Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]=[CH2:6])(=O)C.BrBr.O=[C:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[NH3:18]>O>[CH3:17][C:10]1[NH:18][CH:5]=[CH:6][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: N
Reactant: C=COC(C)=O
Reactant: CCOC(=O)CC(C)=O
Agent: BrBr
Solvent: O
Product: CCOC(=O)c1cc[nH]c1C
Yield: 35 %

Procedure:
Vinyl acetate (13.4 g) was added dropwise over 2 hr to bromine (25 g) under ice-cooling with stirring. The reaction mixture was further stirred at the same temperature for 1 hr. Ethyl 3-oxobutanoate (18.5 g) was added, and 25% aqueous ammonia solution (44 mL) was added dropwise over 1 hr. The reaction mixture was further stirred at room temperature for 30 min, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→3:1) and recrystallized from hexane to give the title compound as a colorless solid (yield 7.56 g, 35%).
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][C:11]([F:24])=[C:12]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[CH:13]=2)[N:8]=[C:7]([N:25]2[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]2)[N:6]=1>C1COCC1>[NH2:3][C:5]1[C:14]2[C:9](=[CH:10][C:11]([F:24])=[C:12]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[CH:13]=2)[N:8]=[C:7]([N:25]2[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]2)[N:6]=1
Reactant: CCOC(=O)c1cnn(-c2nc(Cl)c3cc(Oc4c(C)cccc4C)c(F)cc3n2)c1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cnn(-c2nc(N)c3cc(Oc4c(C)cccc4C)c(F)cc3n2)c1
Reaction time: 6 h
Yield: 63.3 %

Procedure:
A methanol solution of ammonia (7M, 0.39 mL, 2.7 mmol) was added to a solution of the above 1-[4-chloro-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, ethyl ester (120 mg, 0.27 mmol) and THF (2 mL). The mixture was stirred 6 h, then concentrated. The residue was triturated with Et2O, providing the titled compound (72 mg, 64%). 1H NMR (500 MHz, DMSO-d6): 8.96 (d, J=0.8 Hz, 1H), 8.44-8.02 (m, 3H), 7.71 (d, J=11.9 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.17 (dd, J=8.6, 6.2 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.12 (s, 6H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[CH:2]([CH3:14])[C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[I-].[NH2:16][N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[C:4]([C:3](=[O:13])[CH2:2][CH3:14])=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[CH:7][CH:8]=1
Reactant: CC(Cl)C(=O)C#Cc1ccc(F)cc1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
To a mixture of 8.7 g (38 mmol) of 4-chloro-1-(4-fluorophenyl)pent-1-yn-3-one and 10 g (45 mmol) of N-aminopyridinium iodide in 140 ml of acetonitrile was added dropwise 11 g of DBU in 50 ml of acetonitrile at 0° C. for 20 minutes under a nitrogen atmosphere. The reaction was then stirred at RT overnight. After evaporation of the solvent, the crude mixture was purified on an Al2O3 column, and the desired product recrystallized from ethyl acetate-hexane to obtain 200 mg of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)propan-1-one. Compound 1070.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:29])=[CH:25][NH:26]2)=[CH:22][CH:21]=1)=[O:19].O>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:25]1[NH:26][C:27]2[C:23]([C:24]=1[CH3:29])=[CH:22][CH:21]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:28]=2)=[O:9]
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C)c(C(=O)c3ccc(Cl)cc3Cl)[nH]c2c1
Reaction time: 2.5 h
Yield: 77.3 %

Procedure:
Aluminium chloride (1.72 g) is suspended in methylene chloride (50 ml), to which are added 2,4-dichlorobenzoyl chloride (1.35 g) and then 6-(methoxycarbonyl)-3-methylindole (1.00 g), and stirred at room temperature for 16 hours and then at 40° C. for 2.5 hours. The reaction mixture is poured into water with ice, and then extracted with ethyl acetate (150 ml). The organic layer is washed three times with a saturated aqueous sodium hydrogencarbonate solution (50 ml) and then with a saturated saline solution, and thereafter dried with anhydrous sodium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting crystal is washed with methyl t-butyl ether and dried to obtain 2-(2,4-dichlorobenzoyl)-6-(methoxycarbonyl)-3-methylindole (71) (1.48 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[Br:14]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH:1]([N:4]1[C:8]2[C:9]([Br:14])=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)n1cnc2ccc(N)cc21
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)n1cnc2ccc(N)c(Br)c21
Yield: 47 %

Procedure:
To a solution of 3-isopropyl-5-aminobenzimidazole (1.5 g, 7.9 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 1.1 g (4.0 mmol, 47%) of the product.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 95 °C
Yield: 62.9 %

Procedure:
A mixture of 5-bromothiophene-2-carboxaldehyde 60.1 (1.03 g, 5.4 mmol), 4-(trifluoromethyl)benzeneboronic acid 61.1 (2.05 g, 10.9 mmol), K2CO3 (2.24 g, 16.2 mmol), and Pd(PPh3)4 (0.60 g, 0.54 mmol) in toluene (15 mL) was stirred for 5 Hours at 95° C. The mixture was cooled to room temperature, filtered through a pad of silica gel (EtOAc), and concentrated. The crude product was chromatographed on silica gel (0-30% EtOAc/hexane) to afford 61.2 (0.87 g, 63%) as off-white crystals. 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.78 (m, 3H), 7.70 (d, 2H), 7.48 (d, 1H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([OH:31])[C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])=[CH:18][CH:17]=2)=[C:10]([CH2:32][CH2:33][CH3:34])[C:9]=1[OH:35])(=[O:7])[CH3:6].O>CN1CCCC1=O.[Br-].[Zn+2].[Br-]>[OH:35][C:9]1[C:10]([CH2:32][CH2:33][CH3:34])=[C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([OH:31])[C:23]3[CH:30]=[CH:29][CH:28]=[C:25]([C:26]4[NH:27][N:3]=[N:2][N:1]=4)[CH:24]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:8]=1[C:5](=[O:7])[CH3:6]
Reactant: CCCc1c(SCc2ccc([C@H](O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCc1c(SCc2ccc([C@H](O)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 140 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
Add sodium azide (66 mg, 0.25 mmol) and zinc bromide (131 mg, 0.50 mmol) to a solution of (S)-3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-phenyl]-hydroxy-methyl}-benzonitrile (110 mg, 0.25 mmol) in N-methylpyrrolidinone (2.0 ml). Heat the mixture at 140° C. for 12 hours, then cool to room temperature and stir for 18 hours. Pour the mixture into water (25 ml) and stir the solid suspension for 20 minutes. Filter and wash the filtered solid with water. Dissolve the solid in a 1N HCl (25 ml) and ethyl acetate (20 ml) mixture. Extract the aqueous layer with ethyl acetate (25 ml), combine the organic extracts, then wash with water, brine, dry over sodium sulfate and concentrate. Purify the crude product via reverse phase HPLC using a gradient of 90:10 to 20:80 (water/0.1% TFA):acetonitrile as eluent to give the title compound (37 mg, 31%). MS (m/z) 473 (M−H), 1H NMR (400 MHz, DMSO-d6) 12.83 (s, 1H), 8.13-8.11 (m, 1H), 7.89-7.86 (m, 1H), 7.72 (d, 1H), 7.59-7.51 (m, 2H), 7.41-7.37 (m, 4H), 6.96 (d, 1H), 5.60 (s, 1H), 4.30 (s, 2H), 2.65-2.60 (m, 5H), 1.45 (sextet, 2H), 0.90 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:24])[C:13]([CH3:23])(C(OC)=O)[CH2:14][S:15][C:16](=[O:18])[CH3:17])([CH3:4])([CH3:3])[CH3:2].[OH-:26].[Na+].[CH3:28][OH:29]>O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:24])[CH:13]([CH2:23][C:28]([OH:29])=[O:26])[CH2:14][S:15][C:16](=[O:18])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: [OH-]
Reactant: COC(=O)C(C)(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: CO
Agent: [Na+]
Solvent: O
Product: CC(=O)SCC(CC(=O)O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of 1-[3-(acetylthio)-2-methoxycarbonyl-methylpropanoyl]-L-proline tert-butyl ester (3.7 g) in methanol (60 ml), N sodium hydroxide (40 ml) is added. After four hours, the reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate. The aqueous layer is acidified and extracted with ethyl acetate. This last ethyl acetate layer is dried and concentrated to dryness in vacuo. The residue is dissolved in a mixture of pyridine and acetic anhydride (3:1) and the solution is stored at room temperature overnight. The reaction mixture is diluted with ethyl acetate (200 ml) and washed with 10% potassium bisulfate. The organic layer is dried and concentrated to dryness in vacuo to yield 1-[3-(acetylthio)-2-carboxymethylpropanoyl]-L-proline tert-butyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)#[N:2].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[CH2:24]1[N:17]2[C:18]3[C:14]([C@@H:15]4[CH2:28][NH:27][CH2:26][CH2:25][C@@H:16]42)=[CH:13][C:12]([NH:11][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:1]#[N:2])=[CH:20][C:19]=3[CH2:21][S:22][CH2:23]1
Reactant: N#Cc1ccccc1C=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: N#Cc1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-cyanobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 162. 1H NMR(CDCl3) δ: 8.14 (d, 1H, J=7.7 Hz) 7.63-7.50 (m, 3H), 6.88-6.80 (m, 2H), 7.13 (s, 1H), 6.95 (s, 1H), 4.90 (broad s, 2H), 3.81 (ABq, 2H, JAB=15.7 Hz), 3.71-3.62 (m, 2H), 3.59-3.53 (m, 1H), 3.38-3.30 (m, 1H), 3.29-3.20 (m, 1H), 3.12-2.80 (m, 5H), 1.91-1.80 (m, 2H). LRMS (ES)+: 377.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][N:13](C(OCC4C=CC=CC=4)=O)[CH2:14][CH2:15][N:8]3[CH2:7][CH:6]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:5]23)[CH:11]=1.FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:8]3[CH2:7][CH:6]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:5]23)[CH:11]=1
Reactant: O=C(OCc1ccccc1)N1CCN2CC3CCCCCC3c3cc(Cl)cc(c32)C1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: O
Solvent: ClCCl
Product: Cl
Product: Clc1cc2c3c(c1)C1CCCCCC1CN3CCNC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 148.8 %

Procedure:
The compound of Example 19 (0.585 mg, 1.38 mmol) was dissolved in methylene chloride (2 mL) and cooled to 0° C. Trifluoromethane sulfonic acid (0.853 mL, 9.63 mmol) and anisole (0.449 mL, 4.13 mmol) were then added. The reaction mixture was stirred at 0° C. for 5 minutes and then held at room temperature for 1 hour. The reaction mixture was again cooled to 0° C. and the pH was adjusted until basic with 1N NaOH. The reaction mixture was transferred to a separatory funnel with methylene chloride and water, and extracted with methylene chloride (4×). The combined organic layers were then dried with magnesium sulfate, filtered and concentrated to give a yellow oil (0.584 g crude). Further purification (5% ammonia in 2M solution of methanol/ethyl acetate) yielded 0.336 g of the free amine product (84%). The free amine (0.392 g, 1.35 mmol) was dissolved in diethyl ether and HCl in 2M solution of diethyl ether (0.740 mL, 1.48 mmol) was added. After stirring for 30 minutes, the solid was filtered and air dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1
Reactant: Cc1ccc2ccc3nc(NC(=O)C(C)(C)C)[nH]c(=O)c3c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1

Procedure:
To a hot solution of N-(1,2-dihydro-9-methyl-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.94 g, 3.0 mmol) in benzene (250 ml) under nitrogen were added N-bromosuccinimide (0.57 g, 3.2 mmol) (Kodak) and 2,2′-azobisisobutyronitrile (AIBN) (35 mg, 0.21 mmol) (Kodak). The solution was stirred at reflux for 1.5 hours and then concentrated in vacuo to give crude N-(9-bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. The pivalamide and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (2.5 g, 7.8 mmol) (Aldrich) in DMF (10 ml) were stirred under nitrogen at 105-110° C. for 5 minutes and then allowed to cool. Triethylamine (0.5 ml, 3.6 mmol) was added and the solution was concentrated under high vacuum. The residue was purified by chromatography on silica gel (130 g) eluting with ethyl acetate:methylene chloride (1:19→2:3), followed by recrystallization of the solid from ethanol/diethyl ether. This was filtered and dried under high vacuum to give diethyl N-(4-(((1,2-dihydro-1-oxo-3-pivalamido-benzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate (0.32 g) as a white solid. The filtrate was concentrated and the residue purified by chromatography and crystallization to give an additional 0.243 g. 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, esterCH3), 1.16 (t, J=7 Hz, 3H, esterCH3), 1.28 (s, 9H, t-butyl), 1.87-2.13 (m, 2H, gluCH2), 2.39 (t, J=7 Hz, 2H, gluCH2), 4.03 (q, J=7 Hz, 2H, esterCH2), 4.07 (q, J=7 Hz, 2H, esterCH2), 4.30-4.40 (m, 1H, gluCH), 4.57 (d, J=6 Hz, 2H, C9—CH2), 6.63 (d, J=9 Hz, 2H, Ar), 7.04 (t, J=6 Hz, 1H, ArNH), 7.53 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8, 2 Hz, 1H, Ar), 7.62 (d, J=9 Hz, 2H, Ar), 7.99 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=8 Hz, 1H, gluNH), 8.22 (d, J=9 Hz, 1H, Ar), 9.75 (s, 1H, Ar), 11.25 (s, 1H, N2H), 12.30 (br s, 1H, NH). Mass spectrum (CI-CH4) 630 (M+1, 6.5%), 243 (100%). Anal. Calculated for C34H39N5O7: C, 64.85; H, 6.24; N, 11.12. Found: C, 64.74; H, 6.25; N, 11.10.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.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>[CH3:17][C:3]1[C:2]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:4]=1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(-c2c(C)nn(-c3ccc(CCO)cc3)c2C)cc1

Procedure:
To a suspension of 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11, 300 mg, 0.88 mmol) and p-tolylboronic acid (313 mg, 2.3 mmol) in dimethoxyethane (6.3 mL) were added 2 M aqueous K2CO3 (2.2 mL, 4.4 mmol) and bis(triphenylphosphine)palladium(II) chloride (124 mg, 0.18 mmol), and the mixture were refluxed for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated to give brown oil. It was partitioned between dichloromethane and water. The separated organic layer was dried (Na2SO4), evaporated, and purified by TLC with hexane/ethyl acetate (1:1) to afford 349 mg (quant.) of the title compound as white solids: MS (ESI) m/z 307 [M+H]+, 1H-NMR (CDCl3) δ 7.43-7.20 (8H, m), 3.87 (2H, t, J=6.4 Hz), 2.91 (2H, t, J=6.4 Hz), 2.40 (3H, s), 2.31 (3H, s), 2.28 (3H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C@H:11]2[CH2:13][C@H:12]2[C:14](O)=[O:15])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]2[CH:11]3[CH:12]([C:14](=[O:15])[NH:20][N:21]=2)[CH2:13]3)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 84.6 %

Procedure:
6.0 g (24.3 millimoles) of cis-2-(p-acetylaminobenzoyl)-cyclopropanecarboxylic acid, 1.33 g (26.6 millimoles) of hydrazine hydrate and 150 ml of ethanol are refluxed for 6 hours. After filtering off the product at 0° C. and drying it under reduced pressure at 50° C., 5.0 g (85% of theory) of 2-(p-acetylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as colorless crystals, melting point 269°-270° C. after recrystallization from a methanol/water mixture.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:13]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1)#[N:12]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=C(O)c1ccncc1F
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CNc2cnccc2C(=O)O)cc1
Temperature: 166 °C
Reaction time: 1.5 h
Yield: 17.8 %

Procedure:
3-Fluoroisonicotinic acid (100 mg, 0.71 mmol), 4-(aminomethyl)-benzonitrile hydrochloride (240 mg, 1.42 mmol), and DIEA (250 μL, 1.42 mmol) were combined in DMA (2 mL) and the reaction mixture was stirred at 166° C. in a microwave for 90 min. The solution was concentrated in vacuo and purified by silica gel chromatography (10-20% MeOH/DCM). The semi-pure fractions were concentrated and then taken up in water to give a pale yellow precipitate, which was collected by filtration and dried under vacuum to give 32 mg (18%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.10 (br s, 1H), 8.04 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 4.69 (s, 2H). [M+H] calc'd for C14H11N3O2, 254; found 254.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:25](=[O:26])[C:24]2[C:11](=[C:12]([NH2:30])[C:13]3[C:14](=[O:29])[C:15]4[C:20]([C:21](=[O:28])[C:22]=3[C:23]=2[NH2:27])=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:9]1=[O:10].[C:31](Cl)(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[CH2:39](O)[CH3:40]>N1C=CC=CC=1>[C:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:25](=[O:26])[C:24]2[C:11](=[C:12]([NH2:30])[C:13]3[C:14](=[O:29])[C:15]4[C:20]([C:21](=[O:28])[C:22]=3[C:23]=2[NH2:27])=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:9]1=[O:10])(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:39][CH3:40]
Reactant: CCCCCC(=O)Cl
Reactant: CCO
Reactant: Nc1c2c(=O)c3ccccc3c(=O)c2c(N)c2c(=O)n(CCCCCCO)c(=O)c12
Solvent: c1ccncc1
Product: CCCCCCCC(=O)CCCCCCn1c(=O)c2c(N)c3c(=O)c4ccccc4c(=O)c3c(N)c2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A suspension of N-(6'-hydroxyhexyl)1,4-diaminoanthraquinone-2,3-dicarboximide (10.0 parts) in pyridine (200.0 parts) was heated to 90° C. under nitrogen and maintained at this temperature for 1 hour or until complete dissolution of the dye. The reaction mixture was cooled to 40° C. Caproyl chloride (6.9 parts) was then added dropwise at a rate such that the temperature did not exceed 50° C. The reaction mixture was cooled to room temperature. After 3 hours, ethanol (20.0 parts) was added dropwise. The mixture was cooled in ice for 3 hours. The dark blue solid obtained was separated by filtration and washed with methanol (100 parts). After drying in high vacuo for 6 hours at 45° C., there was obtained N-(6'-n-octanoylhexyl)1,4-diaminoanthraquinone-2,3-dicarboximide (11.5 parts, 88% from N-(6'-hydroxyhexyl)1,4-diaminoanthraquinone-2,3-dicarboximide) (Formula 6); m.p.: 157°-158° C.; lambdamax 680 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=[O:24])[C:15]3[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:30])([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=[O:24])[C:15]3[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(F)cc1)N2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cccc2c1C(=O)C(C)(c1nccn1C)C(c1ccc(F)cc1)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.38 mmol) and cesium carbonate (268 mg, 0.76 mmol) in DMF (10 mL) was added iodomethane (0.2 mL, 2.28 mmol) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 4 h and then at room temperature overnight. The resulting solution was added 50 mL of water, and then extracted with ethyl acetate (100 mL×3). The extracts were concentrated to give the crude product as a yellow solid (145 mg, yield 90%), which was used in the next step without further purification. LC-MS (ESI) m/z: 408 (M+1)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[C:5]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:4]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl>C1COCC1>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([N:16]2[CH2:17][CH2:18][N:19]([S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH2:20][CH2:21]2)[CH:4]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(Cl)cc1N1CCN(S(=O)(=O)c2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
To a mixture of the product from step c) (0.34 g) and benzenesulfonyl chloride (0.11 ml) in THF (3 ml) was added triethylamine (0.42 ml) dropwise. After 5 min, further THF (3 ml) was added and the reaction stirred for 16 h. It was poured into 2M HCl and extracted with ethyl acetate. The organic layer was separated and washed with sat aqueous sodium bicarbonate solution, brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was stirred in THF (2 ml) and 4M NaOH (4 ml) for 16 h. After acidification to pH 3, the aqueous layer was extracted with ethyl acetate. The organic layer was separated and the solvent removed in vacuo. Purification by RPHPLC (symmetry column) gave the title product as a white foam (0.12 g).