Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[S:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[S:10][CH:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C)cc2SC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)S2
Temperature: 25 °C
Reaction time: 4.8 h
Yield: 10.8 %

Procedure:
The ester from Step 3 (2.02 g, 6.0 mmol) was dissolved in THF (10 mL) and ethanol (10 mL), treated with 2.5 N sodium hydroxide (5.5 mL, 13.8 mmol), and stirred at room temperature for 4.8 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl yielding a suspension. The solid was collected by filtration and was recrystallized from ethanol-water to yield the title compound as a yellow solid (0.20 g, 11%): mp 240.5–241.7° C. 1H NMR (acetone-d6/300 MHz) 7.99 (s, 1H), 7.67 (s, 1H), 7.43 (s, 1H), 4.99 (q, 1H, J=8.5 Hz), 2.39 (s, 3H). FABLRMS m/z 307 (M−H). FABHRMS m/z 306.9831 (M−H, Calc'd 306.9807). Anal. Calc'd for C12H8ClF3O2S: C, 46.69; H, 2.61; Cl, 11.48. Found: C, 46.78; H, 2.61; Cl, 11.41.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[N:23]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=[N:21][CH:20]=4)=[CH:13][CH:12]=3)=[C:9](Br)[N:8]([C@@H:33]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:45]B(O)O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[N:23]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=[N:21][CH:20]=4)=[CH:13][CH:12]=3)=[C:9]([CH3:45])[N:8]([C@@H:33]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(OCc4cnnn4COC(=O)C(C)(C)C)cc3)c3c(N)ncnc32)C1
Reactant: CB(O)O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(OCc3cnnn3COC(=O)C(C)(C)C)cc2)c2c(N)ncnc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 61 %

Procedure:
To a solution of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-((1-(pivaloyloxymethyl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (82) (344 mg, 0.51 mmol) in toluene (10 mL) were added methylboronic acid (306 mg, 5.1 mmol), Pd2(dba)3 (23.3 mg, 0.0255 mmol), PCy3 (14.3 mg, 0.051 mmol) and K3PO4.3H2O (407 mg, 1.53 mmol). The resulting mixture was purged with N2 for three times before heated to 120° C. overnight. The solvents were removed under vacuum and the residue was purified by flash chromatography (silica gel, 0 to 15% MeOH in DCM, with 0.5% TEA) to provide (R)-tert-butyl 3-(4-amino-6-methyl-5-(4-((1-(pivaloyloxymethyl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (83) (188 mg, 61%). LC-MS (ESI): m/z (M+1) 605.0.
Reaction SMILES: [CH3:1][O:2][C:3]([O:20][CH3:21])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:29][S:30]([O:6][CH:4]([CH3:5])[C:3]([O:20][CH3:21])([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COC(OC)(c1cccc(Oc2ccccc2)c1)C(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(OC)(c1cccc(Oc2ccccc2)c1)C(C)OS(C)(=O)=O

Procedure:
The oil, 1,1-dimethoxy-1-(3-phenoxyphenyl)propan-2-ol, from Example 26 and 11.3 g of triethylamine are dissolved in 65 ml of toluene. Then the solution is cooled to 10°-12° C. and 9.7 g of methanesulfonyl chloride in 35 ml of toluene is added over 30 minutes. After the addition is completed, the mixture is poured into 100 ml of saturated sodium bicarbonate solution, and 100 ml of toluene is added. The organic layer is separated, dried over magnesium sulfate and evaporated to yield 23.25 g of 1,1-dimethoxy-1-(3-phenoxyphenyl)prop-2-yl methanesulfonate, as an oil.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc4ccccc4c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(2-naphthyl)ethanone (1.16 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.19 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.84 g, 39%).
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([OH:3])[OH:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:44][C:45]1([F:50])[CH2:49][CH2:48][NH:47][CH2:46]1>C(#N)C>[F:44][C:45]1([F:50])[CH2:49][CH2:48][N:47]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([B:1]([OH:2])[OH:3])=[CH:12][CH:11]=2)=[O:10])[CH2:46]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: FC1(F)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(B(O)O)cc1)N1CCC(F)(F)C1
Reaction time: 0.5 h
Yield: 0 %

Procedure:
A mixture of 4-boronobenzoic acid (500 mg, 3.01 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (866 mg, 4.52 mmol) and 1-hydroxybenzotriazole (554 mg, 3.62 mmol) in acetonitrile (25 mL) was sonicated until it became a solution. N,N-Diisopropylethylamine (1.579 mL, 9.04 mmol) and 3,3-difluoropyrrolidine (484 mg, 4.52 mmol) were added. After 30 min at room temperature, the mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3×). The combined extracts were washed with brine, water, dried (Na2SO4) and concentrated. Reverse phase HPLC purification gave the expected product (0.250 mg, 33% yield). MS (ES+) m/z: 256 (M+H); LC retention time: 1.87 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4].C(N(C(C)C)CC)(C)C.[CH3:40][O:41][CH2:42]Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH2:40][O:41][CH3:42])[CH2:25][CH2:26]3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4]
Reactant: COC(=O)c1nc2n(CCN3CCNCC3)c3ccccc3n2c(=O)c1OC(C)=O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN1CCN(CCn2c3ccccc3n3c(=O)c(OC(C)=O)c(C(=O)OC)nc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.9 %

Procedure:
3-Acetoxy-4-oxo-10-(2-piperazin-1-yl-ethyl)-4,10-dihydro-benzo[4,5]imidazo[1,2-α]pyrimidine-2-carboxylic acid methyl ester (Example 15.3) (97 mg, 0.235 mmol) was dissolved in Dichloromethane (1 mL) and to it was added diisopropylethylamine (95 μL, 0.52 mmol), followed by methoxymethyl chloride (20 μA, 0.258 mmol). The reaction was stirred at room temperature for 24 h before the solvents were evaporated and the residue purified by column chromatography (98:1.5:0.5 dichloromethane: methanol: aqueous ammonia) to afford the desired product (30 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[NH2:8].O.[CH:21]([CH:23]=O)=O.C1(C)C=CC=CC=1>O>[CH2:16]([NH:15][C:3]1[C:2]2[C:7](=[N:8][CH:21]=[CH:23][N:1]=2)[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNc1c(N)c(N)nc(C)c1C(=O)OCC
Reactant: O=CC=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCNc1c(C(=O)OCC)c(C)nc2nccnc12
Reaction time: 3 h
Yield: 70 %

Procedure:
13.3 g. of 5,6-Diamino-4-butylamino-2-methylpyridine-3-carboxylic acid, ethyl ester (0.05 Mol.) of Example 1 d and 4g. of glyoxal monohydrate, dissolved in 100 ml. of toluene, are refluxed, while the water formed is removed by means of a water separator. After about 3 hours, the reaction is complete and the solution is concentrated. The remaining oily residue is extracted twice with 50 ml. portions of gasoline and addition of activated charcoal. The gasoline extracts are cooled and the crystalline 8-butylamino-6-methylpyrido[2,3-b]pyrazine-7-carboxylic acid, ethyl ester is filtered off, yield 70%; m.p. 56°-58°.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C(N(CC)CC)C>O1CCOCC1>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: ON=Cc1ccccc1
Temperature: 35 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
To a solution of benzaldehyde (2.0 g, 19 mmol) in 1,4-dioxane (6.0 ml) was added hydroxylamine hydrochloride (1.3 g, 19 mmol) and triethylamine (2.6 ml, 19 mmol). The mixture was sonicated for 0.5 h and stirred at room temperature for 116 h and at 35° C. for 24 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed with water, dried (MgSO4), filtered and evaporated in vacuo affording 1.9 g (84%) of benzaldehyde oxime as an oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][C@@H:13]([F:15])[CH2:12][NH:11]1.Br[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:19]2[CH:18]=1>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][C@@H:13]([F:15])[CH2:12][N:11]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:19]2[CH:18]=1
Reactant: Fc1ccc(F)c([C@H]2C[C@@H](F)CN2)c1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Agent: Cl
Product: CCOC(=O)c1cnn2ccc(N3C[C@H](F)C[C@@H]3c3cc(F)ccc3F)cc12

Procedure:
The title compound (Int-74) was prepared by the method similar to that for Int-84 using (2R,4R)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine hydrochloride (Int-48) and Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate to afford as yellow liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)=[O:8].OO.S([O-])(O)=[O:22].[Na+].C(OO)=O>C(O)=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][S:12]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)=[O:22])=[O:8]
Reactant: Cn1nnnc1SCCCS(=O)c1ccccn1
Reactant: O=S([O-])O
Agent: O=COO
Agent: OO
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cn1nnnc1S(=O)CCCS(=O)c1ccccn1
Reaction time: 5 h

Procedure:
3-(1-Methyl-1,2,3,4-tetrazol-5-yl)thiopropyl 2-pyridyl sulfoxide (2.8 g) is dissolved in formic acid (20 ml) and thereto is added with stirring 30% hydrogen peroxide (1.3 g) at room temperature, and the mixture is stirred for 5 hours. To the mixture is added sodium hydrogen sulfite under ice-cooling in order to decompose excess performic acid. Water is added to the resulting mixture and it is extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium bicarbonate and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography [Wakogel C-200, eluting agent, chloroform-methanol (50:1)] to give 3-(1-methyl-1,2,3,4-tetrazol-5-yl)sulfinylpropyl 2-pyridyl sulfoxide (0.8 g) as colorless liquid, nD28.5 =1.5795.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:17][C:18]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[CH3:25][C:18]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][NH:30][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(NC(=O)CCN)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CCNC(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
0.3 g of benzoyl chloride was slowly dropped onto 10 ml of a toluene solution containing 0.4 g of N-(α,α-dimethylbenzyl)-3-aminopropionamide (prepared as described in Preparation 3) and 0.22 g of triethylamine. The reaction solution was then stirred for 2 hours, and, after dilution with 20 ml of diethyl ether, was washed with water and dried over anhydrous sodium sulfate. The reaction solution was then concentrated by evaporation under reduced pressure, and purified by silica gel chromatography, to give 0.52 g (yield 87%) of the title compound melting at 147°-148° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[Br:25][C:13]1[N:9]2[N:10]=[CH:11][CH:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:8]2=[N:15][C:14]=1[CH2:16][OH:17]
Reactant: OCc1cn2nccc(N3CCOCC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: OCc1nc2c(N3CCOCC3)ccnn2c1Br
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A suspension of compound 5d (1.0 g, 4.3 mmol) in acetonitrile (100 mL) was stirred at −10° C. (in an ice/salt water bath) for 10 min, followed by addition of NBS (0.68 g, 3.8 mmol) in acetonitrile (20 mL) dropwise via an additional funnel. After the mixture was stirred in the ice-water bath for 2 h, 5% Na2S2O3 solution (10 mL) was added to quench the reaction. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine, and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to leave compound 14a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C11H13BrN4O2: 313.0 (M+H). found: 313.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[C:16]([NH2:24])(=[S:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[N+:11]([C:9]1[CH:10]=[C:5]([C:3]2[N:24]=[C:16]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:23][CH:2]=2)[CH:6]=[C:7]([OH:15])[C:8]=1[OH:14])([O-:13])=[O:12]
Reactant: NC(=S)c1cccnc1
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(-c2csc(-c3cccnc3)n2)cc(O)c1O
Temperature: 25 °C

Procedure:
A suspension of 2.91 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is treated with 1.31 g of thionicotinamide in 50 ml of alcohol and heated to boiling under reflux for 2 hours. After cooling to room temperature the crystals are filtered under suction and recrystallized from N,N-dimethylformamide/alcohol. There is obtained 3-nitro-5-[2-(3-pyridyl)-4-thiazolyl]pyrocatechol of m.p. 279°-281°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:37][N:38]1C2C=CC=CC=2N=N1.NO>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH3:16])[CH:17]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:33])[O:34][CH2:35][CH3:36])=[CH:25][CH:26]=2)[C:18]([NH:38][OH:37])=[O:19])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: NO
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)NO)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino}(4-{3-[(ethoxycarbonyl)amino]propoxy]phenyl)acetic acid (0.35 g, 0.67 mmol) and 1-(3-dimethyl aminopropyl)3-ethyl carbodiimide (0.2 g, 1.01 mmol) in DMF (8 ml), 1-hydroxybenzotriazole (0.13 g, 0.95 mmol) was added and the reaction was stirred at room temperature for 2 h. Hydroxylamine (0.23 ml. of 50% in water, 3.71 mmol) was added and the reaction was stirred overnight. After evaporating the solvent, the residue was extracted with ethyl acetate and water, the organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4, and concentrated. The residue was purified with preparative TLC plates (eluting with ethyl acetate:methanol (85:15) to provide 0.1 g of ethyl 3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}-(methyl)amino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}propylcarbamate as a yellow solid. mp 60-62° C. Electrospray Mass Spec 532 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)[C@@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 30.7 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2.25 hours with nitrogen bubbling through it. A solution of dipropylamine (5.04 g, 0.050 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was refluxed under nitrogen for two days. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. It was then dried over magnesium sulfate, charcoaled, filtered, and evaporated to an oil which crystallized upon trituration with isopropyl ether. The solid was collected by filtration and dried under high vacuum at 50° C. overnight to give 1.96 g (31%) of title compound, mp 95°-97° C.
Reaction SMILES: [CH3:1][C:2]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)([CH3:6])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:27](I)[CH3:28].O>CN(C)C=O>[CH3:6][C:2]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)([CH3:1])[C:3]([O:5][CH2:27][CH3:28])=[O:4]
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
To a mixture of 2-methyl-2-(6-methyl-5-phenyl-2,3-dihydro-4-oxo-4H-1,3-oxazin-3-yl)-propionic acid (0.83 g) and potassium carbonate (0.45 g) in 4 ml of dimethylformamide (DMF) was added ethyl iodide (0.56 g), and the mixture was stirred at 60° C. for 5 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica gel column to get the captioned compound (0.87 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]([CH2:22][C:23](Cl)=[O:24])#[N:21]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][S:8][C:7]=1[NH:19][C:23](=[O:24])[CH2:22][C:20]#[N:21])=[O:5])[CH3:2]
Reactant: N#CCC(=O)Cl
Reactant: CCOC(=O)c1c(C=Cc2ccccc2)csc1N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C=Cc2ccccc2)csc1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-4-styryl-thiophene-3-carboxylic acid ethyl ester (0.1298 g, 0.475 mmol) S was dissolved in anhydrous CH2Cl2 (2.0 mL). This was treated with cyanoacetyl chloride (0.713 mL, 0.713 mmol, 1 M in CH2Cl2) and stirred at room temperature for 1 hr. More cyanoacetyl chloride (0.238 mL, 0.238 mmol) was added and stirring was continued at room temperature for 1 hr then refluxed for 30 min. The reaction was diluted with EtOAc (25 mL). This was washed with sat. NaHCO3 (1×25 mL), H2O (1×25 mL), and brine (1×25 mL). The organic layer was dried (Na2SO4), filtered and the solvent removed in vacuo to give 0.0803 g (50%) of crude 7 which was carried on to the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([F:38])=[CH:40][CH:41]=2)[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Product: O=C1C(Cc2ccc(F)cc2)CCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Yield: 67 %

Procedure:
In a manner similar to the method described in Example 36-2, using 281 mg of 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1, and using 4-fluorobenzyl bromide in place of iodoethane, 205 mg (yield: 67%) of the captioned compound was obtained as a diastereomer mixture.