Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][C:22]([O:24]CC)=[O:23])[CH:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrrol-1-yl)acetate (35 mg, 0.071 mmol) in THF (236 μL) and MeOH (118 μL) was added 1N NaOH (142 μL, 0.142 mmol). The mixture was stirred at RT for 10 min. The THF and MeOH were removed by evaporation under diminished pressure and the aqueous layer was washed with Et2O (2×2 mL). The aqueous layer was acidified to pH 1 with 1N HCl and extracted with EtOAc (3×2 mL). The combined organic fractions were dried over Na2SO4 and the solvent was evaporated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O.[OH2:25]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:10])[C:5]([OH:8])=[C:4]([CH:3]=1)[CH:9]=[O:25]
Reactant: Cc1cc(F)ccc1O
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)cc(C=O)c1O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
84 g of 4-fluoro-2-methylphenol are dissolved in 512 ml of trifluoroacetic acid and admixed with 181 g of hexamethylenetetramine in portions. On completion of addition, the reaction solution is heated to 100° C. for 5 hours. After cooling, first 80 ml of 50% sulphuric acid and then 480 ml of water are added dropwise, then the solution is stirred further at room temperature for 3 hours. The reaction solution is extracted three times with dichloromethane. The combined extracts are washed once with water and dried, and the solvent is distilled off under reduced pressure. The residue is extracted repeatedly with n-hexane, the extracts are combined and the solvent is distilled off under reduced pressure. The crude product is subsequently fractionally distilled. 25 g (25% of theory) of a bright yellow solid are obtained having a melting point of 49-52° C. and a boiling point of 70-72° C. at 7 mbar.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[F:15])[CH3:2].C[Al](C)C.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=[C:21]2[CH3:23])=[CH:10][C:9]=1[F:15])[CH3:2]
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: CCOCCCNc1ccc(N)cc1F
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCOCCCNc1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.7 %

Procedure:
To a solution of N1-(3-ethoxypropyl)-2-fluorobenzene-1,4-diamine (5.52 g, 26 mmol) in CH2Cl2 (40 mL) was added trimethylaluminium (52 mL, 104 mmol, 2 M in toluene) slowly. The mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (4.87 g, 31 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 72 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (150 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as pale yellow oil (2.22 g, 27%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]([O:18][CH3:19])=[CH:4][C:3]=1[CH2:20][NH2:21].F[C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31].C(N(CC)C(C)C)(C)C>C(#N)C.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]([O:18][CH3:19])=[CH:4][C:3]=1[CH2:20][NH:21][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Reactant: COc1ccc(COc2cc(F)c(CN)cc2OC)cn1
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2cc(F)c(CNc3ccc(I)cc3[N+](=O)[O-])cc2OC)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.2 %

Procedure:
To a stirred solution of (2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (0.89 g, 3.04 mmol) in acetonitrile (15 mL) was added 1-fluoro-4-iodo-2-nitrobenzene (0.89 g, 3.35 mmol) and N,N-diisopropylethylamine. The resulting yellow solution was heated to reflux. After 16 h, the mixture was allowed to cool to room temperature and was diluted with water. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 40 g SiO2 column, 0-33% ethyl acetate/hexanes elute) afforded 0.38 g (23%) of N-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodo-2-nitroaniline as a solid.
Reaction SMILES: [CH2:1]([Br:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1>CCOCC>[Br-:10].[CH2:1]([N+:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: c1ccc2cnccc2c1
Solvent: CCOCC
Product: O=C(C[n+]1ccc2ccccc2c1)c1ccccc1
Product: [Br-]
Reaction time: 0.5 h

Procedure:
A solution of phenacyl bromide (20 g) in dry ether (100 ml) was added, with stirring, to a solution of isoquinoline (13 g) in ether (50 L ml). The solution was stirred for 30 minutes, and allowed to stand overnight. The precipitated product was filtered off, washed well with ether, and dried. Yield 26.8 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N:12]=[C:13]=[O:14])[CH:8]=[CH:7][CH:6]=2.[N:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C.CC#N>C(OCC)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:13]([NH:26][CH2:25][C:24]1[CH:23]=[CH:22][C:21]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:28][CH:27]=1)=[O:14])[CH:8]=[CH:7][CH:6]=2
Reactant: NCc1ccc(N2CCOCC2)cc1
Reactant: O=C=Nc1cccc2cnc(Cl)cc12
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: O=C(NCc1ccc(N2CCOCC2)cc1)Nc1cccc2cnc(Cl)cc12
Reaction time: 3 h

Procedure:
The product from Example 176A in diethyl ether (40 mL) was treated with the product from Example 172B (300 mg, 1.56 mmol) and triethylamine (3 mL) in 1:1 diethyl ether:CH3CN (10 mL). After stirring for 3 hours, the mixture was filtered, and the collected solid was washed with diethyl ether. The solid was purified by silica gel chromatography (95:5 CH2Cl2:MeOH) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.71 (s, 1H), 8.37 (d, 1H, J=6.7 Hz), 8.08 (s, 1H), 7.79 (d, 2H, J=8.2 Hz), 7.63 (t, 1H, J=8.0 Hz), 7.23 (d, 2H, J=8.7 Hz), 6.94 (d, 2H, J=8.4 Hz), 6.91 (t, 1H, 5.5 Hz), 4.26 (d, 2H, 5.7 Hz), 3.73 (m, 4H), 3.07 (m, 4H); MS (ESI+) m/z 397/399 (M+H, 35Cl/37Cl).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][Cl:12])=[CH:9][CH:8]=2)C=CC=CC=1.[CH3:15][N:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[Cl-:12].[CH3:1][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N+:16]([CH3:18])([CH3:17])[CH3:15])=[CH:9][CH:8]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: CN(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(C[N+](C)(C)C)cc1
Product: [Cl-]
Temperature: 60 °C
Reaction time: 3.7 h

Procedure:
A mixture of 3.0 g (14.8 mmol) of 4-phenylbenzyl chloride, 10 ml of toluene and 5.6 ml (26.6 mmol) of a 30 wt % trimethylamine aqueous solution was stirred for 3.7 hours at 60° C. The reaction solution was separated, and the resulted aqueous layer was washed with t-butyl methyl ether. The aqueous layer was filtrated through celite, and the filtrate was concentrated to obtain 4.07 g of (4-methylbenzyl)-trimethylammonium chloride having a melting point of 204.8° C.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[C:14]([S:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:21])[CH:10]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[C:14]([S:19]([CH3:20])=[O:1])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:21])[CH:10]=1
Reactant: OO
Reactant: CSc1cccc2c(NCc3ccc(Cl)c(Cl)c3)cc(C)nc12
Solvent: CC(=O)O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(S(C)=O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
H2O2 (30%, 20.0 mg, 0.55 mmole) was added dropwise to a solution of (3,4-dichlorobenzyl)-(2-methyl-8-methylsulfanylquinolin-4-yl)-amine (100 mg, 0.275 mmole) in acetic acid (3.5 mL) at 0° C. The mixture was stirred at RT for 16 hrs, concentrated by half, 2N NaOH was added and the resulting mixture was extracted with ethyl acetate. The organic phases were dried and concentrated. Precipitation in isopropyl ether gave the product as a white solid (37 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH:17](O)[CH2:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:6]([C:8]2[CH:9]=[CH:10][C:11](=S)[NH:12][N:13]=2)[CH:7]=1.[OH2:25].[NH2:26][NH2:27]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][CH:18]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[OH:25])=[C:6]([C:8]2[N:13]=[N:12][C:11]([NH:26][NH2:27])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O
Reactant: NN
Reactant: CC(C)(C)NCC(O)COc1ccc(N)cc1-c1ccc(=S)[nH]n1
Product: CC(C)(C)NC(O)CCOc1ccc(N)cc1-c1ccc(NN)nn1

Procedure:
Reaction of 6-[5-amino-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(2H)-pyridazinethione with hydrazine hydrate under similar conditions to those described in Example 2(vi) gave the title compound.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([CH3:14])([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1.C(O)([C:17](F)([F:19])[F:18])=O.C(OO)(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH:1]1([CH2:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:17]([F:19])[F:18])=[N:12][CH:13]=2)([CH3:14])[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: CC(C#N)(CC1CC1)c1cncnc1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C#N)(CC1CC1)c1cnc(C(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of 3-cyclopropyl-2-methyl-2-(pyrimidin-5-yl)propanenitrile (2.5 g, 13.4 mmol) and DMFS (7.8 g, 26.7 mmol) in DCM (40 ml) and H2O (12 ml) at room temperature was added TFA (1.5 g, 13.4 mmol) followed by slow addition of t-BuOOH (8.6 g, 67 mmol) with vigorous stirring. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added additional DMFS (7.8 g, 26.7 mmol) and t-BuOOH (8.6 g, 67 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was added aq. NaHCO3 and extracted with EtOAc (3×50 ml). The organic layer was dried over Na2SO4 and concentrated. The crude product was purification by column chromatography on silica gel (petroleum ether: EtOAc=4:1) to give 3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropanenitrile (1.1 g, yield: 35%). 1H NMR (CDCl3 400 MHz): δ8.97 (s, 2H), 6.82-6.55 (m, 1H), 1.92-1.90 (m, 2H), 1.85 (s, 3H), 0.71-0.65 (m, 1H), 0.60-0.57 (m, 1H), 0.51-0.47 (m, 1H), 0.26-0.20 (m, 1H), 0.03-0.00 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9](F)=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=1.O>O1CCOCC1.C(OCC)C>[C:5]([NH:4][C:3]1[C:2]([F:1])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[C:9]([CH:8]=1)[NH:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[CH:28][CH:29]=1)(=[O:7])[CH3:6]
Reactant: COC(=O)C(C)Oc1ccc(N)cc1
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C(C)Oc1ccc(Nc2cc(NC(C)=O)c(F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of 2',5'-difluoro-4'-nitroacetanilide (7.35 g, 0.034 mol) and methyl 2-(4-aminophenoxy) -propionate (16.6 g, 0.085 mol) in dioxane is refluxed for 2 days, cooled to room temperature and poured into water. The resultant aqueous mixture is extracted with ethyl acetate and the organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a dark red gum. The gum is dissolved in hot diethyl ether and, after stirring briefly, an orange solid forms. The solid is collected via filtration and dried to give the title product as an orange solid, mp 126.5°-128.4° C.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[C:9]#[N:10]>O>[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[C:9]([NH2:10])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(F)cccc1F
Solvent: O
Product: NC(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To 240 g of concentrated sulfuric acid and 24 ml of water are added dropwise, at room temperature, 100 g (0.72 mol) of 2,6-difluorobenzonitrile. The reaction mixture is stirred at 80°-85° C. for 12 hours, and then poured into 1.2 kg of ice-water; the mixture is stirred for 30 minutes and subsequently filtered. The crystals are washed neutral with water, and are afterwards dried at 85° C. in vacuo; yield: 91.0 g (80.6%), melting point: 140°-141.5° C.
Reaction SMILES: [OH:1][CH:2]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[CH:17]=2)([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:7][C:6]=1[CH3:27].N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C>[Si:41]([O:1][CH:2]([C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[CH:17]=2)([CH2:12][CH3:13])[CH2:14][CH3:15])=[CH:7][C:6]=1[CH3:27])([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of the methyl 4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoate (4.79 g, 11.24 mmol), Example 1, in DMF (40 mL) is added imidazole (1.14 g, 16.87 mmol) followed by the addition of TBSCl (1.78 g, 11.80 mmol). The mixture is stirred at RT overnight and concentrated. The mixture is partitioned between 0.1 M HCl (100 mL) and EtOAc (100 mL). The aqueous layer is extracted with EtOAC. The combined organic layers is MgSO4 dried, concentrated, and chromatographed (10% EtOAc/Hex) to give the title compound (4.37 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:17]3[CH:23]=[CH:22][CH:21]=[C:19]([NH2:20])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(Nc2ncnc3cc(N)ncc23)c1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 16.4 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (307 mg, 1.60 mmol) (described in a previous experimental) and 3-nitroaniline (2.00 g, 14.5 mmol) is stirred at 200° C. for 1.5 h, and the crude product is suspended in MeOH/THF (4:1, 250 mL) and hydrogenated over 5% Pd/C (2 g) at 60 psi and 20° C. for 24 h. The solution is filtered over celite, washing thoroughly (hot MeOH), and is then absorbed onto alumina and chromatographed on alumina (4-8% EtOH/CHCl3) to give 7-amino-4-(3-aminoanilino)pyrido[4,3-d]pyrimidine (66 mg, 16%) as a green solid, . 1H NMR (DMSO) δ 9.57 (1H, brs), 9.30 (1H, s), 8.33 (1H, s), 7.04 (1H, t, J=2.0 Hz), 6.99 (1H, t, J=8.0 Hz), 6.88 (1H, brd, J=8.0 Hz), 6.55 (2H, brs), 6.40 (1H, s), 6.34 (1H, dd, J=7.9, 1.3 Hz), 5.10 (2H, brs).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25](O)(=[O:34])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:28]1([CH:27]=[CH:26][C:25]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1
Yield: 67.6 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (4.8 mL), cinnamic acid (2.6 g), WSC.HCl (3.3 g), and methylene chloride (150 mL), to give the captioned compound (3.7 g, 67%) as an oily product.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12]C(C)(C)C)[C:9]([OH:11])=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17]([O-:22])(O[O-])(=O)=[O:18].[K+].[K+].[OH2:25]>CO>[CH2:1]([CH:8]([CH2:12][S:17]([C:2]([CH3:7])([CH3:3])[CH3:1])(=[O:22])=[O:18])[C:9]([OH:11])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: O
Reactant: CC(C)(C)CC(Cc1ccccc1)C(O)=S
Agent: [K+]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
280 mg of 2-benzyl-3-tert.-butylthiopropionic acid was dissolved in 5 ml of methanol and, while cooling with ice, 1 g of potassium peroxomonosulfate in 4 ml of water was added and the whole was stirred overnight at room temperature. The solution was diluted with water and extracted with methylene chloride, and the extracts were dried and concentrated by evaporation (260 mg, 82% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal. calcd. for C14H20O4S: C, 59.13; H, 7.09. Found: C, 59.39; H, 7.08.
Reaction SMILES: [CH:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=CC=C(C([Cl:19])=O)C=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3]([C:20](Cl)=[O:21])[CH:2]=1.[CH2:23]([N:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][OH:31])[CH2:24][CH2:25][CH3:26]>C(Cl)(Cl)Cl>[ClH:19].[ClH:19].[CH2:23]([N:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][O:31][C:20]([C:3]1[CH:2]=[CH:1][C:15]2[C:14]3[C:1]([C:8]4[C:16]=2[C:4]=1[CH:5]=[CH:6][CH:7]=4)=[CH:2][C:3]([C:20]([O:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:4][CH:9]=3)=[O:21])[CH2:24][CH2:25][CH3:26]
Reactant: O=C(Cl)c1ccc2c(c1)-c1cccc3c(C(=O)Cl)ccc-2c13
Reactant: CCCCN(CCCC)CCCO
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)-c1cccc3c(C(=O)OCCCN(CCCC)CCCC)ccc-2c13
Product: Cl

Procedure:
To 700 ml of chloroform is added 10.0 g (0.033 mole) of fluoranthene-3,8-dicarbonyl chloride and 12.4 g (0.066 mole) of 3-dibutylaminopropanol and the resulting solution is refluxed overnight. Upon cooling a solid forms which is crystallized from chloroform-ethyl acetate and twice from methanol-ethyl acetate. Further purification is achieved by dissolving the solid in water with subsequent conversion of the solid to the free base by the action of cold 3 N. aqueous potassium hydroxide, extraction of the free base with ether and after drying the ether solution converting the basic ester to the dihydrochloride salt with ethereal-hydrogen chloride. The product is crystallized from methanol-butanone-ether to give bis(3-dibutylaminopropyl)fluoranthene-3,8-dicarboxylate dihydrochloride hemidrate. M.P. 169°-173°C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:25][NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:26][CH3:25])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C=O)cc1OCC2
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CNCc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Yield: 35.8 %

Procedure:
A mixture of 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbaldehyde (0.35, 0.90 mmol), methylamine (0.9 mL, 1.80 mmol, 2M solution in THF) and 4 Å molecular sieves in CHCl3 were stirred at RT for 1.5 h before sodium triacetoxyborohydride (0.57 g, 2.7 mmol) was added. The resultant mixture was stirred for 16 h then washed with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with 10% methanol in DCM and the combined organic phases dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 20% methanol in DCM) to give [2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylmethyl]-methyl-amine (109 mg, 36%). LCMS: RT=1.90 min, [M+H]+=339
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[CH3:10]C1C2C(=CC=CC=2)NC=1>>[CH3:10][N:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: Cc1c[nH]c2ccccc12
Reactant: c1cnc2[nH]ccc2c1
Product: Cn1ccc2cccnc21
Yield: 58 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 7-azaindole (2.28 g, 1.83 mmole) for the 3-methylindole, the title compound (1.4 g, 58%) was prepared as a yellow oil: MS (ES) m/e 133 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[OH:13])([O-:3])=[O:2].[C:14](Cl)(=[O:18])[O:15][CH2:16][CH3:17]>N1C=CC=CC=1>[OH:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([C:14]([O:15][CH2:16][CH3:17])=[O:18])[N:8]=1
Reactant: CCOC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Temperature: 70 °C
Yield: 89.6 %

Procedure:
To a solution of 5-nitro-1H-indazol-3-ol (1.00 g, 5.60 mmol) in pyridine (6.0 mL) was added ethyl carbonochloridate (0.590 μL, 6.14 mmol) and the reaction mixture was heated to 70° C. After 3 hr the reaction mixture was cooled to RT and evaporated in vacuo. The residue was triturated with water (50 mL) to afford ethyl 3-hydroxy-5-nitro-1H-indazole-1-carboxylate as a yellow solid (1.26 g, 85%); Rt 1.70 min (Method 2, acidic); m/z 252 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].Cl[CH2:15][C:16]([O:18][CH3:19])=[O:17].[O-]CC.[Na+]>CS(C)=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCl
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C

Procedure:
In a manner similar to Examples 15 and 16, to a solution of 2.86 g. (50 mmoles) of N-methylsaccharin and 10.8 ml. (100 mmoles) of methyl chloroacetate in 17 ml. of dimethylsulfoxide was added 11.56 g. (170 mmoles) of sodium ethoxide in 63 ml. of dimethylsulfoxide over a period of 2.5 hours.