakwood), the protected intermediate was prepared. The Boc-group was removed using 5.0 M HCl in dioxane and the resulting free-base purified by flash chromatography CHCl3/MeOH (97.3) yielding the title compounds.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[O:6][N:5]=[C:4]([C:7]([O:9]CC)=[O:8])[CH2:3]1.N.[H][H]>C(O)C>[NH2:5][CH:4]([CH2:3][C:2]([OH:6])([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH3:1])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C1=NOC(C)(Cc2c[nH]c3ccccc23)C1
Reactant: [H][H]
Agent: N
Solvent: CCO
Product: CC(O)(Cc1c[nH]c2ccccc12)CC(N)C(=O)O

Procedure:
The aforementioned 5-(RS)-methyl-5-(3-indolylmethyl)-4,5-dihydroisoxazole-3-carboxylic acid in an amount of 540 mg was dissolved in 4 ml of ethanol, and 10 ml of 28% aqueous ammonia and 300 mg of 5% Rh—C were added thereto. Reduction performed at room temperature in an atmosphere of hydrogen at 10 atm for 12 hrs. The catalyst was removed by filtration, and after vacuum concentrating the filtrate, the product was again dissolved in water followed by freeze-drying resulting in 370 mg of 2-amino-4-hydroxy-4-(3-indolylmethyl)pentanoic acid (1.41 mmol) as light brown powder (Compound No. 5 in Table 1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([Cl:25])[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3CO)ncc2c1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (2.0 g, 5.5 mmol) in methanol (30 mL) was added NaBH4 (700 mg, 16.5 mmol) at room temperature. The reaction mixture was stirred for 1 h and quenched with water (30 mL). It was then concentrated under reduced pressure and the residue was extracted with dichloromethane (3×30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 116a as a white solid (1.8 g, 90%). MS: [M+H]+ 362.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH:26]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH2:28][CH2:27]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]([S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH:26]2[CH2:27][CH2:28]2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]([CH3:15])[CH3:14])=[CH:11][CH:12]=1
Reactant: COC(=O)CNCc1ccc(N(C)C)cc1
Reactant: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(Cc1ccc(N(C)C)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 49.4 g (222 mmol) of [(4-dimethylamino-benzylamino)-acetic acid methyl ester], 41.4 ml (244 mmol) of diisopropylethyl amine and 0.271 g (2.2 mmol) of DMAP in 600 ml of CH2Cl2, 54.8 g (222 mmol) of 4-cyclopropylmethoxy-benzenesulfonyl chloride in 100 ml of CH2Cl2 are added at 0-5° C. After stirring for 15 h at r.t., the reaction mixture is quenched with Ice water and sat. aqueous NH4CO3. The mixture is extracted with AcOEt and combined extracts are washed with sat. aqueous NH4CO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by CC on silicage gel (n-Hexane:AcOEt=4:1) to give the title compound as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24](=[O:33])([O:29][CH2:30][CH2:31][CH3:32])[O:25][CH:26](Cl)[CH3:27]>>[CH2:30]([O:29][C:24]([O:25][CH:26]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:27])=[O:33])[CH2:31][CH3:32]
Reactant: CCCOC(=O)OC(C)Cl
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Product: CCCOC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 6, piroxicam (3.00 g, 9.1 mmol) and alpha-chloroethyl propyl carbonate (4.52 g, 27.2 mmol) were converted to chromatographed title product, 3.47 g pale yellow foam (7.5 mmol, 83.0%) which gave 3.00 g white crystals from isopropyl alcohol: mp 150°-151° C.; IR (KBr) 1760, 1678 cm-1 : 1H NMR (CDCl3) delta 0.84 (t, J=7 Hz, 3H), 1.46-1.65 (m, 2H), 1.75 (d, J=6 Hz, 3H), 3.11 (s, 3H), 3.97 (t, J=7 Hz, 2H), 6.35 (q, J=6 Hz, 1H), 7.04-7.16 (m, 1H), 7.62-7.97 (m, 5H), 8.30-8.41 (m, 2H), 9.40 (br s, 1H): precise mass calcd for C21H23N3O7S m/e 461.1264, found 461.1260.
Reaction SMILES: [C:1]1([C:7]2[NH:13][CH2:12][CH2:11][NH:10][C:9](=[O:14])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH2:20]([O+](CC)CC)[CH3:21]>C(Cl)Cl>[CH2:20]([O:14][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:13][CH2:12][CH2:11][N:10]=1)[CH3:21]
Reactant: O=C1C=C(c2ccccc2)NCCN1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1=NCCNC(c2ccccc2)=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
3.8 g. (20 mmol.) of 7-phenyl-1,2,3,4-tetrahydro-1,4-diazepine-5-one (Compound XXV) were suspended in 100 ml. of dry methylene chloride stirred under nitrogen at room temperature. 4.0 g. (21 mmol.) of triethyloxonium tetrafluoroborate were added portionwise to the stirred suspension so as to maintain the reaction mixture at a temperature of 20°-25° C., the reaction being slightly exothermic. After the addition was completed, the reaction mixture was stirred for an additional 30 minutes at room temperature. The reaction mixture was then washed with cold dilute sodium hydroxide solution and dried over anhydrous sodium sulfate. The methylene chloride was evaporated off at reduced pressure and ether was added to the residue. A small amount of solid that did not dissolve was removed by filtration, and the filtrate was evaporated at reduced pressure to yield an oil which crystallized overnight in a refrigerator yielding the crude product (3.5 g.), m.p. 89°-93.5° C. Recrystallization from ether/heptane yielded the pure product as white crystals (1.6 g.), m.p. 94°-95.5° C. A second crop (1.6 g.) was obtained from the mother liquor, m.p. 89°-93° C.
Reaction SMILES: Cl.[CH2:2]1[CH2:6][O:5][C:4]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][C@@H:12]([CH2:14][CH2:15][NH2:16])[C:13]=3[C:3]1=2.O.[OH-].[Na+].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>O1CCCC1>[CH2:2]1[CH2:6][O:5][C:4]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][C@@H:12]([CH2:14][CH2:15][NH:16][C:20](=[O:23])[CH2:21][CH3:22])[C:13]=3[C:3]1=2
Reactant: NCC[C@@H]1CCc2ccc3c(c21)CCO3
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)NCC[C@@H]1CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a mixed solution of (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (74 kg, 309 mol) in tetrahydrofuran (185 L) and city water (259 L) were added 30% aqueous solution of sodium hydroxide (70 L) and propionyl chloride (32.8 kg), and stirred at room temperature for 1 hr. To the reaction solution was added city water (592 L), and cooled. The precipitated crystals were collected by filtration, and dried under reduced pressure to give title compound (78.0 kg, yield 97.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.N#N.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][N:11]([C:31](=[O:34])[CH2:32][CH3:33])[N:10]=1
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Reactant: CCC(=O)Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)N1Cc2cc(OC)ccc2C(Cc2c(Cl)cncc2Cl)=N1
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (1 g, 3.1 mmoles), prepared as described in example 22, in THF (35 ml), under stirring and dry N2 at room temperature, was dropwise added with triethylamine (1.08 ml, 7.76 mmoles), then, at 0° C., with propionyl chloride (0.323 ml, 3.72 mmoles). After 10 minutes the mixture was brought to room temperature and after 3 hours poured into water/ice and THF was evaporated. The mixture was extracted more times with CH2Cl2 and the organic phases were washed with 5% NaOH and water, anhydrified and brought to dryness to give a solid which was crystallised from acetonitrile (50 ml). 1 g of the title compound was obtained (yield: 86%). m.p.: 195-197° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].C>O>[Cl:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(Oc2cccc(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1csc(Oc2cccc(Cl)c2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
A mixture of 26,36g (92.9 mmol) ethyl-2-(3-chlorophenoxy)thiazole-4-carboxylate (prepared analogously to the procedures of Example 1c), 7.5 g (187.5 mmol) NaOH and 300 ml of water was stirred 1 hour at 60° C. and 16 hours at room temperature. After adding a small amount of charcoal the yellow solution was stirred 10 minutes at room temperature and the charcoal separated by silica gel filtration. The filtrate was acidified with conc. HCl and the precipitate was collected and dried to give 22.5 g (94.7%) of 2-(3-chlorophenoxy)thiazole-4-carboxylic acid of m.p. 135°-137° C.
Reaction SMILES: C(O[C:4]1[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8][N:9]=1)C.[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23]([NH:25][NH2:26])=O>C(O)CCC>[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23]1[N:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:5][C:4]2=[N:26][N:25]=1
Reactant: NNC(=O)c1cnccn1
Reactant: CCOC1=NCCN(C(=O)OC(C)(C)C)C1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
To a solution of tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate (1.14 g, 5 mmol) in 1-butanol (30 mL) was added pyrazine-2-carbohydrazide (685 mg, 5 mmol). The reaction mixture was heated at reflux for 16 h. After cooling to rt, the reaction mixture was concentrated and purified by chromatography (SiO2; 2.5% MeOH in DCM) to afford the desired product as a white solid (700 mg, 50% over 2 steps). MS (ESI): mass calcd. for C14H18N6O2, 302.2; m/z found, 303.2 [M+H]+. 1H NMR (500 MHz, CDCl3) d 9.57 (d, J=1.4 Hz, 1H), 8.62 (d, J=2.5 Hz, 1H), 8.59-8.54 (m, 1H), 4.94 (s, 2H), 4.63-4.50 (m, 2H), 3.89 (t, J=5.4 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[I:20]I.S([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)Cl.CO>[CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([I:20])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: CC(C)c1c[nH]c(COCc2ccccc2)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc(COCc2ccccc2)[nH]c1I
Reaction time: 0.08 h

Procedure:
(2)In 250 ml of methylene chloride was dissolved 70 g (304 mmol)of 2-(benzyloxymethyl)-4-isopropyl-1H-imidazole (3c). Then, an aqueous solution prepared by dissolving 13 g of sodium hydroxide in 160 ml of water was added at 0° C. and the mixture was stirred for 5 minutes. Then, a solution of iodine (49 g, 386 mmol)in methylene chloride (350 ml)-methanol (150 ml)was added at 0° C. and the mixture was then stirred at room temperature for 20 minutes. To this reaction mixture was added an aqueous solution of sodium sulfite and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over dry sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide 2-benzyloxymethyl-5-iodo-4-isopropylimidazole (4c). Yield 93 g (85.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][C:10]=1[OH:20].[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23]O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:16]2[O:18][CH2:23][C:22]([CH3:26])([CH3:25])[N:21]=2)[CH3:19])=[CH:11][C:10]=1[OH:20]
Reactant: CC(C)(N)CO
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)c(O)c1
Solvent: Cc1ccccc1C
Product: CC(C1=NC(C)(C)CO1)c1ccc(-c2ccc(F)cc2F)c(O)c1

Procedure:
A solution of 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl) propionic acid (1 g.) and 2-amino-2-methylpropan-1-ol (1 ml.) in xylene (20 ml.) was stirred under reflux for 3 days. The solvent was distilled and the solid residue was recrystallised from aqueous methanol to give 2-[1-(2',4'-difluoro-2-hydroxy-4-biphenylyl)ethyl]-4,4-dimethyl-2-oxazoline, m.p. 188°-194° C. (decomposes).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:18][CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:19]([C@@H:21]([OH:24])[CH2:22][CH2:23][C@@:9]34[OH:25])[O:20][C:4]([C:5]=25)=[C:3]([OH:26])[CH:2]=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:18][CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:19]([C@@H:21]([OH:24])[CH2:22][CH2:23][C@@:9]34[OH:25])[O:20][C:4]([C:5]=25)=[C:3]([OH:26])[CH:2]=1.[C:27]([O-:32])(=[O:20])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)C(=O)Cl
Agent: Oc1ccc2c3c1O[C@H]1[C@@H](O)CC[C@@]4(O)[C@@H](C2)N(CC2CCC2)CC[C@]314
Solvent: ClCCl
Product: CC(C)(C)C(=O)[O-]
Temperature: 0 °C

Procedure:
75 mL of methylene chloride and 3.75 g (0.01 mole) of nalbuphine were placed in a 250-mL ice-bathed round-bottomed flask. While stirring, 0.01 mole of pivaloyl chloride dissolved in 20 mL of methylene chloride was added gradually. Following the procedure as described in Example 1, pure nalbuphine pivalate was obtained. The physical data are shown in Table 1 and FIGS. 6, 7 and 8.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([N+:16]([O-])=O)=[C:13]([C:19]([NH2:21])=[O:20])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.[Pt]>[NH2:16][C:14]1[S:15][C:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)=[CH:12][C:13]=1[C:19]([NH2:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cc1
Agent: [Pt]
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1

Procedure:
Nitro reduction, Method A: 5-[4-(Methylsulfonyl)phenyl]-2-nitrothiophene-3-carboxamide (0.96 g, 2.94 mmol) and Pt/C, doped with V (0.191 g, 0.029 mmol) were stirred in MeOH (60 mL) at room temperature under a balloon of H2 for 90 minutes. The catalyst was removed by filtering through Celite, which was subsequently washed with DMF. The solvent was removed in vacuo and the residue triturated in EtOH to give the title compound as a dark brown solid.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[C:4]([N:6]1[CH:11]=[CH:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5].C(N(CC)CC)C.C(O)=O>CN(C=O)C>[Cl:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:7]12
Reactant: O=C1C=CN(C(=O)c2c(Cl)cccc2Br)CC1
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCN2C(=O)c3c(Cl)cccc3C2C1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
A mixture of 1-(2-bromo-6-chlorobenzoyl)-2,3-dihydro-4-pyridinone (Preparation 3) (300 mg, 0.954 mmol), triethylamine (0.39 mmol, 0.54 ml), formic acid (0.05 ml, 1.3 mmol) and di(triphenylphosphine)diacetoxypalladium (47 mg, 0.063 mmol) in DMF (3 ml) was heated to 80° C. for 2 h. The cooled solution was filtered through celite, diluted with water, extracted twice with ethyl acetate, the extracts dried over sodium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound as a colourless oil (70 mg). MS (+CI) m /z 235/237 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: Clc1cccc(CBr)c1
Solvent: CN(C)C=O
Product: OC1CCN(Cc2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine and 0.55 9 (0.0022 mol) of 3-chlorobenzyl bromide were dissolved in 5 ml of dimethylformamide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with saturated bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.50 g (99%) of 1-(3-chloro-benzyl)-piperidin-4-ol was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(O)C(C)C)cc1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(=O)C(C)C)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.4 %

Procedure:
To a solution of 1-(4′-fluoro-6-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol (3.82 g) in dichloromethane (60 ml) was added manganese(IV) dioxide (12.1 g), and the mixture was stirred at room temperature for 17 h. Manganese(IV) dioxide (17.7 g) was added and the mixture was stirred at room temperature for 1.5 h. The mixture was heated under reflux for 22 h and filtered through Celite. The solvent was evaporated under reduced pressure to give the title compound (3.73 g) as a yellow oil.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=O)=[CH:30][CH:29]=3)=[N:26][CH:27]=2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].N1C=CC=CC=1>C(Cl)Cl>[CH2:11]([C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:27]=[N:26][C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32]#[N:34])=[CH:30][CH:29]=3)=[N:24][CH:23]=2)[CH2:20][CH2:21]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC[C@H]1CC[C@H](c2cnc(-c3ccc(C(N)=O)cc3)nc2)CC1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2cnc(-c3ccc(C#N)cc3)nc2)CC1
Temperature: 55 °C

Procedure:
9.5 Ml. of benzenesulfonyl chloride are added dropwise while stirring to a suspension of 17.2 g. of crude trans-p-[5-(4-n-pentylcyclohexyl)-2-pyrimidinyl]benzamide in 150 ml. of pyridine. The mixture is then warmed to 55° C. for 6 hours in an oil-bath. The mixture is poured into 500 ml. of ice-cold 0.5-N hydrochloric acid and the product is taken up in methylene chloride. The extract is washed three times with 200 ml. of 3-N hydrochloric acid each time, then with 100 ml. of saturated sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated. The crude product is chromatographed on a column of 600 g. of silica gel with toluene/5% acetone (v/v). The fractions which are pure according to thin-layer chromatography are dissolved in hexane, filtered hot with active carbon and recrystallized. There is obtained trans-p-[5-(4-n-pentylcyclohexyl)-2-pyrimidinyl]benzonitrile; melting point 100.5° C., clearing point 231° C.