Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([Cl:21])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
To a 3-necked flask equipped with a magnetic stirrer, thermometer, and water condenser with a drying tube is added 3,5-di-t-butyl-4-hydroxybenzoic acid (12.5 g, 0.05 m), thionyl chloride (10 ml) and 5 drops of pyridine. This mixture is heated at 45° C. for 1.5 hr. After cooling to RT, 50 ml of benzene is added. After stirring for 15 min., the benzene is evaporated under water aspirator vacuum leaving a yellow solid. This is dissolved in petroleum ether (at 35°-55° C.), filtered, and evaporated to afford 11 g of a yellow solid, mp 90°-93° (lit.mp. 96°-99°).
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:32])[CH:23]([C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1)[CH3:24]>C(N(CC)CC)C.C(OCC)C.[Cu]I.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>[CH3:20][O:21][C:22](=[O:32])[CH:23]([C:25]1[CH:26]=[CH:27][C:28]([C:19]#[C:18][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=2)=[CH:29][CH:30]=1)[CH3:24]
Reactant: COC(=O)C(C)c1ccc(I)cc1
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (described in U.S. Pat. No. 6,252,090; 0.068 g, 0.27 mmol), and methyl-2-(4-iodo phenyl)propionate (Reagent 1, 0.086 g, 0.3 mmol) in triethyl amine (3 mL), was treated with copper(I)iodide (0.028 g, 0.15 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.057 g, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. It was diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated in vacuo to brown oil that was subjected to flash column chromatography over silica gel (230–400 mesh) to afford the title compound as an oil (0.072 g, 56%).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([N:20]1[C:24]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:23][C:22]([CH:29]=O)=[N:21]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([N:20]1[C:24]([CH2:25][CH:26]([CH3:27])[CH3:28])=[CH:23][C:22]([CH2:29][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[N:21]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3)CC2)nn1C(C)(C)C
Yield: 25.8 %

Procedure:
Compound 5 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[OH-].[NH4+:14]>S(Cl)(Cl)=O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:14])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)CCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-bromophenyl)propanoic acid (15.0 g) in thionyl chloride (24.5 g) was added catalytic amount of N,N-dimethylformamide (one drop) and refluxed for 1.5 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured slowly into 28% aqueous ammonium hydroxide solution (150 ml) at 0° C. The mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave 3-(4-bromophenyl)propanamide (13.7 g) as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][N:15]=[C:16]3[Cl:19])=[CH:11][CH:10]=2)[C:4]1=[O:20].C(N(CC)CC)C.[S:28]1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[S:37](Cl)(=[O:39])=[O:38]>CC#N>[Cl:19][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:37]([C:29]4[S:28][C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)(=[O:38])=[O:39])[C:4]3=[O:20])[CH:18]=2)[CH:13]=[CH:14][N:15]=1
Reactant: O=S(=O)(Cl)c1cc2ncccc2s1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ncccc3s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (0.15 g, 0.48 mmol) suspended in CH3CN (2.5 mL) is added triethylamine (0.23 mL, 1.6 mmol) followed by thieno[3,2-b]pyridine-2-sulfonyl chloride (0.14 g, 0.55 mmol). The mixture is stirred overnight, then concentrated. The residue is diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound (0.076 g, 0.16 mmol) as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1.O[Li].O.Cl>O.C1COCC1>[Cl:24][C:19]1[CH:18]=[C:17]([CH:4]([CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:11][CH2:12]2)[C:3]([OH:25])=[O:2])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: COC(=O)C(CCN1CCN(S(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN(CCC(C(=O)O)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
A mixture of 1.42 g (3.4 mmol) 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-butyric acid methyl ester and 0.182 g (4.3 mmol) LiOH.H2O in 30 mL water and 30 mL THF was heated to reflux for 1 h. The mixture was treated with 4N HCl aq. and evaporated to dryness. The residue was used without further purification in the subsequent step. MS(m/e): 395.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20](OC)(=[O:23])[CH:21]=[CH2:22].N1C=CC=CC=1>O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[C:3]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:2]3[NH:1][C:20](=[O:23])[CH2:21][CH2:22][N:6]3[N:5]=2)=[CH:8][CH:9]=1
Reactant: C=CC(=O)OC
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=C1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (1.016 g), methyl acrylate (10 ml), pyridine (20 ml) and water (5 ml) was refluxed for 8 hours. The mixture was cooled and concentrated in vacuo. The residue was dissolved in a mixture of acetic acid (10 ml) and concentrated hydrochloric acid (1.5 ml). The solution was refluxed for 2 hours, cooled and neutralized with an aqueous saturated sodium bicarbonate solution. The separated solid was collected, washed with water and dried to give 2-(4-fluorophenyl)-5-oxo-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (750 mg).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)OC(C)(C)C)=[CH:19][C:18]=2[F:31])[N:10]=3)=[O:5])[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:11]2[N:10]=[C:9]3[S:8][C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])=[N:15][C:14]3=[CH:13][CH:12]=2)=[C:18]([F:31])[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(F)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of tert-butyl [4-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-3-fluorophenyl]carbamate (0.50 g, 1.12 mmol) in trifluoroacetic acid (10 mL) was added anisole (0.5 mL), and the mixture was stirred at 0° C. for 2 hr. Trifluoroacetic acid was evaporated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→1/9) to give the title compound (294 mg, 76%) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[N:16]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH:20]1[OH:25])=[N+:17]=[N-:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N:16]([C@H:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[C:4]([N:11]3[CH:15]=[N:14][N:13]=[CH:12]3)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:21][C@H:20]1[OH:25])=[N+:17]=[N-:18]
Reactant: O=[N+]([O-])c1cc(F)cc(-n2cnnc2)c1
Reactant: [N-]=[N+]=NC1CCNCC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=N[C@H]1CCN(c2cc(-n3cnnc3)cc([N+](=O)[O-])c2)C[C@H]1O
Temperature: 100 °C
Yield: 42.6 %

Procedure:
A mixture of 4-(3-fluoro-5-nitrophenyl)-4H-1,2,4-triazole (200 mg, 0.96 mmol), 4-azidopiperidin-3-ol (164 mg, 1.15 mmol) and K2CO3 (199 mg, 1.44 mmol) in DMSO was heated at 100° C. for 4 hours. The reaction mixture was poured into water and extracted with EtOAc (two times). The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography, (SiO2, 24 g column, 0-12% MeOH/DCM) to give Intermediate 33A (135 mg, 43%) as a yellow solid. HPLC: Rt=1.722 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=331 [M+H]+.
Reaction SMILES: [OH:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:18]O>S(=O)(=O)(O)O.COC(OC)(C)C>[CH3:18][O:16][C:15]([CH:11]1[CH2:12][C:13](=[O:14])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][OH:1])=[CH:8][CH:7]=2)[CH2:10]1)=[O:17]
Reactant: CO
Reactant: O=C(O)C1CC(=O)N(c2ccc(OO)cc2)C1
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)OC
Product: COC(=O)C1CC(=O)N(c2ccc(OO)cc2)C1
Yield: 84 %

Procedure:
In a 10 1 4-necked flask equipped with a reflux condenser, a thermometer, and a mechanical stirrer, the crude (RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid is dissolved in a mixture of 5000 ml of methanol, 24 ml of concentrated sulfuric acid and 400 ml of 2,2-dimethoxypropane and stirred under reflux during 2 h. For the working-up, the reaction solution is reduced to half of its volume by distillation, then transferred into a 20 1 vessel. Under stirring at 40° C., a mixture of 2500 ml of water/ice (1:1) is added. Crystallisation started immediately, and, thereupon, the fine white crystals are collected on a filter funnel. They are washed with total 2000 ml of cold water until the filtrate, at the beginning brownish-rose, becomes colorless and neutral. The well pressed and pre-dried product from the filter funnel is dried under reduced pressure to yield 980 g (84% of theory, 2 steps) of the (RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid; MS: m/e=234 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3]([NH:5][NH2:6])=[O:4].[Cl:9][CH2:10][C:11](Cl)=[O:12]>C(OCC)(=O)C>[Cl:9][CH2:10][C:11]([NH:6][NH:5][C:3](=[O:4])[C:2]([CH3:8])([CH3:7])[CH3:1])=[O:12]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)C(=O)NN
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NNC(=O)CCl

Procedure:
5.8 g (49.929 mmol) of 2,2-dimethylpropanehydrazide were dissolved in 600 ml of dry ethyl acetate and heated to reflux. 6.767 g (59.915 mmol) of chloroacetyl chloride, dissolved in 45 ml of dry ethyl acetate, were added dropwise to the solution. The mixture was stirred under reflux for 30 min. After cooling, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 10.14 g of the title compound. The crude product was reacted further without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[N:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:13]O>>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([NH2:11])[N:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(C(=O)O)cc(N)n1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(N)nc(N)c1
Yield: 77 %

Procedure:
A suspension of 11 g (70 mmol) 2,6-diamino-isonicotinic acid in 270 ml methanol was treated at 0° C. for 2 h with gaseous HCl. The mixture was concentrated, the residue was dissolved in water and saturated NaHCO3 was added to pH=8. Exhaustive extraction with ethylacetate, drying of the combined organic phases with MgSO4 and removal of the volatiles yielded 9.3 g (77%) 2,6-diamino-isonicotinic acid methyl ester as yellow solid.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([Br:42])=[C:27]([C:29]2[CH2:33][C:32]([CH2:38]C(O)=O)([CH2:34][C:35]([OH:37])=[O:36])[O:31][N:30]=2)[CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([Br:42])=[C:27]([C:29]2[CH2:33][C:32]([CH2:38][C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])([CH2:34][C:35]([O:37][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:36])[O:31][N:30]=2)[CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)CC1(CC(=O)O)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
1,1-Di-tert-butoxy-N,N-dimethylmethanamine (22.11 g) was added dropwise to a mixture of 2,2′-(3-(5-(benzyloxy)-2-bromophenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetic acid (9.75 g) and toluene (100 mL) at 100 C, and the obtained mixture was stirred at 100 C for 30 minutes. Further, 1,1-di-tert-butoxy-N,N-dimethylmethanamine (5.53 g) was added thereto, and the obtained mixture was stirred at 100 C for 30 minutes. Further, 1,1-di-tert-butoxy-N,N-dimethylmethanamine (2.211 g) was added thereto, and the obtained mixture was stirred at 100 C for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then, the residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was washed with hexane to obtain the title compound (5.73 g).
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[Li+].[C:9]([NH:12][NH2:13])([NH2:11])=[NH:10].Cl.C(O)C>O>[C:9]([NH:12][N:13]=[C:3]([CH3:5])[CH2:2][C:1]([OH:7])=[O:6])(=[NH:10])[NH2:11]
Reactant: CC(=O)CC(=O)[O-]
Reactant: N=C(N)NN
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: CC(CC(=O)O)=NNC(=N)N
Reaction time: 24 h

Procedure:
Lithium acetoacetate (0.655 g) in 2 ml water was treated with 0.665 g aminoguanidine HCl in 1.33 ml water. The solution was heated to reflux over 30 minutes and then allowed to cool. Ethanol (10 ml) was added and the mixture was stored at -20° C. for 24 hrs., then at 4° C. for 24 hrs. The mixture was allowed to reach room temperature and filtered. The filtrate was concentrated to a paste and triturated with 5 ml ethanol. Filtration and washing with ethanol gave 0.522 to the hydrazone as a microcrystalline powder, melting point 138.6°-140° C.
Reaction SMILES: [O:1]([CH2:19][C:20]([CH:23]1[CH2:32][CH:31]([O:33][CH2:34][CH3:35])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([N+:36]([O-:38])=[O:37])[CH:29]=2)[NH:24]1)([CH3:22])[CH3:21])[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:34]([O:33][CH:31]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([N+:36]([O-:38])=[O:37])[CH:29]=2)[NH:24][CH:23]([C:20]([CH3:21])([CH3:22])[CH2:19][OH:1])[CH2:32]1)[CH3:35]
Reactant: CCOC1CC(C(C)(C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Nc2ccc([N+](=O)[O-])cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC1CC(C(C)(C)CO)Nc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
The compound of Example 1 (34 mg) was dissolved in 1.0 ml of tetrahydrofuran, and 1.2 ml of a 1M tetrahydrofuran solution of tetrabutylammonium fluoride was added at 0° C. After overnight stirring at room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=3:1−1:1−1:2) to obtain 14 mg of the title compound. Its physical properties are shown below.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])=[C:17]([CH3:19])[CH:18]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>>[CH3:19][C:17]1[CH:18]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:28]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[C:7]=3[CH2:8]2)[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)C(F)F
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)C(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (220 mg, yellow oil) from 4-chloro-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.62 mmol, Intermediate-68) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=1)[C:5]([NH2:7])=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=1)[CH2:5][NH2:7]
Reactant: NC(=O)c1cc(Cl)cc(CO)c1
Solvent: C1CCOC1
Product: NCc1cc(Cl)cc(CO)c1

Procedure:
Step N5. To 3-chloro-5-(hydroxymethyl)benzamide (0.7 g, 3.77 mmol) in THF (20 mL) was added borane-dimethylsulfide complex (0.9 g, 11.8 mmol) slowly. The mixture was refluxed for 20 hours. Excess borane reagent was quenched with methanol and solvent was removed by rotovap. The resulting residue was purified by column with dichloromethane/methanol (1:1) as the eluant. 3-chloro-5-(hydroxymethyl)benzylamine was obtained in white solid (240 mg, 37%). 1H NMR (300 MHz, CD3OD): δ 3.81 (s, 2H), 4.61 (s, 2H), 7.25 (s, 1H), 7.28(s, 1H), 7.59, 7.30(s, 1H). MH+=172.08.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[O:3]1.[CH2:20]([N:22]([CH2:37][CH3:38])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:21].N1CCCCC1>CCO>[CH2:37]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31](/[CH:34]=[C:12]2\[C:13](=[O:18])[NH:14][C:15]3[C:11]\2=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:19])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:17][CH:16]=3)[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:38]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc32)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (195 mg, 0.75 mmol) in EtOH (3 ml) was added N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (200 mg, 0.76 mmol) and piperidine (82 μL, 0.83 mmol). The mixture was stirred at 80° C. for 1 hour. After cooled down to room temperature, the reaction mixture was concentrated, filtrated, and washed with EtOH to give (Z)—N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-3-ylidene)methyl)-1H-pyrrole-3-carboxamide (218 mg) as yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:11][CH:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>CS(C)=O>[N:22]1([C:2]2[C:3]([N:8]3[CH2:11][CH:10]([C:12]4[CH:21]=[CH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Clc1nccnc1N1CC(c2ccc3ccccc3n2)C1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: c1ccc2nc(C3CN(c4nccnc4N4CCCCC4)C3)ccc2c1
Temperature: 150 °C
Yield: 29.4 %

Procedure:
To a mixture of 2-[1-(3-chloro-pyrazin-2-yl)-azetidin-3-yl]-quinoline (150 mg, 0.51 mmol) and piperidine (43.35 mg, 0.51 mmol) was added DMSO (2 mL) and triethylamine (0.05 g, 0.50 mmol). The solution was heated to 150° C. under microwave for 3 h. Then the mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (20 mL) and brine (60 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in hexanes) to give the title product (50 mg, 0.15 mmol, 28% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11](O)=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(N)([NH2:20])(=O)=O.N1C=CC=CC=1>O>[CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]([NH2:20])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: NS(N)(=O)=O
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)c2nc[nH]c12
Solvent: c1ccncc1
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(C(N)=O)c2nc[nH]c12
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A mixture of 7-Methyl-6-nitro-1H-benzimidazole-4-carboxylic Acid (23) (0.692 g, 3.12 mmol), sulfamide (0.600 g, 6.26 mmol), and pyridine (8 mL) is heated at reflux for about 16 hours. The resulting heterogeneous reaction mixture is cooled to ambient temperature, diluted with water (10 mL) and cooled to 0° C. for 1 hour. The solids that form are filtered, washed with water (10 mL) and methanol (10 mL), and dried to obtain 7-Methyl-6-nitro-1H-benzimidazole-4-carboxamide (25) as a cream colored solid (0.586 g, 85% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:10][C:2]1=2.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([Br:31])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([Br:31])[C:28]=1[O:29][CH3:30])[C:23]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:10][C:2]1=2)=[O:24]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: N#Cc1ccc(-c2cnc3c(c2)NCCO3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(C#N)cc4)cc32)cc1Br
Yield: 75.6 %

Procedure:
By the same method as in the step c) of Example 45, 4-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-benzonitrile (71.4 mg, 0.30 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (148 mg, 0.45 mmol) and triethylamine (84 μl, 0.60 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature for 3 hours to obtain 4-[1-(3,5-dibromo-4-methoxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-benzonitrile as white solid (120 mg, 75.6%).