Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[CH3:10].[C:11]([NH:13][C:14]([NH2:16])=[NH:15])#N.[OH-].[Na+]>Cl>[CH3:10][C:3]1[C:2]2[NH:1][C:11]([NH:13][C:14]([NH2:16])=[NH:15])=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH3:9]
Reactant: N#CNC(=N)N
Reactant: Cc1ccc(N)c(N)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2nc(NC(=N)N)[nH]c2c1C
Yield: 38.3 %

Procedure:
3,4-Diamino-o-xylene (6.80 g 0.05 mol) and cyanoguanidine (4.20g 0.05 mol) were refluxed together for 2 hours in 5N hydrochloric acid (20 ml). The hot reaction mixture was basified with excess 40% sodium hydroxide and the resulting precipitate filtered, washed with water and dried. Recrystallisation from aqueous ethanol gave 4,5-dimethyl-2-guanidinobenzimidazole (3.89 g, 38%) as pale brown microcrystals m.p. 122°-124°C.
Reaction SMILES: C(OC([NH:8][N:9]([C:19]([NH:21][C@H:22]([C:26]([NH:28][C@@H:29]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:30][C@H:31]([OH:50])[C@@H:32]([NH:40][C:41]([O:43][CH2:44][C:45]1[S:49][CH:48]=[N:47][CH:46]=1)=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH2:10][C:11]1[N:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[S:14][CH:15]=1)=O)(C)(C)C.[ClH:58].C(OCC)C>O1CCOCC1.CO>[ClH:58].[NH2:8][N:9]([C:19]([NH:21][C@H:22]([C:26]([NH:28][C@@H:29]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:30][C@H:31]([OH:50])[C@@H:32]([NH:40][C:41]([O:43][CH2:44][C:45]1[S:49][CH:48]=[N:47][CH:46]=1)=[O:42])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:27])[CH:23]([CH3:24])[CH3:25])=[O:20])[CH2:10][C:11]1[N:12]=[C:13]([CH:16]([CH3:17])[CH3:18])[S:14][CH:15]=1
Reactant: CC(C)c1nc(CN(NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)c1nc(CN(N)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 60 mg (0.073 mmol) of (2S,3S,5S)-5-(N-(N-((N-(tert-butyloxycarbonyl-amino)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane was added 5 ml of 4 M HCl in dioxane. The resulting solution was stirred at ambient temperature for 2 h. After concentration of the solution in vacuo, the residue was taken up in 0.5 ml of methanol, added to 20 ml of diethyl ether, and filtered to provide 40 mg (77%) of the desired compound (Rf 0.60, 10% methanol in chloroform). Mass spectrum: (M+H)+ =722.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].N1C=CC=CC=1>C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([O:21][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:22])[CH:15]=2)=[O:12])=[CH:2]1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: Cc1cccc(O)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1cccc(OC(=O)C(=O)c2c[nH]c3ccccc23)c1
Reaction time: 0.5 h

Procedure:
3-Indolylglyoxylyl chloride (104 g. ) was stirred in diethyl ether (500 ml.) and treated with m-cresol (108 g.) followed by pyridine (79 g.). After stirring for 30 minutes the solid product was collected by filtration, washed with water then with acetonitrile and dried to give m-cresyl 3-indolylglyoxylate as a yellow powder, m.p. 194°-197°. Yield 119 g. (85.5%)
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6](Br)[N:7]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C1CC=CCC=1>[Pd].O1CCCC1>[CH3:19][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[N:4]1[CH:5]=[CH:6][N:7]=[C:2]([O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]1=[O:20]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: C1=CCC=CC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C)c(-n2ccnc(Oc3ccccc3)c2=O)c1
Temperature: 120 °C

Procedure:
A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 400 mg), phenol (400 mg), N,N-diisopropylethylamine (0.4 mL) and tetrahydrofuran (2 mL) was heated within a microwave for 3 h at 120° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 38 mg) and tetrahydrofuran (1 mL). 1,4-Cyclohexadiene (2 mL) was added and the mixture was heated under atmosphere of nitrogen within a microwave for 15 minutes at 90° C. before being cooled to room temperature. The mixture was filtered and concentrated to give a crude product that was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([C:21](=[O:23])[CH3:22])[CH:29]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(C(C)=O)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-acetyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18].[C:21]([Cu])#[N:22].Cl>CN(C=O)C.O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[C:3]([O:16][C:17]([F:18])([F:19])[F:20])[CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c(OC(F)(F)F)c1
Reactant: N#C[Cu]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 45.9 %

Procedure:
1,1-Dimethylethyl {4-bromo-3-[(trifluoromethyl)oxy]phenyl}carbamate (Intermediate 50, 1.0 g, 2.8 mmol) was dissolved in dry DMF (25 mL). To this solution was added CuCN (1.0 g, 11.1 mmol), and the reaction mixture was heated to reflux for 5 h. A second portion of CuCN (500 mg, 5.6 mmol) was added and heating at reflux was continued for 10 h. The reaction mixture was cooled to room temperature, and FeCl3 was added. This was followed by 1N HCl at 0° C. and the mixture was stirred for 2 hr at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (60-120 silica gel), eluting with 30% ethyl acetate/pet ether to give the title compound (260 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].C(O[CH2:20][CH3:21])C>CN(C)C=O.C(Br)C=C>[CH2:11]([O:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[Br:1])[CH:20]=[CH2:21]
Reactant: Oc1cc(F)c(F)cc1Br
Reactant: CCOCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: C=CCOc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 79.4 gm (0.38 mole) 2-bromo-4,5-difluorophenol and 79 gm (0.57 mole) potassium carbonate in 200 mL dimethylformamide was stirred at room temperature for 30 minutes. At this point 33 mL (0.38 mMol) allyl bromide were added and the resulting mixture was stirred for 18 hours at room temperature. The reaction mixture was then diluted with diethyl ether and washed with water followed by saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 90 gm (96%) of the desired compound.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([C:5]([OH:7])=[O:6])[NH2:4].C(N(CC)CC)C.[C:15]([O:19][C:20](ON=C(C1C=CC=CC=1)C#N)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>O1CCOCC1>[C:15]([O:19][C:20]([NH:4][C@H:3]([C:5]([OH:7])=[O:6])[CH2:2][Cl:1])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: N[C@@H](CCl)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCl)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 1.0 g (6.25 mmol) of 3-chloro-L-alanine and 1.3 mL of triethylamine in 50% aqueous 1,4-dioxane were added 1.69 g (6.90 mmol) of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile with stirring at room temperature. After 2 hours, the reaction mixture was poured into 20 mL of water and extracted twice with ethyl acetate. The organic layer was washed twice with water and then with saturated brine, dried over anhydrous magnesium sulfate and evaporated to give 0.66 g (40.5%) of white solid. Recrystallization from a mixture of ethyl acetate and n-hexane afforded 0.58 g of the pure product (35.6%) melting at 123°-124° C., with decomposition, and having the structural formula: ##STR75## The identity of the product was confirmed by IR and NMR analyses.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[S:5][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([C:9]([O:11][CH2:12]C)=[O:10])[N:8]=1.[OH2:20].[CH3:21]O>>[CH3:21][O:20][C:4]1[S:5][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1
Reactant: O
Reactant: CCOC(=O)c1nc(Cl)sc1-c1ccccc1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1nc(OC)sc1-c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 60% oily NaH in MeOH was added ethyl 2-chloro-5-phenylthiazole-4-carboxylate, followed by stirring at 70° C. for 1 hour. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH) to obtain methyl 2-methoxy-5-phenylthiazole-4-carboxylate as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[K+].Cl[CH2:14][CH2:15][OH:16].CCOC(C)=O>CS(C)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH2:15][OH:16])[CH:6]=[CH:5]2
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: OCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OCCn1ccc2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an N2 atmosphere 30 g (121 mmol) 5-iodoindole are added to a suspension of 27.1 g (484 mmol) KOH in 150 mL DMSO. The reaction mixture is kept for 1 h at RT, cooled to 0° C. with ice water, 9.7 mL (145 mmol) of 2-chloroethanol in 30 mL DMSO are slowly added dropwise and stirred for 4.5 h at RT. The reaction mixture is combined with 1 L EtOAc, washed four times with in each case 800 mL water and once with 400 mL saturated NaCl solution and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 3:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10].S(Cl)([Cl:22])=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:22])=[O:10]
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3-(2-Methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (100 g) and toluene (300 mL) were mixed, and thionyl chloride (47.5 g) and DMF (2.5 g) were added, followed by heating and stirring at 100° C. for 2 hours. After completion of the reaction, 180 mL of toluene was distilled off under reduced pressure to obtain a solution of 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoyl chloride.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]([CH2:12][CH3:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=[CH:4]1)[CH3:2].[CH:14]([N:17]=[C:18]=[S:19])([CH3:16])[CH3:15]>CC#N>[CH2:1]([N:3]1[C:7]2[CH:8]([CH2:12][CH3:13])[N:9]([C:18](=[S:19])[NH:17][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:11][C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CC(C)N=C=S
Reactant: CCC1NCCc2ncn(CC)c21
Solvent: CC#N
Product: CCC1c2c(ncn2CC)CCN1C(=S)NC(C)C
Reaction time: 8 h

Procedure:
A solution of 9.3 g of 3,4-diethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 7.59 g of isopropyl isothiocyanate in 75 ml of anhydrous CH3CN is refluxed for 7.5 hours. The solution is allowed to stand overnight at -15° C., then is filtered. 5.59 g of the crude title compound are collected; m.p. 195° C. (recrystallized from CH3CN).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[C:8](Cl)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>N1C=CC=CC=1>[C:8]([O:1][C@@H:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CC(O)CO1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C1C[C@H](OC(=O)c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To the solution of (S)-(3-Hydroxy-γ-butyrolactone (1.0 g, 9.8 mmol) in 25 mL pyridine was added dropwise BzCl (1.4 mL, 12.2 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was concentrated and coevaporated with toluene two times in vacuo. The residue was partitioned between H2O (15 mL) and EtOAc (40 mL). The organic layer was washed with water and brine, and concentrated in vacuo. The residue was purified by chromatography on a silica gel column (n-hexane/EtOAc=8:1) to afford 101 (1.78 g, 8.6 mmol) as a white solid, in 89% yield, which was characterized as follows:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O-:9])=[O:8])=[CH:5][S:4][N:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][S:4][N:3]=1
Reactant: Cc1nscc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nscc1C(=O)O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 3-methylisothiazole-4-carboxylate (C-3) (4.73 g, 30.1 mmol) in THF-MeOH—H2O (2:1:1, 50 mL), NaOH (3.61 g, 90.3 mmol) is added and the resulting mixture is stirred at 40° C. for 16 h. The mixture is allowed to cool to RT and then acidified with concentrated HCl to adjust the pH to 2-3. The precipitate is collected by filtration, rinsed with water and dried in vacuo to afford the product, 3-methylisothiazole-4-carboxylic acid (C-4).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[Cl:20])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1
Reactant: Cc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)c(C)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (200 mg) and a 40% aqueous solution (160 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (50 mg), and the mixture was stirred overnight at room temperature. The solvent and the like were distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. Solids deposited were collected by filtration and washed with ethanol and diethyl ether to obtain the title compound (8 mg) as a colorless powder.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].CO[C:13](OC)([CH3:15])[CH3:14]>CC(C)=O.[Cu](Cl)Cl>[CH3:14][C:13]1([CH3:15])[O:1][C@@H:2]([C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: C[C@@H](C(=O)O)[C@H](O)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: C[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
To a solution of (2S,3R)-2-hydroxy-3-methylsuccinic acid (2.40 g; 16.2 mmol; 1.0 eq.) in acetone (80.0 mL) was added 2,2-dimethoxypropane (3.98 g; 32.4 mmol; 2.0 eq.) and copper(II) chloride (218 mg; 1.62 mmol; 0.1 eq.). The resulting reaction mixture was stirred for 4 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3. Activated charcoal is added and the resulting mixture stirred for one hour. Filtration on a pad of celite gave the title product (mixture of diastereoisomers) as a greenish oil (2.48 g, 82%) used in the next step without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([S:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=O)(=[O:23])=[O:22])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1>O1CCOCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([S:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]2[O:28][CH:29]=[N:2][N:3]=2)(=[O:23])=[O:22])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1-c1nnco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Hydrazine hydrate (2.25 mL, 46 mmol) was added to a solution of methyl 2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}benzoate (Example 38, 0.42 g, 1.0 mmol) in 1,4-dioxane (1 mL), stirred for 1 hour at room temperature then heated at 90° C. overnight. Solvent was removed in vacuo and the residue azeotroped using toluene. Triethyl orthoformate (10 mL) and a catalytic quantity of (±)-10-camphorsulfonic acid were added to the resultant crude hydrazide then stirred and heated at 90° C. overnight. Solvent was removed in vacuo, water (100 mL) added and extracted with ethyl acetate (2×75 mL). Extracts were washed with water and saturated brine then dried (MgSO4), filtered and evaporated to a yellow residue. Purification by flash column chromatography eluting with a 20-60% ethyl acetate/isohexane gradient gave 2-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}phenyl)-1,3,4-oxadiazole (0.22 g, 51%). 1H NMR (500 MHz, d6-DMSO) δ 9.46 (1H, s), 8.59 (1H, s), 8.40 (1H, dd, J=1.0, 8.0 Hz), 8.37 (1H, s), 8.30 (1H, d, J=8.7 Hz), 8.20 (1H, d, J=8.8 Hz), 8.05 (1H, dd, J=1.7, 8.6 Hz), 8.00-7.96 (1H, m), 7.93-7.91 (3H, m), 7.87-7.85 (2H, m), 7.42-7.33 (2H, m); m/z (ES+) 431 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([O:14]C)=[O:13])[O:7][CH2:6][CH2:5]2.O[Li].O>CO.C1COCC1.O>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=[O:13])[O:7][CH2:6][CH2:5]2
Reactant: COC(=O)C1OCCc2c1ccc(Br)c2OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1c(Br)ccc2c1CCOC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-bromo-5-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylate (650 mg, 2.06 mmol) in 20 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (347 mg, 8.25 mmol), and the mixture was stirred at ambient temperature overnight. The solvents were removed under vacuum, and the residue was added 50 mL of water and extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=3 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 6-bromo-5-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]3[CH:15]=[CH:16][S:17][C:11]3=[N:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[CH2:19](Br)[CH3:20].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13](=[O:14])[N:12]3[CH:15]=[CH:16][S:17][C:11]3=[N:10][C:9]=2[CH3:18])=[CH:6][CH:7]=1)[CH3:20]
Reactant: CCBr
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Temperature: 80 °C

Procedure:
To a solution of Step 1 intermediate (250 mg, 0.967 mmol) in DMF (4 ml) was added ethyl bromide (0.147 g, 1.355 mmol) and NaH (0.053 g, 1.355 mmol) and heated to 80° C. for 15.0 h. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 to afford 300 mg of the desired compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=6.6 Hz, 3H), 2.17 (s, 3H), 4.05 (q, J=6.6 Hz, 2H), 6.93-6.96 (m, 2H), 7.17-7.20 (m, 2H), 7.50 (d, J=4.5 Hz, 1H), 7.98 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 311.28 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH:18]=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26](=O)[C:27](=O)[CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[NH4+:35].[NH4+:36].[OH-]>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]2[NH:35][C:27]([CH3:28])=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:36]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C=O
Reactant: [NH4+]
Reactant: CC(=O)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1[nH]c(C2Cc3ccccc3CN2C(=O)OC(C)(C)C)nc1-c1ccccc1
Temperature: 0 °C

Procedure:
3-Formyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.83 g, 7 mmol) was combined with AcOH (25 mL) to which was immediately added 1-phenyl-propane-1,2-dione (3.11 g, 21 mmol) and NH4OAc (13.49 g, 175 mmol). The reaction mixture was then placed on a steam bath and heated under an argon atmosphere for 20 minutes. The reaction mixture was cooled in an ice bath and then added to an ice slurry (44 g). The resulting mixture was basified by addition of concentrated NH4OH (50 mL) and then extracted twice with diethyl ether (150 mL each). The combined organic phases were dried over MgSO4, filtered and concentrated to yield crude product. This material was purified by preparative HPLC to yield the title compound as a white solid. Measured MW (MH+): 390
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH3:17][NH:18][OH:19]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:18]([CH3:17])[OH:19])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CNO
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(C)O)n1

Procedure:
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (XLVIII) was prepared from 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and N-methyl-hydroxylamine hydrochloride as described in Example 13 (90% yield). 400 MHz 1H NMR (DMSO-d6, ppm) 8.93 (1H, s), 6.92-6.43 (2H, m), 3.23-3.07 (7H, m), 1.55-1.38 (4H, m), 0.84 (6H, t, J=7.4 Hz). ESI-MS (m/z) 241 [M+H]+.