Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:14].Cl.[Cl:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][SH:32])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:16].[ClH:14].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[SH:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:34][CH:33]=3)[CH2:24][CH2:25]2)[OH:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Reactant: CCCCc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(NC(O)=[SH]CCCN2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Yield: 49.7 %

Procedure:
The procedure described in Example 2 was followed, using 1.4 g of 4-n-butylphenyl isocyanate, 3.0 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 0.8 g of triethylamine and 50 ml of methylene chloride, to give 1.1 g (25% of theory) of N-(4-n-butylphenyl)-S-{3-[4-(4-chlorophenethyl)piperazin-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 252°-254° C.
Reaction SMILES: [C:1]1([C:7]([OH:12])([CH2:9][CH:10]=C)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:13]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[C:1]1([C:7]([OH:12])([CH3:8])[CH2:9][CH2:10][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[O+][O-]
Reactant: C=CCC(C)(O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-phenylpent-4-en-2-ol (74 g, 0.457 mol) in dry CH2Cl2 (1 L) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH4 (42.8 g, 1.143 mol) was added to the mixture in portions at −20° C. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3-phenylbutane-1,3-diol (67.8 g), which was used for the next step without purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=2[C:9]=1[CH3:10].[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(OCC)(=O)C.C(O)C>[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][C:4]2[C:5](=[O:19])[O:6][C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=3[C:9]=2[CH3:10])[CH2:23][CH2:22]1
Reactant: COc1cc(OC)c2c(C)c(CCCl)c(=O)oc2c1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(OC)c2c(C)c(CCN3CCC(O)(c4ccccc4)CC3)c(=O)oc2c1
Yield: 41 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 39) and 4-hydroxy-4-phenylpiperidine; yield 41%; m.p. 177.5°-179° C. (from ethyl acetate/ethanol).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]2[C:33]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]([F:52])([F:51])[F:50])=[N:39][C:34]=3[N:35]=[C:36]([Cl:38])[N:37]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C(#N)C>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]2[C:33]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]([F:52])([F:51])[F:50])=[N:39][C:34]=3[N:35]=[C:36]([Cl:38])[N:37]=2)=[CH:29][CH:30]=1)([CH3:24])([CH3:22])[CH3:23].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)Nc1ccccc1
Agent: CC(C)(C)c1ccc(Nc2nc(Cl)nc3nc(-c4ccccc4C(F)(F)F)ccc23)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of diisopropylethylamine (260 mg, 2.0 mmol) in acetonitrile (5 mL), add t-butylaniline (124 mg, 1.0 mmol) followed by (4-tert-Butyl-phenyl)-[2-chloro-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-amine (310 mg, 1.0 mmol). Heat the mixture to 80° C. for six hours. Evaporate the solvent, and partition between 1M NaOH and EtOAc. Dry the solvent (Na2SO4) and evaporate. Purify by silica gel chromatography (1:1 hexanes/EtOAc to furnish the monoaniline (4-tert-Butyl-phenyl)-[2-chloro-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-amine as a yellow solid.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([O:13][C:14](=[O:22])[NH:15][C@@H:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21])([CH3:12])([CH3:11])[CH3:10]>CO>[C:9]([O:13][C:14]([NH:15][C@@H:16]([CH2:20][CH2:19][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[C:17]([OH:21])=[O:18])=[O:22])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCOC1=O
Reactant: Sc1ccccn1
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCSc1ccccn1)C(=O)O
Temperature: 100 °C
Yield: 26.8 %

Procedure:
Clean sodium metal (0.205 g, 8.95 mmol) was added, in portions, to anhydrous methanol (20 mL) in a thick walled tube. The suspension was stirred under anhydrous nitrogen until all the metal had dissolved, then pyridine-2-thiol (1.0 g, 8.95 mmol) was added. After stirring for 20 min, (2-oxotetrahydro-furan-3(R)-yl)-carbamic acid tert-butyl ester (1.8 g, 8.95 mmol) was added as a solid and the tube was capped and heated to 100° C. for 16 h. The reaction mixture was concentrated, then purified via flash chromatography (MeOH, CH2Cl2 as eluent) to give 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyric acid (0.75 g) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.C[O-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CO>[CH2:23]([S:12][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC(SCc1ccccc1)=N2
Reaction time: 0.5 h

Procedure:
To a solution of 1.43 parts of 7-chloro-5phenyl-3-H-1,4-benzodiazepine-2-thione in 12.5 parts by volume of 0.4 N sodium methoxide in methanol is added dropwise with stirring 0.6 part by volume of benzyl bromide and the stirring is continued for an additional 30 minutes. Water is added to the reaction mixture and the resulting oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried over sodium sulfate. Evaporation of the solvent yields 2-benzylmercapto-7-chloro-5-phenyl-3H-1,4-benzodiazepine as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.C1C(=O)N([Br:41])C(=O)C1.CCOCC>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[Br:41])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Temperature: -60 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
A solution of 15 (137 mg, 0.366 mmol) in freshly distilled THF (7.3 mL) and cooled to -78° C. under Ar was treated with 10 μL of a 1 μL/mL solution of H2SO4 in THF and the solution was stirred for 20 min before the addition of NBS (78 mg, 439 mmol, 1.2 equiv). The reaction mixture was allowed to warm to -60° C. and was stirred for 4 h at which time the reaction was complete by TLC. Et2O (7.3 mL) was added and the resulting organic phase was washed with 5% aqueous NaHCO3 (1×10 mL), saturated aqueous NaCl (1×10 mL), dried (MgSO4), and concentrated in vacuo. Chromatography (SiO2, 2×20 cm, 10% EtOAc-hexane) afforded 16 (145 mg, 166 mg theoretical, 87%) as a white crystalline solid: mp 179° C. dec (white needles, 10% EtOAc-hexane); 1H NMR (CDCl3, 250 MHz) δ8.40 (s, 1H, C8-H), 8.26 (d, 1H, J=8.5 Hz), 8.23 (s 1H, C3-H), 7.5-7.3 (m, 6H), 5.23 (s, 2H), 1.58 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ154.4, 152.4, 137.0, 136.0, 132.2, 132.0, 128.7, 128.6, 128.4, 128.0, 124.9, 124.8, 124.2, 119.1, 111.9, 102.0, 81.9, 70.8, 28.3; IR (KBr) vmax 3416, 2978, 2230, 1738, 1623, 1603, 1570, 1498, 1405, 1364, 1335, 1229, 1158, 990, 970, 878, 850, 823, 758, 696 cm-1 ; FABHRMS (NBA-CsI) m/z 584.9793 (M+ +Cs, C23H21BrN2O3 requires 584.9790).
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH:34]([C:37]([OH:39])=O)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.CONC.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][O:8][N:9]([CH3:10])[C:37]([CH:34]1[CH2:35][CH2:36][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:33]1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
HATU (4.56 g, 12.0 mmol) was added to 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.15 g, 10.0 mmol), N-methoxy-N-methylamine hydrochloride (1.16 g, 12.0 mmol), and triethylamine (4.18 mL, 30.0 mmol) in DCM (50.0 mL), and the resulting mixture was allowed to stir at rt. After 12 h, the reaction mixture was diluted with DCM, and the combined organics were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-18a. m/z (ES) 259 (MH)+.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:25][CH2:26][CH2:27][Cl:28])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 80 °C
Reaction time: 18 h
Yield: 44.5 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.82 g, 2.7 mmol) in dry DMF (12 mL) is added 1-bromo-3chloropropane (1.28 g, 8.1 mmol) and potassium carbonate (1.12 g, 8.1 mmol). The mixture is heated at 80° C. for 6 h. The mixture is then stirred at room temperature for 18 h followed by another 6 h at 80° C. The mixture is partitioned between water and CH2Cl2. The organic layer is washed 3 times with water (100 mL). The organic layer is then dried over anhydrous sodium sulfate and concentrated. Column chromatography (60 mL silica) using hexanes/CH2Cl2 (1:1) as eluent gave an oil which is rechromatographed (60 mL silica) using hexanes/CH2C]2 (60/40) as eluent gave 0.454 g (44%) of the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:18][CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:8][C:9]([NH:17][C:20](=[O:21])[CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:18])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C(=O)Cl)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C(=O)NC(C)(C)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Into a 200 ml four-necked flask, there were charged toluene (100 ml), α,α-dimethylbenzylamine (9 g) and pyridine (5.8 g), and α-methyl-tert-butylacetyl chloride (9.9 g) was dropwise added thereto while stirring at room temperature. Stirring was continuted for 3 hours. The reaction mixture was washed with water to remove pyridine hydrochloride. After the toluene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 13.8 g of N-(α,α-dimethylbenzyl)-α-methyl-tert-butylacetamide. M.P., 162.5°-163.5° C.
Reaction SMILES: C([O:4][CH:5]1[O:22][C@H:21]([C:23]([O:25][CH3:26])=[O:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(N)C1C=CC=CC=1>CN(C=O)C>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([C:23]([O:25][CH3:26])=[O:24])[O:22][CH:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: COC(=O)[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: NCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Methyl 1,2,3,4-tetra-O-acetyl-D-glucopyranuronate F13-2 (1.2 g, 3.2 mmol) was dissolved in dry DMF (10 mL) under N2. To the solution, benzylamine (0.42 mL, 3.8 mmol) was added. The mixture was stirred at r.t. for 16 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (Hexane:EtOAc=1:2, by volume) to afford a white solid F13c in 84% yield. 1H NMR (600 MHz, CDCl3) δ 5.50-5.55 (m, 1H), 5.11-5.27 (m, 1H), 4.85-4.91 (m, 1H), 5.39-4.56 (m, 2H), 3.70-3.72 (m, 3H), 1.99-2.05 (m, 9H). 13C NMR (150 MHz, CDCl3) δ 170.68, 170.45, 170.34, 170.30, 169.94, 169.81, 168.77, 167.83, 95.59, 90.36, 72.98, 72.66, 71.81, 70.97, 69.73, 69.61, 69.34, 68.12, 53.21, 53.11, 20.85, 20.84, 20.77, 20.70, 20.66, 20.65.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[O:32])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)[C@@H:7]([C:33](=[O:43])[NH:34][O:35]CC2C=CC=CC=2)[CH2:6]1.C1CN([P+](ON2N=[N:69][C:64]3C=[CH:66][CH:67]=[CH:68][C:63]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.C(ON)C1C=CC=CC=1.CN1CCOCC1>CN(C=O)C>[OH:35][NH:34][C:33]([C@H:7]1[CH2:6][CH:5]([CH2:4][C:3](=[O:2])[N:69]2[CH2:66][CH2:67][CH2:68][CH2:63][CH2:64]2)[CH2:10][CH2:9][C@@H:8]1[C:11]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([CH3:31])[CH:22]=2)=[CH:17][CH:18]=1)=[O:32])=[O:43]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: COC(=O)CC1CC[C@H](C(=O)Nc2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NOCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)N4CCCCC4)C[C@@H]3C(=O)NO)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 93 %

Procedure:
Part 8: {3-(S)-Benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-acetic acid methyl ester. To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed sequentially: 5-methoxycarbonylmethyl-2-(S)-[4-(2-methylquinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexane-(S)-carboxylic acid (212 mg, 0.43 mmol), anhydrous DMF (3 mL), PyBOP reagent (320 mg, 0.61 mmol), O-benzylhydroxylamine hydrochloride (100 mg, 0.627 mmol), and 4-methyl morpholine (0.160 mL, 1.47 mmol). After stirring the reaction mixture overnight, the reaction was quenched with 5% citric acid (1 mL) and the reaction mixture was diluted with ethyl acetate (15 mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with saturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), and concentrated in-vacuo. Purification by Combiflash (0 to 15% methanol in methylene chloride over 30 min) to afford 238 mg (93%) of the pure amide. LCMS (ESI): 596 (M+H+).
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][N:7]1[C@@H:24]2[CH2:25][C:12]3=[CH:13][CH:14]=[C:15](O)[C:16]4[O:17][C@H:18]5[C:19]([CH2:21][CH2:22][C@@H:23]2[C@:10]5([C:11]=43)[CH2:9][CH2:8]1)=[O:20].C(#N)C.[OH-].[Na+]>CCO>[CH3:6][N:7]1[C@@H:24]2[CH2:25][C:12]3=[CH:13][CH:14]=[C:15]([O:3][S:2]([OH:5])(=[O:1])=[O:4])[C:16]4[O:17][C@H:18]5[C:19]([CH2:21][CH2:22][C@@H:23]2[C@:10]5([C:11]=43)[CH2:9][CH2:8]1)=[O:20]
Reactant: O=S(=O)(O)O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: CN1CC[C@]23c4c5ccc(OS(=O)(=O)O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 81 °C

Procedure:
Morphine base (30.0 g, wet, 75% wt, 78.85 mmol) was dried in a vacuum oven at 90° C. for 3 h. The dried solid was added to a reaction flask, along with water (30 mL) and EtOH (60 mL). The reaction mixture was stirred to form a suspension. The reactor was flushed with nitrogen and the reaction mixture was kept under nitrogen throughout the reaction. The reaction flask was charged with H2SO4 (98%, 7.73 g, 78.85 mmol) and the catalyst (RuCl3.xH2O, 0.20 g). The reaction mixture was heated to reflux (80-82° C.) for 16 h. HPLC analysis indicated that 96.8% (area) hydromorphone was formed. The reaction mixture was cooled down overnight. Acetonitrile (30 mL) was added to the reaction mixture and the mixture was heated at reflux for 1 h. The pH of the reaction mixture was adjusted the pH to 1.6 with 50% NaOH. EtOH (90 mL) was added to the mixture, which as cooled down to 15° C. for 1 h. The mixture was filtered, and the solid was washed with 95% EtOH (2×15 mL). The solid was dried under vacuum at 65° C. for 18 h to give 11.6 g of hydromorphone sulfate as solids (purity>99% area).
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].NC(N)=O.[CH2:12](Br)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: CC(C)NC(N)=O
Agent: NC(N)=O
Product: CCCCNC(=O)NC(C)C
Yield: 58 %

Procedure:
N-butyl-N'-isopropylurea was prepared in a yield of 58% as described in Example 1, but using 2.04 g of N-isopropylurea (20 mmol) as the urea and 2.74 g of butylbromide (20 mmol) as the alkylating agent. 1H-NMR (CDCl3 ; 200 MHz; delta): 5.708 (t; 1H; butyl-NH; JCH2NH =5.5 Hz); 5.490 (d; 1H; isopropyl-NH; JCHNH =7.9 Hz), 3.858 (dq; 1H; isopropyl-CH; JCHNH =7.9 Hz; JCHCH3 =6.5 Hz); 3.135 (dse; 2H; butyl-N--CH2 ; JCH2NH =5.5 Hz; JCH2CH2 =6.7 Hz); 1.498-1.275 (m(tt and tq); 4H; butyl-CH2 --CH2); 1.122 (d; 6H; isopropyl-CH3 ; JCHCH3 = 6.5 Hz); 0.906 (t; 3H; butyl-CH3 ; JCH2CH3 =7.0 Hz) ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:5]=[C:4]([F:15])[C:3]=1[CH2:16][NH:17][C:18]1[C:19]([F:26])=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[F:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:5]=[C:4]([F:15])[C:3]=1[CH2:16][NH:17][C:18]1[C:19]([F:26])=[C:20]([CH:21]=[CH:22][C:23]=1[F:24])[O:25][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: Oc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2F)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2F)c1F
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 3-[[2,6-difluoro-3-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenol (300 mg, 0.82 mmol, 1.0 eq) in DMF (5 mL) was added Cs2CO3 (375 mg, 1.15 mmol, 1.4 eq) at room temperature. The reaction mixture was stirred for 1 h, then ethyl 2-bromoacetate (151 mg, 0.90 mmol, 1.1 eq) was added. The reaction mixture was stirred for a further 1 h and the resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (240 mg, 65%).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(=O)C.[Na+]>O>[C:16]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
5-(4-Aminophenyl)-2(1H)-pyrazinone hydrobromide (2.5 g) in water (20 ml) was treated with acetic anhydride (1.2 g) and anhydrous sodium acetate (1.4 g). The mixture was stirred at room temperature for 1 hour, and the crude product (1.58 g; m.p. 268°-275° C.) was filtered off. This material was thoroughly washed with water and recrystallised from glacial acetic acid to give 5-(4-acetamidophenyl)-2(1H)-pyrazinone (0.84 g; m.p. 287°-8° C.).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[N+](C(C)C)([O-])=O.ClC[C:13]1[CH:18]=[CH:17][CH:16]=C[C:14]=1[S:19]([NH:22][C:23]([NH:25][C:26]1[N:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1)=[O:24])(=[O:21])=[O:20]>C(O)C>[CH:2]([C:3]1[CH:16]=[CH:17][CH:18]=[CH:13][C:14]=1[S:19]([NH:22][C:23]([NH:25][C:26]1[N:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[N:31]=1)=[O:24])(=[O:21])=[O:20])=[O:1]
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2CCl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)[N+](=O)[O-]
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=O)n1

Procedure:
To a solution of 6.26 mmol of sodium ethoxide in 10 ml of absolute ethanol under an argon atmosphere was added 0.80 ml of 2-nitropropane. Next 0.74 g (2.09 mmol) of 2-chloromethyl-N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide was added and the solution was heated to reflux. The mixture became pasty shortly after heating was begun and an additional 3 ml of ethanol was added to facilitate stirring. After heating for 4 hours, the solvent was removed under reduced pressure and the residue was dissolved in 12 ml of water. The crude product was precipitated by neutralizaiton of the solution with 3 N hydrochloric acid. The crude product was purified by preparative thin layer chromatography on silica gel and subsequent recrystallization from acetone to provide the title compound, m.p. 157° C. (decomp.). The infrared spectrum showed a new carbonyl band at 1675 cm-1, indicative of the formation of an aldehyde, in addition to the urea carbonyl band at 1710 cm-1. The nuclear magnetic resonance spectrum showed peaks at 10.57 ppm and 10.67 ppm which are consistent with an aromatic aldehyde with restricted rotation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH:10]([NH2:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([OH:14])[CH:10]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
3-Amino-4-(4-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.116 g, 0.35 mmol) was dissolved in CH2Cl2. Propionyl chloride (0.034 mL, 0.39 mmol) and triethylamine (0.109 mL, 0.78 mmol) were added and the solution was stirred for 24 h at room temperature. The reaction was concentrated in vacuo, then purified by Biotage flash chromatography (30% ethyl acetate/70% hexane to 50% ethyl acetate/50% hexane) to yield the title compound (0.133 g, 97%). 1H-NMR (CDCl3): δ 0.87 (t, 3H), 1.44 (s, 9H), 1.78–1.95 (m, 3H), 2.20 (dt, 1H), 3.24 (t, 1H), 3.50 (d, 1H), 3.90 (t, 1H), 4.08 (q, 2H), 4.28 (d, 1H), 5.48 (bd, 1H), 7.26 (d, 2H), 7.37 (d, 2H). ESI-MS m/z: 383 (M+1), retention time 2.21.