Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5](O)[CH2:4][C:3]1([CH3:12])[CH3:11].N(OC(C)(C)C)=O.[N+:20]([C:23]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=1N)([O-:22])=[O:21]>[Cu](F)F.C(#N)C>[N+:20]([C:23]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:24]=1[O:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:12])[CH3:11])([O-:22])=[O:21]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CC1(C)CCCC(C)(C)N1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 69.3 %

Procedure:
The procedure of Example 1 is repeated using 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 7.84 g (76 mmol) of tert-butyl nitrite, 25 mg (0.25 mmol) of copper(II) fluoride, 120 mL of acetonitrile and 10.3 g (50 mmol) of 2-nitro-4-trifluoromethylaniline at 65° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 6.0 g of light yellow crystals melting at 54-55° C., a 68.9% yield based on nitroxyl. The structure is confirmed by 1Hnmr, mass spectroscopy and elemental analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[F:20][C:21]([F:33])([F:32])[CH:22]([OH:31])[CH2:23][N:24]1[CH:28]=[C:27]([CH:29]=O)[CH:26]=[N:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:48]CCCl>>[ClH:48].[F:33][C:21]([F:20])([F:32])[CH:22]([OH:31])[CH2:23][N:24]1[CH:28]=[C:27]([CH2:29][N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:13][CH:12]=[CH:11][N:10]=3)[CH2:19][CH2:18]2)[CH:26]=[N:25]1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: ClCCCl
Reactant: O=Cc1cnn(CC(O)C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cl
Product: OC(Cn1cc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.143 g, 0.554 mmol) in DCE (5 mL). Add racemic 1-(3,3,3-trifluoro-2-hydroxy-propyl)-1H-pyrazole-4-carbaldehyde (0.236 g, 1.13 mmol) followed by sodium triacetoxyborohydride (0.235 g, 1.11 mmol) and stir at room temperature for 18 hr. Purify via SCX chromatography, followed by silica gel chromatography (eluting with 100:0 to 0:100 hexanes:ethyl acetate then 3:97 methanol:ethyl acetate), to give a racemic mixture of the free bases of the racemic title compounds (166 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:11][CH2:12][N:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:14][CH2:15]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: C[C@H](c1ccc(F)cc1)N1CCNCC1
Product: C[C@H](c1ccc(F)cc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 87 %

Procedure:
A mixture of (R)-1-[1-(4-fluorophenyl)ethyl]piperazine (obtained as described in J. Med. Chem. 2007, 50, 3528) and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method described in Example 306 to give 6-[4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 87% yield.
Reaction SMILES: [CH2:1]([S:16][CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=[O:19])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:16]([CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=[O:19])=[O:31])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CCSC(CC)C(=O)O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CCS(=O)C(CC)C(=O)O
Temperature: -20 °C
Reaction time: 0.58 h
Yield: 47.6 %

Procedure:
2-((3Z,6Z,9Z,12Z)-Pentadeca-3,6,9,12-tetraenylthio)butanoic acid (0.20 g, 0.62 mmol) was dissolved in dry CHCl3 (10 mL) and the solution was cooled down to −20° C. under inert atmosphere. mCPBA (˜77%, 0.15 g, 0.68 mmol) dissolved in dry CHCl3 (2 mL) was added dropwise and the resulting solution was stirred at −20° C. for 35 minutes. The solvents were evaporated in vacuo, the residue was added heptane (10 mL) and the resulting white precipitate was removed by filtration. The filtrate was concentrated in vacuo and the residue was added heptane (10 mL). The resulting white precipitate was again removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (heptane:EtOAc+w/1% HCOOH 4:1-1:1). Concentration of the appropriate fractions afforded 100 mg (48% yield) of the title compound as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][N:11]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH3:40])[CH:25]=3)[N:20]=2)[CH2:10][CH2:9]1>ClCCl>[S:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][N:11]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][CH2:31][NH2:32])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH3:40])[CH:25]=3)[N:20]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCCNC(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCCN)c2c1
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a cooled solution of trifluoroacetic acid in dichloromethane (2 mL, V/V=1/4) was added tert-butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate (120 mg, 0.258 mmol) in an ice bath. The mixture was stirred for 3 hours whilst allowing the temperature of the mixture rising naturally to room temperature, and then concentrated in vacuo. The residue was dissolved in water (10 mL), and washed with dichloromethane (10 mL). The aqueous layer was adjusted to pH 10 with a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate (20 mL×2). The organic extracts were dried with sodium sulfate, concentrated in vacuo to afford 68 mg of the product as a white solid (yield was 72%). MS obsd. (ESI+) [(M+H)+] 366, 1H NMR (400 MHz, CD3OD) δ ppm 7.67-7.64 (t, J=12.0 Hz, 2 H), 7.49-7.47 (d, J=8.4 Hz, 1 H), 7.38-7.30 (m, 2 H), 7.23-7.19 (dd, J=8.4, 7.6 Hz, 2 H), 7.13-7.09 (dd, J=8.8 Hz, 1 H), 5.04 (s, 2 H), 4.38 (s, 2 H), 3.75-3.72 (m, 2 H), 2.98-2.92 (m, 4 H), 2.39 (s, 3 H).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][N:19]1[CH2:27][CH2:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH2:12].[CH3:18][N:19]1[CH2:27][CH2:26][C:22]([C:23]([N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)=[O:24])=[CH:21][CH2:20]1.[CH3:18][N:19]1[CH2:27][CH2:26][C:22]([C:23]([N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)=[O:24])=[CH:21][CH2:20]1
Reactant: CN1CC=C(C(=O)Cl)CC1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CN1CC=C(C(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1
Product: O
Temperature: 0 °C

Procedure:
A mixture of 10.65 g (0.051 mol) of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 19.6 g (0.10 mol) of 1-methyl-1,2,5,6-tetrahydroisonicotinic acid chloride hydrochloride, 20.7 g (0.15 mol) of potassium carbonate and 200 ml of anhydrous toluene were refluxed for 24 hours, with thorough stirring. After cooling, the mixture was stirred into 500 ml of ice-cold water, the organic layer was separated off and the aqueous layer was exhaustively extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate then concentrated by evaporation in vacuo. The residue was purified by column chromatography, first on silica gel with a particle size of 0.1 to 0.4 mm, using 1,2-dichloroethane/methanol as eluant (ratio by volume 9:1), and secondly on silica gel with a particle size of from 0.05 to 0.2 mm, using 1,2-dichloroethane/methanol (volume ratio 95:5) as eluant. When the appropriate fractions were worked up in the usual way, colorless crystals were obtained, m.p. 233°-234° C. (diisopropylether/ethyl acetate). Yield: 2.4 g (14% of theory).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH:21](Br)([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:14][CH:15]1[CH2:16][CH2:17][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:20]1
Reactant: Cc1c[nH]c(=O)c2cc(F)c(OC3CCNCC3)cc12
Reactant: CC(C)Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(=O)c2cc(F)c(OC3CCN(C(C)C)CC3)cc12

Procedure:
By alkylation of 50 mg of 7-fluoro-4-methyl-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (22) with isopropylbromide in the presence of triethylamine in DMF at 60° C. 31 mg of 7-Fluoro-6-(1-isopropyl-piperidin-4-yloxy)-4-methyl-2H-isoquinolin-1-one were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]1([CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19](=[O:27])[CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:27])[CH2:18][CH:17]3[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C1CC(c2ccccc2)c2ccccc2N1
Reactant: O=C(O)c1ccc(Cl)cc1
Product: O=C1CC(c2ccccc2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Temperature: 0 °C
Yield: 50.8 %

Procedure:
4-Chlorobenzoic acid (21.23 g) and 3,4-dihydro-4-phenyl-2(1H)-quinolinone (15 g) were heated in polyphosphoric acid (150 g) at 140° C. for 24 hours. The mixture was poured into ice water and filtered off. The precipitate was taken up in DCM. The organic layer was washed with NaHCO3 (10%) and water, dried (MgSO4) and evaporated. The residue was crystallized from 2-propanone, yielding 12.34 g (50%) of (±)-6-(4-chlorobenzoyl)-3,4-dihydro-4-phenyl-2(1H)-quinolinone; mp. 204° C. (interm. 2-a).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19].Cl>C(OCC)C>[CH:1]1([CH2:7][NH:8][C:18](=[O:19])[CH2:17][Cl:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCl)NCC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.66 Grams of cyclohexylmethylamine is dissolved in 200 ml of diethyl ether. Thereto is added 5.06 g of triethylamine. To the resulting mixture is dropwise added, with ice cooling, a solution of 5.65 g of chloroacetyl chloride dissolved in 150 ml of diethyl ether. The mixture is stirred for 1 hour at room temperature and then acidified with 5% hydrochloric acid. The mixture is extracted with diethyl ether. The extract is washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by evaporation and the residue is recrystallized from n-hexane to obtain 6.7 g of N-cyclohexylmethyl-N-(α-chloroacetyl)amine.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[O:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:27]([NH:26][CH3:25])=[O:28])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: CN=C=O
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
{2-{5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}amine (0.3 g, 0.88 mmol) was dissolved in THF (4 ml), and the solution was cooled to 0° C. Methyl isocyanate (0.062 ml, 1.06 mmol) was added and the reaction mixture was stirred overnight at ambient temperature. Additional methyl isocyanate (0.062 ml) was added and the mixture was stirred for an additional 24 h. The reaction mixture was concentrated under vacuum and the residue was crystallized from hexane-chloroform to give 1-{2-[5-(4-chlorobenzoyl)-1,4-di-methyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}-3-methylurea (240 mg, 69%), mp 234.0-235.5° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[CH:16]=[C:15]4[O:20][CH2:21][O:22][C:14]4=[CH:13][C:12]=3[C:11]2=[O:23])[CH2:4][CH2:3]1.Br.Br[CH2:26][C:27]1[N:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]3[C:18](=[O:19])[C:17]4[CH:16]=[C:15]5[O:20][CH2:21][O:22][C:14]5=[CH:13][C:12]=4[C:11]3=[O:23])[CH2:4][CH2:3]2)[N:28]=1
Reactant: O=C1c2cc3c(cc2C(=O)N1CCC1CCNCC1)OCO3
Reactant: BrCc1cccnn1
Agent: Br
Agent: Cl
Product: O=C1c2cc3c(cc2C(=O)N1CCC1CCN(Cc2cccnn2)CC1)OCO3

Procedure:
Compound I-37 was prepared according to the method in example 3, using 6-[2-(4-piperidyl)ethyl]-[1,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride (compound II-1) and 3-bromomethylpyridazine hydrobromide as the raw materials: 1H NMR (CDCl3): δ 1.26-1.32 (m, 3H), 1.58 (q, 2H, J=5.0 Hz), 1.75 (d, 2H, J=8.9 Hz), 2.12 (t, 2H, J=10.6 Hz), 2.81 (d, 2H, J=11.1 Hz), 3.65 (t, 2H, J=7.2 Hz), 3.84 (s, 2H), 6.15 (s, 2H), 7.19 (s, 2H), 7.45 (dd, 1H, J=8.4, 4.9 Hz), 7.66 (dd, 1H, J=8.4, 1.2 Hz), 9.07 (dd, 1H, J=4.8, 1.6 Hz): m/z 395 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:17](NC(=O)COC3C=CC=CC=3)[C:16](=[O:29])[N:6]2[C:7]=1[C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9].[CH3:30][OH:31].C[Li].Cl[O:35][C:36]([CH3:39])(C)[CH3:37]>O1CCCC1>[CH3:1][C:2]1[CH:3]([NH:6][C:16](=[O:29])[CH3:17])[S:4][C@@H:5]2[C:17]([O:31][CH3:30])([O:35][C:36]3[CH:39]=[CH:7][CH:2]=[CH:1][CH:37]=3)[C:16](=[O:29])[N:6]2[C:7]=1[C:8]([O:10][CH2:11][C:12]([Cl:13])([Cl:14])[Cl:15])=[O:9]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: CC(C)(C)OCl
Reactant: CO
Agent: [Li]C
Solvent: C1CCOC1
Product: COC1(Oc2ccccc2)C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C(NC(C)=O)S[C@@H]21

Procedure:
According to the procedure described by Example 4, 479 mg. of 2,2,2-trichloroethyl 3-methyl-7-phenoxyacetamido-3-cephem-4-carboxylate was reacted with methanol, methyl lithium and t-butyl hypochlorite in anhydrous tetrahydrofuran at -80° C. to provide 2,2,2-trichloroethyl 3-methyl-7-methoxy-7-phenoxy-acetamido-3-cephem-4-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:21]1(Br)[CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[CH:21]1([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:12]=3)[C:8]([C:13]#[N:14])=[CH:9]2)[CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCC1
Reactant: CCOc1ccc2c(C#N)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(C#N)cn(C3CCC3)c2c1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
6-Ethoxy-1H-indole-3-carbonitrile (2.8 g, 15 mmol), prepared as shown in example 1A, step A, is combined with Cs2CO3 (11.6 g, 35.6 mmol), DMF (21 mL), and cyclobutyl bromide (1.73 mL, 17.9 mmol) in a capped tube. The reaction mixture is heated at 80° C. for 8 h. This is then quenched with H2O (200 mL) and is extracted with EtOAc. The EtOAc layer is backwashed with H2O, and then with brine. The organic phase is dried and concentrated. Purification by silica gel chromatography (hexanes/CH2Cl2, 50-100%) yields 1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (3.00 g, 83%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12](O)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(N(CC)C(C)C)(C)C.CN([C:31]([O:35]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:50]([NH:53][NH2:54])(=[O:52])[CH3:51]>CN(C=O)C>[C:50]([NH:53][NH:54][C:31](=[O:35])[CH2:12][CH:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])(=[O:52])[CH3:51]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(N2CCC[C@H]2C(=O)O)ccc(C#N)c1Cl
Reactant: CC(=O)NN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)CC1CCCN1c1ccc(C#N)c(Cl)c1C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-chloro-4-cyano-2-methylphenyl)proline (0.600 g, 2.268 mmol), N,N-diisopropylethylamine (0.876 g, 6.816 mmol) and TBTU (1.092 g, 3.402 mmol) in DMF add a solution of acetic hydrazide (0.252 g, 3.402 mmols) in DMF. Leave to stand for 30 mins then partition between ethyl acetate and 2N aqueous hydrochloric acid. Extract the organic with 10% (w/w) aqueous sodium carbonate solution, then brine. Dry over magnesium sulphate, filter and concentrate under reduced pressure gives the title compound. (0.598 g, 82%) mass spectrum (m/e): 321 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.77 (s, 1H) 7.60 (bs, 1H) 7.40 (d, 1H), 6.88 (d, 1H), 4.35 (t, 1H), 3.86 (m, 1H), 3.04 (m, 1H), 2.51 (m, 1H), 2.44 (s, 3H), 2.00 (s, 3H), 2.22-1.85 (m. 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:13][C:12]=12.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:21]3[CH2:22][CH2:23][N:24]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:25][CH2:26]3)=[N:13][C:12]=12
Reactant: ClCCN1CCCC1
Reactant: Fc1ccccc1-c1nnn2c1nc(N1CCNCC1)c1ccccc12
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nnn2c1nc(N1CCN(CCN3CCCC3)CC1)c1ccccc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
3-(2-Fluorophenyl)-5-(piperazin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.10 g, 0.26 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.088 g, 0.52 mmol) and triethylamine (0.18 ml, 1.3 mmol) were dissolved in N,N-dimethylformamide (4 ml) and stirred at 80° C. under nitrogen for 18 h. The mixture was cooled, then diluted with water (20 ml) and extracted with CH2Cl2 (2×50 ml). The combined organics were washed with brine (20 ml), dried over MgSO4 and evaporated to give a brown oil. Purification by preparative thin layer chromatography eluting with CH2Cl2:MeOH:NH3(c) (92:8:0.8) gave 3-(2-fluorophenyl)-5-{4-[2-(pyrrolidin-1-yl)ethyl]piperazin-1-yl}-[1,2,3]triazolo[1,5-α]quinazoline as a white solid (0.055 g, 47%). Oxalate salt (EtOH): δH (400 MHz; DMSO) 1.87-1.98 (4H, m), 2.49-2.52 (6H, m, partly obscured by DMSO peak), 2.66-2.78 (6H, m), 3.30-3.35 (2H, m, partly obscured by H20 peak), 3.60-3.72 (2H, m), 7.33-7.39 (2H, m), 7.43-7.49 (1H, m), 7.77 (1H, ddd, J=8, 8 and 1), 8.05-8.13 (2H, m), 8.19 (1H, d, J=8), 8.59 (1H, dd, J=8 and 1); m/z (ES+) 446 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1C(=O)C.[N:12]1C=CC=[CH:14][CH:13]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:14][C:13]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:12]=1
Reactant: c1ccncc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2ccc(O)cc2o1
Temperature: 5 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
To a stirred solution of 1-(2,4-dihydroxyphenyl)ethanone (20 g, 131 mmol) in pyridine (80 mL) hydroxylamine hydrochloride (9.1 g, 131 mmol) was added over a period of 15 min in small portions at room temperature. The reaction mixture was stirred for 20 h and then diluted with water (600 mL) and extracted with ethyl acetate (2×250 mL). The combined organic extracts were washed with water (2×250 mL) and 5% aqueous HCl (250 mL). The solvent was removed in vacuo. Water (200 mL) was addded to the residue and then concentrated in vacuo, then toluene (200 mL) was added and concentrated in vacuo. The residue was dissolved in a mixture of acetonitrile (150 mL) and dimethylacetamide (25 mL). The solution was cooled to 5° C., phosphorus oxychloride (20.4 g, 12.2 mL, 133 mmol) was added dropwise allowing the temperature to exceed 10° C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h and then it was slowly poured into a mixture of sodium carbonate (55 g) and ice (ca 800 g). After the ice melted, the resulting slurry was filtered and the solid collected was washed with water (2×150 mL). The product was dried in vacuo to afford a yellow powder (14.4 g, 97 mmol, 76%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[OH:40][CH2:39][C:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[C:4]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:9]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH3:42])[CH3:41]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)CO)c3)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzeneboronic acid (example G.9) (0.442 g, 1.2 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example H.4) (0.381 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.150 g, 22%). MS (ISP) 499.2 [(M+H)+]; mp 181° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=1.IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1cc(I)ccc1C(=O)Cl
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: COc1cc(I)ccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 93 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 4-iodo-2-methoxybenzoyl chloride, the title compound (yield 93%) was obtained in the same manner as that of Example 1, (4).