Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=O)=[CH:4][CH:3]=1.[BH4-].[Na+].II.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:13][CH3:14])=[CH:6][CH:7]=1
Reactant: CNC(=O)CCCc1ccc(Cl)cc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCCCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23 %

Procedure:
At 0° C., a solution of of 4-(4-chlorophenyl)-N-methylbutyramide (3.80 g, 18.0 mmol) in tetrahydrofuran (60 ml) was added to a suspension of sodium borohydride (1.60 g, 43.1 mmol) in THF (60 ml). The mixture was stirred for 20 min at 0° C. A solution of iodine (4.6 g, 18.0 mmol) in THF (100 ml) was added dropwise. After the addition was finished, the reaction mixture was warmed to 70° C. It was stirred for 16 hours at this temperature. It was cooled to 0° C. Methanol (100 ml) was added dropwise. The solvents were removed in vacuo. The residue was dissolved in a 20% aqueous solution of sodium hydroxide (160 ml) and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×70 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using DCM/methanol/25% aqueous ammonia as eluent, to give 820 mg of N-[4-(4-chlorophenyl)butyl]-N-methylamine.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1(C)C=CC=CC=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=1>O1CCCC1.CO.C(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:12]([C:11]2[CH:15]=[CH:16][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:9][C:10]=2[N+:17]([O-:19])=[O:18])=[O:14])=[N:35][CH:36]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
4-(t-Butoxycarbonyl)-2-nitrobenzoic acid (1.0 g) is dissolved in tetrahydrofuran (50 ml), and thereto is added 28% sodium methoxide in methanol (0.72 g). After pouring toluene, the mixture is concentrated under reduced pressure. The resulting residue is suspended in chloroform (50 ml), and thereto are added oxalyl chloride (489 μl) and N,N-dimethylformamide (2 drops) followed by stirring at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, and chloroform (20 ml) is poured to the residue to give a suspension. 5-Chloro-2-aminopyridine (480 mg) and pyridine (453 μl) are dissolved in chloroform (30 ml), and the solution is ice-cooled. To the solution is added dropwise the suspension prepared above. The reaction solution is stirred at room temperature for 8 hours and concentrated under reduced pressure. The residue is diluted with ethyl acetate, washed successively with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to give t-butyl 4-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-nitrobenzoate (803 mg). APCI-MS M/Z: 378[M+H]+
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15](O)=[O:16])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:35][NH2:36]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15](=[O:16])[NH:36][CH3:35])=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: COc1ccc(-c2nn(Cc3ccccc3)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn(Cc2ccccc2)c1=O
Yield: 90.9 %

Procedure:
Using 2-benzyl-5,6-bis(4-methoxyphenyl)-4-carboxy-2H-pyridazin-3-one and methylamine hydrochloride as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained in a yield of 90.9%.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[N:11]([CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[C:10](=[O:30])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:31]>C(Cl)Cl>[ClH:31].[ClH:31].[CH:1]1([NH:7][C:8]2[C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[N:11]([CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[C:10](=[O:30])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Product: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(cyclohexylamino)-2-oxo-1-pent-4-en-1-yl-1,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate (785 mg, 1.88 mmol) in DCM (2 mL) was added HCl (1.64 mL, 6.56 mmol, 4N dioxane). The reaction mixture was stirred at rt for 1 h, concentrated in vacuo, taken in DCM and concentrated in vacuo again, to provide the desired product LRMS (M+1)=319.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:16]=1Cl>>[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:16]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=C(O)c1ccc2sc(S)nc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Product: O=C(O)c1ccc2sc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)nc2c1

Procedure:
2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carboxylic acid (255) was prepared (100%) from 2-mercapto-benzothiazol-5-carboxylic acid (240) and 1,2,3-trichloro-5-nitrobenzene, obtained from Aldrich, in a similar manner as described in example 251.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][C:27]1([CH3:36])O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.[OH:50][C:51]1[CH:83]=[CH:82][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]2=[O:81])=[CH:53][CH:52]=1>O1CCCC1.CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:36][O:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=3)([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:57]2=[O:81])=[CH:82][CH:83]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1(C)O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.4 %

Procedure:
A solution of 6.6 g of 1,1'-(azodicarbonyl)dipiperidine in 10 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous dimethylformamide was added dropwise to a mixture of 6.5 g of 1-t-butoxycarbonyl-2-hydroxy-methylindoline (prepared as described in Preparation 3), 6.5 ml of tributylphosphine, 12.2 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in European Patent Publication No. 549 365A1] and 100 ml of anhydrous tetrahydrofuran, and the resulting mixture was stirred at room temperature for about 20 hours. At the end of this time, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The concentrate thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.70 g of the title compound, melting at 85.4-87.2° C.
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=O)[CH2:13][CH2:14][C:15]=3[C:16]([Cl:18])=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:18][C:16]1[C:15]2[CH2:14][CH2:13][CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]=2[C:10]2[CH2:20][CH2:21][NH:6][CH2:7][CH2:8][C:9]=2[CH:17]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)N1CCc2cc(Cl)c3c(c2CC1)C(=O)CC3
Product: Clc1cc2c(c3c1CCC3c1ccccc1)CCNCC2

Procedure:
Example 10 was prepared in a similar fashion to Example 4, except Intermediate 4 was used as the starting material and phenylmagnesium bromide (3M in diethyl ether) was used instead of cyclopropylmagnesium bromide (Example 4, step (a)). NMR (300 MHz, CDCl3) δ 7.26-7.21 (m, 2H); 7.19-7.13 (m, 1H); 7.01 (s, 1H); 6.99-6.96 (m, 2H); 4.51-4.47 (m, 1H); 3.07-2.82 (m, 6H); 2.69-2.53 (m, 4H); 2.47-2.42 (m, 1H); 2.24-2.17 (m, 1H); 2.08-2.05 (m, 1H); MS: ESI (positive): 298, (M+1).
Reaction SMILES: [ClH:1].Cl.[NH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][C:5]1([CH3:11])[CH3:10].C(N(CC)CC)C.[F:19][C:20]([F:53])([F:52])[C:21]1[CH:22]=[C:23]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH:34]=O)[CH2:28][C@H:27]1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=1)=[O:25]>ClCCl>[ClH:1].[ClH:1].[F:53][C:20]([F:19])([F:52])[C:21]1[CH:22]=[C:23]([CH:45]=[C:46]([C:48]([F:49])([F:50])[F:51])[CH:47]=1)[C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH:34]=[N:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]2([CH3:11])[CH3:10])[CH2:28][C@H:27]1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=1)=[O:25]
Reactant: Cc1ccc(C[C@@H]2CN(CCC=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC1(C)COCCN1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CCC=NN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a stirred mixture of 4-amino-3,3-dimethylmorpholine dihydrochloride (122 mg) in dichloromethane (5 ml) was added triethylamine (61 mg) at ice bath temperature. A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethyl benzyl)-4-(2-formylethyl)piperazine (150 mg) in dichloromethane (2 ml) was added and the resulting mixture was stirred at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel using a mixture of hexane and ethyl acetate as eluent and the desired product was treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3,3-dimethylmorpholino-imino)propyl]piperazine dihydrochloride (122 mg).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3](OS(C)(=O)=O)[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1.[N-:29]=[N+:30]=[N-:31].[Na+].CS(C)=O>O>[N:29]([CH:3]([C:2]([F:28])([F:27])[F:1])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[N+:30]=[N-:31]
Reactant: CS(=O)(=O)OC(COC1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC(COC1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Temperature: 100 °C
Reaction time: 72 h
Yield: 25.6 %

Procedure:
A mixture of benzyl 4-{3,3,3-trifluoro-2-[(methylsulfonyl)oxy]propoxy}piperidine-1-carboxylate (1.31 g), sodium azide (1.00 g), 15-crown-5-ether (3.39 g) and dimethyl sulfoxide (5 mL) was stirred at 100° C. for 3 days. Water was added thereto, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (294 mg).
Reaction SMILES: [C:1]1([C:7]2([NH2:11])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:12]=[C:13]1[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31](O)=[O:32].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:12]=[C:13]1[C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31]([NH:11][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10][CH2:9][CH2:8]1)=[O:32]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NC1(c2ccccc2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NC1(c2ccccc2)CCC1
Reaction time: 8 h

Procedure:
A solution of 1-phenylcyclobutanamine (0.030 g, 0.204 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.055 g, 0.185 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.036 g, 0.185 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.31-7.39 (m, 7H), 7.17-7.31 (m, 8H), 6.42-6.44 (br s, 1H), 3.94 (s, 2H), 3.46 (t, J=6.5 Hz, 2H), 2.79 (t, J=6.5 Hz, 2H), 2.42-2.52 (m, 2H), 2.19-2.30 (m, 2H), 1.71-1.95 (m, 2H); MS (ESI−) m/z 423 (M−H)−.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:6]1[O:8][CH2:7]1>>[OH:8][CH:6]([CH2:5][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][NH:4][CH2:3][CH2:1][OH:2]
Reactant: CCCCCCCCCCCCCCCCOCC1CO1
Reactant: NCCO
Product: CCCCCCCCCCCCCCCCOCC(O)CNCCO
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
61.1 g (1.0 mol) of ethanolamine was introduced into a 200-ml four-necked flask equipped with a stirrer, a dropping funnel, a thermometer and a reflux condenser and heated to 60° to 70° C. under stirring. 24.3 g (0.082 mol) of hexadecyl glycidyl ether was added dropwise thereto over a period of 45 minutes. After the completion of the addition, the resulting mixture was stirred by heating under the same conditions as those described above for additional two hours. Then unreacted ethanolamine was distilled off under reduced pressure (79° to 81° C./20 Torr). The residue was purified by silica gel flash column chromatography to thereby give 18.4 g of the compound (IVa) at a yield of 63%. The 1H-NMR data of the obtained compound are as follows:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH:20]2[CH:16]1[CH2:17][N:18]([C:21]([C:23]1[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[Cl:32])[CH:24]=1)=[O:22])[CH2:19]2)(C)(C)C>C(Cl)Cl>[NH2:14][CH:15]1[CH:16]2[CH:20]1[CH2:19][N:18]([C:21]([C:23]1[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[Cl:32])[CH:24]=1)=[O:22])[CH2:17]2
Reactant: CC(C)(C)OC(=O)NC1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC12
Yield: 119.1 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a suspension of {3-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-carbamic acid tert-butyl ester (1.43 g, 3.63 mmol) in CH2Cl2. After 24 h the reaction mixture was concentrated, and the resulting oil was purified on silica gel by flash column chromatography CH2Cl2/MeOH (80/20) to afford the title compound as a white solid (1.27 g, 99%). MS: 294.2/296.2 (MH+); HPLC Rf: 3.085 min.; HPLC purity: 97%.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:7][O:8]C(=O)C)(=[O:3])[NH2:2].C(OC[C@@H](C1C=CC=CC=1)COC(=O)C)(=O)N>>[C:1]([O:4][CH2:5][C@@H:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:7][OH:8])(=[O:3])[NH2:2]
Reactant: CC(=O)OC[C@@H](COC(N)=O)c1ccccc1C
Agent: CC(=O)OC[C@@H](COC(N)=O)c1ccccc1
Product: Cc1ccccc1[C@@H](CO)COC(N)=O
Yield: 78.3 %

Procedure:
The title compound was synthesized in a similar manner to that of Example XXII, except that (S)-3-acetoxy-2-(o-methylphenyl)propanol carbamate, instead of (S)-3-acetoxy-2-phenylpropanol carbamate, was used as a starting material. Yield 78.3%. Purity 99.0%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)[CH3:18].O>CN(C=O)C>[CH2:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[O:9][CH3:10])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCc1ccc(CCl)cc1
Reactant: COc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(COc2ccc(I)cc2OC)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 4-iodo-2-methoxyphenol (90 g) in DMF (450 mL) were added K2CO3 (60 g) and 4-ethylbenzyl chloride (58 g) at RT. The reaction mixture was stirred at 80° C. for 3 hr. Water (900 mL) was added to the reaction mixture. The precipitated solid was collected on a filter and dried under reduced pressure. The suspension of this solid in heptane (520 mL) was stirred at RT. The precipitated solid was collected on a filter and dried under reduced pressure to give the title compound (115 g, 87%).
Reaction SMILES: C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:15][N:16]1[C@@H:32]2[CH2:33][C:21]3[CH:22]=[CH:23][C:24]([O:35][CH3:36])=[C:25]4[O:26][C@H:27]5[C@@H:28]([OH:34])[CH:29]=[CH:30][C@@H:31]2[C@:19]5([C:20]=34)[CH2:18][CH2:17]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1CCCCC1>[CH3:15][N:16]1[C@@H:32]2[CH2:33][C:21]3[CH:22]=[CH:23][C:24]([O:35][CH3:36])=[C:25]4[O:26][C@H:27]5[C:28]([CH2:29][CH2:30][C@@H:31]2[C@:19]5([C:20]=34)[CH2:18][CH2:17]1)=[O:34]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: [Rh]
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCCCC1
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Yield: 94 %

Procedure:
Benzophenone (6.22 g), cyclohexane (22 mL), dried codeine (1.38 g) and chlorotris(triphenylphosphine)rhodium (I) (Wilkinson's catalyst) (0.22 g) were charged into a glass hydrogenation bottle. The bottle was evacuated and filled with hydrogen. The mixture was magnetically agitated at ambient temperature (24–28° C.) while the hydrogen pressure was maintained at 5–15 psi until the pressure drop caused by the hydrogen consumption stopped. A solution of potassium tert-amylate in cyclohexane (12 mL, 15.4% w/w) was charged into the bottle with the reaction mixture in one portion, the mixture was magnetically agitated under nitrogen at ambient temperature for 4 hours and quenched by adding 1.5N acetic acid (13 mL) to the solution with mixing and cooling in an ice bath. Alternatively, in another embodiment the solution may be quenched by adding the solution to 1.5N acetic acid with mixing and cooling in an ice bath. The mixture was filtered, aqueous layer was separated and the organic layer was extracted with 1.5N acetic acid (2 mL). Combined aqueous layer (14.5 mL) according to the assay by HPLC contains 89.7 mg/mL hydrocodone (94% yield), purity 95 area %.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH:13]1[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1
Reactant: OC1CCOCC1
Reactant: Oc1cc(F)cc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(F)cc(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 3,5-difluorophenol (1.0 equiv.), tetrahydro-2H-pyran-4-ol (1.2 equiv.), and triphenylphosphine (2.0 equiv.) in THF (0.33 M) at 0° C. was added DIAD (2.0 equiv.) dropwise. The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by flash chromatography over silica gel (heptanes:ethyl acetate gradient) to give 4-(3,5-difluorophenoxy)tetrahydro-2H-pyran in 90% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.72-1.84 (m, 2H), 1.96-2.09 (m, 2H), 3.59 (ddd, J=11.64, 8.31, 3.52 Hz, 2H), 3.90-4.04 (m, 2H), 4.44 (tt, J=7.78, 3.77 Hz, 1H), 6.32-6.53 (m, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH:5]1[N:6]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]3[N:29]=[N:30][NH:31][N:19]=3)=[CH:20][CH:21]=2)[C:7](=[O:10])[CH2:8][CH2:9]1
Reactant: N#Cc1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C1CCC(CCC(O)Cc2ccccc2)N1CCCc1ccc(-c2nn[nH]n2)cc1
Yield: 82.3 %

Procedure:
Analogous to the procedure described for Example 4A, Step E, 4-{3-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-propyl}-benzonitrile (157.8 mg, 0.419 mmol) was reacted with azidotrimethylsilane (0.11 mL, 0.84 mmol) and dibutyltin oxide (20 mg, 0.08 mmol) in toluene (8.6 mL) heated under reflux for 60 h. Purification by medium pressure chromatography (CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2 to 6% MeOH in CH2Cl2) provided 5-(3-hydroxy-4-phenyl-butyl)-1-{3-[4-(2H-tetrazol-5-yl)-phenyl]-propyl}-pyrrolidin-2-one (144.7 mg). 1H NMR (CDCl3) δ8.02 (m, 2H), 7.27 (m, 7H), 3.84 (m, 1H), 3.67 (m, 2H), 3.10 (m, 1H), 2.84 (m, 1H), 2.67 (m, 2H), 2.53 (m, 1H), 2.42 (m, 1H), 2.14 (m, 1H), 1.97-1.40 (m, 9H); MS 420.3 (M+1), 418.3 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:12][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: NC1CC1
Reactant: Clc1ncc(Br)cn1
Solvent: C1CCOC1
Product: Brc1cnc(NC2CC2)nc1
Yield: 95.1 %

Procedure:
A solution of 5-bromo-2-chloropyrimidine (3.87 g, 20 mmol) and cyclopropylamine (5.7 g, 0.1 mol) in 20 mL THF was heated at 65° C. for 5 hrs in a sealed tube. The mixture was evaporated in vacuo, to the residue ethanol was added, after filtration, the cake was washed with ethanol to give 4.07 g product as a colorless solid (95.5%). 1H NMR (300 MHz, CDCl3) δ: 8.32 (2H, s), 5.58 (1H, brs), 2.72 (1H, brs), 0.82-0.84 (2H, m), 0.54 (2H, brs). LCMS: m/z [M+H]+ 214.0011.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][CH2:28]Br>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([F:23])[CH:25]=2)[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Fc1cccc(CCBr)c1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(N(CCc2cccc(F)c2)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example 36A) and 3-fluorophenethylbromide (1.38 g, 6.7 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 409 (M+H)+.