Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.C([Li])CCC.BrCCC(Br)C>C(Cl)Cl.CCCCCC>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:11][CH2:10][CH:9]1[CH3:8]
Reactant: CSCS(C)=O
Reactant: C1CCOC1
Agent: CC(Br)CCBr
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CSC1(S(C)=O)CCC1C
Reaction time: 1.33 h

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (1.571 g) was dissolved in 15 ml. of tetrahydrofuran, and 8.9 ml. of an n-hexane solution of n-butyl lithium (1.4 millimols/milliliter) was added at -10° C. The mixture was stirred for 80 minutes, and then at -70° C., 1.125 g of 1,3-dibromobutane was added, and the mixture was stirred for 46.5 hours at room temperature. Methylene chloride (100 ml) was added. The mixture was washed with water and dried with anhydrous magnesium sulfate. It was concentrated at reduced pressure, and the residue was separated by column chromatography (Florisil, eluted with methylene chloride) to afford 746 mg of 2-methylcyclobutanone dimethyl mercaptal S-oxide. The product was oxidized with hydrogen peroxide and Na2WO4 to form its disulfone derivative.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH:26]=[C:27]([C:29]([NH:31][CH3:32])=[O:30])[CH:28]=3)[C:22](OC)=[O:23])=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:28]=[C:27]([C:29]([NH:31][CH3:32])=[O:30])[CH:26]=[C:21]([CH2:22][OH:23])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)c1cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cc(CO)cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-5-[(methylamino)carbonyl]benzoate (intermediate 31) (0.206 g, 0.43 mmol) in THF (5 mL), was added a 1M solution of LiAlH4 in THF (0.65 mL, 1.5 eq.). The reaction was stirred at RT for one night. Water was added and the compound was extracted with AcOEt, dried over sodium sulfate and concentrated in vacuo. After trituration from hot methanol, filtration and dry, the title compound was obtained as a white solid (0.03 g, 15.8%). HRMS calculated for C20H19Cl2N5O3 (M+H)+448.0943, found: 448.0910, Rt: 2.66 min. MP: 223-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=O)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C1(C)C=CC=CC=1>CCOCC>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[S:31])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=S)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 153.7 %

Procedure:
4-chloro-N-p-tolyl-3-trifluoromethyl-benzamide (1.0 g, 3.19 mmol), Lawesson's reagent (774 mg, 0.6 eq.) and toluene (2.5 mL) is mixed in a microwave vial. The mixture is heated to 120° C. for 1000 seconds using microwave irradiation. The mixture turned into clear solution. Ether (50 ml) is added to dilute the reaction mixture. The solution is then washed with brine, dried over MgSO4, filtered and concentrated. The mixture is purified by column chromatography (EtOAc/Hexanes=5/95) to afford 970 mg (92%) of 4-chloro-N-p-tolyl-3-trifluoromethyl-thiobenzamide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:38]([O:24][CH:23]([C:17]1[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=[C:19]([CH3:22])[N:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:40])[CH3:39]
Reactant: COc1cc2nccc(Oc3ccc(C)nc3C(O)c3ccccc3)c2cc1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3C(OC(C)=O)c3ccccc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl-methanol (47 mg) (compound 217) was dissolved in chloroform (7 ml) to prepare a solution. Triethylamine (1 ml), acetic anhydride (0.8 ml), and 4-dimethylaminopyridine (20 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (48 mg, yield 89%).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[O:8])[CH2:6][CH3:7].[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(#N)C>[OH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:2][CH2:3][NH:4][C:5](=[O:8])[CH2:6][CH3:7])[CH2:12][CH2:11]1
Reactant: CCC(=O)NCCCl
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CCC(=O)NCCN1CCC(O)CC1

Procedure:
A mixture of N-(2-chloroethyl)propanamide (27.1 g, 0.20 mol), 4-hydroxypiperidine (20.2 g, 0.20 mol) and anhydrous sodium carbonate (10.6 g, 0.10 mol) in acetonitrile (120 ml) was stirred at reflux under nitrogen for 20 hours. Additional 4-hydroxypiperidine (20.2 g, 0.20 mol) was added and the mixture stirred at reflux for 3 days. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate and a minimum amount of water. The aqueous layer was saturated with sodium chloride and re-extracted several times with ethyl acetate. The organic extracts were combined, dried (Na2SO4), filtered and concentrated to give 13.1 g of crude product. Pure product was obtained by flash chromatography over silica gel and elution with 20% methanol-80% chloroform.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[NH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([C:24]([F:27])([F:26])[F:25])=[C:19]([F:28])[CH:18]=1>C(O)C>[F:13][C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=[C:2]([NH:16][C:17]3[CH:18]=[C:19]([F:28])[C:20]([C:24]([F:27])([F:25])[F:26])=[C:21]([F:23])[CH:22]=3)[N:7]2[N:8]=1)([F:14])[CH3:12]
Reactant: Cc1cc(Cl)n2nc(C(C)(F)F)nc2n1
Reactant: Nc1cc(F)c(C(F)(F)F)c(F)c1
Solvent: CCO
Product: Cc1cc(Nc2cc(F)c(C(F)(F)F)c(F)c2)n2nc(C(C)(F)F)nc2n1

Procedure:
A solution of Intermediate 3 (0.1 g, 0.43 mmol) and 4-amino-2,6-difluorobenzotrifluoride (FLUOROCHEM, 0.085 g, 0.43 mmol) in ethanol (7 mL) was stirred at room temperature overnight. Solvent was removed in vacuo and the residue was taken up in DCM. The resulting solution was washed with 1N Na2CO3, then with brine and dried over anhydrous Na2SO4 to yield a yellow oil which was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 100:0 to 50:50%) to afford the title compound as a pale yellow solid.
Reaction SMILES: C1[C@H](N)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)[C@H]([O:20][C@@H:21]2[O:25][C@H:24](CO)[C@@H:23](O[C@H]3O[C@@H](CN)[C@@H](O)[C@H](O)[C@H]3N)[C@H:22]2[OH:40])[C@@H](O)[C@@H]1N.OS(O)(=O)=O.[CH2:48]([O:55][C:56]([NH:58][C:59]([N:71]1C=CC=N1)=[N:60][C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:56]([N:58]([CH2:24][CH2:23][C@H:22]([OH:40])[C:21]([OH:25])=[O:20])[C:59]([NH2:71])=[N:60][C:61]([O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)=[O:62])([O:55][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:57]
Reactant: O=C(N=C(NC(=O)OCc1ccccc1)n1cccn1)OCc1ccccc1
Reactant: NC[C@@H]1O[C@H](O[C@H]2[C@@H](O)[C@H](O[C@@H]3[C@@H](O)[C@H](N)C[C@H](N)[C@H]3O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)O[C@@H]2CO)[C@H](N)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=NC(=O)OCc1ccccc1)N(CC[C@H](O)C(=O)O)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2(S)-hydroxy-4-amino-butyric acid (1, 0.059 g, 0.50 mmol) in DMF (2 ml) was added N,N′-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.26 g, 0.70 mmol) followed by DIPEA (0.87 mL, 4.99 mmol) and the reaction was heated to 80° C. and stirred overnight. The crude mixture was purified on a 2-inch reverse-phase HPLC column to yield N,N′-bis-Cbz-2(S)-hydroxy-4-guanidino-butyric acid (2): MS: m/z (M+H)+ calc. 430.15, obs. 430.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[O:14]>C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([O:12][CH3:11])=[O:14])(=[O:23])=[O:22])=[O:26])[N:7]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Reaction time: 16 h
Yield: 21.1 %

Procedure:
To a stirred suspension of 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 30 ml of anhydrous methylene chloride was added at ambient temperature 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. After stirring for 16 hours, the foregoing mixture was filtered to remove unreacted amine, and the filtrate evaporated at temperatures up to 40° and reduced pressure. The resultant residue was stirred in 25 ml of water, the pH adjusted to 10 by the addition of 50% sodium hydroxide and the solution filtered. Acidification of the filtrate to pH 3 with hydrochloric acid caused precipitation of the desired product which was removed by filtration and dried to yield 0.8 g of product melting at 173°-179°. It showed infrared absorption peaks at 1720, 1680, 1630 and 1550 cm-1, consistent for N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:16])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1CCCCC1>O1CCOCC1>[OH:1][NH:2][C:3](=[O:16])[CH2:4][CH:5]([S:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(C=CCCCCc1ccccc1)NO
Reactant: Sc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: O=C(CC(CCCCc1ccccc1)Sc1ccccc1)NO
Temperature: 85 °C

Procedure:
7-Phenyl-hept-2-enoic acid hydroxyamide (0.3 g; 1.4 mmol) is combined with thiophenol (0.26 g; 2.4 mmol) and piperidine (0.04 g; 0.5 mmol) in 1,4-dioxane (6 mL) and heated to 85° C. for 4 hours. After cooling, the reaction is concentrated in vacuo and purified by column chromatography using 5% MeOH/CH2Cl2 to obtain 7-phenyl-3-phenylsulfanylheptanoic acid hydroxyamide.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:17]=[C:14]([CH:15]=[O:16])[C:13]([OH:18])=[CH:12][CH:11]=1>CN(C)C=O.C(OCC)(=O)C>[I:1][C:12]1[CH:11]=[C:10]([Cl:9])[CH:17]=[C:14]([CH:15]=[O:16])[C:13]=1[OH:18]
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(Cl)cc(I)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
N-Iodosuccinimide (144.0 g, 0.641 mole) was added to a solution of 5-chlorosalicylaldehyde (100 g, 0.638 mole) in dimethylformamide (400 mL). The reaction mixture was stirred for 2 days at room temperature. Additional N-iodosuccinimide (20.0 g) was added and the stirring was continued for an additional 2 days. The reaction mixture was diluted with ethyl acetate (1 L), washed with hydrochloric acid (300 mL, 0.1N), water (300 mL), sodium thiosulfate (5%, 300 mL), brine (300 mL), dried (MgSO4) and was concentrated to dryness to afford the desired aldehyde (162 g, 90% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1]OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)CC=C1C[C@@H](O)C[C@H]2C.[CH3:25]OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)CC(C)=C1C[C@@H](O)CC2.[C:49]([O:52][C@H:53]1[CH2:70][CH2:69][C@@:68]2([CH2:71][O:72][CH3:73])[C:55](=[CH:56][CH2:57][C@@H:58]3[C@@H:67]2[CH2:66][CH2:65][C@@:63]2([CH3:64])[C@H:59]3[CH2:60][CH2:61][C@@H:62]2[O:74][C:75](=[O:77])[CH3:76])[CH2:54]1)(=[O:51])[CH3:50]>>[C:49]([O:52][C@H:53]1[CH2:70][C@@H:69]([CH3:1])[C@@:68]2([CH2:71][O:72][CH3:73])[C:55](=[CH:56][CH2:57][C@@H:58]3[C@@H:67]2[CH2:66][CH2:65][C@@:63]2([CH3:64])[C@H:59]3[CH2:60][CH2:61][C@@H:62]2[O:74][C:75](=[O:77])[CH3:76])[CH2:54]1)(=[O:51])[CH3:50].[C:49]([O:52][C@H:53]1[CH2:70][CH2:69][C@@:68]2([CH2:71][O:72][CH3:73])[C:55](=[C:56]([CH3:25])[CH2:57][C@@H:58]3[C@@H:67]2[CH2:66][CH2:65][C@@:63]2([CH3:64])[C@H:59]3[CH2:60][CH2:61][C@@H:62]2[O:74][C:75](=[O:77])[CH3:76])[CH2:54]1)(=[O:51])[CH3:50]
Reactant: COC[C@]12CC[C@H](OC(C)=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reactant: COC[C@]12CC[C@H](O)CC1=C(C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: COC[C@]12C(=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]31)C[C@@H](O)C[C@H]2C
Product: COC[C@]12C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]31)C[C@@H](OC(C)=O)C[C@H]2C
Product: COC[C@]12CC[C@H](OC(C)=O)CC1=C(C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12

Procedure:
Substituting 19-methoxy-1β-methyl-5-androstene-3β,17β-diol and 19-methoxy-6-methyl-5-androstene-3β,17β-diol in lieu of the 19-methoxyandrost-5-ene-3β,17β-diol above results in the preparation of 19-methoxy-1β-methyl-5-androstene-3β,17β-diol diacetate and 19-methoxy-6-methyl-5-androstene-3β,17β-diol diacetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:23])[C:10](=[O:22])[N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[N:11]([CH3:21])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2c(-c3ccc(O)cc3)n(C)c(=O)n2C)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2c(-c3ccc(OCc4ccc5ccccc5n4)cc3)n(C)c(=O)n2C)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a stirred solution of 4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.35 h, 1.12 mmol) in AcN (20 mL) was added K2CO3 (0.46 g, 3.3 mmol) at RT. The reaction mixture was heated to 80° C. for 30 min, and then 2-(chloromethyl)quinoline hydrochloride (0.29 g, 1.35 mmol) was added and the mixture stirred for an additional 3 h at 80° C. Then the mixture was concentrated in vacuo and the residue was dissolved in EtOAc (30 mL). The organic layer was washed with water, dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 80% EtOAc/20% hexanes to afford 4-(4-methoxyphenyl)-1,3-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)-1H-imidazol-2(3H)-one (0.2 g, 39%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.21 (d, J=7.2 Hz, 1 H), 8.05 (d, J=8.4 Hz, 1 H), 7.84 (d, J=7.2 Hz, 1 H), 7.74-7.72 (m, 1 H), 7.64 (d, J=7.6 Hz, 1 H), 7.59-7.56 (m, 1 H), 7.11-7.05 (m, 4 H), 6.93 (d, J=7.2 Hz, 2 H), 6.82 (d, J=7.6 Hz, 2 H), 5.39 (s, 2 H), 3.81 (s, 3 H), 3.19 (s, 6 H). MS: M+H: m/z=452.2 and HPLC: 97%, (Condition-H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](Cl)(=[O:12])[CH3:11]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([NH:8][C:10](=[O:12])[CH3:11])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Cl)c(Br)cn1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred solution of 5-bromo-4-chloropyridin-2-amine (11.6 g, 55.9 mmol) in pyridine (100 mL) at 0° C. was added acetyl chloride (3.98 mL, 55.9 mmol) and the reaction was stirred at rt for 3 h. The reaction mixture was quenched with cold water and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL) and dried over sodium sulfate. The organics were concentrated under reduced pressure to afford N-(5-bromo-4-chloropyridin-2-yl)acetamide (14.6 g, 55.9 mmol, 100% yield) as a white solid that was carried on without further purification. LC/MS (ESI) m/e 249 [(M+H)+, calcd for C7H7BrClN2O 248.9], LC/MS retention time (method B): tR=1.64 min; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.58 (s, 1H), 8.33 (s, 1H), 2.11 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:19]=[N:20][C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=3)[CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1>[Pd].CCOC(C)=O.CO>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: CN1CCC(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc(N)nc3)ccn2)CC1
Yield: 70.9 %

Procedure:
A solution of 1-methyl-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (0.20 g, 0.560 mmol) in 2:1 EtOAc/MeOH (15 mL) was treated with Palladium on carbon (50% wet) (0.066 g, 0.056 mmol) was hydrogenated (1 atm) overnight. The solids were removed via filtration through diatomaceous earth, washed with MeOH and the filtrate concentrated to dryness to afford N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-1-methylpiperidine-4-carboxamide (130 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 8.13 (d, J=5.7 Hz, 1H), 7.77 (d, J=2.9 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.26 (dd, J=8.9, 3.0 Hz, 1H), 6.63 (dd, J=5.7, 2.4 Hz, 1H), 6.51 (d, J=8.9 Hz, 1H), 6.01 (s, 2H), 2.77 (m, 2H), 2.39 (m, 1H), 2.14 (s, 3H), 1.83 (m, 2H), 1.67 (m, 2H), 1.57 (m, 2H); MS (ESI) m/z: 328.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:30]1([CH2:36][CH2:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[CH3:20][O:19][C@@H:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:14]([CH3:18])[C:15](=[O:17])[NH:38][CH2:37][CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCc1ccccc1
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]([C@@H](C)C(=O)NCCc1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
To #11 (22 g, 77 mmol, 1 eq.) in dichloromethane (383 mL, 0.2 M) and N,N-dimethylformamide (30 mL) were added diisopropylethylamine (26.9 mL, 153 mmol, 2 eq.), 2-phenylethylamine (11.6 mL, 91.9 mmol, 1.2 eq.) and HATU (39.0 g, 99.5 mmol, 1.3 eq.). The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (700 mL) and washed sequentially with 1 M aqueous hydrochloric acid solution (2×200 mL) and brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was taken up in dichloromethane and filtered. The filtrate was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to give #20 (24 g, 80%) as an off-white solid. LC-MS: m/z 392.2 [M+2H+], 291.1 [(M-Boc)+H+], retention time=0.88 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers: δ 7.80-7.89 (br m, 1H), 7.23-7.29 (m, 2H), 7.15-7.23 (m, 3H), 3.72-3.82 and 3.55-3.62 (2 br m, total 1H), 3.45-3.55 (br m, 1H), 3.31-3.44 (br m, 2H), 3.29 (s, 3H), 3.12-3.25 (br m, 1H), 2.98-3.12 (br m, 1H), 2.71 (t, J=7.1 Hz, 2H), 2.09-2.19 (m, 1H), 1.71-1.83 (br m, 2H), 1.60-1.70 (br m, 1H), 1.49-1.60 (br m, 1H), 1.41 (s, 9H), 1.03 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[NH3:15]>>[NH2:15][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NCCO
Product: Nc1ncc([N+](=O)[O-])c(NCCO)n1
Temperature: 55 °C
Yield: 93 %

Procedure:
21.86 g (0.1 mole) of 2-chloro-4-(2-hydroxyethylamino)-5-nitropyrimidine was dissolved in 500 ml of ammonia saturated ethanol solution, and maintained between 50-60° C. A stream of ammonia was bubbled through the mixture for 13 hours. After completion of the reaction, the reaction product was maintained below 5° C., and the resulting crystal was filtered, washed and dried, thereby giving 18.81 g (93% yield) of light yellow-colored 2-amino-4-(2-hydroxyethylamino)-5-nitropyrimidine.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C@@H:19]([OH:22])[CH:20]=[CH:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1.[OH:23][S:24]([OH:27])(=[O:26])=[O:25].CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5C(CC[C@@H]2[C@]5(C=34)CC1)=O.[OH-].[Na+]>CCO.C(#N)C.O>[CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C:19]([CH2:20][CH2:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1)=[O:22].[S:24]([O-:27])([O-:26])(=[O:25])=[O:23]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: O=S(=O)(O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: O=S(=O)([O-])[O-]
Temperature: 81 °C

Procedure:
A reaction flask was charged with codeine base (10.0 g, 33.4 mmol), water (10 mL), and EtOH (20 mL). The reaction mixture was agitated 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%, 1.8 mL, 33.4 mmol) and the catalyst (RuCl3.xH2O, 0.20 g). The reaction mixture was heated to reflux (80-82° C.) for 24 h. HPLC analysis indicated that 92% (area) hydrocodone was formed. The reaction mixture was cooled down overnight. Acetonitrile (30 mL) was added to the reaction mixture and the mixture was heated for 1 h. The pH of the reaction mixture was adjusted the pH to 2.5 with 50% NaOH. EtOH (90 mL) was added to the mixture, which as cooled down to 0-5° 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 8.32 g of hydrocodone sulfate as solids (purity>99% area).