Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[NH2:8].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[NH:8][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]=1
Reactant: Clc1cccc(-c2ccccc2)n1
Reactant: Cn1ncc(Br)c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc(Br)c1Nc1cccc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
4-Bromo-2-methyl-2H-pyrazol-3-ylamine (0.2 g, 1.14 mmol) and 2-chloro-6-phenyl-pyridine (0.32 g, 1.7 mmol) were dissolved in DMF (5 mL) then sodium hydride (60% dispersion in oil, 0.09 g, 2.3 mmol) was added. The reaction was heated to 100° C. for 30 minutes then cooled and submitted to standard aqueous workup. The residue was purified on silica gel (0-40% EtOAc in hexanes) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:31]>P(Cl)(Cl)(Cl)=O>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[NH:13][C:3]3[C:4](=[O:12])[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([Cl:31])=[N:7][C:2]=3[N:1]=2)=[CH:16][CH:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)[nH]c2c1=O
Yield: 30.2 %

Procedure:
The above N-(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-benzyloxy-benzamide (1.0 g, 0.0025 mol) and phosphorous pentachloride (0.64 g, 0.0025 mol) were taken in phosphorous oxy chloride (25 ml) and refluxed for 20 hours The mixture was cooled and solvent was removed. The residue was dissolved in water (20 ml) and extracted with DCM. (3×5 ml). The organic layer was washed with sat. NaHCO3 (30 ml) followed by saturated brine solution (2×30 ml) and dried over Na2SO4. Solvent was removed and the residue was further purified by column chromatography to obtain pure 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.298 g, 30%) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]1.[CH3:18][C:19]1[N:24]=[C:23]([SH:25])[N:22]=[C:21]([OH:26])[CH:20]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)[C:3]=1[CH2:2][S:25][C:23]1[N:22]=[C:21]([OH:26])[CH:20]=[C:19]([CH3:18])[N:24]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCN1CCN(c2cccc(Cl)c2CBr)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1CCN(c2cccc(Cl)c2CSc2nc(C)cc(O)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
A mixture of 1-[2-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine (24.8 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (2.35 g, 16.5 mmol), and triethylamine (17 mL, 124 mmol) in absolute ethanol (300 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered and evaporated. The solid residue was treated with water (500 mL). The mixture was extracted with DCM (3×200 mL) and EtOAc (1×200 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-20% MeOH/DCM and 0-15% MeOH/DCM), affording 2-({[2-chloro-6-(4-ethylpiperazin-1-yl)phenyl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (505 mg, 5% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.00 (t, 3H, J=7.2 Hz), 2.24 (s, 3H), 2.85 (m, 2H), 2.50 (m, 4H), 2.87 (m, 4H), 4.67 (s, 2H), 6.02 (s, 1H), 7.22 (m, 2H), 7.32 (t, 1H, J=8.0 Hz); M+379.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[F:8][C:9]([F:38])([F:37])[O:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C@:16]23[CH2:23][C@H:22]([NH2:24])[CH2:21][N:20]2[C:19](=[O:25])[N:18]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:38][C:9]([F:37])([F:8])[O:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C@:16]23[CH2:23][C@H:22]([NH:24][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:21][N:20]2[C:19](=[O:25])[N:18]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: CCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
Valeryl chloride (0.031 g) was added to a solution of the compound from Example 63 (0.1 g) and DIEA (0.84 g) in THF (5 mL) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was concentrated and the residue was purified via HPLC (CH3CN/0.1 M AcOH) to yield 0.075 g of the titled compound. MS (m/z) 559 (MH+) and 581 (MNa+). mp 66.8° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH2:1]([O:8][C:9](=[O:10])[CH2:11][S:12](=[O:14])(=[O:13])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][C:27](=[O:30])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CS(=O)(=O)Cl)OCc1ccccc1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: O=C1CCN(c2ccc(NS(=O)(=O)CC(=O)OCc3ccccc3)cc2)CC1

Procedure:
The title compound was prepared from benzyloxycarbonylmethylsulfonylchloride (J. Antibiot., 1994, 47, 1041) and 1-(4-amino-phenyl)-piperidin-4-one (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.42 (t, J=6.0 Hz, 4 H), 3.55 (t, J=6.0 Hz, 4 H), 4.16 (s, 2 H), 5.16 (s, 2 H), 6.99 (d, J=9.0 Hz, 2 H), 7.10 (d, J=9.0 Hz, 2 H), 9.73 (s, 1 H); MS (ES) m/z: 403.2 (MH+); HRMS Calcd. for C20H22N2O5S(M+): 402.1250. Found: 402.1237.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH3:23])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1](=[N:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH2:23][Br:24])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(C#N)ccc1N=C(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(N=C(c2ccccc2)c2ccccc2)c(CBr)c1
Yield: 56.9 %

Procedure:
To a solution of 4-(benzhydrylidene-amino)-3-methyl-benzonitrile (1.36 g, 4.27 mmol) in 40 mL of CCl4 is added N-bromosuccinimide (0.84 g, 4.7 mmol) and benzoyl peroxide (0.22 g, 0.64 mmol). The solution is heated to reflux for 16 h. The solution is cooled to ambient temperatures. The solution is diluted with CH2Cl2. The solution is washed with 1N NaOH and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude material is purified by column chromatography eluting with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes. The title compound (0.91 g, 2.43 mmol) is obtained as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:15]=[C:16]([F:18])[CH:17]=2)[O:9][N:8]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Fc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
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: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: Fc1cc(-c2cccnc2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 19.1 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (102 mg, 0.624 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 35.8 mg, 0.031 mmol), in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (3 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with chloroform, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 19 mg (19%) 3-(2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): 8.92 (s, 1H), 8.84 (d, 1H), 8.70 (d, 1H), 8.39 (s, 1H), 8.25 (d, 1H), 8.00 (m, 2H), 7.90 (td, 1H), 7.65 (m, 1H), 7.55 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:12]=[CH:13][NH:14][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:29])=CC=1>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:12][C:13](=[S:29])[NH:14][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: c1nc(Cc2ccc3c(c2)OCO3)c[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: S=c1[nH]cc(Cc2ccc3c(c2)OCO3)[nH]1
Reaction time: 3 h

Procedure:
A solution of 4-benzo[1,3]dioxol-5-ylmethyl-1H-imidazole (Intermediate D4) (0.24 g, 1.18 mmol) in THF (4 mL) and water (4 mL) was treated with NaHCO3 (1 g, 11.9 mmol) at rt for 10 m. Phenyl chlorothionoformate (0.42 mL, 3.1 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (3×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (8 mL) and treated with NEt3 (1 mL) for 16 h. The solvent was removed under vacuum and the product was washed on a glass frit with 50% CH2Cl2:hexanes to give a white solid (˜36%) 4-benzo[1,3]dioxol-5-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 5)
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][OH:16])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH3:3].[O:17]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]1[C:19]([O:21][CH3:22])=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[OH:17][CH:18]([C:23]([O:16][CH2:15][CH2:14][N:4]([CH2:1][CH2:2][CH3:3])[S:5]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: CCCN(CCO)S(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCN(CCOC(c1ccccc1)(c1ccccc1)C(O)C(=O)OC)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.3 g (30 mmol) of N-propyl-N-(2-hydroxyethyl)benzenesulfonamide and 7.6 g (30 mmol) of methyl 2,3-epoxy-3,3-diphenylpropionate were dissolved in 40 ml of methylene chloride and, with ice-cooling, 0.57 g (3 mmol) of p-toluenesulfonic acid was added. The reaction mixture was stirred at room temperature for 24 hours and then diluted with methylene chloride and extracted with 2M aqueous sodium hydroxide solution, the organic phase was separated off and dried over sodium sulfate and the solvent was distilled off. The residue (12.0 g of an oil) was directly reacted further.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([C:16]1[O:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([CH3:15])[CH2:12][CH:13]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:13]/[CH2:12][C:11]([CH3:15])([C:16]1[O:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: Cc1ccc(C(C)(C)CC=O)o1
Solvent: ClCCl
Product: Cc1ccc(C(C)(C)C/C=N/CC(=O)OC(C)(C)C)o1
Yield: 101.4 %

Procedure:
Step F In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.79 g, 6 mmol) was reacted with 3-methyl-3-(5-methyl-furan-2-yl)-butyraldehyde 1 g, 6 mmol) in CH2Cl2 at room temperature for 5 h to give [3-methyl-3-(5-methyl-furan-2-yl)-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.7 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[F:15][C:16]1[CH:30]=[C:29]([CH2:31][OH:32])[CH:28]=[C:27]([F:33])[C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23]>CN(C=O)C>[F:15][C:16]1[CH:30]=[C:29]([CH2:31][O:32][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)[CH:28]=[C:27]([F:33])[C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cccc(Oc2c(F)cc(CO)cc2F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3cccc(C#N)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (60 mg, 0.323 mmol), sodium hydride (25.9 mg, 0.647 mmol) and 3-(2,6-difluoro-4-(hydroxymethyl)phenoxy)benzonitrile (84 mg, 0.323 mmol) in DMF (2 mL).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:19])[C:3]=1[C:20](=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.[NH2:30][NH2:31].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:21]([C:20]1[C:3]2[C:4](=[O:19])[N:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]3[N:7]=[C:8]([CH3:12])[CH:9]=[CH:10][C:11]=3[C:2]=2[NH:31][N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NN
Reactant: Cc1ccc2c(O)c(C(=O)Cc3ccccc3)c(=O)n(-c3ccccc3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c3[nH]nc(Cc4ccccc4)c3c(=O)n(-c3ccccc3)c2n1
Temperature: 105 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-7-methyl-1-phenyl-3-phenylacetyl-1,8-naphthyridin-2(1H)-one (370 mg, 1.0 mmol) produced in Synthesis Example 3 in DMF (8 mL) was added hydrazine monohydrate (purity of 80%, 160 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-benzyl-7-methyl-5-phenyl-1H-pyrazolo [4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (281 mg, yield 83%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=4)[CH:18]=3)(=[O:16])=[O:15])[CH2:10][C:9]2=[O:28])=[CH:5][CH:4]=1.Cl.[C:32](=[NH:37])(OCC)[CH3:33].C(N(CC)CC)C>CO>[ClH:27].[C:32]([NH:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=4)[CH:18]=3)(=[O:15])=[O:16])[CH2:10][C:9]2=[O:28])=[CH:5][CH:4]=1)(=[NH:37])[CH3:33]
Reactant: Nc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=N)Nc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
To a solution of 1-(4-aminobenzyl)-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (233 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (618 mg) and triethylamine (0.836 ml), and the mixture was stirred at room temperature overnight. The solvent was concentrated and purified with CHP20 column chromatography (water:acetonitrile:1 N hydrochloric acid=70:30:1) to give pale yellow amorphous of the title compound (134 mg).
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:9][C:10]1([CH3:26])[S:14][C:13]2[C:15]([CH2:24][OH:25])=[C:16]3[S:20][C:19]([CH3:22])([CH3:21])[S:18][C:17]3=[CH:23][C:12]=2[S:11]1.C([Li])CCC.CCCCCC.[CH3:38][Si:39]([CH3:42])([CH3:41])Cl>C(OCC)C>[CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:38][Si:39]([CH3:42])([CH3:41])[C:23]1[C:12]2[S:11][C:10]([CH3:26])([CH3:9])[S:14][C:13]=2[C:15]([CH2:24][OH:25])=[C:16]2[C:17]=1[S:18][C:19]([CH3:21])([CH3:22])[S:20]2
Reactant: CC1(C)Sc2cc3c(c(CO)c2S1)SC(C)(C)S3
Reactant: C[Si](C)(C)Cl
Agent: NC(CO)(CO)CO
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)Sc2c(CO)c3c(c([Si](C)(C)C)c2S1)SC(C)(C)S3
Temperature: 0 °C
Reaction time: 3 h
Yield: 138.5 %

Procedure:
Compound 1d (0.15 g, 0.17 mmol) was dissolved in dry diethyl ether (5 mL) and tetrametyhlethylendiamine (0.26 mL, 1.69 mmol) was added under argon atmosphere. The mixture was cooled at 0° C., n-butyl lithium 2.5 M in hexane (0.68 mL, 1.69 mmol) was added drop wise over 10 min and the mixture was left to reach RT. After stirring for 3 h at RT, the resulting brown solution was added drop wise at 0° C. to a solution of trimethylchlorosilane (0.65 mL, 5.08 mmol) in diethyl ether (2 mL). The solution was stirred at RT for 4 h and the formation of a white solid was observed. The solid was filtered off, washed with diethyl ether and the organic solution was concentrated under vacuum. The crude product was purified by gravimetric chromatography on silica gel eluting with 15:1 hexanes-ethyl acetate to afford the title compound as an orange powder (0.12 g).
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:6]=1[C:7]([NH2:9])=[NH:8].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>>[ClH:1].[NH2:8][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH3:3])[NH:14][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:9]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: COc1cccc(N)c1C(=N)N
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(cccc1OC)N2

Procedure:
This was prepared by the method of Example 173 using 2-methoxy-6-aminobenzamidine dihydrochloride (Example E) and ethyl 4-oxopiperidine-1-carboxylate to give the title compound as a yellow solid, MS (+CI) 319 ([M+H]+), 1H NMR (d6 -DMSO) 9.97 (1H, s), 8.69 (1H, s), 8.64 (1H, s), 7.70 (1H, s), 7.40 (1H, dd), 6.48 (1H, d), 6.42 (1H, d), 4.05 (2H, q), 3.88 (3H, s), 3.6-3.72 (2H, m), 3.4-3.55 (2H, m), 1.85-2.0 (2H, m), 163-1.80 (2H, m), 1.19 (3H, t).
Reaction SMILES: Br[CH:2]([CH3:5])[C:3]#[N:4].[CH3:6][C:7]1([CH3:18])[O:12][C:11](=[O:13])[NH:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:6][C:7]1([CH3:18])[O:12][C:11](=[O:13])[N:10]([CH2:5][CH2:2][C:3]#[N:4])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2
Reactant: CC1(C)OC(=O)Nc2ccccc21
Reactant: CC(Br)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OC(=O)N(CCC#N)c2ccccc21

Procedure:
10.2 mL (123 mmol) of bromopropionitrile is added dropwise to a solution of 20.0 g (112 mmol) of 4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 17.4 g (126 mmol) of potassium carbonate in 250 mL of acetonitrile and the mixture is refluxed overnight. Another 4 mL (48 mmol) of bromopropionitrile is added and the mixture is refluxed for another 2 hours. The solid is suction filtered, the filtrate is evaporated down, and the residue is recrystallized from diisopropylether. White solid. Yield: 22.8 g (88%); mass spectroscopy: [M+H]+=231.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:21]4[CH2:26][CH2:25][CH:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23][CH2:22]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:21]4[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23][CH2:22]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(c2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
tert-Butyl (1-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-8-yl)piperidin-4-yl)methylcarbamate (97 mg, 0.204 mmol) was weighed into a flask and dissolved in 10 mL of anhydrous DCM. TFA (314 μL, 4.07 mmol) was added and the reaction was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo, followed by trituration with anhydrous Et2O, affording the desired product (43 mg, 0.114 mmol, 56.1% yield) as a yellow solid. APCI (+) m/z 377 (M+1) detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([NH2:26])[CH:25]=1)[NH:22][CH:21]=[CH:20]2.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH:37][C:38]1([CH2:43][OH:44])[CH2:42][CH2:41][CH2:40][CH2:39]1)(=[O:36])=[O:35]>>[NH2:26][C:24]1[CH:25]=[C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:28]3[C:29]([S:34]([NH:37][C:38]4([CH2:43][OH:44])[CH2:42][CH2:41][CH2:40][CH2:39]4)(=[O:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:7][C:2]=2[F:1])[CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2
Reactant: CC1(C)OB(c2ccc(-c3cc(N)c4[nH]ccc4c3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(NC1(CO)CCCC1)c1ccccc1Br
Product: Nc1cc(-c2ccc(-c3ccccc3S(=O)(=O)NC3(CO)CCCC3)cc2F)cc2cc[nH]c12

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indol-7-amine and 2-bromo-N-(1-(hydroxymethyl)-cyclopentyl)benzene-sulfonamide in Step B. MS (ESI): mass calcd. for C26H26FN3O3S, 479.17; m/z found, 480.3 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, J=8.1, 1.4, 1H), 8.13 (s, 1H), 7.65-7.50 (m, 3H), 7.42 (s, 1H), 7.41-7.31 (m, 3H), 6.87 (m, 1H), 6.61 (dd, J=3.1, 2.0, 1H), 4.05 (s, 1H), 3.48 (s, 2H), 1.50-1.34 (m, 4H), 1.37-1.22 (m, 2H), 0.93-0.73 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>P(Cl)(Cl)(Cl)=O>[N:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:1][C:15]=1[C:14]1[CH:18]=[CH:19][C:11]([O:10][CH3:9])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=1
Reactant: Nc1cccnc1N
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3cccnc3[nH]2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
2,3-Diaminopyridine (10 g, 91.6 mmol) and 18.07 g of 4-methoxy-3-nitro benzoic acid were mixed together, and the mixture was added in portions to 200 mL of phosphorous oxychloride at. room temperature. The resulting mixture was heated to reflux for 4 hours, and then cooled to room temperature and allowed to stir overnight. The reaction was rotary evaporated in vacuo, and the residue was carefully quenched with saturated sodium bicarbonate solution, filtered, and dried on the vacuum filter overnight to give a brown solid. The solid was washed with several fractions of ethyl acetate to yield 21.36 g of 5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-nitrobenzene as a dark brown solid that was used without further purification. 1H-NMR (DMSO-d6); δ 8.71 (d, 1H), 8.48 (dd, 1H), 8.31 (dd, 1H), 7.99 (d, 1H), 7.58 (d, 1H), 7.23 (dd, 1H), 4.00 (s, 3H) ppm.