Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])#[N:2].C(C1SC=C(C(N2CC3(CCN(CCC4C=CC(CCOCCC(OC(C)(C)C)=O)=CC=4)CC3)OCC2)=O)N=1)(C)C>>[C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])#[N:2]
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(C#N)c1
Agent: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Product: N#Cc1cccc(CCOCCC(=O)O)c1

Procedure:
Prepared by the method of Example 1, step e using tert-butyl 3-(3-cyanophenethoxy)propanoate [Examples 81-175, step a] (7.0 g) in place of tert-butyl 3-(4-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoate. After concentration in-vacuo, the residue was azeotroped with toluene (×2) to afford the subtitled compound. Yield 2.8 g.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[S:10]1[C:14]2=[N:15][C:16]3[C:22](=[O:23])[O:21][C:19](=[O:20])[C:17]=3[CH:18]=[C:13]2[CH:12]=[CH:11]1.N#N>C1COCC1>[C:3]([C:2]([NH:1][C:22]([C:16]1[N:15]=[C:14]2[S:10][CH:11]=[CH:12][C:13]2=[CH:18][C:17]=1[C:19]([OH:21])=[O:20])=[O:23])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: O=C1OC(=O)c2nc3sccc3cc21
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2sccc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
2-Amino-2,3-dimethylbutyramide (9.84 g, 0.076 mol) is added to a stirred suspension of thieno[2,3-b]pyridine-5,6-dicarboxylic acid anhydride (14.8 g, 0.072 mol) in THF under an inert atmosphere of N2 at room temperature. The dark solution is stirred at room temperature overnight and the resulting solid filtered off, washed with THF and air dried to give 17.35 g (72%) of 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]thieno[2,3-b]pyridine-5-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[NH:4][C:3]1=[O:17].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([N:4]1[C@@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][N:2]([CH3:1])[C:3]1=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1C[C@H](C(=O)OCc2ccccc2)NC1=O
Reactant: BrCc1ccccc1
Solvent: O
Product: CN1C[C@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To the solution of (R)-benzyl 1-methyl-2-oxo-imidazolidine-4-carboxylate (1000 mg, 4.27 mmol) in 11 ml of DMF sodium hydride (129 mg, 5.12 mmol) was added, resulting in a slightly exothermic reaction (temperature rise to about 27° C.) and formation of a turbid solution. After stiffing for 1 h at room temperature (bromomethyl)benzene (0.609 ml, 876 mg, 5.12 mmol) was added resulting again in a slightly exothermic reaction (temperature rise to about 29° C.). After stirring overnight the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed successively with a 10% citric acid solution, twice with saturated NaHCO3 solution and brine, dried over Na2SO4 and the solvent was then removed under reduced pressure. Column chromatography on silica gel using dichloromethane and dichloromethane/methanol 98/2 gave (R)-benzyl 3-benzyl-1-methyl-2-oxoimidazolidine-4-carboxylate (425 mg, 1.38 mmol, yield: 31%, ESI-MS [M+H]+=325.1), which was converted into to the corresponding carboxylate by stiffing overnight at room temperature in a mixture of 2.7 ml of THF and 1.44 mL of 2N NaOH. Water was added to the reaction mixture followed by extraction with MTBE. The aqueous layer subsequently was acidified to pH 3 using 2M HCl, and extracted three times with dichloromethane. The combined organic layers were then washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The title compound was obtained as colorless oil which solidified by standing over time (245 mg, yield: 75%).
Reaction SMILES: [Br:1][C:2]1[C:14](F)=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:9]=1[NH:10]2.BrC1C([Cl:38])=CC(C(O)=O)=C2C=1C1CCC(C(OCC)=O)CC=1N2>>[Br:1][C:2]1[C:14]([Cl:38])=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)cc(F)c(Br)c23)C1
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(Cl)c(Br)c23)C1
Product: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)cc(Cl)c(Br)c23)C1
Yield: 78 %

Procedure:
Following the procedure used to prepare Intermediate 24D, 5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid was converted into ethyl 5-bromo-8-carbamoyl-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate as a light brown solid (8.54 g, 78% yield). Mass spectrum m/z 399, 401 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.44 (br. s., 1H), 11.24 (s, 1H), 7.69 (s, 1H), 4.12 (qd, J=7.1, 2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09 (m, 1H), 1.91-1.75 (m, 1H), 1.22 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:27])[CH2:4][O:5][C:6]1[C:14]([Br:15])=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:16][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:39]([O:41][CH2:42][CH3:43])=[CH2:40]>ClCCl>[Br:15][C:14]1[C:6]([O:5][CH2:4][CH:3]([O:27][CH:39]([O:41][CH2:42][CH3:43])[CH3:40])[CH2:2][Br:1])=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:16][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH3:18])[N:11]=[CH:10]2
Reactant: C=COCC
Reactant: CC(Cn1ncc2ccc(OCC(O)CBr)c(Br)c21)O[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(C)OC(CBr)COc1ccc2cnn(CC(C)O[Si](C)(C)C(C)(C)C)c2c1Br
Yield: 77.1 %

Procedure:
To a solution of the product from Step E (3.78 g, 7.2 mmol) and p-toluenesulfonic acid (0.14 g) in dichloromethane (50 mL) at 0° C. was added ethyl vinyl ether (2.75 mL, 28.8 mmol). After 30 min the reaction was quenched with a saturated solution of sodium bicarbonate (50 mL) and the mixture was extracted with dichloromethane (3×80 mL). Evaporation and purification by chromatography (silica, 1% to 8% EtOAc/hexane) gave a viscous oil (3.30 g, 77%): LC/MS (+APCI) m/z 593, 595, 597 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:16][CH:17]=2)[N:11]=1.C1C(=O)N([Br:29])C(=O)C1.O>C(Cl)Cl>[Br:29][C:9]1[O:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)c1ccc(-c2coc(-c3ccccn3)n2)cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)c1ccc(-c2nc(-c3ccccn3)oc2Br)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[5-(2-pyridin-2-yl-1.3-oxazol-4-yl)pyridin-2-yl]propan-2-ol from Step D (75 mg, 0.267 mmol) in DCM (1 mL) was added NBS (62 mg, 0.347 mmol). The reaction mixture was stirred at rt for 16 h. Water was added and the mixture extracted with DCM. The organics were dried (MgSO4), and concentrated to afford 2-[5-(5-bromo-2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol, which was used without further purification LCMS: m/z 360.0 (M+H)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl.CO[C:12](=N)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1.O.Cl>CO>[CH3:24][O:23][C:17]1[CH:16]=[C:15](/[CH:14]=[CH:13]/[C:12]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COC(=N)C=Cc1ccc(OC)c(OC)c1
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C/c2nc3ccccc3[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of 1,2-phenylenediamine (0.63 g; 5.8 mmol) and methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride (1.5 g; 5.8 mmol) in methanol (35 mL) was stirred at ambient temperature for 18 hours. The methanol solution was concentrated to dryness. The residue was recrystallized from MeOH-Diethyl Ether to obtain 1.3 g (67% yield) of the title compound as a mono-hydrochloride, hydrate, yellow solid, m.p. 248° C. dec. Anal. Calcd. for C17H16N2O2 HCl H2O: C, 60.98, H, 5.12; N, 8.37. Found: C, 60.78; H, 5.12; N, 8.45. Mass Spectrum: (EI; M+) m/z 280..1H-NMR (DMSO-d6; 400 MHz) δ15.2 (broad s, 1H), 8.18-8.2 (d, 1H), 7.76-7.8 (m, 2H), 7.45-7.54 (m, 2H), 7.32 (d 1H), 7.2-7.3 (m, 3H), 7.08-7.12 (d, 1H), 3.83 (s, 3H), 3.86 ppm (s, 3H).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C(=O)N(C)C.[H-].[Na+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:19]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C(=O)N(C)C
Solvent: CS(C)=O
Product: O=C1CCCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
33.9 g (0.3 mol) of caprolactam are dissolved in 200 ml of absolute dimethylsulphoxide and 100 ml of absolute tetramethyl urea and 14.4 g (0.33 mol) of 55% sodium hydride/oil dispersion is added in batches. The resulting jelly-like precipitate is stirred for 2 hours at ambient temperature. Then 38 g=34.4 ml (0.3 mol) of benzyl chloride are added dropwize, the mixture is stirred for 2 hours at ambient temperature and then poured onto ice water. The aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, washed four times with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue remaining is distilled in vacuo. Yield: 49.9 g (81.8% of theory), Bp 0.27 mm Hg: 110°-114° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[CH:2].I[C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>C1COCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]Cl>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=3)[CH:22]=2)[CH:18]=[N:19]1
Reactant: Ic1ccc2cn[nH]c2c1
Reactant: C#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl[Cu]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
A mixture of 4-ethynyl-2-nitro-phenylamine (1.306 g, 8.05 mmol), 6-iodo-1H-indazole (1.965 g, 8.05 mmol), dichlorobis(triphenylphosphine)palladium(II) (122 mg, 0.24 mmol) and copper(I) chloride (54.4 mg, 0.28 mmol) in THF (8 mL) and triethyl amine (8 mL) was stirred at room temperature overnight. Purification by column chromatography on silica gel gave 4-(1H-indazol-6-ylethynyl)-2-nitrophenylamine as red solid (777 mg, 2.79 mmol, yield 35%). LC-MS m/z: 279 (M+1)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Cl[C:16]1[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:17]=1[C:18]#[N:19]>C1COCC1>[C:18]([C:17]1[C:16]([CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:23][CH:22]=[C:21]([C:24]([F:27])([F:25])[F:26])[CH:20]=1)#[N:19]
Reactant: N#Cc1cc(C(F)(F)F)cnc1Cl
Reactant: COC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a suspension of sodium hydride (0.752 g, 29.8 mmol) in THF (18 mL) under nitrogen was added dropwise a solution of tert-butyl methyl malonate (3.18 mL, 17.9 mmol) in dry THF (15 mL) via syringe during a period of 15 min. The reaction mixture was stirred for 30 min before a solution of 2-chloro-5-(trifluoromethyl)nicotinonitrile (4.0 g, 14.5 mmol) in THF (30 mL) was added slowly. After being stirred at room temperature overnight, the reaction mixture was quenched with aqueous NH4Cl. THF was removed in vacuo and the aqueous solution was extracted with EtOAc three times. The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The crude brown product (7.1 g) was purified by flash chromatography (10:90 EtOAc/hexanes) to afford 4.20 g (84%) of desired product as a yellow oil. LC-MS calculated for C15H15F3N2O4: (M+H)+345; found 245.0 (M−CO2tBu+H+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]2[O:30][CH2:31][O:32][C:25]=12.Cl[CH2:34][C:35]#[N:36]>>[C:35]([CH2:34][N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]5[O:30][CH2:31][O:32][C:25]=45)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:18][CH2:19]1)#[N:36]
Reactant: N#CCCl
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCN1CCNCC1
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCN1CCN(CC#N)CC1

Procedure:
Using an analogous procedure to that described in Example 12, 6-methoxy-4-(2,3-methylenedioxyanilino)-7-(3-piperazin-1-ylpropoxy)quinazoline was reacted with 2-chloroacetonitrile to give the title compound as a solid; NMR Spectrum: (DMSOd6) 2.1 (m, 2H), 2.45–2.7 (m, 1H), 3.5 (s, 2H), 4.0 (s, 3H), 4.25 (t, 2H), 6.0 (s, 2H), 6.7 (d, 1H), 6.9 (t, 1H), 7.0 (m, 21), 7.75 (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:30]([O-])([OH:32])=[O:31]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:21][CH3:22])=[CH:11][C:12]([C:15]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]2)=[C:13]([N+:30]([O-:32])=[O:31])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C2(C#N)CCC2)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
A solution of 1-(4-(benzyloxy)-3-methoxyphenyl)cyclobutanecarbonitrile (5 g, 17.04 mmol), from Step 1, in acetic acid (20 mL)/acetic anhydride (20 mL) was cooled in an ice bath to 0° C. and treated slowly with 65% nitric acid (2.54 mL, 34.1 mmol). The reaction was stirred at 0° C. for 20 min, poured into ice and extracted with EtOAc. Organic layer was washed with saturated aqueous NaHCO3 and water. Organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 5-50% EtOAc/hexane) afforded 1-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (5.29 g, 92%). MS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[N:34]=[N:35][NH:36][N:27]=4)[CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Yield: 44.9 %

Procedure:
Heat a mixture of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-3-cyano-benzenesulfonamide (1.00 g, 2.15 mmol), sodium azide (1.40 g, 21.5 mmol), and ammonium chloride (1.15 g, 21.5 mmol) in dimethylformamide (10 mL) at 110° C. overnight. Cool the reaction to room temperature and dilute with water (120 mL). Filter the resulting mixture, wash the filtered material several times with water and dry. Dissolve the residue in hot acetone (20 mL) and purify via chromatography, eluting with 1:1 hexanes:acetone with 1% acetic acid to afford the title compound as a tan solid (490 mg, 45%): 1H NMR (DMSO-d6) δ 0.80 (t, 3H), 1.42 (sextet, 2H), 2.49 (s, 3H), 2.50 (t, 2H), 5.16 (s, 2H), 6.59 (d, 1H), 7.10 (d, 1H), 7.12 (d, 1H), 7.24 (s, 1H), 7.25 (t, 1H), 7.70 (d, 1H), 7.73 (t, 1H), 7.87 (d, 1H), 8.22 (d, 1H), 8.49 (s, 1H), 10.56 (s, 1H), 12.82 (s, 1H); MS (APCI-neg mode) m/z (rel intensity) 506 (100).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].N1C=CC=CC=1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[O:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[O:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28]([O:4][CH2:1][CH:2]=[CH2:3])=[O:29])=[CH:24][CH:23]=1
Reactant: C=CCO
Reactant: CC(Oc1ccc(Oc2cnc3ccccc3n2)cc1)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.2 g allyl alcohol and 1.6 g pyridine in 50 cc methylene chloride, add 6.6 g of 2-[4-(2-quinoxalinyloxy)phenoxy]propionyl chloride in 60 cc methylene chloride. Stir the mixture at room temperature overnight. Wash the methylene chloride solution with water and dry the solution over magnesium sulfate concentrate under vacuum to give allyl 2-[4-(2-quinoxalinyloxy)phenoxy]propanoate.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:13]([OH:12])=[CH:14][CH:15]=3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(O)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-hydroxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.91-1.98 (m, 5H), 2.14 (s, 1H), 2.27-2.34 (m, 2H), 2.36-2.43 (m, 1H), 3.50 (s, 2H), 3.60 (s, 3 H), 4.36 (s, 1H), 6.70-6.98 (m, 2H), 7.56-7.82 (m, 2H); MS (APCI/NH3) m/z 273 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=5[O:23][C:22]4=[O:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc2c(c1)oc(=O)n2CCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 30.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9 mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol), K2O3 (3.6 g), a few crystals of KI, and acetonitrile (50 ml) was stirred and refluxed for 13 hours. The reaction was poured into water, and a dark, brown solid that separated was collected to afford 3.3 g of crude product. The solid was chromatographed on a Waters Prep 500 HPLC. Concentration of appropriate fractions afforded 2,3 g of a yellow solid, and recrystallization from ethyl acetate yielded 1.2 g (31%) of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone, m.p.=152°-154° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:14])=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].Cl[S:16]([OH:19])(=[O:18])=[O:17]>>[C:1]([C:3]1[C:4]([OH:14])=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][C:9]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:8][CH:7]=2)#[N:2]
Reactant: N#Cc1c(O)nc2ccccc2c1O
Reactant: O=S(=O)(O)Cl
Product: N#Cc1c(O)nc2ccc(S(=O)(=O)O)cc2c1O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
280 parts of 3-cyano-2,4-dihydroxyquinoline were introduced into 1,000 parts of chlorosulfonic acid. This was followed by stirring at 80° C. for 5 hours, cooling down, pouring onto ice-water, filtering off with suction and washing with water. The crude product obtained after drying need not be purified for chlorination.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:21]2[C:20]1[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=1)([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1
Product: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2c1ccc(Cl)cc1
Yield: 83 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with p-chlorobenzaldehyde as described in Example 11 to give 1-nitro-5-(p-chlorophenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 217°-219° C. Yield: 83%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:27].[K+].[K+]>C(#N)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:27])[CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OCCC3)c1=O
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OCC(=O)C3)c1=O
Yield: 97.9 %

Procedure:
By the method of Example 3, Step A, 0.5 gram (0.0013 mole) of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)-1-methyl-6-trifluoromethyluracil was reacted with 1.1 grams (0.0040 mole) of potassium persulfate and 0.3 gram (0.0013 mole) of copper(11) sulfate pentahydrate in 30 mL of acetonitrile and 30 mL of water, yielding 0.5 gram of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-3-on-8-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure. This product was combined with another run of this reaction. The combined runs were subjected to column chromatography on silica gel, with 1:4 to 1:2 ethyl acetate:hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.8 gram of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-4-on-8-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.