Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:15]([Cl:24])[CH:14]=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[Cl:24][C:15]1[CH:14]=[C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][CH2:21][O:22][CH3:23]
Reactant: COCCOc1ccc(Br)cc1Cl
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (453 mg), methoxyethyl 4-bromo-2-chlorophenyl ether (0.97 g), bis(triphenylphosphine)palladium (II) chloride (105 mg), copper (I) iodide (55 mg), triethylamine (5 ml) and dimethylformamide (10 ml) was stirred at 70° C. under an atmosphere of argon for 2 hours. The triethylamine and dimethylformamide were removed by evaporation. The residue was purified by flash column chromatography on silica gel (Merck Art. No. 9385) using a mixture of 10% methanol in dichloromethane containing 1% ammonia (density, 0.880 g/cm3) as eluent. The residue was crystallised from acetonitrile to give 3-[2-(3-chloro-4-(2-methoxyethoxy)phenyl)ethynyl]quinuclidin-3-ol (0.52 g) as a colourless solid, m.p. 138-139° C.; microanalysis, found: C, 64.1; H, 6.7; N, 4.1%; C18H22ClNO3 requires: C, 63.9; H, 6.6; N, 4.1%; NMR ([CD3 ]2SO): 7.5(1H,d), 7.3(1H,d of d), 7.1(1H,d), 5.5(1H,s), 4.2(2H,m), 3.7(2H,m), 3.3(3H,s), 2.8(2H,m), 2.7(4H,m), 2-1.8(3H,m), 1.6(1H,m) and 1.3(1H,m); m/z 336(M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]2[O:7][C:8]([C:15]([O:17]CC)=[O:16])([C:10]([O:12]CC)=[O:11])[O:9][C:5]=2[CH:4]=1)=O.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[OH:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+:50]>ClCCCl>[Cl:32][C:28]1[CH:27]=[C:26]([CH:24]([OH:25])[CH2:23][NH:22][CH2:1][C:3]2[CH:21]=[CH:20][C:6]3[O:7][C:8]([C:15]([O-:17])=[O:16])([C:10]([O-:12])=[O:11])[O:9][C:5]=3[CH:4]=2)[CH:31]=[CH:30][CH:29]=1.[Na+:50].[Na+:50]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C=O)cc2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C([O-])C1(C(=O)[O-])Oc2ccc(CNCC(O)c3cccc(Cl)c3)cc2O1

Procedure:
One equivalent of the above aldehyde, one equivalent of 2-amino-1-(3-chlorophenyl)ethanol, one equivalent of acetic acid, and 1.5 equivalents of sodium triacetoxyborohydride in 1,2-dichloroethane is stirred at room temperature for 1 hour. The solvent is evaporated in vacuo. The residue dissolved in 2.5N sodium hydroxide in ethyl alcohol, heated at reflux temperature for one hour, and evaporated in vacuo. The residue is passed through an ion exchange column to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([OH:25])=O.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([Cl:29])=[O:25]
Reactant: O=C(O)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoic acid (700 mg, 1.99 mmol, 1.00 equiv) in anhydrous DCM (30.0 mL), then oxalyl dichloride (0.7 mL) was added dropwise at room temperature. Two drops of anhydrous DMF were then added. The resulting solution was heated to reflux for 40 min. The solvent was removed under vacuum to yield 750 mg of 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoyl chloride as pale yellow oil, which was used directly for the next reaction step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)[N:7]=1.[C:17]([O:20][CH2:21][C:22](Cl)=[O:23])(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[NH2:15][C:14](=[N:13][C:10]1[S:11][CH:12]=[C:8]([C:6]2[N:7]=[C:3]([CH2:2][NH:1][C:22](=[O:23])[CH2:21][O:20][C:17](=[O:19])[CH3:18])[S:4][CH:5]=2)[N:9]=1)[NH2:16]
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Yield: 17.1 %

Procedure:
A suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (1.0 g), acetoxyacetyl chloride (0.45 g) and triethylamine (0.93 g) in methylenechloride (30 ml) was stirred with cooling on an ice-water bath for 8 hours. The solvent was removed under reduced pressure. The residue was suspended in water (100 ml). The mixture was neutralized with a saturated aqueous sodium bicarbonate solution and then was extracted with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (60 ml). The extract was dried with magnesium sulfate and then was evaporated. The residue was chromatographed on a silica gel column eluting with chloroform:methanol =10:1. Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-(diaminomethyleneamino)-4-(2-acetoxyacetylaminomethylthiazol-4-yl)thiazole (0.2 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[OH:18][C:19]1[C:20]([SH:25])=[N:21][CH:22]=[CH:23][CH:24]=1>>[OH:18][C:19]1[C:20]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Oc1cccnc1S
Product: O=C1CCc2cc(OCCCCSc3ncccc3O)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 3-hydroxy-2-mercapto-pyridine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([NH2:19])=[O:18].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][C:31](OC)=O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:30][C:31]1[NH:19][C:17](=[O:18])[C:3]2[C:4]([CH3:16])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CC)n1nc(C)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)c(OC)c3)nc21
Yield: 47.5 %

Procedure:
10 mg (0.036 mmol) of 5-amino-3-methyl-(3-nonyl)-1H-pyrazole-4-carboxamide and 57 mg (0.274 mmol) of methyl 3,4-dimethoxyphenylacetate are refluxed for 6 hours in 0.5 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 7.3 mg (48%) of a solid, Rf=0.57 (dichloromethane/methanol=15:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]O.S(Cl)([Cl:27])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][Cl:27]
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: Cc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 6, 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is warmed with thionylchloride to give 2',5-dichloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone of melting point 127°-130° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH3:21])[N:12]=2)=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:22][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[CH3:21]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1C
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(-c3ccncc3)cc2)nc1CCN1CCCCC1C
Yield: 8.2 %

Procedure:
Add 1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl }-2-methylpiperidine (0.724 g, 1.99 mmol), Pd(Ph3)4 (0.101 g, 0.088 mmol), 4-pyridylboronic acid (0.367 g, 2.99 mmol), 2N Na2CO3 (5 mL), and 1,4-dioxane (1.5 mL) to a microwave vessel. Subject the reaction mixture to microwave irradiation at 30 W, 90° C. for 30-45 minutes. Concentrate and purify on silica gel eluting with 10% 2N NH3 in methanol/dichloromethane to give 4-(4-{5-methyl-4-[2-(2-methyl-piperidin-1 -yl)-ethyl]-oxazol-2-yl}-phenyl)-pyridine (0.059 g, 10%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.CS[C:17]1[NH:18][CH:19]=[CH:20][C:21](=[O:23])[N:22]=1>>[O:23]=[C:21]1[CH:20]=[CH:19][NH:18][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)=[N:22]1
Reactant: CSc1nc(=O)cc[nH]1
Reactant: COC(=O)C/C=C/c1ccc(N)cc1
Product: COC(=O)C/C=C/c1ccc(Nc2nc(=O)cc[nH]2)cc1
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
A mixture comprising 3.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate and 2.34 g of 2-methylthio-1,4-dihydro-4-oxopyrimidine was stirred at 150° to 160° C. for 20 minutes. The reaction mixture was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1)] to obtain 1.58 g of the title compound as a light brown powder (yield: 35%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].[Cl-].[NH4+]>O1CCCC1>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]([OH:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCBr
Reactant: O=Cc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCC(O)c1ccccc1Br
Temperature: 25 °C
Yield: 49 %

Procedure:
Magnesium pieces (6.56 g) were added to anhydrous tetrahydrofuran (10 ml) in a stream of nitrogen and the mixture was stirred at room temperature. A solution (200 ml) of 1-bromoheptane (48.4 g) in anhydrous tetrahydrofuran was dropwise added thereto while heating gradually and the mixture was stirred at 40° C. for 1 hour. Thereto was dropwise added a solution (100 ml) of 2-bromobenzaldehyde (25 g) in anhydrous tetrahydrofuran at room temperature and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:8) to give the subject compound (18.9 g) as an oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([CH:11]([O:27][CH3:28])[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2OS(C(F)(F)F)(=O)=O)=[O:10])=[CH:5][CH:4]=1)#[N:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9](=[O:10])[CH:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH3:28])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1-c1ccccc1

Procedure:
Using a similar procedure as described in example 57.1 (RS)-trifluoro-methanesulfonic acid 2-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-3-fluoro-phenyl ester (example 279.1) was reacted with phenyl boronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3-fluoro-biphenyl-2-yl)-2-methoxy-acetamide. Solid. MS 375.3 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[OH:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(O)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(O)c1
Temperature: 110 °C
Yield: 76.4 %

Procedure:
A mixture of methyl 4-bromo-3-hydroxybenzoate (CombiBlocks, 25 g, 108 mmol), o-tolylboronic acid (22 g, 162 mmol), anhydrous potassium carbonate (44 g, 324 mmol) and Pd(PPh3)4 (6.25 g, 5.4 mmol) was prepared in a mixture of toluene (500 mL) and water (100 mL), and then degassed with N2. The reaction mixture was heated at 110° C. for 12 hours. The reaction mixture was cooled at RT, filtered through a Celite pad and washed with a 10% aqueous solution of NaHCO3, water and brine. The organic layer was dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (silica, pet ether/EtOAc) affording of the title compound as pale yellow solid (20 g, 77%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.85 (s, 1H), 7.52 (s, 1H), 7.45 (d, 1H), 7.20-7.25, (m, 3H), 7.15 (d, 1H), 7.10 (d, 1H), 3.84 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:17][CH:16]=1.[F-].[K+].C(O)(C(F)(F)[F:41])=O>C(#N)C.O>[F:41][CH2:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:3]2[O:4][C:5]3[C:10]([C:11](=[O:12])[C:2]=2[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:16][CH:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CNc3oc4ccccc4c(=O)c3C)cc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1c(NCc2ccc(CCCCF)cc2)oc2ccccc2c1=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 2 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-{4-[(3-methyl-4-oxo-4H-chromen-2-ylamino)-methyl]-phenyl}-butyl ester (24 mg, 0.049 mmol) in ACN (1.1 mL) was added K222 (37 mg, 0.098 mmol) followed by KF (6 mg, 0.098 mmol). The reaction stirred in a 90° C. oil bath for 30 minutes under nitrogen atmosphere, monitored by LC-MS. The reaction was then cooled to room temperature and injected directly onto the preparative HPLC column chromatography (Luna, 10 u, C18, 250×21.2 mm 10 micro, 60% of water in 90% acetonitrile in water with 0.1% TFA as the modifier in both mobile phases). The desired fractions were collected and neutralized to pH 7.6, then lyophilized. The material was re-purified by flash column chromatography (3:1 Hexane:ethyl acetate) to obtain the desired product as a solid (0.3 mg, <2% yield). 1H NMR (600 MHz, CDCl3/DMSO-d6): δ 8.03 (m, 1H), 7.35 (m, 1H), 7.16 (m, 4H), 7.07 (m, 2H), 4.52 (m, 2H), 4.35 (m, 1H), 4.27 (m, 1H), 2.58 (m, 2H), 1.75 (s, 3H), 1.24 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 25 mL rbf was added 0.4137 g (1.31 mmol) of 4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-nitro-phenylamine, 4 mL of THF/EtOH (1:1). Vacuum flushed 3×, then added 0.1655 g of PtO2 (40% by weight) as a slurry in 2 mL of THF/EtOH (1:1). Flushed with H2 3×. Allowed to stir at r.t. for 18 h. Added 10 ml DCM, and Celite let stir 1 h, then filtered over Celite pad, and rinsed with 20 mL DCM. Reduced in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.85 (br. s., 1.7H) 5.31 (br. s., 1.7H) 6.62 (d, J=8.08 Hz, 1H) 7.19 (dd, J=8.08, 1.89 Hz, 1H) 7.26 (d, J=2.02 Hz, 1H) 7.66-7.70 (m, 2H) 8.02-8.06 (m, 2H). MS (m/z) 287.2 M (+1), tR=1.18, Meth 10
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1.B(Cl)(Cl)[Cl:25].CO>ClCCCl>[ClH:25].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Reactant: ClB(Cl)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCCl
Product: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A slurry of 10 g (25 mmol) of 1-aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene hydrochloride, from Step 2, in 150 mL of 1,2-dichloroethane was cooled to 10° C. under a nitrogen atmosphere. Boron trichloride was passed through the reaction mixture until 27 g (230 mmol) had been added. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was then cooled in ice and 100 mL of methanol was added dropwise. The reaction mixture was again allowed to warm to ambient temperature and concentrated in vacuo. Twice, 500 mL portions of methanol were added to the residue and it was reconcentrated. The resultant foam was dissolved in 40 mL of ethanol, filtered and the solution was treated with 40 mL of methylene chloride and 80 mL of heptane. Off-white crystals of 1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalene hydrochloride (5.1 g, 56% yield) were collected by filtration, m.p. 204°-205° C. The 1H NMR spectrum was identical to the spectrum for the product of Example 2A.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][S:18][C:19]1[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1>ClCCl>[N:25]([C:22]1[CH:21]=[N:20][C:19]([S:18][CH3:17])=[CH:24][N:23]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CSc1cnc(N)cn1
Solvent: ClCCl
Product: CSc1cnc(N=C=S)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (1.069 g, 4.60 mmol) in dichloromethane at room temperature was added 5-(methylthio)pyrazin-2-amine (0.50 g, 3.54 mmol). The reaction was stirred at room temperature for 18 hours. LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 2-isothiocyanato-5-(methylthio)pyrazine (0.545 g, 0.257 mmol, 84% yield) as an orange oil. LCMS R.T.=2.65; [M+H]+=184.02.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)[NH2:14].CN(C)C=O>O>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:14][N:13]([CH3:12])[C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)=[O:11])([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(N)c1nc(-c2ccccc2)cs1
Solvent: O
Solvent: CN(C)C=O
Product: CN(NC(=O)c1ccccc1C(=O)O)c1nc(-c2ccccc2)cs1

Procedure:
A solution of 1.5 g. of phthalic anhydride and 2.0 g. of 1-methyl-1-(4-phenylthiazol-2-yl)hydrazine in 50 ml. of dimethylformamide is stirred for 16 hours. Addition of water precipitates a gummy solid which is taken up in ethyl acetate and the ethyl acetate solution is extracted with water, dried over anhydrous sodium sulfate and evaporated, giving a residue which is crystallized from ether/petroleum ether, yielding 0.6 g. of product, m.p. 122°-4°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH:15]([OH:17])[CH3:16].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:19](=[O:21])[O:17][CH:15]([CH3:16])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(-c2cccc(F)c2)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1OC(=O)Nc2ccc(-c3cccc(F)c3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A mixture of the above alcohol (0.2 g, 0.87 mmol) and triphosgene in anhydrous THF (20 mL) was stirred at room temperature under nitrogen. After 15 minutes, the mixture was treated with a saturated aqueous sodium bicarbonate solution (30 mL) and ethyl acetate (40 mL). The organic layer was separated, dried (MgSO4), and evaporated to give 6-(3-fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid (0.18 g, 81%): mp 160-161° C.; 1H-NMR (DMSO-d6) δ 10.31 (s, 1H), 7.62 (dd, 1H, J=8.2, 1.9 Hz), 7.57 (s, 1H), 7.44-7.53 (m, 3H), 7.13-7.20 (m 1H), 6.97 (d, 1H, J=8.2 Hz), 5.57 (q, 1H, J=6.6 Hz), 1.63 (d, 3H, J=6.6 Hz). MS (ESI) m/z 256 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCn1ccc([N+](=O)[O-])n1
Yield: 78.5 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 270 mg, 2.39 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL) and a 60% dispersion of sodium hydride in mineral oil (116 mg, 2.90 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min, the 1-bromo-3-methyl-but-2-ene (390 mg, 2.60 mmol) was added. The reaction continued to stir under nitrogen for 2 h. The solution was diluted with ethyl acetate (75 mL), washed with water (2×25 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes) afforded 1-(3-methyl-but-2-enyl)-3-nitro-1H-pyrazole (340 mg, 79%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 1.79 (3H, s), 1.83 (3H, s), 4.80 (2H, d, J=7.2 Hz), 5.45 (1H, t, J=7.2 Hz), 6.88 (1H, s), 7.43 (1H, s).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO[CH:13](OC)[CH2:14]Br.Cl>C(O)C.ClCCl>[CH:1]1([NH:7][C:8]2[S:9][CH:13]=[CH:14][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCC1
Reactant: COC(CBr)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: c1csc(NC2CCCCC2)n1
Yield: 102.6 %

Procedure:
To a suspension of 5 g (0.032 mol) of N-cyclohexyl thiourea in 50 mL of ethanol at rt was added 5.38 g (0.0318 mol) of 1,1-dimethoxy-2-bromoethane. To the reaction mixture was then added 1.25 mL of 12N HCl and the reaction mixture was heated at reflux for 12 h. The reaction mixture was then concentrated to provide an orange-brown oil which was dissolved in 50 mL of dichloromethane. The organic solution was washed twice with 1N NaOH solution (50 mL) and then with H2O. The organic fraction was dried (Na2SO4), filtered and the filtrate was concentrated to give 5.95 g of off-white solid. The residue was purified by chromatography (silica, 0 to 5% EtOAc in cyclohexane) to give the title compound. 1H NMR (CDCl3) δ 6.45 (1H, d), 5.69 (1H, d), 4.20-4.10 (1H, m), 1.99-1.55 (6H, 3 sets of m).