Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[C:15]([CH2:18][C:19](=[O:21])[CH3:20])(=[O:17])[CH3:16].N1CCCCC1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[C:18]([C:19](=[O:21])[CH3:20])[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)CC(C)=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: C1CCCCC1
Solvent: C1CCNCC1
Product: COc1cc(C=C(C(C)=O)C(C)=O)cc(OC)c1OC
Reaction time: 8 h

Procedure:
3-(3,4,5-trimethoxybenzylidene)-2,4-pentanedione (hereinafter “HSS”) was prepared by the condensation of 3,4,5-trimethoxy benzaldehyde with acetyl acetone in the presence of piperidine and cyclohexane as the reaction medium at reflux temperature under continuous azeotropic water removal. The reaction takes about eight hours to complete. The reaction product was purified by crystallization with methanol. The typical yield of HSS is about 68% with a purity, as determined by GC, of 99.1%. HSS is an off-white free-flowing powder with a melting point of 83-86° C. with a λmax at 319 nm.
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[CH3:12][C:13]1([CH2:16][NH:17][C:18](=[O:28])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:15][O:14]1.C([O-])(=O)C.[Na+].O>C(O)C>[CH3:15][C:13]1([CH2:16][NH:17][C:18](=[O:28])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[O:14][C:4]2=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]2[CH2:12]1
Reactant: CC1(CNC(=O)OCc2ccc(Cl)cc2)CO1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(CNC(=O)OCc2ccc(Cl)cc2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 16.4 %

Procedure:
2,4-Dinitro-1H-imidazole (0.518 g, 3.28 mmol) and 4-chlorobenzyl (2-methyloxiran-2-ylmethyl)carbamate (2.097 g, 8.20 mmol) and sodium acetate (0.538 g, 6.56 mmol) in ethanol (6 ml) was stirred under reflux for 1 hour. To the solution, water was added and the precipitates were filtered off. The resulting solid was treated with diethyl ether to afford 4-chlorobenzyl (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)carbamate (0.197 g, yield 16%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)no1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
2.86 g of methyl 3-hydroxyisoxazole-5-carboxylate was dissolved in 10 ml of N,N-dimethylformamide, and 4.25 g of methyl iodide and 4.15 g of potassium carbonate were then added under ice-cooling. The mixture was stirred at room temperature overnight. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.23 g of methyl 3-methoxyisoxazole-5-carboxylate.
Reaction SMILES: C1COCC1.[N:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]2=[C:8]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=2)[CH:7]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>CCN(CC)CC>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:8]3[CH:7]=[N:6][N:10]4[CH:11]=[CH:12][CH:13]=[N:14][C:9]=34)[CH:20]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: Nc1ccnc(-c2cnn3cccnc23)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccnc(-c2cnn3cccnc23)c1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a THF suspension of 2-(pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-4-amine (8g) was added Et3N and 4-fluorobenzoyl chloride. The reaction mixture was stirred at 50° C. for 2 hours until LS/MS indicated the desired product was the major peak. After aqueous work up, the residue was dissolved in 1 ml of DMSO and purified by preparative HPLC. The product was obtained as a solid (10 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1[CH:61]=[CH:62][C:63]([CH2:66]O)=[N:64][CH:65]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][C:63]2[CH:62]=[CH:61][C:60]([CH3:59])=[CH:65][N:64]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1ccc(CO)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2ccc(C)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (5-methylpyridin-2-yl)methanol (0.5 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.59 g, 47%).
Reaction SMILES: O1C2C=CC=CC=2N=C1.NC1C=CC=CC=1.C(OC([N:24]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[C:41]3[O:40]C(C(C)(C)C)=[N:38][C:37]=3[CH:36]=[CH:35][C:34]=2[Cl:46])(=[O:32])=[O:31])[CH2:26][CH2:25]1)=O)(C)(C)C.OS(O)(=O)=O>O1CCOCC1.O>[NH2:38][C:37]1[C:41]([OH:40])=[C:33]([S:30]([N:27]2[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]2)(=[O:32])=[O:31])[C:34]([Cl:46])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Agent: O=S(=O)(O)O
Agent: c1ccc2ocnc2c1
Solvent: Nc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCNCC2)c1O
Yield: 97.2 %

Procedure:
Following the general procedure for the hydrolysis of the benzooxazole to the desired aniline outlined in example 51, 4(2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 4.3 mmol), water (3.65 mL), and H2SO4 (3.65 mL) in 1,4-dioxane (60 mL) were reacted to afford the title compound (1.22 g, 96%). LCMS m/z 292(M−H)+.
Reaction SMILES: [O:1]1[CH:3]([CH:4]([CH3:13])[CH2:5][CH2:6][CH2:7][C:8]([O:11][CH3:12])([CH3:10])[CH3:9])[CH2:2]1.[C:14](=O)([O-])[O-:15].[Na+].[Na+].[H][H]>[Ni].C(O)(C)C>[CH3:14][O:15][CH2:10]/[C:8](=[CH:7]\[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][OH:1])[CH3:13])/[CH3:9].[CH3:13][CH:4]([CH:3]([OH:1])[CH3:2])[CH2:5][CH2:6][CH2:7][C:8]([O:11][CH3:12])([CH3:9])[CH3:10]
Reactant: COC(C)(C)CCCC(C)C1CO1
Reactant: [H][H]
Reactant: O=C([O-])[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(C)O
Product: COC(C)(C)CCCC(C)C(C)O
Product: COC/C(C)=C\CCC(C)CCO

Procedure:
A solution of 186 g, 7, 8-epoxy-2-methoxy-2, 6-dimethyloctane and 5 g sodium carbonate in 100 ccs isopropanol was hydrogenated in the presence of 2 g Raney nickel at 120°C and 150 psi hydrogen pressure over 16 hours. The product was filtered and fractionally distilled to give 75 g methoxy-citronellol and 105 g methoxyelgenol. (R=Methyl). Methoxyelgenol has a marked long lasting sandalwood odour with rose undertones.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=1)[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)CC
Product: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)CC

Procedure:
The title compound was prepared by the method of Preparation 1b using 3-oxopentanoic acid ethyl ester and 1-bromo-4-bromomethylbenzene.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1)=[CH2:2].[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16]>C(Cl)(Cl)Cl>[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)[CH2:24][CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: C=Cc1ccnc2ccc(C#N)cc12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCc2ccnc3ccc(C#N)cc23)CC1
Temperature: 50 °C
Yield: 99.9 %

Procedure:
A mixture of (d) (150 mg, 0.8 mmol), piperidin-4-yl-carbamic acid tert-butyl ester (166 mg, 0.8 mmol) and chloroform (0.5 ml) were heated at 50° C. in a loosely capped vial for 6 hours. The product was purified by flash silica chromatography eluting with a 0-2% methanol in chloroform gradient affording the product as a foam (304 mg, 96%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](=[CH:15]\[N:16](C)C)/[C:6](=O)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH3:2].Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[CH:24][CH:23]=1>CO>[CH2:1]([O:3][C:4]([C:5]1[CH:15]=[N:16][N:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[C:6]=1[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:19])[CH3:2]
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)C(OCC)OCC
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1C(OCC)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[1-dimethylamino-meth-(Z)-ylidene]-4,4-diethoxy-3-oxo-butyric acid ethyl ester (625 mg, 2.28 mmol) in methanol (10 mL) is added 4-fluorophenylhydrazine hydrochloride (410 mg, 2.5 mmol). The mixture is warmed at reflux. After 2 hours, the reaction mixture is cooled to room temperature, concentrated in vacuo, diluted with water (15 mL) and extracted with ether (3×15 mL). The combined ether layers are washed with brine (2×15 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a gradient of 0-10% EtOAc in hexanes to afford 5-diethoxymethyl-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1]([C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:8])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](/[CH:17]=[CH:16]/[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:3]([CH2:1][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:4][CH:5]=2)=[N:19]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30 %

Procedure:
(E)-4-Formyl-N-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}benzamide (60 mg, 0.16 mmol) was dissolved in dichloroethane (1.5 mL) and acetic acid (10 μL) and morpholine (22 μL) and sodium triacetoxyborohydride (104 mg, 0.49 mmol) were added thereto. The mixture was stirred at room temperature for 20 hours, added with water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate to obtain Compound 80 (21 mg, 30%).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1.[N:13]1[N:14]=[CH:15][N:16]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH:17]=1
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cncn2)cc1
Product: CCOC(=O)c1ccc(-n2cnnc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-fluorobenzoate (8.4 g), 1,2,4-triazole (4.14 g) and potassium carbonate (20.7 g) in DMF (30 ml) was stirred at 100° C. for 3 hours and concentrated. To the residue was added dichloromethane, and the mixture was washed with water, dried and concentrated. The residue was purified with silica gel column chromatography (dichloromethane:methanol=50:1→20:1) to give a colorless solid of ethyl 4-(1,2,4-triazol-1-yl)benzoate (4.0 g) and ethyl 4-(1,2,4- triazol-4- yl)benzoate (369 mg).
Reaction SMILES: [CH:1]12[C:9](=[O:10])[O:8][C:6](=O)[CH:3]([CH2:4][CH2:5]1)[CH2:2]2.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:18][CH2:17]1.C(Cl)Cl.C1(C)C(C)=CC=CC=1>O>[F:31][C:28]([F:29])([F:30])[C:24]1[CH:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:6](=[O:8])[CH:3]4[CH2:2][CH:1]([CH2:5][CH2:4]4)[C:9]3=[O:10])[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C1OC(=O)C2CCC1C2
Reactant: NCCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1C2CCC(C2)C(=O)N1CCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
1,3-Cyclopentane dicarboxylic anhydride (2.2 g., 15 mmole) and 1-(4-aminobutyl)-4-[3-(trifluoromethyl)phenyl]piperazine (4.5 g., 15 mmole) were combined in 300 ml. of methylene chloride and stirred for 30 minutes at room temperature. The solvent was replaced with 200 ml. of xylene and the mixture was refluxed for 48 hours with water removal via a Dean-Stark trap. The solvent was removed in vacuum and the residue filtered through 75 g. of silica gel with 2% ethanol/chloroform as eluent. The product was concentrated in vacuum and crystallized from 50 ml. of isopropanol with the addition of 5 ml. of 4N isopropanolic HCl. A second recrystallization from ethanol gave 2.7 g. of the title compound as the hydrochloride, quarter hydrate; m.p. 208°-209° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15].O>C(O)C.C(O)(CC)(C)C>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Solvent: CCC(C)(C)O
Solvent: CCO
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Temperature: 82.5 °C

Procedure:
Crude oxymorphone, which contains residual water and, in some instances, can also contain residual ethanol, is dissolved in tert-amyl alcohol and the solution dried to remove water. This oxymorphone solution is then treated with excess allyl chloroformate (compound (102)) and sodium bicarbonate at 70-85° C. (Step 3). Once the reaction is complete (i.e., conversion of oxymorphone to the 3-allylcarbonate-N-allylcarbamate noroxymorphone (compound (109)), in which none, some, or all of the 14-OH can also be converted to a 14-allylcarbonate group (i.e., compound (110)), water and sodium carbonate are added and, in Step 4A, the mixture is heated to 80-85° C. for at least 15 hours to destroy excess allyl chloroformate and to hydrolyze the 3-carbonate moiety as well as any 14-carbonate groups that might be present, providing the 17-allylcarbamate derivative of noroxymorphone (compound (105)). The product, noroxymorphone-17-allylcarbamate, can be extracted into a suitable organic solvent which can be filtered, washed, and dried using normal work-up procedures. If desired, the product can be recovered by evaporation of that solvent.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:13][C:14](=[O:34])[CH:15]([NH:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:16][C:17]1[O:21][N:20]=[C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH:18]=1)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:31]([O:30][C:28]([NH:27][CH:15]([CH2:16][C:17]1[O:21][N:20]=[C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=1)[C:14]([OH:34])=[O:13])=[O:29])[CH:32]=[CH2:33]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)c2ccccc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
Benzoyl chloride (21 μl, 0.18 mmol, 1.0 equivalents) was added in one portion to a solution of 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride (1C) (74 mg, 0.20 mmol, 1.1 equivalents) in pyridine (29 μl, 0.36 mmol, 2.0 equivalents) and dichloromethane (2 mL) at 0° C. The reaction was stirred at room temperature for 4 hours then diluted with ethyl acetate (30 mL). The reaction was extracted with 1N hydrochloric acid (30 mL) and brine (30 mL). The organic portion was dried over sodium sulfate and concentrated in vacuo to give the title compound (66 mg, 84%). MS (Cl) m/z 442.3 (M+1).
Reaction SMILES: C(OC([N:8]1[C:22]2[C:23]3[C:10]([CH2:11][C@@H:12]4[C@@H:17]([C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]([C:24]([OH:26])=[O:25])[CH2:14][N:13]4C(OC(C)(C)C)=O)=[CH:9]1)=O)(C)(C)C.S(Cl)([Cl:36])=O.[C:38](OC)(C)(C)C>CO>[ClH:36].[C@@H:15]1([C:24]([O:26][CH3:38])=[O:25])[CH2:16][C@H:17]2[C@@H:12]([CH2:11][C:10]3[C:23]4[C:22](=[CH:21][CH:20]=[CH:19][C:18]2=4)[NH:8][CH:9]=3)[NH:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)C[C@@H]2c3cccc4c3c(cn4C(=O)OC(C)(C)C)C[C@H]21
Reactant: O=S(Cl)Cl
Reactant: COC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H]1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1
Product: Cl
Temperature: 52.5 °C
Reaction time: 4.5 h
Yield: 94.5 %

Procedure:
To a mixture of 1,6-di-(tert-butoxycarbonyl)-ergoline-8β-carboxylic acid (300 g) in methanol (1.2 L) is slowly added thionyl chloride (94 g). The mixture is slowly heated to 50-55° C. and stirred until reaction completion (ca. 4-5 h). The resulted suspension is cooled to room temperature and to it is added methyl t-butyl ether (600 mL) and heptanes (1.8 L). The suspension is further cooled to 0-5° C. Filtered and washed with methyl t-butyl ether. The isolated solid is dried to give methyl ergoline-8β-carboxylate hydrochloride (190.5 g) in 94.5% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.[N+:12]([C:15]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>COCCOC.O>[F:11][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:12]([O-:14])=[O:13])[CH:21]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2ccc([N+](=O)[O-])c(F)c2)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 45.3 %

Procedure:
4-Bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol), 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (660 mg, 2.50 mmol) and K2CO2 (940 mg, 6.81 mmol) were suspended in DME-H2O (4:1, 15 mL) and purged with nitrogen. The solution was degassed by sonication before Pd(dppf)Cl2 (185 mg, 10 mol %) was added. The mixture was heated to 130° C. for 10 min under microwave irradiation. The cooled mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resulting black solid was absorbed onto silica and purified by column chromatography (4:1 to 1:1 petrol-EtOAc) to give the product as an orange solid (285 mg, 45%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[S:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:11][CH:10]1[C:3]2[C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][S:9]1
Reactant: CC1SCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1SCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Yield: 70.8 %

Procedure:
A solution of 4-chloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine (4 g, 21 mmol) and 1-Boc-piperazine (8.5 g, 46 mmol) in NMP (20 mL) was heated to 120° C. overnight. After cooling, the mixture was diluted with ethyl acetate (500 mL) and washed with water (6×300 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (2:1) to provide tert-butyl 4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (5 g, 69%). The crude material was purified by chiral separation on chiral HPLC (ODH, 250×20 mm, 100% acetonitrile, 15 mL/min) to give (R)-tert-butyl 4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (retention time: 4.016 min) and (S)-tert-butyl 4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (retention time: 4.551 min). 1H NMR (CDCl3, 400 MHz) δ 8.53 (s, 1H), 4.83 (m, 1H), 4.18 (m, 2H), 3.73-3.56 (m, 4H), 3.51-3.43 (m, 4H), 1.50 (m, 9H). MS (APCI+) [M+H]+ 337.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21].C(N(CC)CC)C>CN(C)C=O>[O:21]=[C:10]1[NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[NH:14][C:15](=[O:16])[CH:9]1[NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reaction time: 6 h

Procedure:
Add valeryl chloride (3.92 mL, 33.0 mmol) dropwise to a solution of 3-Amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (5.74 g, 30.0 mmol) and triethylamine (4.60 mL, 33.0 mmol) in anhydrous dimethylformamide (123 mL) and stir. After 6 hours, concentrate under reduced pressure to a residue and reconstitute the residue in a solution of isopropanol:chloroform (1:3, 500 mL). Stir overnight to give a solid and isolate the solid by suction filtration, washing the solid with dichloromethane. Vacuum dry the solid at ambient temperature 2 hours to afford the title compound. Wash the filtrate with a saturated aqueous solution of sodium bicarbonate (2×200 mL), and filter the extraction mixture to remove salt formed in the wash. Separate the organic phase and wash it with saturated aqueous sodium chloride (150 mL). Back extract the bicarbonate aqueous phase with dichloromethane. Combine all organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Triturate the residue in diethyl ether, filter the resulting solid, and wash it with diethyl ether; repeat 2×. Dry the solid at ambient temperature under vacuum to give the title compound: mass spectrum (APCI, m/e): 276 (M+1); 1H NMR (300 MHz, DMSO-d6): 10.68 (s, 2H), 8.23 (d, 1H, J=7.5 Hz), 7.20 (m, 4H), 4.71 (d, 1H, J=7.5 Hz), 2.25 (t, 2H, J=7.5 Hz), 1.43 (m, 2H), 1.25 (m, 2H), 0.83 (t, 3H, J=7.5 Hz).