Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[C:4]([NH:19][CH:20]([CH3:22])[CH3:21])[CH:3]=1.[S:23]1[C:27]2[CH:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]=2[N:25]=[CH:24]1.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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].O>[S:23]1[C:27]2[CH:28]=[C:29]([NH:32][C:2]3[N:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=4)=[C:4]([NH:19][CH:20]([CH3:22])[CH3:21])[CH:3]=3)[CH:30]=[CH:31][C:26]=2[N:25]=[CH:24]1
Reactant: Nc1ccc2ncsc2c1
Reactant: CCOC(=O)c1nc(-c2cnc(Cl)cc2NC(C)C)oc1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)oc1C
Temperature: 115 °C

Procedure:
Ethyl 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate (28a) (50 mg, 0.15 mmol) was dissolved in 1,4-Dioxane (5 mL): H2O (1 mL), to it benzo[d]thiazol-6-amine (0.15 mmol), Na2CO3 (0.6 mmol) and xanthphos (0.06 mmol) were added and degassed for 10 min. Pd2(dba)3 (0.06 mmol) was added and degassed once again for 15 min and heated at 115° C., overnight. The reaction mass was filtered through a small pad of celite and concentrated the filtrate to remove solvent. The crude material obtained was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent. The material obtained was further purified by preparative TLC to obtain the title compound, ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate. 1H NMR: 400 MHz, DMSO-d6: δ 1.28-1.35 (m, 9H), 2.66 (s, 3H), 3.71-3.72 (m, 1H), 4.30 (q, J=7.20 Hz, 2H), 6.16 (s, 1H), 7.59 (dd, J=2.40, 9.00 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.10 (d, J=7.20 Hz, 1H), 8.53 (s, 1H), 8.66 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.36 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min; retention time: 2.127 min; LCMS (ES-API), m/z 438.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 7.483 min; Purity: 99.7%.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][CH2:25]3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)=[O:21]
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCN(Cc2ccc(F)cc2)CC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: NCC(=O)NCC1CCN(Cc2ccc(F)cc2)CC1
Yield: 46 %

Procedure:
A solution of the 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1-(4-fluorobenzyl)piperidine and piperidine (5 mL) in DMF (5 mL) was stirred at room temperature for 17 h. Concentration and column chromatography (SiO2, Et3N:CH3OH:CH2Cl2=0.5:2:8) afforded 4-{(glycylamino)methyl)-1-(4-fluorobenzyl)piperidine (453 mg, 46%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:52][N:53]([CH3:58])[CH2:54][CH2:55][CH2:56][NH2:57]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:57][CH2:56][CH2:55][CH2:54][N:53]([CH3:58])[CH3:52])=[O:20])[CH:17]=2)[NH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)CCCNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 34 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (250 mg, 0.7 mmol), O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (292 mg, 0.77 mmol) and 3-dimethylaminopropyl amine (176 μL, 1.4 mmol); (87 mg, 34% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), (8.7–8.8 (m, 2H), 8.0 (d, 1H), 7.6–7.8 (m, 4H), 7.3–7.5 (m, 2H), 2.3 (s, 2H), 1.75 (m, 2H), ES-MS (m/z) 363 [M+1]+.
Reaction SMILES: C[O:2][CH:3]([NH2:13])[CH:4]([CH2:8][CH:9]([OH:12])[CH2:10][OH:11])[CH2:5][O:6]C.O>Cl>[OH:2][CH:3]([NH2:13])[CH:4]([CH2:8][CH:9]([OH:12])[CH2:10][OH:11])[CH2:5][OH:6]
Reactant: COCC(CC(O)CO)C(N)OC
Agent: Cl
Solvent: O
Product: NC(O)C(CO)CC(O)CO

Procedure:
1,3-dimethoxy-2-(2',3'-dihydroxypropyl)-amino-propane (96.6 g, 0.5 moles) in 1000 ml of 20% hydrochloric acid is refluxed for 65 hours and subsequently worked up according to the method described in Example 2 B. The readily water soluble 1,3-dihydroxy-2-(2',3'-dihydroxypropyl)-amino-propane, which boils at about 155° C. at 0.05 torr, is obtained in a yield of 64.4 g, corresponding to 78% of the theoretical.
Reaction SMILES: [CH3:1][C:2]1([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[OH-].[K+:16]>CO>[CH3:1][C:2]1([C:10]([O-:12])=[O:11])[CH2:6][CH2:5][C:4]([CH3:7])([CH3:8])[C:3]1=[O:9].[K+:16]
Reactant: CCOC(=O)C1(C)CCC(C)(C)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C(=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the product of Example 8b (6.72 g, 33.9 mmol) in methanol (34 mL) was added a cooled aqueous potassium hydroxide solution (1.0 M, 68 mL, 68 mmol). The reaction was then stirred at room temperature overnight. The material was used directly for the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[CH3:40])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>CO>[CH3:26][C:23]1[C:22]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[N:29]=2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5C)n4)cc3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1-c1cccc(Nc2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(4′-{3-Methyl-4-[6-(2-methyl-phenyl)-pyridin-2-ylamino]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester (0.015 g, 0.03 mmol) was dissolved in MeOH (3 mL) and treated with LiOH (0.50 mL of 1.0 N aq solution) and stirred at room temperature for 72 hrs. The resulting mixture was neutralized with HCl (0.50 mL of 1.0 N aq solution) and purified on reverse-phase preparative HPLC to afford the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])=O)[CH2:2][CH3:3].[OH-].[Na+].Cl>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]1[NH:14][C:12](=[O:13])[C:11]2[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Nc1ccccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2ccccc2c(=O)[nH]1

Procedure:
2-(2-Propoxybenzamido)benzamide (2.73 g) was added to a refluxing mixture of 2 Normal aqueous sodium hydroxide (55 ml) and pyridine (2 ml). The resulting solution was stirred under reflux for 15 minutes and was then poured onto ice (150 ml) and acidified with concentrated hydrochloric acid to yield a sample of the title compound, 2.28 g, m.p. 88°-89° C. This together with another sample (0.77 g) similarly prepared was recrystallised from ethanol/water to yield the pure title compound as a white solid, 2.57 g, m.p. 89°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:13].[C:26]([O:30][C:31](=[O:34])[CH:32]=[CH2:33])([CH3:29])([CH3:28])[CH3:27].[Br-].C([NH3+])(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([CH:33]=[CH:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:34])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:13]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(Br)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[NH3+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C=CC(=O)OC(C)(C)C)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 6 h
Yield: 88.3 %

Procedure:
A mixture of 1.28 g (3.0 mmol) of the product of Example 202, 1.31 ml (9.0 mmol) of t-butylacrylate, 33.75 mg (0.15 mmol) of palladium diacetate, 1.0 g (3.15 mmol) of t-butyl ammonium bromide and 1.24 g (9.0 mmol) of K2CO3 in 10 ml of DMF was stifled at 85° C. for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was dissolved in 20 ml of dichloromethane and stired with 1.0 g of celite and 1.0 g of silica gel for 20 min, filtered and concentnted in vacuo. The resulting residue was chromatographed on silica gel eluting with ETOAc/Hexane (1:5) to provide 1.26 g (88%) of the desired product as a white solid. Electrospray Mass Spec 476(M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[C:5]([NH:12][CH:13]2[CH2:15][CH2:14]2)[N:4]=1.[F:16][C@@H:17]1[C@H:21]([OH:22])[C@@H:20]([CH2:23][OH:24])[O:19][C@H:18]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:18]2[O:19][C@H:20]([CH2:23][OH:24])[C@@H:21]([OH:22])[C@H:17]2[F:16])=[C:5]([NH:12][CH:13]2[CH2:15][CH2:14]2)[N:4]=1
Reactant: Nc1nc(NC2CC2)c2nc[nH]c2n1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: Nc1nc(NC2CC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1

Procedure:
2-Amino-6-(cyclopropylamino)-9H-purine hydrochloride (0.3 g, 1.3 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.4 g, 1.6 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were dissolved in 20 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (2,000 I.U.) and purine nucleoside phosphorylase (5,540 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,444) were added and the reaction incubated at 37° C. On day 5, 2,000 I.U. thymidine phosphorylase and 5,540 I.U. purine nucleoside phosphorylase were added. On day 21, the reaction was applied to a 2.5×8 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). After washing the column with water, the product was eluted with water/methanol (7/3). The product-containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilized to obtain title compound that analyzed as a 0.6 hydrate.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]([CH2:23][CH2:24][OH:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:8][S:9]([O:13][CH:14]([CH2:23][CH2:24][O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCCC(O)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, triethylamine (0.7 ml, 5.05 mmol) and methanesulfonyl chloride (0.3 ml, 3.71 mmol) were added to a solution of (±)-methyl 6,8-dihydroxyoctanoate (320 mg, 1.68 mmol) in dichloromethane (8.4 ml) at 0° C. The mixture was stirred at 0° C. for 30 min, then quenched with ice water (20 ml) and extracted with dichloromethane (20 ml). The organic extract was washed with 2 M hydrochloric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (2:3) to give (±)-methyl 6,8-bis(methylsulfonyloxy)octanoate (581 mg, 99% yield) as a clear yellow oil. Rf 0.30 (hexane-ethyl acetate, 3:2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[CH:14][C:15]([OH:17])=[O:16])[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.CO.[N+](=[CH2:29])=[N-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[CH:14][C:15]([O:17][CH3:29])=[O:16])[CH2:9][N:8]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
To a stirred suspension of 6.29 g. (0.017 mole) 7-chloro-2-[[1-carboxymethylene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine, methanol solvate, in 300 ml. of methylene chloride is slowly added an ethereal solution of diazomethane (9.27 ml., 0.22 mole) under nitrogen, at ambient temperature. After an hour, the solvent is removed in vacuo and the residue is recrystallized from ethyl acetate to give 3.20 g. of 7-chloro-2-[[1-(methoxycarbonyl)methylene]hydrazino]-5-phenyl-3H-1,4benzodizepine. The analytical sample is recrystallized from ethyl acetate-hexane.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].Cl.[N:12]([O-])=O.[Na+]>C(OCC)C.O>[N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Cl:2])=[N+:10]=[N-:12]
Reactant: NNc1ccccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=Nc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
2-Chlorophenylhydrazine hydrochloride (1.0 g) suspended in 6.0 ml of diethyl ether was dropped into 5 ml of concentrated hydrochloric acid cooled at 0° C. After the reaction solution was stirred for 10 minutes, 462 mg of sodium nitrite dissolved in 2.0 ml of water was dropped into the reaction solution and the mixture was stirred for 2 hours together with raising the temperature up to room temperature. Water was added to the reaction solution, the mixture was extracted with ethyl acetate and the ethyl acetate layer washed with a saturated aqueous saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 506 mg of the title compound as a red oily crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[S:16])[NH:11][CH2:12][C:13](N)=[O:14])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:17](I)[CH3:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][N:11]=[C:10]2[S:16][CH2:17][CH3:18])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=S)NCC(N)=O)cc1Cl
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1ccc(C)c(Cl)c1
Yield: 80.6 %

Procedure:
A mixture of 2-[3-(3-chloro-4-methylphenyl)-thioureido]-acetamide (10.0 g), ethyl iodide (17.5 g), and ethanol (200 mL) was heated at reflux for 2.5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and water (500 mL). The organic phase was washed with water (2×300 mL). The organic phase was extracted with 2N HCl (2×500 mL). The acid extract was neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous Na2SO4 then evaporated to dryness. The residue was stirred in diethyl ether and faltered to give the title compound (8.4 g) as a white solid, m.p. 133°-135° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.66; H, 4.78; N, 10.39. Mass spectrum (EI, M.+) m/z 268/270. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.47 (d, 1H), 7.43 (d, 1H), 7.20 (dd, 1H), 4.29 (s, 2H), 3.07 (q, 2H), 2.36 (s, 3H), and 1.28 ppm (t, 3H).
Reaction SMILES: Cl.N1C=CC=CC=1.[Cl-].Cl.C[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:31]=[CH:30][C:29]2[C:20](=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[CH:24][CH:23]=[N:22]3)[N:19]=1>O>[OH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:31]=[CH:30][C:29]2[C:20](=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[CH:24][CH:23]=[N:22]3)[N:19]=1
Reactant: COc1ccccc1-c1ccc2ccc3cccnc3c2n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccccc1-c1ccc2ccc3cccnc3c2n1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
Concentrated HCl (17.6 mL) and pyridine (16 mL) were mixed together at room temperature. The resulting solution was heated on a sand bath while passing nitrogen over the surface of the solution and the distillate collected in a Dean-Stark trap. The internal temperature of the reaction was allowed to reach 215-220° C. over a 1 hour period. The solution was allowed to cool to 140° C. and 2-(2-methoxyphenyl)-1,10-phenanthroline hydrochloride chloride (6 g, 18.59 mMole) then added. With good stirring, the temperature of the resulting solution was allowed to rise back again to 215-220° C. and held at this temperature for 3 hours. The solution was then cooled to 100° C. and treated carefully with water (10 mL), then finally poured into an excess of water (70 mL) to precipitate a gummy solid. With good stirring, the pH of the solution was adjusted to 6-7 with solid Na2CO3. The orange solid was filtered off, washed well with water and dried. Yield of the 2-(2-hydroxyphenyl)-1,10-phenanthroline was 4.6 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[CH2:66]([O:73][NH2:74])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24](=[O:26])[NH:74][O:73][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:20][CH:21]=2)=[CH:27][CH:28]=1)[C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1)C(=O)N1CCOCC1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)NOCc3ccccc3)cc2)cc1)C(=O)N1CCOCC1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
The acid 14 (2.0 g, 4.0 mmol) was dissolved in dry DMF (35 mL) and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.6 g, 4.4 mmol), EDCI (0.77 g, 4.0 mmol), and triethylamine (1.68 mL, 12.0 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.7 g, 4.4 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (100 mL). The organic layer was extracted with 2.0 M HCl (1×20 mL), saturated NaHCO3 (1×20 mL), and brine (1×50 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Flash chromatography on silica gel (hexanes:ethyl acetate—1:1 containing 1% acetic acid) yielded the desired benzyl hydroxamate 15 (1.6 g, 66%). 1H NMR (400 MHz, DMSO-d6): 10.93 (s, 1H), 7.28-7.35 (m, 5H), 7.19 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.68 (s, 2H), 4.52 (m, 1H), 3.21-3.49 (m, 8H), 2.72-2.80 (m, 4H), 2.21 (t, J=7.6 Hz, 2H), 1.29 (s, 9H).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:10]([OH:17])=[CH:9][C:8]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH3:4].Cl[CH2:23][C:24]([CH3:26])=[CH2:25].[Cl-].[NH4+]>CN(C)C=O>[C:3]([O:6][C:7]1[C:12]([C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:11][C:10]([O:17][CH2:25][C:24]([CH3:26])=[CH2:23])=[CH:9][C:8]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH3:4]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Reactant: C=C(C)CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
60% Oily sodium hydride (0.18 g) was suspended in N,N-dimethylformamide (10 ml). A solution of 4-acetoxy-3,5-di-tert-butylphenol (1 g) in N,N-dimethylformamide (5 ml) was added dropwise to the suspension under ice cooling and the mixture was stirred for 30 min. Subsequently, the reaction mixture was allowed to warm to room temperature and 3-chloro-2-methyl-1-propene (0.45 ml) was added dropwise. After stirring at room temperature for 2 h, a saturated aqueous solution of ammonium chloride (15 ml) was added to the reaction mixture. The mixture was subjected to extraction with diethyl ether and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-1-(2-methyl-2-propenyloxy)benzene [1.08 g (yield, 90%)] as a colorless liquid.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][O:5][C:6]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=O>C(O)C.N1C=CC=CC=1>[CH3:4][O:5][C:6]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:7]=1[C:8](=[N:2][OH:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17]
Reactant: NO
Reactant: COc1ccc(C(=O)c2ccccc2OC)c(OC)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(C(=NO)c2ccccc2OC)c(OC)c1

Procedure:
Hydroxylamine hydrochloride (4.98 g, 71.7 mmol) is added to a solution of 2,2′,4-tri-methoxybenzophenone (J. Org. Chem. 1996, 61, 6326; 6.5 g, 23.9 mmol) in ethanol (50 ml) and pyridine (10 ml). The mixture is heated at reflux for 2 hours and the solvent evaporated. The residue is partitioned between dichloromethane and 2 M aqueous HCl and the organic phase is washed with water, brine, dried (MgSO4) and evaporated to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[O:10]1[CH:12]([CH:13]([CH3:15])[CH3:14])[CH2:11]1>>[OH:10][CH:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)C1CO1
Product: CC(C)C(O)COc1cccc(C=O)c1
Reaction time: 2 h

Procedure:
A mixture of 3-hydroxybenzaldehyde (11) (1 g, 8.2 mmol) and 1,2-epoxy-3-methylbutane (1.3 mL, 12.3 mmol) was microwaved at 140° C. and 120 psi pressure for 2 h (CEM, Discover). Purification by flash chromatography (0 to 15% Acetone-hexanes gradient) gave 3-(2-hydroxy-3-methylbutoxy)benzaldehyde (135) as a yellow oil. Yield (1.1 g, 65%): 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 7.41-7.50 (m, 3H), 7.19-7.24 (m, 1H), 4.10 (dd, J=9.4, 3.0 Hz, 1H), 3.97 (dd like t, J=8.4 Hz, 1H), 3.75-3.80 (m, 1H), 2.23 (t, J=4.0 Hz, 1H), 1.86-1.95 (m, 1H), 1.05 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H).