Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.O1CCCC1>[CH:14]1([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (0.72 g, 0.0039 mol) and cyclobutanone (0.87 mL, 0.012 mol) in acetonitrile (10 mL) and tetrahydrofuran (10 mL) was added sodium triacetoxyborohydride (2.4 g, 0.012 mol). The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with aq. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give tert-butyl 4-cyclobutylpiperazine-1-carboxylate, which was treated with 4.57 M hydrogen chloride in 1,4-dioxane (10 mL, 0.04 mol) at room temperature for 2 hours and then evaporated to dryness to give the desired product. LCMS calculated for C8H17N2 (M+H)+: m/z=141.1; Found: 141.2
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[C:3]([O:13][CH3:12])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Clc1c(Br)cnc2[nH]ccc12
Agent: [Na+]
Solvent: CO
Product: COc1c(Br)cnc2[nH]ccc12
Temperature: 175 °C
Yield: 26.4 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.16 mmol) was combined with sodium methoxide (583 mg, 10.8 mmol) and suspended in anhydrous methanol (10 mL). The reaction was heated in the microwave to 175° C. for 4 h. The reaction mixture was concentrated and purified by flash silica gel chromatography using a gradient of (ethyl acetate/methanol 9:1) in hexanes to afford 5-Bromo-4-methoxy-1H-pyrrolo[2,3-b]pyridine (130 mg, 0.57 mmol, 27%) as a light yellow powder. 1H NMR (500 MHz, DMSO-d6) δ 11.84 (bs, 1H), 8.14 (s, 1H), 7.40 (m, 1H), 6.80 (m, 1H), 4.30 (s, 3H). MS: m/z 226.9/228.9 (M+H).
Reaction SMILES: N([O:3][C:4](C)(C)[CH3:5])=O.ClC1C=C2C(=O)N(O)C(=O)C2=CC=1.C1(=NO)CCCCC1.[N+](C1CCCCC1)([O-])=O.[C:38]1(=[O:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(O)(=O)C.C1CCCCC1>[C:4]([O:44][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)(=[O:3])[CH3:5]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)ON=O
Agent: O=C1c2ccc(Cl)cc2C(=O)N1O
Agent: O=[N+]([O-])C1CCCCC1
Agent: ON=C1CCCCC1
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: CC(=O)OC1CCCCC1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
Cyclohexane (1 ml), t-butyl nitrite (1 mmol), 4-chloro-N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 100° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclohexanone oxime, nitrocyclohexane, cyclohexanone, and cyclohexyl acetate were formed in yields of 26%, 4%, 4%, and in a trace amount, respectively.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[C:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(OC(=O)c2ccccc2)cc1
Yield: 91.9 %

Procedure:
A mixture of 65.0 g (0.60 mol) of p-cresol, 92.7 g (0.66 mol) of benzoyl chloride, and 6 mL of anhydrous pyridine was refluxed for 1.5 hr and then added to 600 mL of 2% hydrochloric acid. The product was extracted with 2×100 mL of ether, the combined extract was washed by 2% NaOH, then dried over Na2SO4, and evaporated to dryness. Drying the residue in vacuum gave 117 g (92%) of p-tolyl benzoate (bp 127-135° C./25 mm Hg). A mixture of 117 g (0.552 mol) of p-tolyl benzoate and 92.0 (0.689 mol) of AlCl3 was slowly (for ca. 0.5 hr) heated to 120-125° C. This mixture was stirred at this temperature for 1 hr, and then 1000 mL of 2M HCl was added at 0° C. The product was extracted with 3×200 mL of diethyl ether, the combined extract was dried over Na2SO4 and then evaporated to dryness. This procedure gave 116 g (99%) of the title product which was further used without an additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]=1[N+:11]([O-])=O.O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>C(O)C.Cl>[OH:18][C:17]1[C:16]([OH:20])=[N:1][C:2]2[CH:10]=[CH:9][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[C:3]=2[N:11]=1
Reactant: Nc1ccc2sccc2c1[N+](=O)[O-]
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1nc2ccc3sccc3c2nc1O
Yield: 38.8 %

Procedure:
A solution of 5-amino-4-nitrobenzo[b]thiophene (0.50 g, 2.6 mmol) in 50 ml of 96% ethanol was hydrogenated at room temperature and atm. pressure in the presence of 5% palladium-on-carbon until the theoretical amount of hydrogen was absorbed. The catalyst was filtered off, and the filtrate was acidified with 1N hydrochloric acid and evaporated to dryness. The residue was refluxed with oxalic acid dihydrate (0.40 g, 3.1 mmol) in 25 ml of 4M hydrochloric acid for 2 h. The mixture was cooled, and the precipitated solid was isolated by filtration, washed with water, ethanol and ether, and dried. The crude product was dissolved in a minimum amount of 2N sodium hydroxide, treated with decolourising charcoal, and filtered. The filtrate was acidified with 4M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, ethanol and ether to give 0.22 g (39%) of the thienoquinoxaline; m.p. 186.6° C.; IR (KBr): 1680 cm-1 ; H-NMR (DMSO-d6 ) 7.13 (d,J=9 Hz, 1H, ArH), 7.62 (D,J=9 Hz, 1H, ArH), 7.72 (d,J=5 Hz, 1H, ArH), 7.95 (d,J=5 Hz, 1H, ArH); MS m/z: 218 (M+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].C([O:13][B:14](OCC)[O:15]CC)C.S(=O)(=O)(O)O>C(OCC)C.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:14]([OH:15])[OH:13])=[CH:3][CH:4]=1
Reactant: CCOB(OCC)OCC
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(B(O)O)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
100 ml of a solution of 10 g of p-bromoanisole in anhydrous diethyl ether is added dropwise under reflux to a suspension, under inert gas, of 1.3 g of magnesium turnings in 5 ml of anhydrous diethyl ether, and the mixture is left under reflux for 2 hours. The reaction medium is then poured into a solution of 9.02 ml of triethylborate in 60 ml of anhydrous ether cooled down to −70° C. After agitation for 1 hour at −70° C., then for 1 hour at ambient temperature, the solution is poured into a mixture comprising 11 ml of sulphuric acid and 50 g of ice and water followed by agitation for 1 hour. The organic phase is extracted with 100 ml of an aqueous solution saturated in sodium bicarbonate, the aqueous phases are combined, then reacidified with 6N hydrochloric acid, extracted with ether, dried and evaporated under reduced pressure. 3.9 g of expected product is obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[CH:22]=O.O>CO>[CH3:18][C:19]1[CH:26]=[C:25]([CH:24]=[C:21]([CH3:22])[CH:20]=1)[CH2:27][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: Cc1cc(C)cc(C=O)c1
Solvent: CO
Solvent: O
Product: Cc1cc(C)cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.8 %

Procedure:
To a solution of the amine (4) (131 mg, 0.50 mmol) and 3,5-dimethylbenzaldehyde (90 μL, 0.65 mmol) in methanol (5 mL) was added borane-pyridine complex (160 μL, 1.50 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (9) as a white solid (62 mg, Yield: 33%).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4][O:5][N+:6]=2[O-:10])[CH:2]=1.C1CC[N:19]2[C:14](=[N:15]CCC2)CC1.N#CN.C(O)(=O)C>CC(C)=O>[CH:1]1[CH:9]=[CH:8][C:7]2[N+:6]([O-:10])=[N:15][C:14]([NH2:19])=[N+:4]([O-:5])[C:3]=2[CH:2]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: [O-][n+]1onc2ccccc21
Agent: N#CN
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: Nc1n[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 42.4 %

Procedure:
To a solution containing 3.77 g (27.7 mmoles) of benzofuroxan in 8.44 g (55.4 mmoles) of DBU was added portionwise with cooling 2.33 g (55.5 mmoles) of cyanamide. The reaction mixture was stirred at room temperature for 5 days and then diluted with 26 ml of acetone and treated with 4.16 g (69.3 mmoles) of acetic acid. After stirring at room temperature overnight the mixture was further diluted with 30.2 ml of acetone and stirred at room temperature an additional 2.5 hours. The resulting precipitate was collected and washed with 50 ml of acetone and 15 ml of water and then dried under vacuum overnight to give 2.09 g of tirapazamine.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1([CH2:16]O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:13]1([CH2:16][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:15][CH2:14]1
Reactant: OCC1CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCC1CC1
Temperature: 6 °C
Reaction time: 15 h
Yield: 172.6 %

Procedure:
To a stirring solution/suspension comprised of N-hydroxyphthalimide (Aldrich, 57.15 g, 339.8 mmol), cyclopropanemethanol (Aldrich, 25.10 g, 341.1 mmol), and triphenylphosphine (“DEAD,” Aldrich, 91.0 g, 344 mmol) in 1.00 L of tetrahydrofuran under a nitrogen atmosphere and cooled to 6° C. (internal mixture temperature) with an ice-water bath was added diethyl azodicarboxylate (Aldrich, 56 ml, 356 mmol) dropwise over 20 minutes via addition funnel. The reaction mixture temperature was kept below 20° C. during the addition. Following addition of the DEAD, the cold bath was removed and the reaction mixture was stirred for 15 hours. The mixture was concentrated to a paste under reduced pressure. Chloroform (ca. 300 ml) was added and the mixture swirled to loosen all solids. Vacuum filtration removed the insolubles. The filtrate was likewise filtered to remove white precipitate that formed and to give a clear filtrate. Concentration under reduced pressure afforded a clear oil. Flash filtration through silica gel (100% chloroform) gave filtrates containing unseparated product. These filtrates were combined and concentrated under reduced pressure to afford 127.4 g of a clear oil. The oil was dissolved in absolute ethanol (400 ml) and the solution was refrigerated for two hours. A white crystalline solid had precipitated and was subsequently collected by vacuum filtration. The product was dried in the vacuum oven (60° C.) to afford 42.66 g (58%) of the desired material; m.p. 71-77° C.; 1H-NMR (400 MHz; CDCl3 signal offset to δ6.96) δ7.54-7.43 (m, 4H), 3.74 (d, 2H, J=7.6 Hz), 1.02-0.95 (m, 1H), 0.34-0.30 (m, 1H) 0.04-0.00 (m, 1H).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C>O1CCOCC1.[Cu]I.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>[CH3:4][Si:3]([CH3:6])([CH3:5])[C:1]1[O:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1
Reactant: C#C[Si](C)(C)C
Reactant: Oc1cccnc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[Si](C)(C)c1cc2ncccc2o1
Temperature: 500 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
Ethynyltrimethylsilane (32.5 ml, 0.2298 mol), copper(I)iodide (2.2 g, 0.0114 mol) and bis(triphenylphospine)palladium(II)chloride (4.1 g, 0.0057 mol) are added to a degassed solution of 2-Bromopyridine-3-ol (20 g, 0.1149 mol) in dioxane (20 ml). The mixture is stirred for 5 min under nitrogen and then triethyl amine (80 ml, 0.574 7 mol) is added. The mixture is heated to 500° C. for 18 h, cooled to RT, filtered through celite and the filtrate is concentrated under reduced pressure. The crude material is purified by column chromatography by using petrolether and ethyl acetate (90:10) as an eluent to afford (22 g, 56%) of the title compound as a brown liquid. TLC: hexane/ethyl acetate: (9/1): Rf=0.50; LCMS (method B): 4.875 min (purity 98.4%); M+H+ 192.1; 1H NMR (DMSO-d6, 400 MHz) δ [ppm] 8.50-8.48 (1H, dd, J1=1 Hz, J2=4.6 Hz), 8.015-7.9923 (1H, dd, J1=1 Hz, J2=8.32 Hz), 7.352-7.350 (1H, d, J1=0.8 Hz), 7.314-7.280 (1H, m), 0.372-0.355 (9H, s).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:25])[NH:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd].[Fe+3]>[OH:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:25])[NH:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cn1cccc(OCc2ccccc2)c1=O)NOc1ccccc1
Reactant: [H][H]
Agent: [Fe+3]
Agent: [Pd]
Solvent: CCO
Product: O=C(Cn1cccc(O)c1=O)NOc1ccccc1
Yield: 57 %

Procedure:
17 (350 mg, 0.8 mmol) was suspended in 175 mL of EtOH. 10% (w/w, 38 mg) of 10% Pd/C catalyst was added to the hydrogenation flask (500 mL Pyrex® Parr reaction bottle tested to 120 psi, max. working pressure of 60 psi). The Parr hydrogenation system located in the VanNieuwenhze lab was used for the deprotection reactions. The hydrogen pressure was set to 35 psi with agitation, and the process went on for 41 h. A white precipitate was present even after the reaction was stopped, but this white product reacted with iron(III) to give a reddish product instead of no reaction as seen with the protected starting material. The catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 125 mL hot CH2Cl2 and MeOH and THF. The clear solution was concentrated by rotary evaporation to yield a white solid. The solid was washed with MeOH to remove residual DCU to yield a white, feathery microcrystalline solid. Yield: 57%. 1H NMR (d6-DMSO, 400 MHz, 25° C.): δ 4.75 (s, 2H, —CH2—), 6.11 (t, J=7.0 Hz, 1H, Ar—H), 6.72 (d, J=7.2 Hz, 1H, Ar—H), 6.97 (m, 4H, Phenoxy-H), 7.11 (m, 2H, Ar—H, Phenoxy-H), 7.36 (t, J=7.2 Hz, 2H, Phenoxy-H), 7.58 (d, J=6.8 Hz, 2H, Phenoxy-H), 9.03 (s, 1H, —OH), 10.36 (s, 1H, APCI-MS: m/z 336.9 [M+H]+. Anal. Calcd for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33. Found: C, 67.75; H, 5.07; N, 8.49.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C(N(CC)CC)C>C(Cl)Cl>[N:17]1([CH2:16][CH2:15][CH2:14][NH:13][C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: NCCCn1ccnc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A solution of 4-nitrobenzoyl chloride (18.5 g, 0.1 mol) in DCM (200 ml) was added dropwise to a stirred solution of 1-(3-aminopropyl)imidazole (14.0 g, 0.112 mol) and triethylamine (15 ml, 0.107 mol) in DCM (200 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour, and the solid which had separated out was collected by filtration and washed with water (100 ml) and acetone (100 ml) to give the product (21.6 g, 79%). NMR: 1.9-2.0 (m, 2H), 3.2-3.3 (m, 2H), 4.0 (t, 2H), 6.85 (s, 1H), 7.2 (s, 1H), 7.65 (s, 1H), 8.05 (d, 2H), 8.3 (d, 2H), 8.8 (br s, 1H).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Brc1ccc(-c2ccccn2)s1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(-c3ccccn3)s1)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
A mixture of 2.3 g of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 3.6 g (15 mmol) of 2-(5-bromo-2-thienyl)pyridine, 0.39 g of triphenylphosphine, 95 mg of cuprous iodide, 3 ml of triethylamine and 100 ml of acetnitrile was degassed with argon for 10 minutes. Palladium acetate, 110 mg, was then added and the mixture was stirred at room temperature for 18 hrs. After evaporation under reduced pressure, the residue was partitioned between methylene chloride and water. The organic layer was dried and evaporated and the residue was chromatographed over 140 g of silica gel using 5% of ethyl acetate in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ether/hexane to yield 2 g of colorless crystals with m.p 159°-162°. The analytical sample was recrystallized from ethanol and had m.p. 160°-162°.
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].O.N>CN(C=O)C.O>[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH2:3])=[O:27]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(Cl)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
EDCI hydrochloride (22.0 g) and 1-hydroxybenzotriazole (11.4 g) were added to a solution of 2-amino-3-chlorobenzoic acid (12.8 g) in DMF (100 mL), and subsequently ammonia water (22.0 ml) was added thereto. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 2-amino-3-chlorobenzamide (9.7 g). Iron(III) chloride hexahydrate (6.3 g) and cyclopropanecarbaldehyde (1.3 ml) were added to a suspension of the obtained 2-amino-3-chlorobenzamide (2.0 g) in water (30 ml), and the mixture was stirred overnight at 100° C. After cooling, water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 8-chloro-2-cyclopropylquinazolin-4(1H)-one (2.0 g). Compound (115) was obtained as a yellow solid (yield based on 6 steps: 18%) according to Example 114(2) using the obtained 8-chloro-2-cyclopropylquinazolin-4(1H)-one instead of compound (114a).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[N+:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:14])([CH3:1])[CH2:3][N:4]2[CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:23][CH2:24]2)=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-6-nitroindoline (450 mg) was dissolved in 20 mL of dichloroethane, N-boc-4-formylpiperidine (750 mg) was added to the mixture, followed by 2 g NaHB(OAc)3 and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. Saturated NaHCO3 solution (20 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 Hexane:EtOAc to afford an orange oil. MS: 290 (M−99). Calc'd. for C21H31N3O4—389.5.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>ClCCl>[Br:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:4]
Reactant: C1COCCN1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Product: O=C(CBr)N1CCOCC1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
A solution of bromoacetyl bromide (3.0 mL, 0.034 mol) in dichloromethane (240 mL) was cooled to −25° C. A solution of morpholine (9.0 mL, 0.10 mol) in dichloromethane (20 mL) was slowly added over a period of one hour. After the addition was complete, the reaction was stirred at −25° C. for 15 minutes and allowed to warm to ambient temperature. Dichloromethane was added, and the resulting solution was washed with water, 1N aqueous hydrogen chloride, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure to provide 4-(2-bromoacetyl)morpholine as a colorless oil.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-:11].[Na+].C1OCCOCCOCCOCCOC1>C(#N)C>[C:1]1([O:7][C:8]([F:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [F-]
Reactant: O=C(Cl)Oc1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: O=C(F)Oc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of phenylchloroformate in acetonitrile is charged sodium fluoride. To this mixture is charged the 15-crown-5 (“15C5”) at ambient temperature. The reaction mixture is then heated to 40° C. for approximately 16 hrs. Reaction completion is monitored by gas chromatography (“G.C.”).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:9])[CH3:8].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)([O-:13])=[O:12]>ClCCl>[C:7]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)(=[O:9])[CH3:8]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 722.1 %

Procedure:
Powdered potassium carbonate (276 mg, 2 mmol) and then acetyl chloride (0.14 mL, 2 mmol) were added to a solution of 1-(4-nitrophenyl) piperazine (2.1 g, 1 mmol) (Acros Organics) in dichloromethane (75 mL). The mixture was stirred at room temperature overnight and then further quantities of powdered potassium carbonate (500 mg, 3.6 mmol) and acetyl chloride (0.2 mL, 2.8 mmol) were added. The mixture was stirred at room temperature overnight, then it was filtered and the filter cake was washed with dichloromethane. The solvent was evaporated from the filtrate, and the residue was chromatographed (0-66% acetone/dichloromethane) to give 1-acetyl-4-(4-nitrophenyl)piperazine (1.8 g, 72%).