Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:30]([NH:32][CH2:33][CH3:34])=[O:31])[CH:23]=2)=[C:18]([OH:35])[CH:17]=1)([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].IC.[C:38]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:33]([NH:32][C:30]([NH:29][CH2:28][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:2]([CH3:1])([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[O:8])[CH3:15])=[CH:17][C:18]=2[O:35][CH3:38])[CH:27]=[CH:26][CH:25]=1)=[O:31])[CH3:34]
Reactant: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCCC(=O)N3CCOCC3)cc2O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCCC(=O)N3CCOCC3)cc2OC)c1
Temperature: 60 °C
Yield: 23 %

Procedure:
A mixture of 20 (0.1 g, 0.208 mmol, 1.0 eq), iodomethane (0.05 mL, 0.832 mmol, 4.0 eq), and K2CO3 (0.115 g, 0.832 mmol, 4.0 eq) in acetone (3 mL) was heated to 60° C. overnight. LC/MS showed SM/product ˜1/1. More K2CO3 (0.2 g, 1.45 mmol, 7 eq) and iodomethane (0.2 mL, 3.21 mmol, 15.4 eq) were added, and the mixture was heated again to 60° C. overnight. Acetone was removed under reduced pressure, and the residue was partitioned in water/ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layer was washed by water (20 mL), brine (20 mL) and dried over anhydrous K2CO3. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, 60-100% ethyl acetate in hexane). Yield: 23%, 98% pure. M+1=496
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH2:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[C:27]=1[C:28](Cl)=[O:29]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH:23][C:28](=[O:29])[C:27]2[C:31]([C:39]([F:41])([F:42])[F:40])=[CH:32][C:33]([C:35]([F:36])([F:37])[F:38])=[CH:34][C:26]=2[O:25][CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reactant: NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester and 2-methoxy-4,6-bis-trifluoromethyl-benzoyl chloride (CAS: 886503-47-5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].OO.[C:11]([OH:14])(=[O:13])[CH3:12]>C(OC(=O)C)(=O)C>[C:11]([O:14][CH2:8][C:2]1[C:3]([CH3:7])=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:13])[CH3:12]
Reactant: Cc1cccnc1C
Reactant: CC(=O)O
Agent: OO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1ncccc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2,3-lutidine (4.8363 g, 45.13 mmol) in glacial acetic acid (30 mL) at room temperature was added 30% H2O2 (4.6 mL) and the resultant solution was heated to 70° C. After 6 hours, the reaction mixture was cooled to room temperature, additional H2O2 (4.6 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was dissolved in CHCl3 (100 mL) and treated with solid Na2CO3 (14.12 g). After 1 hour, the supernatant was decanted and the residue was washed with warm CHCl3 (3×50 mL). The combined. supernatants were filtered and concentrated to provide 4.6951 g as a yellow solid. The solid was dissolved in acetic anhydride (38 mL) and heated at 90° C. overnight. The mixture was cooled to room temperature and concentrated and the crude product was filtered through a silica plug (33 g silica, ethyl acetate) to give 6.13 g of 2-acetoxymethyl-3-methyl-pyridine as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C1([N:18]=C=NC2CCCCC2)CCCCC1.O.OC1C2N=NNC=2C=CC=1.[OH-].[NH4+]>CN(C)C=O>[NH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:18])=[O:7]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-chloroanthranilic acid (70 g, 0.41 mol) in hot (60° C.) dimethylformamide (700 mL), dicyclohexylcarbodiimide (93 g, 0.451 mol, 1.1 equiv), hydroxybenzotriazole hydrate (60.9 g, 0.451 mol, 1.1 eq) and 30% aqueous ammonium hydroxide solution (350 mL) were added. The resulting solution was stirred at room temperature for 18 h. The formed urea was filtered off and the filtrate concentrated. The resulting mixture was partitioned between ethyl acetate and 5% K2CO3 solution. The organic phase was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give the desired product as a slightly yellow solid (58.1 g, 83%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](O)=[O:19])[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].Cl>O1CCCC1>[CH2:7]([C@H:12]1[CH2:13][CH2:14][C@H:15]([CH2:18][OH:19])[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CO)CC1

Procedure:
3.79 g of lithium aluminium hydride were placed in 100 ml of absolute tetrahydrofuran while gassing with argon and treated within 30 minutes with a solution of 19.83 g of trans-4-pentylcyclohexanecarboxylic acid in 100 ml of absolute tetrahydrofuran. After completion of the addition, the mixture was heated to reflux for 1 hour, then cautiously added to 200 ml of 2N hydrochloric acid and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed with 100 ml of saturated sodium carbonate solution, dried over potassium carbonate and concentrated. Distillation of the residue (19.2 g) gave in the main run 17.7 g (96%) of (trans-4-pentylcyclohexyl)methanol as a colourless oil (purity 99.9%); b.p. 89° C./0.2 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15][CH2:16][C:17](Br)=[O:18].O>ClCCl>[Br:15][CH2:16][C:17]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:8][CH:9]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Fc1ccnc2[nH]ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)c1c[nH]c2nccc(F)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 0.0147 mol) (Org. Lett., 2003, 5, 5023-5025) in dichloromethane was added aluminum chloride (3.92 g, 0.0294 mol) in portions, the mixture was stirred at RT for 30 min, then bromoacetyl bromide (4.45 g, 0.022 mol) was added dropwise. The reaction mixture was stirred at 50° C. for 1 h, when TLC indicated no starting material. To the reaction mixture was added 150 mL water, and the resulting suspension was heated at 100° C. for 1 h, then filtered to afford the desired product, 90% pure. H NMR, DMSO-d6: 4.72(s, 2H), 7.12(m, 1H), 8.36(m, 1H), 8.67(s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH2:31](O)C.C(NC(C)C)(C)C>[Pd].C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH2:29][CH3:31])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@H](C(=O)OC(C)(C)C)N1CC[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: CCO
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCC(C(=O)OC(C)(C)C)N1CCC(NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reaction time: 18 h

Procedure:
A mixture of Intermediate 112 [Mixture 1] (0.051 g), 10% palladium on carbon (0.01 g) and ethanol (5 ml) was stirred under an atmosphere of hydrogen for 18 h. The reaction mixture was filtered through Celite™ and the filtrate was concentrated under reduced pressure to give a yellow gum. The gum (0.034 g) in DCM (2 ml) was treated with 6-chloronaphthylsulphonyl chloride1 (0.04 g) and N,N-diisopropylamine (0.073 ml) and stirred at room temperature for 24 h. The mixture was washed with water and concentrated under reduced pressure to yield an oil which was partially purified using SPE (silica, eluting with cyclohexane:ethyl acetate 1:1) to give the title compound (0.043 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Cl.O1CCOCC1>CC(O)=O.[Ni]>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1cc(CN2CCOCC2)c(C#N)c(=O)[nH]1
Agent: [Ni]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(CN2CCOCC2)c(CN)c(=O)[nH]1
Yield: 95.3 %

Procedure:
A clear solution of 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.60 g, 2.57 mmol) in HOAc (20 mL) was treated on an H-Cube apparatus (50 psi, 60° C., 1 mL/min., Raney Nickel cartridge) for 18 hr overnight. LCMS showed that the reaction was complete. The reaction was evaporated to dryness, taken up in a small volume of MeOH and treated with 4 N HCl in dioxane (5 mL, 20.00 mmol). The mixture was evaporated to dryness under vacuum (began to ppt. out during evaporation), triturated with Et2O, filtered and dried under vacuum to give the product 3-(aminomethyl)-6-methyl-4-(4-morpholinylmethyl)-2(1H)-pyridinone (0.76 g, 2.450 mmol, 95% yield) as a light grey solid. 1H NMR (400 MHz, DMSO-d6) δ 6.39 (s, 1H), 4.28 (s, 2H), 3.99 (s, 2H), 3.87 (br. s., 4H), 3.27 (br. s., 4H), 2.22 (s, 3H). MS(ES)+ m/e 238.0 [M+H]+ (weak), 221.3 [M+H]+—NH3 (strong).
Reaction SMILES: N1(N)C=CC=C1.C([O-])(O)=O.[Na+].ClC(OCC)=O.C(OC(=O)NN1C=CC=C1)C.CC(C)([O-])C.[K+].C(Br)C1C=CC=CC=1.C(OC(=O)[N:47]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[N:48]1[CH:52]=[CH:51][CH:50]=[CH:49]1)C.[OH-].[Na+]>ClCCl.O1CCCC1.C(O)CO.O>[CH2:53]([NH:47][N:48]1[CH:52]=[CH:51][CH:50]=[CH:49]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CCOC(=O)N(Cc1ccccc1)n1cccc1
Agent: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: OCCO
Product: c1ccc(CNn2cccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a mixture of 1H-pyrrol-1-amine (9.2 g, 0.112 mole) and NaHCO3 (15 g, 0.19 mole) in 50 ml dichloromethane (DCM) at 0° C., was added ethyl chloroformate (11.4 ml, 0.12 mole) in fifteen minutes. After stirring at 0° C. for one hour, then at ambient temperature for four hours, the mixture was filtered and the filtrate was washed with water, then dried (saturated NaCl solution, anhydrous MgSO4). After filtering, the solvent was evaporated to give a solid, 17 g (95%), m.p. 60°-61° C., of N-(1H-pyrrol-1-yl) carbamic acid ethyl ester. To a solution of N-(1H-pyrrol-1-yl) carbamic acid ethyl ester (9.0 g, 0.058 mole) in 30 ml tetrahydrofuran (THF) at 5° C., was added potassium t-butoxide (7.8 g, 0.07 mole) and the mixture was stirred at 5° C. for one hour. To this mixture was added benzyl bromide (7.1 ml, 0.06 mole) in ten minutes, and the mixture stirred at 5° C. for one hour, then at ambient temperature for four hours. This mixture was poured into 100 ml ice-water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil, 14 g (98%) of N-benzyl-N-(1H-pyrrol-1-yl) carbamic acid ethyl ester. To a solution of N-benzyl-N-(1H-pyrrol-1-yl) carbamic acid ethyl ester (14 g, 0.058 mole) in 15 ml ethylene glycol was added a solution of NaOH (5 g, 0.12 mole) in 10 ml water. After stirring at 120° C. for seven hours, the mixture was poured into 100 ml of iced-water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil, which was vacuum distilled to give an oil, 7.4 g (74%) of N-benzyl-1H-pyrrol-1-amine, b.p. 85°-125° C./l mm; m.p. 39°-41° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[F:34][C:35]([F:46])([F:45])[O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:40][C:39]5[CH:42]=[CH:43][CH:44]=[C:37]([O:36][C:35]([F:34])([F:45])[F:46])[CH:38]=5)[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3cccc(OC(F)(F)F)c3)CC2)cc1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-[1-(3-trifluoromethoxy-benzyl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 3-(trifluoromethoxy)benzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.95-1.99 (m, 2H), 2.21-2.28 (m, 4H), 2.92-2.98 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.62 (s, 2H), 4.77-4.83 (m, 1H), 7.25-7.51 (m, 4H), 7.62-7.64 (m, 2H), 8.04-8.07 (m, 2H), 8.38 (s, 1H), 8.56 (s, 1H). Mass spectrum MH+=548.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([NH:17][NH2:18])[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH:26]1([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH2:27]1>C(Cl)Cl>[C:15]([C:14]1[C:13]([NH:17][NH:18][C:30](=[O:31])[CH2:29][CH:26]2[CH2:28][CH2:27]2)=[N:12][CH:11]=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)#[N:16]
Reactant: N#Cc1c(OCc2ccccc2)ccnc1NN
Reactant: O=C(Cl)CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(OCc2ccccc2)ccnc1NNC(=O)CC1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
To a solution of D3 (4.099 g, 17.06 mmol) in dry DCM (112 ml) was added Et3N (2.76 g, 27.294 mmol) and cyclopropyl-acetyl chloride (3.438 g, 29 mmol). The resulting reaction mixture was stirred at r.t. for 20 min. The mixture was concentrated in vacuo to yield compound D4 (5 g, 91%).
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8]C)=[O:6])C.[NH2:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]1>CO>[CH3:20][C:14]1([CH3:21])[CH2:13][CH:12]([NH:11][C:4](=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CO
Product: COC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1

Procedure:
Methyl N-(2,2,6,6-tetramethyl-4piperidinyl)oxamate was prepared from diethyloxalate and 4-amino-2,2,6,6-tetramethylpiperidine according to the first step in Example III, Method B. The ethyl ester undergoes ester interchange in methanol to form the methyl ester.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[OH:22][S:23](O)(=[O:25])=[O:24].CN1[C@@H]2CC3=CC=C(O)C4O[C@H]5C(CC[C@@H]2[C@]5(C=43)CC1)=O.[OH-].[Na+]>CCO.CS(C)=O.O>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3=[CH:1][CH:2]=[C:3]([O:4][S:23]([OH:25])(=[O:24])=[O:22])[C:5]4[O:9][C@H:8]5[C:10]([CH2:12][CH2:13][C@@H:14]2[C@:7]5([C:6]=43)[CH2:21][CH2:20]1)=[O:11]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=S(=O)(O)O
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCO
Product: CN1CC[C@]23c4c5ccc(OS(=O)(=O)O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 81 °C

Procedure:
A reaction flask was charged with morphine base (30.0 g, wet, 75% wt, 78.85 mmol), water (23 mL), and EtOH (60 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%, 7.73 g, 78.85 mmol) and the catalysts (RuCl3.xH2O, 0.20 g). The reaction mixture was heated to reflux (80-82° C.) for 24 h. HPLC analysis indicated that 93% (area) hydromorphone was formed. The reaction mixture was cooled down overnight. DMSO (1.0 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 11.8 g of hydromorphone sulfate as solids (purity>99% area).
Reaction SMILES: Cl.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[N:10]=1)[C:3]([NH2:5])=[NH:4].C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[S:26].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>CO.CC(C)=O>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:25]([NH:24][CH3:23])=[S:26])[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CN=C=S
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=S)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole hydrochloride (1.52 g.) in methanol (30 ml.) was treated with triethylamine (1.01 g.) to give a pale yellow solution. Methyl isothiocyanate (0.365 g.) was added and the solution stirred for 16 hours at room temperature. Evaporation of the solvent gave a gum which was dissolved in acetone (20 ml.) and treated with maleic acid (1 g.) in acetone (20 ml.). The precipitate was filtered off and recrystallized from ethanol to give 2-guanidino-4-[2-(3-methylthioureido)ethylthiomethyl]thiazole hydrogen maleate as a pale brown solid (0.420 g.). Found: C, 37.4; H, 4.7; N, 19.8; S, 22.7. C13H20N6S3O4 requires C, 37.14; H, 4.76; N, 20.00; S, 22.85%.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[N:28][O:29][CH3:30])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Cl.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.O1CCOCC1>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][O:29][CH3:30])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=NOC)c4)cc23)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNOC)c4)cc23)CC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 34.6 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)imino]methyl}phenyl)-1H-indole-7-carboxamide (58 mg, 0.123 mmol) in DCM (3.0 mL) and MeOH (3.0 mL) was added HCl in 1,4-dioxane to maintain pH=4 at 0° C. Sodium cyanoborohydride (176 mg, 3.69 mmol) was then added and stirred overnight for 48 h. The compound was purified by Gilson Preparatory HPLC to give 20.0 mg of the title compound (89%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][C:22](OCC)=[O:23])=[CH:16][CH:15]=1.C([O-])(=O)C.[NH4+]>O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:12]=2)[C:22](=[O:23])[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[N:13]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=c1cc(-c2ccncc2)nc2ccc(-c3ccccc3)cn12
Temperature: 140 °C
Yield: 28.6 %

Procedure:
To a mixture of 0.20 g (1.17 mmol) of 5-phenylpyridin-2-amine and 0.227 g (1.17 mmol) of ethyl 3-(4-pyridinyl)-3-oxopropionate were added 0.180 g (2.34 mmol) of ammonium acetate. The reaction mixture was heated at 140° C. for 12 hours. After cooling, water was added and the mixture was extracted with chloroform. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and evaporated. The resulting solid was dissolved in methanol and purified on preparative thin layer chromatography eluting with a mixture of ethylacetate/ethanol in the proportions 95/5 to afford 0.10 g (28%) of the desired compound which was transformed into the oxalate salt in the usual manner to give the pure product as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[Na:20]>C(O)C.[OH-].[Na+]>[C:4]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)([OH:5])=[O:3].[Na:20]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-ethoxycarbonylphenoxy phenyl methane (6.3g) in ethanol (30ml), sodium hydroxide solution (70ml.; 10N) was added and the mixture boiled under reflux with vigorous stirring for 18 hr. After cooling the sodium salt was filtered off and dried, m.p. > 340°
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][OH:8])[CH3:4].FC1C([O:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([C:29]=2[NH:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)=O)=C(F)C(F)=C(F)C=1F>CN1CCCC1=O.CO.C(OCC)(=O)C>[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][O:8][C:19]([C:21]1[NH:22][C:23]2[C:28]([C:29]=1[NH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:18])[CH3:4]
Reactant: CCN(CC)CCO
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1[nH]c2ccccc2c1Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCN(CC)CCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 0 °C
Yield: 31.1 %

Procedure:
Stir under N2 at 0° C. a suspension of NaH (29 mg, 0.72 mmol of 60% oil dispersion) in 1-methyl-2-pyrrolidinone (15 mL), and slowly add N,N-diethylethanolamine(0.095 mL, 0.72 mmol). Stir for 10 min and then add dropwise 3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid pentafluorophenyl ester (100 mg, 0.24 mmol). Allow the reaction to reach ambient temperature and stir overnight. Quench into water and extract with ethyl acetate. Wash the extract with water, brine, dry (MgSO4), filter and concentrate under vacuum to obtain crude product. Chromatograph on silica gel (10 g, Sepack cartridge) and use 1:1 methanol/ethyl acetate as eluent. Combine like fractions and concentrate under vacuum to obtain 26.3 mg (31%) of the titled compound: MS 353 (M+H).