Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH2:8])[NH:5][CH:6]=1.N1([C:14](N2C=CN=C2)=[O:15])C=CN=C1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:7][NH:8][C:14](=[O:15])[N:5]2[CH:6]=1
Reactant: NCc1cc(Br)c[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCc2cc(Br)cn21
Yield: 36.1 %

Procedure:
A solution of (4-bromo-1H-pyrrol-2-yl)methanamine (Enamine, Ltd., Kiev, Ukraine; 57.7 mg, 0.330 mmol), di(1H-imidazol-1-yl)methanone (CDI; Aldrich; 58.8 mg, 0.363 mmol), and NaH (60% wt. in mineral oil; 15.8 mg, 0.396 mmol) in THF (3.0 mL) was stirred under argon at 23° C. for 15 min. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0-60% EtOAc/hexanes) to provide 6-bromo-1H-pyrrolo[1,2-c]imidazol-3(2H)-one (23.9 mg, 0.119 mmol, 36% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (1H, br. s.), 7.29 (1H, s), 6.16 (1H, d, J=1.2 Hz), 4.35 (2H, s). m/z (ESI, +ve) 200.9/202.9 (M+H)+.
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:27])[CH:15]=[C:16]([C:25]#[N:26])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)=[O:12])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCOCC1>[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:27])[CH:15]=[C:16]([C:25]#[N:26])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:20][CH:19]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)cn1C
Reactant: [Zn+]C1CCCC1
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccc(C3CCCC3)cc2)c(C#N)cn1C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Add cyclopentylzinc bromide (0.5M, 7.2 mL, 3.6 mmol) to 3-(4-bromo-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.50 g, 1.80 mmol, prepared in example E-3a or E-3b), tris(dibenzylideneacetone)palladium(0) (0.06 g, 0.07 mmol), and triphenylphosphine (0.07 g, 0.27 mmol) in dioxane and heat to 80° C. with stirring. After 18 hours, cool the reaction mixture, and pour into water. Extract the quenched reaction mixture with ethyl acetate. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexane to provide the title compound. Mass spectrum (m/e): 323.3 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][C:13]([C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([NH2:25])[CH:24]=1)=[CH:12]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][C:13]([C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([NH:25][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:24]=1)=[CH:12]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
2-Thiophenecarboxaldehyde (0.112 g, 1.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.29 g, 1.06 mmol) in methylene chloride (125 mL), followed by acetic acid (0.1 g, 1.67 mmol). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.23 g, 1.09 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 6 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken and the organic layer separated. The solvent was evaporated to give a brown gum. Recrystallization from methanol/water gave the product as a brown solid (120 mg), mp 190-192° C.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C1(C)C=CC=CC=1>[I:1][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:5]([O:4][CH3:3])=[O:6])=[CH:10][CH:11]=1
Reactant: COC(=O)COc1ccc(CCO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(CCI)cc1
Reaction time: 1 h

Procedure:
5.5 g (21.6 mmol) of iodine are added to a solution of 4.16 g (19.6 mmol) of 2-(4-methoxycarbonylmethyloxyphenyl)-ethanol, 5.7 g (21.6 mmol) of triphenylphosphine and 1.84 g (29.3 mmol) of imidazole in 200 ml of toluene at room temperature, while stirring, and stirring is continued at room temperature for one hour. A precipitate separates out and is filtered off with suction and discarded. The mother liquor is concentrated to dryness under reduced pressure and the residue is heated with petroleum ether. The triphenyl oxide which has precipitated out is filtered off with suction and the mother liquor is concentrated to dryness again. A crude oil remains.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:5][C:4](=[O:6])[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[O:11][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1c(O)cccc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1c(F)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2.6 g (16.7 mmol) of 2-fluoro-6-hydroxybenzoic acid and 6.90 g (50 mmol) of potassium carbonate in 15 mL DMF is slowly added 8.5 g (50 mmol) of benzyl bromide. The mixture is stirred at room temperature for 5 h. Another 1 g of benzyl bromide is added and the mixture is stirred at RT for 18 h. The mixture is poured into water and is extracted with ethyl acetate. The organic phase is washed (3×) with water and 1× with saturated NaCl. The solution is dried over sodium sulfate and the solvent removed under vacuum. The residual oil is purified by flash chromatography to give the product. This is used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[NH:27][C:26](=[O:28])[CH:25]=[CH:24][CH:23]=4)[C:12]=3[CH3:29])[CH2:9][C:8]([CH3:31])([CH3:30])[C:5]2=[N:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][C:8]1([CH3:31])[C:5]2=[N:6][CH:7]=[C:2]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:3]=[C:4]2[N:10]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]=[C:13]([C:22]3[NH:27][C:26](=[O:28])[CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:29])[CH2:9]1
Reactant: C1COCCN1
Reactant: Cc1c(-c2cccc(=O)[nH]2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc(=O)[nH]2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Prepared according to procedure N using 6-(4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methylquinolin-2-yl)pyridin-2(1H)-one (43.6 mg, 0.091 mmol), morpholine (0.016 mL, 0.18 mmol), Pd2dba3 (12.5 mg, 0.014 mmol), 2-(dicyclohexylphosphino)-2,4,6-tri-i-propyl-1,1-biphenyl (13.0 mg, 0.027 mmol), and sodium tert-butoxide (17.5 mg, 0.18 mmol) in toluene (1.5 mL). The reaction mixture was stirred 100° C. for 18 h. Purification afforded 6-(4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-quinolinyl)-2(1H)-pyridinone as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.72-7.83 (2H, m), 7.65 (1H, d, J=2.7 Hz), 7.50-7.63 (1H, m), 7.29-7.36 (1H, m), 6.80 (2H, d, J=7.0 Hz), 5.68-5.82 (1H, m), 3.82 (2H, s), 3.64-3.78 (4H, m), 2.89-3.05 (4H, m), 2.51 (3H, s), 1.59 (3H, s), 1.55 (3H, s). Mass Spectrum (ESI) m/e=486 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:19]1([CH2:25][C:26](=[NH:30])OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[ClH:16].[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccc(Cl)cc1Cl
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccc(Cl)cc1Cl
Yield: 14.8 %

Procedure:
A mixture of 2-amino-3-(2,4-dichlorobenzyloxy)pyridine (5.07 g, 18.8 mmol) and ethyl phenylacetimidate hydrochloride (3.52 g, 25.8 mmol) in ethanol (150 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (dichloromethane/methanol) and trituration with ether to obtain the product (0.59 g), m.p. 185°-187° C.
Reaction SMILES: [CH3:1][C:2]1([C@H:5]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]4[O:21][C:22](S(C)=O)=[N:23][N:24]=4)[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[CH3:6])[CH2:4][CH2:3]1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CN(C=O)C>[CH3:1][C:2]1([C@H:5]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]4[O:21][C:22]([NH:28][CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[N:23][N:24]=4)[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[CH3:6])[CH2:4][CH2:3]1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3nnc(S(C)=O)o3)cc12)C1(C)CC1
Reactant: NCCN1CCOCC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3nnc(NCCN4CCOCC4)o3)cc12)C1(C)CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a solution of 4-((R)-1-(1-methylcyclopropyl)ethylamino)-6-(5-(methylsulfinyl)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (16.00 mg, 0.041 mmol) in NMP (0.5 mL, 0.082M) was added 4-(2-aminoethyl)morpholine (26.80 mg, 0.206 mmol) followed with DIPEA (0.029 mL, 0.165 mmol) and stirred at 130° C. for 30 min in a Biotage Initiator microwave. The reaction mixture was dissolved in 1.5 mL of DMF and directly purified on Reverse Phase HPLC to yield desired product (2.23 mg, 12% yield). MS (ES+) m/z: 454.87 (M+H); HPLC: 92% retention time: 1.57 min (analytical HPLC Method B).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[CH2:4][CH:5]=[CH2:6].[C:14]([OH:17])(=[S:16])[CH3:15].CC(N=NC(C#N)(C)C)(C#N)C>N(C(C)(C)C#N)=NC(C)(C)C#N.O1CCOCC1>[C:14]([S:16][CH2:6][CH2:5][CH2:4][C:3]([C:8]([F:9])([F:10])[F:11])([C:2]([F:12])([F:13])[F:1])[OH:7])(=[O:17])[CH3:15]
Reactant: CC(O)=S
Reactant: C=CCC(O)(C(F)(F)F)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Product: CC(=O)SCCCC(O)(C(F)(F)F)C(F)(F)F
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, 20 g of 4,4-bis(trifluoromethyl)-4-hydroxy-1-butene (96.1 mmol), 8.05 g of thioacetic acid (105.7 mmol), 60 g of 1,4-dioxane and 0.79 g of 2,2′-azobisisobutyronitrile (hereinafter abbreviated as AIBN) (4.8 mmol) were put into a flask equipped with a stirring bar, a thermometer and a condenser, and heated with stirring. During the reaction, thioacetic acid and AIBN were appropriately added and after confirming that a substrate was completely consumed, the reaction solution was distilled as it was under reduced pressure to yield an intermediate product, 22 g of 4-acetylthio-1,1-bis(trifluoromethyl)-1-butanol (76.9 mmol).
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([NH:21][C:22]([C:24]2[CH:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:21][C:22]([C:24]2[CH:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1ccc(N2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-phenoxy-2-(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 6.5 with a saturated sodium hydrogen carbonate aqueous solution. A solid substance was separated by filtration to obtain 23 mg of 4-phenoxy-2-(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoic acid as whine solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.FC(F)(F)C(O)=O.[CH3:44][N:45]1[CH2:50][CH2:49][C:48]2[N:51]=[C:52]([C:54]([NH:56][C@@H:57]3[CH2:62][CH2:61][CH2:60][CH2:59][C@H:58]3[NH2:63])=[O:55])[S:53][C:47]=2[CH2:46]1.Cl>CN(C)C=O.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:63][C@@H:58]1[CH2:59][CH2:60][CH2:61][CH2:62][C@H:57]1[NH:56][C:54]([C:52]1[S:53][C:47]3[CH2:46][N:45]([CH3:44])[CH2:50][CH2:49][C:48]=3[N:51]=1)=[O:55])=[O:13])=[CH:5]2
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CCCC[C@H]3N)sc2C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2nc(C(=O)N[C@@H]3CCCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 143.3 %

Procedure:
5-Chloroindole-2-carboxylic acid (109 mg), 1-hydroxybenzotriazole monohydrate (9 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (321 mg) and triethylamine (0.232 ml) were added to a solution with (±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine trifluoroacetate (300 mg) dissolved in N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure using a vacuum pump, and dichloromethane and water were added to the residue to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=25:1) to obtain a colorless foamy substance. 1N hydrochloric acid (1 ml) was added to this substance and the solvent was distilled off under reduced pressure to obtain the title compound (203 mg) as a pale brown foamy substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[C:32]([CH3:35])[CH:31]=[CH:30][C:29]=5[F:36])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:39].[ClH:41].CCOCC>>[ClH:39].[ClH:41].[ClH:39].[F:36][C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[C:33]2[C:28]=1[CH:27]=[N:26][C:25]([C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)=[CH:34]2
Reactant: ClCCl
Reactant: Cc1ccc(F)c2cnc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)cc12
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(F)c2cnc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-[6-amino-5-(8-fluoro-5-methylisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (11.5 mg, 0.0229 mmol) in DCM (0.60 mL, 9.4 mmol) was added 1.0 M of HCl in Et2O (0.80 mL, 0.80 mmol), and the mixture was stirred at ambient temperature for 2 h. Almost immediately a pale yellow solid precipitated. The solvents were evaporated, and the residue was transferred into a vial and dried in vacuo overnight, yielding the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=14.6 (very brs, 1H), 9.59 (d, J=0.8 Hz, 1H), 9.19-9.09 (brm, 1H), 9.02-8.91 (brm, 1H), 8.88 (d, J=2.4 Hz, 1H), 8.56 (brs, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.15 (s, 1H), 7.73 (ddd, J=0.8, 6.4, 8.0 Hz, 1H), 7.51 (dd, J=8.0, 10.2 Hz, 1H), 4.59-4.50 (mc, 1H), 3.40 (brd, J=12.2 Hz, 2H), 3.11 (brq, J=11.4 Hz, 2H), 2.76 (s, 3H), 2.30-2.12 (m, 4H). MS(ES+): m/z=403.16 (23) [MH+], 320.12 (100) [MH+-piperidine]. HPLC: tR=1.89 min (polar—5 min, ZQ2).
Reaction SMILES: [CH:1]1[C:6]2C(OC(=O)[C:5]=2[CH:4]=[C:3]2[C:12]([O:14][C:15](=[O:16])[C:2]=12)=O)=O.O[C:18]1[C:19]([CH3:31])=[N:20][C:21]2[C:26]([C:27]=1C(O)=O)=[CH:25][CH:24]=[CH:23][CH:22]=2.[N+](C1C=CC=CC=1)([O-])=O>>[CH:24]1[CH:25]=[C:26]2[CH:27]=[CH:18][C:19]([CH:31]3[C:15](=[O:16])[C:2]4[C:3](=[CH:4][CH:5]=[CH:6][CH:1]=4)[C:12]3=[O:14])=[N:20][C:21]2=[CH:22][CH:23]=1
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1
Reaction time: 1 h

Procedure:
65.4 Parts of pyromellitic acid dianhydride and 61 parts of 3-hydroxy-2-methyl-quinoline-4-carboxylic acid are heated under reflux at 205° in 1000 parts of nitrobenzene for 1 hour, distilling off the water produced by the reaction. The mixture is held at this temperature for 31/2 hours. The mixture is then cooled to 10° and after stirring at this temperature for 1 hour, is filtered and the product is washed in toluene and ethanol. 93 parts of a dark brown quinophthalone intermediate result.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:15])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2].[Cl:23][CH2:24][C:25](=O)[CH3:26]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:25]([CH3:26])[CH2:24][Cl:23])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reactant: CC(=O)CCl
Product: CC(CCl)=NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-nitro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with chloropropanone to give 7-nitro-2-[(2-chloro-1-methylethylidene)-hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-:20])=[CH:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cccc2cnccc12
Solvent: ClCCl
Product: [O-][n+]1ccc2c(Br)cccc2c1
Temperature: 25 °C

Procedure:
To a solution of 5-bromoisoquinoline (10.65 g, 51.19 mmol) in CH2Cl2 (250 mL), m-CPBA (9.717 g, 56.31 mmol) was added and the mixture refluxed for 20 h and allowed to cool to rt. The mixture was washed with sat Na2SSO3 (75 mL), then 3×1N NaOH, then brine. The organic layer was dried w/Na2SO4, filtered and evaporated. The residue was crystallized from CH2Cl2: Et2O to yield the title compound as a white fluffy solid (4.58 g). MS (ESI pos. ion) m/z: 224 (MH+). Calc'd exact mass for C9H5BrNO: 224.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:14][C:15]1[CH:16]=[C:17]([NH:23][C@H:24]([C@@H:41]([OH:43])[CH3:42])[C:25]([NH:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[O:26])[CH:18]=[CH:19][C:20]=1[C:21]#[N:22].O>CN(C=O)C>[Si:10]([O:43][C@@H:41]([CH3:42])[C@@H:24]([NH:23][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[C:15]([Cl:14])[CH:16]=1)[C:25]([NH:27][NH:28][C:29](=[O:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)=[O:26])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.7 %

Procedure:
Imidazole (3.77 g, 55.44 mol) and TBDMS-Cl (5.01 g, 33.24 mmol) were added sequentially to a pre-cooled (0° C.) solution of N′-((2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoyl)-4-(methylsulfonyl)benzohydrazide (5 g, 11.08 mmol) in DMF (350 mL). The reaction mixture was allowed to warm to room temperature and stirred for 17 h, whereupon the solution was poured into H2O (90 mL). The white precipitate was filtered, washed with H2O (30 mL) and taken up in CH2Cl2 (170 mL). This organic layer was washed with brine (1×50 mL), dried (Na2SO4), filtered and concentrated to provide the title compound (4.3 g, 69%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.8 (br s, 1H), 8.08 (d, J=8.0 Hz, 2H), 8.04 (d, J=9 Hz, 2H), 7.53 (d, J=8 Hz, 1H), 6.99 (s, 1H), 6.85 (d, J=8 Hz, 1H), 6.22 (d, J=8 Hz, 1H), 4.43-4.38 (m, 1H), 4.27-4.22 (m, 1H), 1.37 (d, J=7 Hz, 3H), 0.86 (s, 9H), 0.11 (s, 3H) and 0.05 (s, 3H).
Reaction SMILES: C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Zn+2:15].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[OH:26])[CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH:22]1[CH:23]=[C:24]([O-:26])[C:25]2[N:16]=[CH:17][CH:18]=[CH:19][C:20]=2[CH:21]=1.[CH:22]1[CH:23]=[C:24]([O-:26])[C:25]2[N:16]=[CH:17][CH:18]=[CH:19][C:20]=2[CH:21]=1.[Zn+2:15]
Reactant: Oc1cccc2cccnc12
Agent: CC(=O)/C=C(/C)[O-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: [O-]c1cccc2cccnc12

Procedure:
A cooling tube and a stirrer were set in a 100 ml eggplant flask. 2.8 g (11 mmol) of zinc acetylacetonate (made by Tokyo Chemical Industry Co., Ltd.), 50 mL of dimethylformamide, and 3.19 g (22 mmol) of 8-quinolinol were placed in the flask to obtain a dimethylformamide dispersion liquid of bis(8-hydroxyquinolinato)zinc(II) (Znq2). The dispersion liquid was dropped into 1000 ml of water little by little. The deposited solid was filtered, and recovered. The recovered solid was washed with a small amount of methanol, and dried to obtain 2.5 g of a powder of Znq2 (yield of 64%).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][C@H:13]2[C@H:11]([CH2:12]2)[C@H:10]1[CH2:15][NH:16][C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1)=O)(C)(C)C>O1CCOCC1>[C@H:11]12[CH2:12][C@H:13]1[CH2:14][NH:9][C@@H:10]2[CH2:15][NH:16][C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNc1ncc(Br)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Brc1cnc(NC[C@H]2NC[C@@H]3C[C@@H]32)nc1

Procedure:
A solution of HCl in dioxane (4.0 M, 22 mL) is added to a solution of (1S,2S,5R)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (8.67 mmol) in dioxane (20 mL). After 90 min the solvents are removed in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.64 min; [M+H]+=269.0.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.CC(C)([O-])C.[K+].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>O>[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH:10]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Yield: 79.9 %

Procedure:
To a dimethylformamide (1.0 mL) solution of 3-hydroxy-benzoic acid methyl ester (183 mg, 1.2 mmol) was added potassium t-butoxide (147 mg, 1.2 mmol). Upon stirring the reaction at room temperature for 15 min, 2-bromo-5-trifluoromethyl-pyridine (300 mg, 1.32 mmol) was added. The reaction was stirred at room temperature for 15 h. Crude reaction mass was added to water, aqueous layer was acidified to pH 4.0 and product was extracted with ethyl acetate to give 3-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid methyl ester (285 mg).