Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]([OH:12])=O)=[CH:8][CH:9]=1)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:12])[NH:28][CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: NCc1cccc2ccccc12
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(C(=O)NCc2cccc3ccccc23)s1
Reaction time: 0.17 h

Procedure:
1.9 g Thiophene-2,5-dicarboxylic acid monomethyl ester and 1.2 mL N-methylmorpholine is dissolved in 20 mL of CH2Cl2 at −10° C. To this solution is added 1.5 mL isobutyl chloroformate. After 10 min of stirring, 1.7 mL 1-(aminomethyl)-naphthalene in 5 mL of CH2Cl2 is added. The cooling bath is removed and the reaction mixture is allowed to reach rt. After 90 min, 10 mL of water and 10 mL 2N HCl are added. The phases are separated, and the organic phase is washed with water. After evaporation of the solvent there is obtained 4.4 g crude 5-[(naphtalen-1-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (1b) which is purified by recrystalisation from ethylacetate, petrol ether, yielding 58%, mp 125° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([O:11][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[C:4]=2[CH:3]=1
Reactant: OC1CCCCc2ccc(Br)cc21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Brc1ccc2c(c1)C(OC1CCCCO1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.88 g (7.8 mmol) of (±)-3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol, 1.07 mL (11.7 mmol, 1.5 equiv) of 3,4-dihydro-2H-pyran, and 0.20 g (0.80 mmol, 0.1 equiv) of pyridinium p-toluenesulfonate in 38 mL of methylene chloride was stirred under nitrogen at ambient temperature overnight. The mixture was diluted with 115 mL of ether, washed with 45 mL of half-saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to give 2.8 g of a cloudy oil. Purification by flash chromatography (5-30% ethyl acetate in hexanes) gave the product as a colorless oil. MS (m+1)=327.0; 1H NMR (400 MHz, CDCl3) 7.68 (s, 0.5H), 7.39 (d, 0.5H, J 2 Hz), 7.25 (m, 1H), 6.95 (m, 1H), 4.90 (t, 0.5H, J 3 Hz), 4.80 (m, 1H), 4.48 (t, 0.5H, J 3 Hz), 3.95 (m, 0.5H), 3.67 (m, 0.5H), 3.52 (m, 0.5H), 3.42 (m, 0.5H), 2.85 (m, 1H), 2.67 (m, 1H), 2.10-1.83 (m, 3.5H), 1.82-1.52 (m, 8H), 1.43 (m, 0.5H).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@H:6]1[O:15][C@H:16]1[C@@H:31]([O:32][C@@H:33]2[O:40][C@H:39]([CH2:41][OH:42])[C@@H:37]([OH:38])[C@H:35]([OH:36])[C@H:34]2[NH:43][C:44](=[O:46])[CH3:45])[C@@H:30]([CH2:47][OH:48])[O:29][C@@H:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C@@H:17]1[OH:49])(=[O:3])[CH3:2].C1C(=O)NC(=O)NC=1[C@@H]1O[C@H](COP(OP(O[C@H:73]2[O:78][C@H:77]([CH2:79][OH:80])[C@H:76]([OH:81])[C@H:75]([OH:82])[C@H:74]2[OH:83])(O)=O)(O)=O)[C@@H](O)[C@H]1O>[As](C)(C)(=O)[O-].[Na+].[Cl-].[Mn+2].[Cl-]>[C@@H:18]1([O:12][C@@H:9]2[C@@H:8]([CH2:13][OH:14])[O:7][C@@H:6]([O:15][C@H:16]3[C@@H:31]([O:32][C@@H:33]4[O:40][C@H:39]([CH2:41][OH:42])[C@@H:37]([O:38][C@@H:73]5[O:78][C@H:77]([CH2:79][OH:80])[C@H:76]([OH:81])[C@H:75]([OH:82])[C@H:74]5[OH:83])[C@H:35]([OH:36])[C@H:34]4[NH:43][C:44](=[O:46])[CH3:45])[C@@H:30]([CH2:47][OH:48])[O:29][C@@H:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C@@H:17]3[OH:49])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@H:10]2[OH:11])[O:29][C@H:30]([CH2:47][OH:48])[C@H:31]([OH:32])[C@H:16]([OH:15])[C@H:17]1[OH:49]
Reactant: COC(=O)CCCCCO[C@@H]1O[C@H](CO)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H]1O
Reactant: O=c1cc([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)[nH]c(=O)[nH]1
Agent: [Mn+2]
Agent: C[As](C)(=O)[O-]
Agent: [Cl-]
Product: COC(=O)CCCCCO[C@@H]1O[C@H](CO)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2NC(C)=O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2NC(C)=O)[C@H]1O
Reaction time: 22 h

Procedure:
A solution of compound 18 of Example 18 (60 mg), UDP-galactose, (145 mg), bovine galactosyltransferase (6.25 U) and bovine serum albumin (3 mg) in 30 mM sodium cacodylate buffer (5.25 mL, pH 7.0) containing manganese chloride (40 umol) was incubated at 37° C. for 22 h. The reaction mixture was diluted to 20 mL and purified as described in Example 21. Yield of the product was 47 mg. The structural identity of titled compound 24 was unanbiguously assigned by 1H- and 13C-n.m.r (see Tables 4 and 5, respectively).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[CH:4][C:3]=1[CH3:16].[CH:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH2:14]([O:13][CH2:12][CH2:11][O:10][C:5]1[CH:4]=[C:3]([CH3:16])[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:17]=[O:18])[CH:24]=2)=[C:7]([CH3:8])[C:6]=1[CH3:9])[CH3:15]
Reactant: CCOCCOc1cc(C)c(Br)c(C)c1C
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1C
Temperature: 90 °C
Reaction time: 64 h
Yield: 27.7 %

Procedure:
A mixture of 2-bromo-5-(2-ethoxyethoxy)-1,3,4-trimethylbenzene (1.16 g, 4.04 mmol), 3-formylphenylboronic acid (0.67 g, 4.44 mmol), tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol), cesium carbonate (3.2 g, 9.7 mmol), water (4.8 mL) and 1,2-dimethoxyethane (15 mL) was stirred under a nitrogen atmosphere at 90° C. for 64 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (0.35 g, yield 28%) as a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])O)=[O:5])C.[NH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][N:27]=1>>[Br:24][C:8]1[N:9]([CH:21]([CH3:22])[CH3:23])[C:10]2[CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[CH3:20])[N:25]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][N:27]=3)[C:4](=[O:5])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
Reactant: Nc1cc(Cl)ccn1
Product: Cc1cc(Cl)ccc1C1c2c(nc(Br)n2C(C)C)C(=O)N1c1cc(Cl)ccn1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate C) and 2-amino-4-chloro-pyridine as starting materials. tR: 1.42 min (LC-MS 1); ESI-MS: 527.2 [M+H]+ (LC-MS 1).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N:34]([CH2:37][CH2:38][O:39][CH3:40])=[C:35]=[S:36]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[CH:8]=3)[N:3]=[C:2]([NH:1][C:35]([NH:34][CH2:37][CH2:38][O:39][CH3:40])=[S:36])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N)nc(-c3cccc(Cl)c3)c2c1
Reactant: COCCN=C=S
Solvent: C1CCOC1
Solvent: O
Product: COCCNC(=S)Nc1nc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: 60 °C
Yield: 2.4 %

Procedure:
A mixture of 2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.00021 mol), obtained in Example B19, and 1-isothiocyanato-2-methoxy-ethane (3 equiv, 0.00063 mol) in THF (1 ml) was heated at 60° C. for 5 hours. A few drops of water were added. The mixture was evaporated till dryness and purified by HPLC. The pure fractions were collected and the solvent was evaporated, yielding 0.003 g (2.4%) of N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinazolinyl]-N′-(2-methoxyethyl)-thiourea, MS(ESI) m/z: 593 595 597.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[C:15]([N:17]1[CH2:20][CH:19]([N:21]2[CH2:26][CH2:25][N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22]2)[CH2:18]1)=[O:16])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[C:15]([N:17]1[CH2:20][CH:19]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[CH2:18]1)=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2CCC1C(=O)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N1c2ccc(Br)cc2CCC1C(=O)N1CC(N2CCNCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a solution of compound 25d (261 mg, 0.505 mmol) in MeOH (3 mL) was added K2CO3 (140 mg, 1.01 mmol). The reaction mixture was stirred at room temperature for 30 min. The resultant mixture was filtered, the filtrate concentrated under reduced pressure, and the resultant residue partitioned between CH2Cl2 and H2O. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 25e (158 mg). LC/MS m/z (M+H+) 421.0, (M+2H+) 423.0.
Reaction SMILES: [CH:1]([C:19]([O:21]CC1C=CC=CC=1)=[O:20])([C:9]([O:11]CC1C=CC=CC=1)=[O:10])[C@H:2]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:3]>CO.[Pd]>[CH2:7]([O:6][C:4](=[O:5])[C@@H:2]([CH:1]([C:19]([OH:21])=[O:20])[C:9]([OH:11])=[O:10])[CH3:3])[CH3:8]
Reactant: CCOC(=O)[C@H](C)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@H](C)C(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (R)-1,1-dibenzyl 2-ethyl propane-1,1,2-tricarboxylate (11 g, 0.029 mol) in MeOH (500 ml) was added Pd/C (wet, 2 g), and then the mixture was stirred under hydrogen atmosphere at room temperature overnight. After filtered the Pd/C, the solvent was removed under reduced pressure to afford (R)-2-(1-ethoxy-1-oxopropan-2-yl)malonic acid, which was purified by silica gel chromatography (3.5 g, 60%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:41][CH3:42])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:39][C:37]([F:38])([F:40])[C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=1)[CH2:26][N:13]([C@H:11]1[CH2:10][C@@H:9]([CH2:41][CH3:42])[NH:8][CH2:12]1)[C:14]1[N:15]=[CH:16][C:17]([C:20]2[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=2)=[CH:18][N:19]=1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 2 mmol) in CH2Cl2 (20 mL) is added trifluoroacetic acid (7 mL) at room temperature. The reaction mixture is stirred at room temperature for 1.5 hours. The mixture is quenched with saturated aqueous NaHCO3 solution, then extracted with CH2Cl2. The combined organic layer is washed by saturated aqueous NaHCO3 solution, then dried over Na2SO4 and concentrated under reduced pressure to give (3,5-bis-trifluoromethyl-benzyl)-((3S,5R)-5-ethyl-pyrrolidin-3-yl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine as a yellow oil (1.01 g, quant.). ESI-MS m/z: 499 [M+1]+, Retention time 1.84 min (condition A).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Reaction time: 8 h

Procedure:
To a solution of Intermediate 54 (1.4 g, 4.37 mmol) in methanol (50 mL) was added palladium on charcoal (10%, 0.143 g). The reaction mixture was hydrogenated under a balloon pressure at room temperature overnight. The catalyst was filtered through Celite® and the solvent removed under reduced pressure to give the title compound as a solid, which was used in the next step without further purification. MS (M+): 238.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C@:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)([CH2:22][CH2:23][CH2:24][OH:25])[CH2:12][N:13]([CH3:21])[C:14](=[O:20])[CH2:15][C:16]([F:19])([F:18])[F:17])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.O>CS(C)=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C@:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)([CH2:22][CH2:23][CH:24]=[O:25])[CH2:12][N:13]([CH3:21])[C:14](=[O:20])[CH2:15][C:16]([F:19])([F:17])[F:18])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C[C@](CCCO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)Oc1ccccc1)C(=O)CC(F)(F)F
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C[C@](CCC=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)Oc1ccccc1)C(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.4 %

Procedure:
Under argon, phenyl[1-(3,3,3-trifluoro-N-methylpropanamido)-2-(S)-(3,4-dichlorophenyl)-5-hydroxy-pentan-2-yl]methylcarbamate (100 mg) was dissolved in anhydrous dimethyl sulfoxide (1.0 mL). At room temperature, triethylamine (0.16 mL) and pyridine sulfur trioxide complex (94 mg) were added thereto, and the mixture was stirred for 4 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, to thereby give the title compound (115 mg).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH2:11]1[CH2:14][CH:13]([CH2:15][N:16]2[C@@H:26]3[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[C:30]5[O:35][C@H:20]6[C:21]([CH2:23][CH2:24][C@:25]3([OH:36])[C@:19]6([C:29]=45)[CH2:18][CH2:17]2)=[O:22])[CH2:12]1>C(#N)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[CH:33]1[C:28]2[CH2:27][C@H:26]3[N:16]([CH2:15][CH:13]4[CH2:14][CH2:11][CH2:12]4)[CH2:17][CH2:18][C@:19]45[C@H:20]([C@@H:21]([OH:22])[CH2:23][CH2:24][C@@:25]34[OH:36])[O:35][C:30]([C:29]=25)=[C:31]([OH:34])[CH:32]=1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CCC2)[C@H]1O5
Agent: Cl[Ru]Cl
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Oc1ccc2c3c1O[C@H]1[C@@H](O)CC[C@@]4(O)[C@@H](C2)N(CC2CCC2)CC[C@]314
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Into a dried flask was added triethylamine (0.87 g, 8.6 mmol, 1.2 mL) and acetonitrile (5 mL). To this solution was added >96% HCO2H (0.99 g, 21.5 mmol, 0.81 mL). After stirring under nitrogen for 15 minutes, N-(cyclobutylmethyl)-noroxymorphone (1.02 g, 2.9 mmol) was added. Then, dichloro(p-cymene)ruthenium (II) dimer (10 mg, 0.0163 mmol) followed by (1S,2S)-(+)-N-tosyl-diphenylethylene diamine (12 mg, 0.033 mmol) were added. This reaction was stirred for 72 hours at room temperature. HPLC analysis indicated that the reaction was complete. The reaction mixture was evaporated under reduced pressure forming a thick brown oil. Slurring the oil in acetonitrile (15 mL) for 18 hours yielded a brown solid. The solid was isolated by filtration, which was washed with acetonitrile (10 mL). Drying the solid yielded nalbuphine (0.85 g, 83% yield, 6-α: 99%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])=[O:12])[C:4]=2[CH:3]=1.[CH2:25]([SH:31])[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1.N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17][S:31][CH2:25][C:26]3[O:30][CH:29]=[CH:28][CH:27]=3)=[O:12])[C:4]=2[CH:3]=1
Reactant: SCc1ccco1
Reactant: C=CC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: O=C(CCSCc1ccco1)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
A solution of 8-chloro-N-(2-oxo-3-butenyl)dibenz[b,f][1,4]oxazepin-10(11H)-carboxamide (0.75 gram), furfuryl mercaptan (0.23 mL), piperidine (0.069 mL), and N-benzyltrimethylammonium hydroxide (0.069 mL) in methylene chloride (12 mL) and methanol (3 mL) was stirred at room temperature for 6 hours. The reaction was diluted with methylene chloride (75 mL), washed with 75 mL each of 1N HCl (two times), water, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 95:5 methylene chloride: ethyl acetate to yield a colorless oil. Analysis calculated for C23H21ClN2O4S×0.1 EtOAc: C, 60.34; H, 4.72; N, 6.01; Cl, 7.61; S, 6.88. Found: C, 59.94; H, 4.84; N, 5.87; Cl, 8.13; S, 6.65.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[C:28]2[C:7]([CH2:8][C@:9]3([CH2:27]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[C:10]3=[O:26])=[CH:6][C:5]=1[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])([O-:3])=[O:2].Cl.[OH-].[Na+].C(N)CN>CO>[N+:1]([C:4]1[CH:29]=[C:28]2[C:7]([CH2:8][C@:9]3([CH2:27]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]3=[O:26])=[CH:6][C:5]=1[CH2:30][C:31]([OH:33])=[O:32])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Cc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: NCCN
Product: O=C(O)Cc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Reaction time: 18 h

Procedure:
A solution of tert-butyl ((2S)-6-nitro-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetate from Step C (2.01 g, 3.83 mmol) in MeOH (25 mL) was saturated with HCl (g) and stood at ambient temperature for 18 h. The mixture was concentrated to dryness in vacuo, then redissolved in MeOH (25 mL). This stirred solution was adjusted to pH 10 with 10 N NaOH and ethylene diamine (0.26 mL, 3.83 mmol) was added. The resulting mixture was stirred for 3 h, then concentrated to dryness in vacuo. The residue was dissolved in THF (25 mL) and 1 N NaOH (25 mL, 25 mmol) was added. The mixture was stirred at ambient temperature for 18 h, then the THF was removed under reduced pressure. The residual mixture was partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (100 mL). The organic layer was discarded and the aqueous layer was adjusted to pH 2 with aqueous HCl, then extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=340 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1I.C(N(CC)CC)C.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>CN(C)C=O.ClCCl.CCCCCC>[OH:28][CH2:24][CH2:25][C:26]1[O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:4][C:3]=2[CH:27]=1
Reactant: N#Cc1ccc(-c2ccc(O)c(I)c2)cc1
Reactant: C#CCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc3oc(CCO)cc3c2)cc1
Temperature: 65 °C
Reaction time: 12 h
Yield: 94.2 %

Procedure:
To a solution of Example 1A (5.19 g, 16.2 mmol), triethylamine (5.60 ML, 40.4 mmol) and 3-butyn-1-ol (1.90 g, 27.2 mmol) in dimethylformamide (13 mL) at 20° C. was added cuprous iodide (0.46 g, 2.4 mmol) and bis-triphenylphosphine palladium dichloride (0.56 g, 0.80 mmol). The mixture was stirred at 65° C. for 12 hours then cooled to ambient temperature and diluted with dichloromethane (20 mL) and hexane (100 mL). Celite (5 g) was added with stirring and the solids were removed by filtration. The filtrate was washed with water (600 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (3×100 mL). The combined organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure to give a tan solid. The solid was chromatographed on silica with 3% methanol in dichloromethane to give the titled compound (4.02 g, 95%). MS (DCI) m/z 263 (M+H)+;
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=[O:14].[Na+]>OS(O)(=O)=O.O.[O-]S([O-])(=O)=O.[Cu+2]>[OH:14][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)ccc1C
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: COC(=O)c1cc(O)ccc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a 0° C. solution of methyl 5-amino-2-methylbenzoate (6.25 g, 37.8 mmol) in H2SO4 (10 mL) and H2O (160 mL) was added NaNO2 (aq., 3.78 N, 10 mL). The resulting mixture was stirred at 0° C. for 10 minutes. After 10 minutes, the mixture was added to a refluxing solution of CuSO4 (1 N, 100 mL) and refluxed for 1 hour. The mixture was cooled to room temperature and extracted with CH2Cl2 (2×200 mL). The organic layers were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=5:1) to give methyl 5-hydroxy-2-methylbenzoate (134a, 4.2 g, 67%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([OH:25])[CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH:11]([OH:25])[CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCc2cc(OCC(O)CSc3ccc(Cl)c(Cl)c3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCC(O)CS(=O)c3ccc(Cl)c(Cl)c3)ccc2N1

Procedure:
The 6-[3-(3,4-dichlorophenyl-mercapto)-2-hydroxy-propoxy]-3,4-dihydro-carbostyril thus obtained, was oxidized analogous to Example 123 with hydrogen peroxide.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1C#N>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:20]3[CH:21]=[N:22][C:23]([C:19]#[N:18])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: N#Cc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone and 0.01 mole of 4-amino-5-imidazolecarbonitrile in 30 ml. of glacial acetic acid is refluxed for 6 hours. The solvent is removed under reduced pressure and worked up as for Example 29 to give the product as crystals, m.p. 168°-169° C.