Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)C.[Na+].[Cl-]>C1C=CC=CC=1>[C:1]1([C@H:7]2[C@H:12]([OH:13])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCNCC1c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: O[C@@H]1CCNC[C@H]1c1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 0.9 g of the free base, 3-phenyl-4-piperidone of Example 50c, above, 0.19 g of sodium borohydride and 15 ml of absolute ethanol is stirred at room temperature for 6 hours under a nitrogen atmosphere. The mixture is then treated with 25 ml of saturated aqueous NaCl solution and extracted with dichloromethane. The combined organic extracts are washed with saturated aqueous NaCl solution, dried over anhydrous Na2 SO4 and concentrated in vacuo to a gum which TLC shows to be a mixture of cis and trans isomers, with the trans isomer predominant. Trituration of this material with benzene gives a well formed solid which is filtered off after allowing the mixture to stand 18 hours. The solid is washed with benzene and then hexane, and dried in vacuo to afford a solid, m.p. s 99°, 115°-127° C., which TLC showed contained only a small amount of the cis isomer. This material is taken up in 10 ml of boiling benzene, filtered, and boiled down to a volume of approximately 5 ml of solution to afford a solid of trans-3-phenyl-4-piperidinol, m.p. s 125.5°, 127°-128.5°, which TLC showed to be pure trans isomer.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:19](=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(NC)c2c1C
Yield: 17 %

Procedure:
To 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (500 mg, 2.28 mmol, 1 eq.) was added iodomethane (310 uL, 6.16 mmol, 2.7 eq.), sodium carbonate (314 mg, 2.96 mmol, 1.3 eq.), and ethanol (10 mL) and reaction was heated at reflux for 16 hours. 3-Methyl-4-methylamino-benzofuran-2-carboxylic acid ethyl ester was obtained in 17% yield after flash column chromatography, eluting with ethyl acetate/hexanes. (90 mg) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.7 (s, 3 H) 4.3 (q, J=7.1 Hz, 2 H) 6.5 (dd, J=7.8, 0.8 Hz, 1 H) 6.8 (d, J=8.3 Hz, 1 H) 7.2 (t, J=8.1 Hz, 1 H).
Reaction SMILES: [CH:1]1([C@@:6]([OH:23])([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:7]([O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].CCN(C(C)C)C(C)C.CS(O[CH2:40][CH2:41][CH2:42][N:43]1[C:47]2[CH:48]=[CH:49][C:50]([CH:52]=[O:53])=[CH:51][C:46]=2[N:45]=[N:44]1)(=O)=O>CN(C=O)C>[CH:1]1([C@@:6]([OH:23])([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:7]([O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([N:16]([CH2:40][CH2:41][CH2:42][N:43]3[C:47]4[CH:48]=[CH:49][C:50]([CH:52]=[O:53])=[CH:51][C:46]=4[N:45]=[N:44]3)[CH3:17])[CH2:12][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN[C@H]1CC[C@H](OC(=O)[C@](O)(c2cccs2)C2CCCC2)CC1
Reactant: CS(=O)(=O)OCCCn1nnc2cc(C=O)ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCn1nnc2cc(C=O)ccc21)[C@H]1CC[C@H](OC(=O)[C@](O)(c2cccs2)C2CCCC2)CC1
Temperature: 75 °C
Reaction time: 7 h

Procedure:
To a solution of trans-4-(methylamino)cyclohexyl (2S)-cyclopentyl(hydroxy)2-thienylacetate (Intermediate 172 from WO2011/141180A1, 318 mg, 0.93 mmol) in DMF (3 mL) was added sodium iodide (355 mg, 2.37 mmol) and DIEA (0.25 mL, 1.44 mmol). To this suspension a solution of 3-(5-formyl-1H-1,2,3-benzotriazol-1-yl)propyl methanesulfonate (Intermediate 99, 380 mg, 1.17 mmol) in DMF (2 mL) was added and the mixture was stirred at 75° C. for 7 hours. The reaction mixture was evaporated to dryness, the solid residue was re-suspended in CHCl3 (30 mL) and the suspension was filtered through Celite®. The solvent was removed under reduced pressure and the resulting yellow solid was purified by column chromatography over silica gel eluting with a mixture of CH2Cl2/EtOH (gradient from 0 to 100% of EtOH) to provide the title compound as a yellow solid (473 mg (70% purity by HPLC), 68% yield).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.O=C(Cl)[O:10][C:11](Cl)(Cl)Cl.C(N(C(C)C)CC)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[CH2:29][NH:30][CH3:31]>ClCCl>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[CH2:29][N:30]([CH3:31])[C:11]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][N:4]=1)=[O:10]
Reactant: CNCc1cccc(F)c1
Reactant: Cc1cnc(N)s1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NC(=O)N(C)Cc2cccc(F)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Methylthiazol-2-amine (571 mg, 5.00 mmol) was dissolved into dichloromethane (30 mL) and cooled to near −45° C. Diphosgene (360 μL, 3.0 mmol) was added rapidly over a second or two, and the mixture was stirred for 5 minutes before diisopropylethylamine (1.74 mL, 10 mmol) was added. The solution was stirred for another 30 minutes, 3-fluorobenzyl-methylamine (1.03 mL, 7.5 mmol) was added, and after another couple of minutes, the cold bath was removed. When the reaction solution had warmed to near room temperature, it was quenched with 1 M aqueous potassium phosphate monobasic (15 mL). The aqueous phase was separated and back-extracted with dichloromethane, and the combined organic phases were washed with more 1 M aqueous KH2PO4 (5 mL). The aqueous phase was separated and back-extracted with dichloromethane. The combined organic phases were dried (sodium sulfate), concentrated, and chromatographed on acidic alumina (ethyl acetate/hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O-:12].[Na+]>CO>[CH3:11][O:12][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(C)=O)cn1
Temperature: 160 °C

Procedure:
A mixture of 15 mL of methanol, 500 mg (2.89 mmol) of 1-(6-chloropyrid-3-yl)ethanone and 1.17 g (21.69 mmol) of sodium methoxide is heated in a microwave reactor at 160° C. for 4 hours. The reaction medium is evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 0% B, t 5 min 20% B, t 30 min 40% B), 230 mg of 1-(6-methoxypyrid-3-yl)ethanone were obtained, corresponding to the following characteristics:
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[NH4+].[SH:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21].ClC(Cl)(Cl)C(O)=O>CN(C)C=O>[NH4+:6].[Cl:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][Cl:15])[P:4]1(=[O:5])[N:6]([S:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21])[CH2:7][CH2:1][CH2:2][O:3]1
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: O=S(=O)([O-])CCS
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=P1(N(CCCl)CCCl)OCCCN1SCCS(=O)(=O)[O-]
Reaction time: 20 h

Procedure:
2.8 g (10 mmol), of 4-hydroxycyclophosphamide and 1.6 g (10 mmol) of ammonium-2-mercaptoethanesulphonate were dissolved with a cataytic quantity of trichloroacetic acid in 10 ml of dimethylformamide and were stored in a refrigerator at -25° C. for 20 hours. After a further 5 hours at 0° C., the mixture was mixed with ehter until clouding commenced and was triturbated. The crystrallised material was filtered with suction after 1 day at 0° C., washed dried and recrystallised from n-propanol.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:18]=3[O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[F:33][C:30]([F:31])([F:32])[CH2:29][O:28][C:18]1[C:19]([C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:34])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=C(C)c1cc2c(-c3cc(C)cc(C(C)(C)C)c3OCC(F)(F)F)cccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=CC(=O)O)c1cc2c(-c3cc(C)cc(C(C)(C)C)c3OCC(F)(F)F)cccc2s1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A mixture of 198 mg (0.41 mmol) of 3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thien-2-yl}but-2-enoic acid ethyl ester disolved in 4 mL of methanol, 5 mL of THF and 1 mL of a 2N aqueous solution of LiOH was heated to reflux for 2 hours. After cooling at room temperature and acidic work-up, the crude acid was purified using preparative HPLC (kromosil column, eluent: 8/92 water/methanol+0.1% TFA). Collection of the desired fractions, evaporation of the solvents and recrystallization from acetonitrile affords 110 mg (0.23 mmol, yield: 58%) of 3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thien-2-yl}but-2-enoic acid as a white solid. 1H NMR (400 MHz, CDCl3) d: 7.80 (d, J=8.2 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.40 (s, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.24 (d, J=1.9 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 6.32 (s, 1H), 3.61 (m, 1H), 3.58 (m, 1H), 2.58 (s, 3H), 2.37 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:38][CH2:39][CH2:40][CH2:41][CH:42]([OH:47])[CH2:43][CH2:44][CH2:45][CH3:46].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:29])[O:47][CH:42]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:41][CH2:40][CH2:39][CH3:38])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: CCCCC(O)CCCC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(CCCC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1[N+](=O)[O-]
Yield: 95.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-nonanol (64 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (143 mg, yield 96%).
Reaction SMILES: Br[C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]([C:8]1[N:12]([CH3:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[N:10][N:9]=1)([CH3:7])[CH3:6].[CH3:29][S:30]([O-:32])=[O:31].[Na+].O.C(OCC)(=O)C>CS(C)=O.[Cu](I)I>[ClH:28].[Cl:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])=[N:10][N:9]=2)([CH3:7])[CH3:6])=[C:2]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:27]=1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1Br
Reactant: CS(=O)[O-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1S(C)(=O)=O
Temperature: 140 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
A mixture of 3-[1-(2-bromo-4-chlorophenoxy)-1-methylethyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole (200 mg), sodium methanesulfinate (215 mg) and copper iodide (400 mg) was dissolved in DMSO, followed by stirring under a nitrogen atmosphere at 110° C. for 4 hours and at 140° C. overnight. The reaction solution was returned to room temperature and water and ethyl acetate were added thereto, followed by celite filtration. The organic layer was separated from the filtrate, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=97:3) and further purified by thin layer chromatography (chloroform:methanol=97:3). The resulting residue was dissolved in ethyl acetate and 4M hydrogen chloride-ethyl acetate was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. The resulting residue was crystallized by adding diisopropylether and collected by filtration to obtain 3-{1-[4-chloro-2-(methylsulfonyl)phenoxy]-1-methylethyl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole monohydrochloride (18 mg) as a white crystal.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCBr
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: CCCCCOc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 58 with pentyl bromide gave 2-(3-(3-(pentyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.549 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.81-7.84 (m, 2H), 7.69-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.73 (s, 1H), 6.66 (dd, J=7.8, 2.2 Hz, 1H), 3.91 (t, J=6.8 Hz, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.01-2.07 (m, 2H), 1.73-1.78 (m, 2H), 1.34-1.48 (m, 4H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([S:3]([O-])=[S:4])[CH3:2].S[CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10].[OH-].[Na+]>C(O)C.O>[CH2:1]([S:3][S:4][CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[CH3:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Reactant: CCS([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSSCCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of ethylthiosulfinate (8.4 g) in ethanol (50 ml) is added to an aqueous solution of 3-mercaptopropanoyl-L-proline (10 g) maintained at pH 6-7 by careful addition of sodium hydroxide. The mixture is stirred vigorously at room temperature until negative thiol reaction. The mixture is diluted with water, adjusted to pH 8 and extracted with ethyl acetate, the aqueous phase is acidified to pH 3 and extracted again with ethyl acetate. This latter extract is washed with water, dried and concentrated to dryness to yield 1-[3-(ethyldithio)propanoyl]-L-proline.
Reaction SMILES: [O:1]1C=CN=[C:2]1[C:6]1C=CC(O)=CC=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]([CH3:27])=[C:24]([CH3:26])[N:25]=2)=[CH:17][CH:16]=1.C([O:32]C)(C)(C)C>[Zn]>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[O:22][C:23]([CH3:27])=[C:24]([C:26]([O:1][CH2:2][CH3:6])=[O:32])[N:25]=2)=[CH:19][CH:20]=1
Reactant: COC(C)(C)C
Reactant: COc1ccc(-c2nc(C)c(C)o2)cc1
Reactant: Oc1ccc(-c2ncco2)cc1
Agent: [Zn]
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1C
Yield: 61 %

Procedure:
2-(4-Methoxyphenyl)-4-carbethoxy-5-methyloxazole was prepared in 61% yield by zinc dust reduction of the compound of part (a) in accordance with the procedure of Example 89, part (b), and obtained as a crystalline material, m.p. 74°-76° C. (from methyl t-butyl ether).
Reaction SMILES: ClC(OCC(C)C)=O.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=O)=[N:10]1.C[N:22]1CCOCC1.[Br:28][C:29]1[CH:35]=[CH:34][C:32](N)=[CH:31][CH:30]=1>C1COCC1>[Br:28][C:29]1[CH:35]=[CH:34][C:32]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]([NH2:22])=[O:20])=[N:10]2)=[CH:31][CH:30]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1nn(-c2ccc(Br)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 160.7 %

Procedure:
Under argon, isobutyl chloroformate (357 μl, 2.75 mmol) is added at 0° C. to an indazole-3-carboxylic acid solution (405 mg, 2.5 mmol) in THF (50 ml), followed by N-methylmorpholine (302 μl, 2.75 mmol). The reaction mixture is stirred for 15 min at 0° C. and then 4-bromoaniline (860 mg, 5 mmol) is added. The ice bath is removed and the stirring is maintained overnight. The solvent is evaporated under vacuum. The residue is taken up in an AcOEt/H2O mixture. The evaporation of the organic solution after drying over MgSO4 gives a crude compound (1.27 g) which is chromatographed on silica, eluting with CH2Cl2. The compound thus obtained is recrystallized from isopropanol.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=1)[CH3:12].C(=O)([O-])O.[Na+].O>C(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH:16]=1)[CH3:12]
Reactant: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Ic1ccc2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCNC(=O)c1ccc(C)c(-c2ccc3cn[nH]c3c2)c1
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A stirred mixture of 6-iodo-1H-indazole (0.45 g), N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 10, 0.54 g) tetrakis(triphenylphosphine)palladium(0) (0.05 g) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (10 ml) was heated at 150° C. for 30 min in a microwave oven. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×25 ml). The extracts were washed with water (25 ml) dried (Na2SO4) and concentrated under vacuum. The residual oil was purified by column chromatography on silica (50 g) eluting with ether/ethyl acetate (7:3) to give the title compound as a pale yellow foam (0.25 g).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:22][CH2:21][CH2:20][C@H:2]1[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@H:6]1[C:7]([O:9]N1C(=O)CCC1=O)=O)=[O:4].[NH2:30][C@H:31]([C:36]([OH:38])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33].[CH3:39][N:40]1[C@@H:57]2[CH2:58][C:45]3[CH:46]=[CH:47][C:48]([O:59][CH3:60])=[C:49]4[O:50][C@H:51]5[C:52]([CH2:54][CH2:55][C@@H:56]2[C@:43]5([C:44]=34)[CH2:42][CH2:41]1)=[O:53]>>[NH:1]1[CH2:22][CH2:21][CH2:20][C@H:2]1[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@H:6]1[C:7]([NH:30][C@H:31]([C:36]([OH:38])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33])=[O:9])=[O:4].[CH3:39][N:40]1[C@@H:57]2[CH2:58][C:45]3[CH:46]=[CH:47][C:48]([O:59][CH3:60])=[C:49]4[O:50][C@H:51]5[C:52]([CH2:54][CH2:55][C@@H:56]2[C@:43]5([C:44]=34)[CH2:42][CH2:41]1)=[O:53]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1)C(=O)O

Procedure:
Pro-Pro-Ile-Hydrocodone was prepared by a similar method to Example 9 except the amino acid starting material was Boc-Pro-Pro-OSu and the conjugate starting material was Ile-Hydrocodone.
Reaction SMILES: [NH2:1]/[C:2](=[N:10]\[O:11][C:12]([C@H:14]([CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O)/[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1>C1(C)C(C)=CC=CC=1>[CH:26]1([CH2:25][CH2:24][CH2:23][C@@H:14]([C:12]2[O:11][N:10]=[C:2]([CH2:3][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:1]=2)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)Cc1cccnc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2cccnc2)no1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of tert-butyl (3R)-3-[({[(Z)-1-amino-2-(3-pyridinyl)ethylidene]amino}oxy)carbonyl]-6-cyclohexylhexanoate (Preparation 107) (835 mg, 1.60 mmol) in xylene (15 ml) was heated at 130° C. for 4.5 hours. After cooling to room temperature the reaction mixture was purified by column chromatography on silica gel eluting with a gradient system of 90:10 (pentane:ethyl acetate) gradually changing to 50:50 (pentane:ethyl acetate) to afford the title compound as a yellow oil (443 mg).
Reaction SMILES: P(Cl)(Cl)Cl.[F:5][C:6]1[CH:23]=[CH:22][C:9]([CH2:10][O:11][C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][C:17]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.[OH-].[Na+]>C(OCC)(=O)C>[F:5][C:6]1[CH:23]=[CH:22][C:9]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1OCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccncc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus trichloride (3.65 ml, 41.80 mmol) was slowly added at 0° C. to a solution of 3-(4-fluorobenzyloxy)-4-nitropyridin-N-oxide (7.72 g, 27.87 mmol) prepared in Step 3 in 500 ml of ethyl acetate. The reaction mixture was stirred for 1 hour at room temperature and then alkalized with 2N sodium hydroxide solution. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was used in the subsequent step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:8]1[C:9]([I:24])=[C:10]([C:18]([I:23])=[C:19]([NH2:22])[C:20]=1[I:21])[C:11]([NH:13][C:14](=[O:17])[CH2:15][NH2:16])=[O:12])([OH:7])=[O:6]>CC(N(C)C)=O>[C:5]([C:8]1[C:9]([I:24])=[C:10]([C:18]([I:23])=[C:19]([NH:22][C:1](=[O:3])[CH3:2])[C:20]=1[I:21])[C:11]([NH:13][C:14](=[O:17])[CH2:15][NH2:16])=[O:12])([OH:7])=[O:6]
Reactant: CC(=O)Cl
Reactant: NCC(=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(=O)CN)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under agitation and cooling with wter, 13.5 ml. of acetyl chloride is added dropwise to 40.0 g. (65 millimoles) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine amide (IVc), m.p. 248°-249° C. (decomposition), in 80 ml. of dimethylacetamide. Then, the reaction mixture is stirred at room temperature for 11/2 hours, another 2 ml. of acetyl chloride is added thereto, and the mixture stirred for another hour. After the addition of 10 ml. of water, the reaction mixture is concentrated under vacuum, 70 ml. of water is added to the residue, and the mixture is stirred for 16 hours. The precipitate is vacuum-filtered and washed free of salt with water.