Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23][C:24](=[O:39])[CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].C1(C)C=CC(S([N:49]=[N+:50]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C>C(#N)C>[N+:49](=[C:25]([C:24](=[O:39])[CH2:23][C@@H:19]1[C@@H:18]([C:2]([CH3:1])([O:4][C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:6])[CH3:3])[C:21](=[O:22])[NH:20]1)[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)=[O:27])=[N-:50]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
To a solution of 4-nitrobenzyl 4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate (58.3 mg) in acetonitrile (1.17 ml) was added a solution of p-toluenesulfonyl azide (25.3 mg) in acetonitrile (0.228 ml) at 0° C. After stirring for 5 minutes at 0° C., a solution of triethylamine (53.7 μl) in acetonitrile (0.483 ml) was added dropwise. The stirring mixture was allowed to warm to ambient temperature during 15 minutes and kept at the same temperature for 20 minutes. The solvent was distilled off and the residue (85.9 mg) was flash chromatographed on silica gel (1 g) eluting with a mixture of methylene chloride and ethyl acetate (50:1 to 3:1) to give 4-nitrobenzyl 2-diazo-4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate (58.4 mg) as an amorphous solid
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>CN(C)C=O>[Cl:18][C:13]1[C:14]2[C:5]([N:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1c2ccccc2nc2ccccc12
Reaction time: 0.5 h
Yield: 97 %

Procedure:
0.488 g (2.5 mmol) of 9-(10H)acridone, 2.5 ml of thionyl chloride and a catalytic amount (a few drops) of dimethylformamide were mixed at 80° C. After 30 min of stirring, the reaction mixture was evaporated, the residue was dissolved in chloroform and poured into cold aqueous ammonia. The ammonia solution was extracted several times with chloroform. The combined organic phases were washed with 2M ammonia solution, dried over sodium sulfate and evaporated to obtain 0.517 g (97%) of 9-chloroacridine.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH2:14][NH:15]C2CC2)C=[C:7](/[CH:9]=[CH:10]/[CH2:11]OC)[CH:8]=1.[CH3:19]COC(C)=O>[Pd]>[CH3:19][CH2:11][CH2:10][CH2:9][CH2:7][CH2:8][CH2:3][CH2:4][CH2:5][CH2:14][NH2:15]
Reactant: CCOC(C)=O
Reactant: COC/C=C/c1cc(CNC2CC2)cc(OC)c1
Agent: [Pd]
Product: CCCCCCCCCCN
Reaction time: 1.5 h

Procedure:
To a solution of N-({3-(methyloxy)-5-[(1E)-3-(methyloxy)-1-propen-1-yl]phenyl}methyl)cyclopropanamine (1 eq.) from the previous step in EtOAc (0.04 M) was added palladium (10% w/w over activated carbon, 0.1 eq). The vessel was evacuated and back filled with hydrogen. The reaction suspension was then stirred under a balloon atmosphere of hydrogen for 1.5 h. The reaction was quenched with dichloromethane and filtered through a bed of celite. The insolubles were washed further with EtOAc and methanol. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[C:9](=O)[NH:10][CH:11]=[C:12]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(Cl)([Cl:42])=O)C=CC=CC=1.[OH-].[NH4+]>>[Cl:42][C:9]1[C:8]([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][C:12]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][N:10]=1
Reactant: O=c1[nH]cc(C(c2ccccc2)c2ccccc2)cc1C(c1ccccc1)c1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ncc(C(c2ccccc2)c2ccccc2)cc1C(c1ccccc1)c1ccccc1
Reaction time: 6 h

Procedure:
Combine 49.5 g. (0.11 moles) of 3,5-bis-(diphenylmethyl)-2-pyridone (prepared as described in step B) with 105 ml. of phenylphosphonic dichloride and heat the reaction mixture with stirring at 200°-210° C. for 6 hours. Pour the reaction mixture onto ice and basify with ammonium hydroxide. Extract with ethyl ether, dry the extract and evaporate to yield a residue which is crystallized from ethanol to yield the product of this step, yield about 40 g., m.p. 131°-133° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(Cl)(Cl)Cl.[CH3:22][O:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[CH3:22][O:23][C:24]([NH:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[O:25]
Reactant: COC(=O)Cl
Reactant: Nc1cnc2ccc(Sc3ccccc3)cn12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cnc2ccc(Sc3ccccc3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.0 g. of 3-amino-6-(phenylthio) imidazo [1,2-a] pyridine in 25 ml. of chloroform containing 0.401 g. of triethyl amine is treated dropwise with 0.378 g. of methylchloroformate. The reaction mixture is stirred for 3 hours at room temperature. The chloroform is removed in vacuo and the residue is triturated with water. The solids are collected by filtration, washed well with water and dried. Recrystallization from dimethylformamideethane yields pure 3-(methoxycarbonylamino) 6-(phenylthio) imidazo [1,2-a] pyridine m.p. 211°-215° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:39])([F:38])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[CH2:35][CH2:36][OH:37])=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1.[CH:40]([N:43]=[C:44]=[O:45])([CH3:42])[CH3:41].O>ClCCl>[CH:40]([NH:43][C:44](=[O:45])[O:37][CH2:36][CH2:35][C:31]1[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:16]3[N:17]=[C:13](/[CH:12]=[CH:11]/[C:8]4[CH:9]=[CH:10][C:5]([C:4]([F:38])([F:3])[F:39])=[CH:6][CH:7]=4)[O:14][CH:15]=3)=[CH:21][CH:22]=2)[CH:34]=[CH:33][N:32]=1)([CH3:42])[CH3:41]
Reactant: CC(C)N=C=O
Reactant: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
65% Sodium hydride (21.6 mg) was added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol (300 mg) in dichloromethane (3 ml) at 0° C., and the mixture was stirred at room temperature for 30 min. Isopropyl isocyanate (0.288 ml) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 5 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with 1N aqueous sodium hydroxide solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and recrystallized from ethyl acetate-hexane to give the titled compound (315 mg) as a colorless crystal powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[NH:27][C:26](=[O:28])[O:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1.CO.[C:32]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:32][N:27]1[C:26](=[O:28])[O:25][N:24]=[C:23]1[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:14]2[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]3[N:29]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[C:15]2=[O:16])[CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(=O)[nH]3)c1)C2=O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(=O)n3C)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
(S)-3-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5(4H)-one (150 mg, 0.37 mmol) obtained in Step 1 was suspended in THF (2.0 mL), and the mixture was stirred at room temperature for 2 hours after adding methanol (0.022 mL, 0.55 mmol), triphenylphosphine (144 mg, 0.55 mmol), and diethyl azodicarboxylate (40% toluene solution, 0.25 mL, 0.55 mmol). The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-4-methyl-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5(4H)-one (127 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[CH:16][C:17](=[O:19])[NH:18][C:13]=3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:20][C:21](=[O:29])OC1C=CC=CC=1.[C:30]([C:34]1[CH:38]=[C:37]([NH2:39])[N:36]([C:40]2[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=2)[N:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:38]=[C:37]([NH:39][C:21]([NH:20][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[C:14]4[N:15]=[CH:16][C:17](=[O:19])[NH:18][C:13]=4[N:12]=[CH:11][CH:10]=3)=[CH:7][C:2]=2[F:1])=[O:29])[N:36]([C:40]2[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=2)[N:35]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F)Oc1ccccc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2F)cn1
Yield: 16.7 %

Procedure:
Method F4 was used with 65 mg (0.17 mmol) of phenyl 2-fluoro-4-(3-oxo-3,4-dihydropyrido[3,2-b]pyrazin-8-yloxy)phenylcarbamate and 45 mg (0.2 mmol) of 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (Regan, J. et al., J. Med. Chem. 2002, 45, 2994-3008). Obtained 15 mg, 17% yield of the title compound.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9]>>[Cl:4][CH2:5][CH2:6][NH:7][C:8]([NH:3][CH2:1][CH3:2])=[O:9]
Reactant: CCN
Reactant: O=C=NCCCl
Product: CCNC(=O)NCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A mixture of ethylamine (2.0M in THF, 2.369 mL, 4.74 mmol) and chloroethylisocyanate (0.50 g, 4.74 mmol) was stirred at RT for 2 h, concentrated to dryness and treated with MeCN. The solid was collected via filtration and dried to afford 1-(2-chloroethyl)-3-ethylurea (460 mg, 65%). 1H NMR (400 MHz, DMSO-d6): δ 6.05 (s, 1 H), 5.96 (s, 1 H), 3.54 (t, J=6.3 Hz, 2 H), 3.30-3.23 (m, 2 H), 3.02-2.93 (m, 2 H), 0.96 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 151.1 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:14]1[N:15]([C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[N:16]=[CH:17][CH:18]=1>C(#N)C>[N:14]1[N:15]([C:19]2[N:24]=[C:23]([NH:25][C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=3[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:22]=[CH:21][CH:20]=2)[N:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Nc1cccc(-n2nccn2)n1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(-n2nccn2)n1
Temperature: 140 °C
Yield: 35.4 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (154 mg, 695 μmol) in acetonitrile was added 6-(2H-1,2,3-triazol-2-yl)pyridin-2-amine (112 mg, 695 μmol) and heated to 140° C. for 72 h. The mixture was cooled and precipitated by addition of acetone. The mixture was filtered and the solid collected was washed with methanol and ether then dried to give ethyl 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (85 mg, 246 μmol, 35%) as an off white solid. 1H NMR (400 MHz, DMSO-d) δ ppm 10.60 (s, 1H), 9.50 (s, 1H), 8.26 (s, 2H), 8.08 (t, J=8.2 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 4.48 (q, J=7.3 Hz, 2H), 1.40 (t, J=7.3 Hz, 3H); MS (EI/CI) m/z: 346.0 [M+H].
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])NC2SC(SCC(O)=O)=CN=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=O)CCCCC1.CC(C)CCN.C([O:44][C:45](=[O:56])[C:46]([S:49][C:50]1[S:54][C:53]([NH2:55])=[N:52][CH:51]=1)([CH3:48])[CH3:47])C>>[CH:1]1([N:7]([CH2:21][CH2:22][CH:23]([CH3:28])[CH3:24])[C:8](=[O:20])[NH:55][C:53]2[S:54][C:50]([S:49][C:46]([CH3:47])([CH3:48])[C:45]([OH:44])=[O:56])=[CH:51][N:52]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: CC(C)CCN
Solvent: O=C1CCCCC1
Product: CC(C)CCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from cyclohexanone, 3-methylbutylamine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16](F)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(=O)[NH:27]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C.O>[NH2:27][C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[C:19]([F:20])=[CH:18][C:17]=1[F:21]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(F)c(F)cc2F)CC1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N)c(F)cc2F)CC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(3,5,6-trifluoro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.59 g, 5 mmol, Example 39a), potassium phthalimide (0.93 g, 5 mmol, Aldrich) in DMF (20 mL) was heated at 140° C. with stirring for 16 h. The reaction mixture was cooled to room temperature, diluted with water (60 mL) and extracted with EtOAc (2×70 mL). The combined organic extracts were dried over Na2SO4, and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 20% EtOAc in hexane to give the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 315 (M+1).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:18][CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:19]([C@@H:21]([OH:24])[CH2:22][CH2:23][C@@:9]34[OH:25])[O:20][C:4]([C:5]=25)=[C:3]([OH:26])[CH:2]=1.C(N(CC)CC)C.[C:34]([O:38]C(=O)CC)(=[O:37])[CH2:35][CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:18][CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:19]([C@@H:21]([OH:24])[CH2:22][CH2:23][C@@:9]34[OH:25])[O:20][C:4]([C:5]=25)=[C:3]([OH:26])[CH:2]=1.[C:34]([O-:38])(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)OC(=O)CC
Agent: O=C([O-])[O-]
Agent: Oc1ccc2c3c1O[C@H]1[C@@H](O)CC[C@@]4(O)[C@@H](C2)N(CC2CCC2)CC[C@]314
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)[O-]

Procedure:
75 ml of methylene chloride and 3.57 g(0.01 mole) of Nalbuphine were added to a 250 ml round-bottomed flask. The flask was placed in an ice bath to keep it cool. The content was stirred then gradually 0.16 mole of triethylamine was added. With rapid stirring, another 20 ml of dichloromethane solution containing 0.011 mole of propionic anhydride was added drop by drop. Afterward, the mixture was stirred at room temperature for 1 hour. 20 ml of 10% sodium carbonate solution was added to neutralize the residual acid and remove the water soluble impurities. Sodium sulfate was used to dehydrate the solution. After drying under vacuum, a Nalbuphine propionate solid was obtained. The product was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1.[OH-].[Na+].OS(O)(=O)=O>O.CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Cl)c(C(=O)O)c(Cl)n1
Yield: 65.7 %

Procedure:
A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MeOH (1.5 mL) was heated to 80° C. for 4 h. The mixture was acidified using 50% H2SO4 and filtered. The solid was washed with cold water and dried to give of 2,4-dichloro-6-methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH+: 206.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26]Br.O>CN(C)C=O>[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26][N:12]1[C:11](=[O:20])[CH2:10][C@@:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19]
Reactant: CC(C)=CCBr
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CC=C(C)C)C(=O)C3)c1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of 4 g (14.7 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 50 ml of anhydrous dimethylformamide was added dropwise to 700 mg of a 55% suspension of sodium hydride in mineral oil in 50 ml of dimethylformamide at 70°. The reaction mixture was heated for 1 hour after the addition was complete and then cooled to 25°. 3,3-Dimethylallyl bromide (2.37 g, 15.8 mmoles) in 10 ml of dimethylformamide was added dropwise and the solution stirred overnight at 25°. After heating at 80° for 1 hour it was poured into water and extracted with ether to yield 4.74 g of N-(3,3-dimethylallyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline (oil), which was evaporatively distilled, bp 225° (0.005 mm).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[NH4+].[NH4+].F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH3:16])[C:13]([NH2:30])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
A mixture of (2S)-2-[(benzyloxy)carbonyl]aminopropanoic acid (0.5 g, 0.002 mol), ammonium carbonate (0.43 g, 0.0045 mol), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (1.2 g, 0.0027 mol), N,N-diisopropylethylamine (980 μL, 0.0056 mol) in methylene chloride (3 mL) was stirred at RT overnight. The mixture was quenched with saturated NaHCO3 solution, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column to afford the desired product (0.54 g). Analytical LCMS: (M+H)+=223.1.
Reaction SMILES: Cl.[NH:2]([C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1)[NH2:3].[O:10]([C:17]1[C:22]([CH:23]=O)=[C:21](OC2C=CC=CC=2)[N:20]=[CH:19][N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC>C1COCC1>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N:2]1[C:21]2=[N:20][CH:19]=[N:18][C:17]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:22]2[CH:23]=[N:3]1
Reactant: Cn1ccnc1NN
Reactant: O=Cc1c(Oc2ccccc2)ncnc1Oc1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Agent: Cl
Solvent: C1CCOC1
Product: Cn1ccnc1-n1ncc2c(Oc3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.7 %

Procedure:
2-Hydrazinyl-1-methyl-1H-imidazole hydrochloride (Intermediate AV2) (305 mg, 2.05 mmol) was added to 4,6-diphenoxypyrimidine-5-carbaldehyde (Intermediate Z2) (600 mg, 2.05 mmol) in THF (15 mL) the resulting solution was stirred at room temperature for 5 minutes. 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (2.8 g, 6.2 mmol) was added and sealed into a microwave tube. The reaction was heated to 120° C. for 10 hours in the microwave reactor and cooled to RT. The reaction mixture was filtered and evaporated to dryness. The crude product was purified by flash silica chromatography eluting with 0 to 5% MeOH in DCM to afford the product (190 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 3.59 (3H, s), 6.95 (1H, d), 7.11 (1H, d), 7.24-7.20 (2H, m), 7.32-7.26 (1H, m), 7.44 (2H, m), 8.03 (1H, s), 8.59 (1H, s); m/z (ES+) (M+H)+=293; HPLC tR=1.65 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[C:8]([O:12][C:13]([C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[C:25]3[CH2:26][C:27]([CH3:30])([CH3:29])[O:28][C:24]=3[CH:23]=[C:22]([C:31](O)=[O:32])[CH:21]=2)=[CH:17][C:16]=1[F:36])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:14])[C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[C:25]3[CH2:26][C:27]([CH3:29])([CH3:30])[O:28][C:24]=3[CH:23]=[C:22]([C:31](=[O:32])[NH:7][C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)[CH:21]=2)=[CH:17][C:16]=1[F:36])([CH3:9])([CH3:10])[CH3:11]
Reactant: Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)OC(C)(C)C)c(F)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 15 except that the reaction was carried out at 75° C. for 2 hr, from 1-methyl-3-aminopyrazole (892 mg, 9.18 mmol) and 4-(4-tert-butoxycarbonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (66b) (2.46 g, 6.11 mmol) to give a white solid (1.77 g, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1 H) 7.87 (t, J=8.59 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.07 (s, 1 H) 7.04 (s, 1 H) 6.79 (d, J=2.02 Hz, 1 H) 6.75 (dd, J=8.84, 2.27 Hz, 1 H) 6.68 (dd, J=11.75, 2.40 Hz, 1 H) 3.80 (s, 3 H) 2.87 (s, 2 H) 1.60 (s, 9 H) 1.49 (s, 6H); LCMS for C26H28FN3O5 m/z 505.00 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].[Cl:27]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.N.ClCCl>FC(F)(F)C(O)=O>[Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[C:13]([Cl:27])[CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Cl)cc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Reaction time: 0.25 h

Procedure:
2.1 g of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (5 mmol) and 388 mg of trichloroisocyanuric acid (1.67 mmol) are dissolved in 100 ml of trifluoroacetic acid at room temperature. After 15 minutes, ice is added, it is made alkaline with conc. ammonia and shaken out with dichloromethane. The organic phases are dried and concentrated by evaporation, the residue is chromatographed and the product crystallizes from ethyl acetate/ether, yield 480 mg (21% of theory).