Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[N:20][CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a solution of N-tert-butyl-2-(2-methylpyrimidin-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 171 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (390 mg, 264 μL, 3.42 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (2.5 mL), methanol (1.2 mL) and ammonium hydroxide (0.35 mL) and the mixture stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo then triturated with water. The solid was collected by filtration and washed with water and ether to give N-tert-butyl-2-(2-methylpyrimidin-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (43 mg, 132 μmol, 77%) as a brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.31 (s, 1H), 9.57 (s, 1H), 8.90 (s, 2H), 7.96 (d, J=3.3, 1H), 7.92 (s, 1H), 7.53 (s, 1H), 2.46 (s, 3H), 1.32 (s, 9H); MS (EI/CI) m/z: 326.1 [M+H].
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][C:17]1[CH:18]=[C:19]([CH3:35])[C:20]2[NH:21][C:22](=O)[C:23]3[CH:33]=[CH:32][CH:31]=[N:30][C:24]=3[N:25]([CH2:28][CH3:29])[C:26]=2[N:27]=1.C(Cl)Cl.[CH:39]([N:42](C(C)C)CC)(C)C>[C-]#N.C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[C:39]([C:22]1[C:23]2[CH:33]=[CH:32][CH:31]=[N:30][C:24]=2[N:25]([CH2:28][CH3:29])[C:26]2[N:27]=[C:17]([CH3:16])[CH:18]=[C:19]([CH3:35])[C:20]=2[N:21]=1)#[N:42]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(C)nc21
Reactant: CCN(C(C)C)C(C)C
Agent: CC[N+](CC)(CC)CC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN1c2ncccc2C(C#N)=Nc2c(C)cc(C)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluorornethanesulfonic anhydride (0.24 mL, 14 mmol) was added to a solution of 0.314 g (1.2 mmol) 5,11-dihydro-2,4-dimethyl-11-ethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine-6-one in 15 mL of methylene chloride containing 0.25 mL (14 mmol) of diisopropylethylamine. The resulting mixture was refluxed under Ar for 3 hr. Ethyl acetate (~200 mL) was then added and the solution was washed three times with water and four times with brine. After drying (magnesium sulfate), the solution was concentrated in vacuo and the residue dried under high vacuum for 2 hr. The residue was dissolved in 20 mL of methylene chloride, and 0.23 g (14 mol) of tetraethylammonium cyanide was added. After stirring the resulting solution overnight at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate, and the solution washed with water and brine, and then dried (magnesium sulfate). The solution was concentrated in vacuo and the residue was chromatographed over silica (eluted with 5% ethyl acetate/hexane). The resulting solid was crystallized from heptane to provide 33 mg of the title compound as red crystals, m.p. 154°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[S:11](=[O:15])(=[O:14])([OH:13])[OH:12].[N:16](OCCCCC)=O>C(O)C>[S:11]([O-:15])([OH:14])(=[O:13])=[O:12].[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([F:10])=[CH:5][C:3]=1[N+:4]#[N:16]
Reactant: O=S(=O)(O)O
Reactant: CCCCCON=O
Reactant: Nc1cc(F)c(Cl)cc1Cl
Solvent: CCO
Product: N#[N+]c1cc(F)c(Cl)cc1Cl
Product: O=S(=O)([O-])O

Procedure:
36.0 g (0.20 mol) of 2,4-dichloro-5-fluoroaniline are dissolved at room temperature in 180 ml of ethanol and 36.0 g of concentrated sulfuric acid are added with cooling. To this mixture are added dropwise 27.0 ml (0.23 mol) of amyl 1 nitrite. The diazonium salt precipitated out is then removed by suction and washed with a little diethyl ether.
Reaction SMILES: [OH-].[Na+].Cl.[N+:4]([C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5].C(O)(=O)C.[CH:19](=O)[CH2:20][CH3:21]>C(O)C>[N+:4]([C:7]1[CH:8]=[C:9]([NH:13]/[N:14]=[CH:19]/[CH2:20][CH3:21])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: CCC=O
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC/C=N/Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide solution (10%, 15 mL) was added slowly to a stirred suspension of (3-nitrophenyl)hydrazine hydrochloride (1.89 g, 10 mmol) in ethanol (20 mL) until pH 6. Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0.7 g, 12 mmol). After stirring for 3 h at room temperature, the mixture was poured into ice-water and the resulting precipitate was isolated by filtration, washed with water and dried in air to obtain (E)-1-(3-nitrophenyl)-2-propylidenehydrazine, which was used directly in the next step.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:12]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)=[C:9]2[C:10]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:15])[N:7]([CH3:14])[C:8]2=[O:13])=[N:11]1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: Cn1cc(C#N)cc1C=O
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Product: Cn1cc(C#N)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carbonitrile. Mass: 488.16 (M+H).
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=O)[CH2:5][C@H:6]3[C@:26]([CH3:27])([C@@H:2]12)[C:25]1[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@@H:10]([CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:9]=1[O:8][C:7]3=[O:29].O.NN.C(O)(=O)C.O>C(O)C>[OH:1][C@@H:2]1[C@@:26]2([CH3:27])[C@@H:6]([C:7](=[O:29])[O:8][C:9]3[C@H:10]4[C@:22]([CH3:28])([CH2:23][CH2:24][C:25]=32)[C@@H:13]([C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:11]4)[CH2:5][CH:4]=[CH:3]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@]1(C)[C@H](CC(=O)[C@@H]2O[C@@H]21)C(=O)O3
Agent: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@]1(C)[C@H](CC=C[C@@H]1O)C(=O)O3
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Compound 6 (9.0 mg, 0.022 mmol) obtained in Example 5 was dissolved in ethanol (0.5 mL), and hydrazine monohydrate (10 μL) and acetic acid (10 μL) were added thereto at room temperature, followed by stirring for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative thin layer chromatography to obtain the title compound (6.2 mg, 71%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][CH3:10])=[CH:4][CH:3]=1.[C:11]([CH:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)[CH3:12].C(O)(=O)C.CO>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:22])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:12])[N:9]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Reactant: CNNc1ccc(F)cc1
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(C)n(-c2ccc(F)cc2)c1=O
Temperature: 115 °C
Yield: 49.5 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-methylhydrazine (0.6 g, 4.28 mmol), diethyl 2-acetylmalonate (0.96 g, 4.75 mmol), and acetic acid (0.51 g, 8.49 mmol) in water (15 mL) is heated at 115° C. for 3 hours. The reaction is cooled and extracted with EtOAc twice. The organic phase is washed with saturated aqueous sodium chloride, dried over Na2SO4 and concentrated. The residue is purified by column chromatography on silica gel, eluting with DCM:MeOH (from 150:1 to 60:1) to afford the title compound (0.59 g, 49.5% yield). MS (m/z): 279 (M+H).
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4]>CC(C)=O>[OH:15][C:9]1[CH:8]=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[NH2:1])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: N
Solvent: CC(C)=O
Product: NS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 60 °C

Procedure:
Ammonia gas was bubbled through a solution of 107 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 250 ml acetone at 0° C. for 2 h. Argon gas was then bubbled through the reaction mixture for 1 h to purge excess ammonia. The mixture was then diluted with water, the pH adjusted to pH 14 by addition of 5 M aq NaOH solution, and the mixture was then extracted with ether/ethyl acetate (1:1). The aqueous phase was acidified with concentrated HCl, saturated with NaCl, and extracted twice with THF. The combined THF extracts were dried with Na2SO4. Evaporation of the solvent in vacuo followed by drying of the residue by heating at 60° C. overnight in vacuo yielded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH3:14])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:17]([O:24][CH2:25][C@H:26]([NH:30]C(OC(C)(C)C)=O)[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH2:30][C@@H:26]([CH2:25][O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:27]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][C:9]=1[CH3:14])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Cc1cc(Oc2ccc(F)cc2)ccc1N
Product: Cc1cc(Oc2ccc(F)cc2)ccc1NC(=O)[C@@H](N)COCc1ccccc1
Yield: 58 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)-2-methylaniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)-2-methylphenyl)propanamide (613 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:22])[N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[Br:25][CH2:26][C:27](O)=[O:28]>C1COCC1>[Br:25][CH2:26][C:27]([N:19]1[CH2:18][CH2:17][N:16]([C:15](=[O:22])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=3)[S:10][CH:11]=2)[CH2:21][CH2:20]1)=[O:28]
Reactant: O=C(Nc1nc(CC(=O)N2CCNCC2)cs1)c1ccc(Cl)cc1
Reactant: O=C(O)CBr
Solvent: C1CCOC1
Product: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CBr)CC2)cs1)c1ccc(Cl)cc1

Procedure:
55.1 Using general method A, with THF instead of DMF as solvent, 4-chloro-N-[4-(2-oxo-2-piperazin-1-yl-ethyl)-thiazol-2-yl]-benzamide (example 54.2) was coupled with bromoacetic acid to give N-(4-{2-[4-(2-bromo-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-4-chloro-benzamide. Amorphous white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22].CC(C)([O-])C.[K+].O>CN(C)C(=O)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=2)=[CH:16][C:15]=1[CH3:22]
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)cc(C)c1N
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNc1cc(Oc2cc(C)c(N)c(C)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of N-(5-chloro-2-nitrophenyl)-N-methylamine (8.00 g) in N,N-dimethylacetamide (112 ml) was added 2,6-di-t-butyl-4-methylphenol (0.24 g). Furthermore, to the resulting mixture were added 4-amino-3,5-dimethylphenol (6.47 g) and potassium t-butoxide (5.29 g) with stirring, and the resulting mixture was stirred at 60° C. for 30 minutes. After stirring, water (4 ml) was added to the reaction mixture, and furthermore water (120 ml) was added dropwise over a 2-hour interval, and then the resulting mixture was cooled gradually to room temperature. The crystalline solid precipitated was collected by filtration, washed with water (80 ml) and dried in vacuo to afford the title compound (11.45 g, yield: 93%) as a yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].ClC1C2C(=CC=C(C(C3N(C)C(C)=NC=3)O)C=2)N=C(OC)C=1CC1C=NC(C(F)(F)F)=CC=1.[F:47][C:48]([F:59])([F:58])[O:49][C:50]1[CH:57]=[CH:56][C:53]([CH:54]=O)=[CH:52][CH:51]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH2:54][C:53]1[CH:56]=[CH:57][C:50]([O:49][C:48]([F:47])([F:58])[F:59])=[CH:51][CH:52]=1)=[C:5]2[OH:13]
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Solvent: c1ccncc1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a dark solution of 6-bromo-4-hydroxyquinolin-2(1H)-one (1.0 g, 4.25 mmol, Intermediate 45: step a) and 4-(trifluoromethoxy)benzaldehyde (0.67 mL, 4.67 mmol) in pyridine (7.5 mL) was added diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.08 g, 4.25 mmol). The resulting mixture was warmed with stirring in a 100° C. oil bath for a period of 5 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue diluted with acetonitrile. The semi-solid mixture was sonicated and filtered, rinsing further with acetonitrile, to provide the title compound as a white solid.
Reaction SMILES: C(O[CH:5]1[N:9]([CH3:10])[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[O:13])=[N:7][C:6]1=[O:22])(=O)C.Cl.[CH2:24]([SH:26])[CH3:25]>CCOCC.C(#N)C>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:8]2[N:9]([CH3:10])[CH:5]([S:26][CH2:24][CH3:25])[C:6](=[O:22])[N:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CCS
Reactant: CC(=O)OC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: CCSC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Yield: 73.2 %

Procedure:
A solution of 3.00 g (9.20 mmol) of N-(5-acetyloxy-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl)-N'-(3-chlorophenyl)urea, the compound of Example 1a, in 75 ml of anhydrous ether was treated with anhydrous HCl until no more precipitation occurred. The solid was filtered, washed with anhydrous ether and suspended in a mixture of 1.8 ml (25 mmol) of ethyl mercaptan and 30 ml of acetonitrile. After heating under reflux for 1 hr, the reaction mixture was evaporated in vacuo. The crystalline residue was dissolved in THF/water and extracted with ether. The combined ether layers were washed with water to pH 5-6, dried (MgSO4) and evaporated in vacuo. Crystallization of the residue from methanol/water afforded 2.20 g (73%) of the title compound. Recrystallization from ether/hexane and finally ethanol/water gave an analytical sample mp 102°-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([F:31])=[CH:24][C:23]=1F.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O.CCCCCC>[F:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([F:31])=[CH:24][C:23]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[N:9]=[C:10]([CH3:18])[C:11]=12
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4cc(F)c([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 158 %

Procedure:
A 100 mL flask was charged with 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1.00 g, 3.71 mmol obtained from Example 5, step B), 1,2,4-trifluoro-5-nitrobenzene (1.32 g, 7.43 mmol), potassium carbonate (1.03 g, 7.43 mmol), and DMF (25 mL). The solution was allowed to stir overnight at room temperature for 3 days. The crude material was isolated by filtration and flash chromatography (EtOAc/Hexane 1:3) to afford 2.50 g (55%) of the desired product. LRMS M+1 (426.9) observed.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:12]1([NH:11][C:8]([C:5]2[CH:6]=[N:7][C:2]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:3][CH:4]=2)=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)c1ccc(Nc2ccccc2)nc1
Yield: 48.4 %

Procedure:
6-Chloro-3-pyridinecarboxylic acid (15.76 g, 0.1 mole) and aniline (9.3 g, 0.1 mole) were heated together in 50 mL xylene at 180°-185° C. (oil bath) for 3 hours. After cooling, the solid that formed was filtered and washed with Et2O. The solid was triturated with NaHCO3 solution (pH 8), then filtered to give 7.0 g (24%) of N-phenyl-6-(phenylamino)-3-pyridinecarboxamide. The aqueous NaHCO3 solution was carefully neutralized with glacial HOAc (pH 6), and the solid that precipitated was filtered and washed (H2O and with Et2O); yield 12.13 g (57%), mp 264°-266° C. MS (EI) m/e 214 (M+), 213 (M-1, base), 169 (M-45), 167 (M-47).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22].C(OCC)(=O)C.CO>C(O)C>[CH2:21]([N:23]([CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)C[C@@H]1CCCN1
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)C[C@@H]1CCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
The title compound is prepared analogously to Example 31 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (S)-(+)-2-[(diethylamino)methyl]pyrrolidine to give colorless crystals, mp. 192°-193° C. (ethyl acetate/methanol 99:1 v/v); [α]D20 =29.4° (ethanol).
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:16][CH2:17][C:18]1[CH:37]=[CH:36][C:21]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][C:26]=2[O:34][CH3:35])=[O:23])=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.Br>C(O)(=O)C>[NH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:32])[NH2:33])=[CH:27][C:26]=2[O:34][CH3:35])=[O:23])=[CH:36][CH:37]=1
Reactant: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.7 %

Procedure:
To 1.5 g of 4-amidino-2-methoxyphenyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate, was added 15 ml of acetic acid followed by 1 ml of anisole. To the mixture, while being cooled in ice, was added 3.0 ml of an acetic acid solution containing 30% of hydrogen bromide. The mixture was then stirred overnight at room temperature. The insoluble substance precipitated from the reaction mixture was collected by filtration and recrystallization from a methanol-ethyl ether mixture to obtain 1.1 g of colorless crystals of 4-amidino-2-methoxyphenyl 4-aminomethylbenzoate dihydrobromide.
Reaction SMILES: C(OP([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:20]=[CH:21][C:11]1=2)(=O)OCC)C.[H-].[Na+].[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH:36]=O>O1CCCC1>[ClH:32].[ClH:32].[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH:36]=[CH:9][C:10]1=[N:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:20]=[CH:21][C:11]1=2
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCOP(=O)(C=C1NCCN(C)c2cc(-c3cccc(OC)c3)ccc21)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3c(c2)N(C)CCN=C3C=Cc2ccc(Cl)c(Cl)c2)c1
Product: Cl
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To 100 mg (0.24 mmol) of [8-(3-methoxyphenyl)-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl]phosphonic acid diethyl ester in 2 ml of tetrahydrofuran was added 17 mg (0.42 mmol) of sodium hydride (60% dispersion in mineral oil). After 10 minutes 44 mg (0.25 mmol) of 3,4-dichlorobenzaldehyde was added and the mixture was stirred for 3 hours. The product was purified by column chromatography (20 g IST pre-packed column) eluting with 1% methanol/ethyl acetate and treated with 0.10 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated to leave a red gum which was recrystallized from ethyl acetate to give 25 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-8-(3-methoxyphenyl)-1-methyl-1H-1,4-benzodiazepine dihydrochloride as an orange solid; MS: m/e 436 (M+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]=1[C:20]1[O:21][CH:22]=[CH:23][N:24]=1.[CH3:25][N:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[N:27]1>>[O:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:4]1[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31]([C:29]1[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=1)=[O:32])=[CH:10][CH:9]=[CH:8][N:7]=2
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Reactant: Cn1cc(C(=O)O)cn1
Product: Cn1cc(C(=O)NCc2c(-c3ncco3)n(-c3ccccc3)c3ncccc3c2=O)cn1

Procedure:
Methyl-1H-pyrazole-4-carboxylic acid (2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridin-3-ylmethyl)-amide was prepared starting from intermediate B and 1-methyl-1H-pyrazole-4-carboxylic acid. MS calcd. for C23H19N6O3 [(M+H)+] 427.1, obsd. 427.2.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[NH2:27][CH:12]([C:10]1[C:9]([N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([F:1])[CH:11]=1)[CH3:13]
Reactant: CC(=O)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-fluoro-8-[(3R)-3-hydroxypyrrolidin-1-yl]quinolin-7-yl}ethanone (10 mg, 0.04 mmol) and ammonium acetate (28.1 mg, 0.364 mmol) in methanol (0.20 mL) and acetonitrile (0.21 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (4.6 mg, 0.073 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C15H19FN3O (M+H)+: m/z=276.1; Found: 276.1.