Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](O)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CC(C)=O>[C:13]([O:1][CH2:2][C@@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@@H:9]([OH:10])[CH:11]=[O:12])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCC(=O)O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O
Yield: 100.2 %

Procedure:
2 ml of acetone were added to the reactor which contained 100 mg of Novozim 435, 60 mg of glucose and 200 mg of lauric acid. The reaction was carried out under mild continual agitation at 40° C. and water was continually removed from the reaction medium. 121 mg of glucose 6-monolaurate were obtained after 3 days of reaction corresponding to a yield of 99%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=3[CH:25]([CH3:27])[CH3:26])=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].S(OC)(O[CH3:34])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[CH:25]([C:16]1[CH:17]=[C:18]([C:21]([F:23])([F:22])[F:24])[CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][N:1]2[CH3:34])=[O:12])([CH3:27])[CH3:26]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)c1cc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2c1cnn2C
Reaction time: 1.5 h

Procedure:
To a solution of Example 4C (0.468 g, 2.2 mmol) in DMF (6 mL) was added NaH (0.104 g, 2.6 mmol) and the mixture was stirred for 90 minutes. Dimethyl sulfate (Me2SO4, 0.22 mL, 2.3 mmol) was added, and the mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (1200 mL), washed sequentially with H2O (400 mL) and brine (400 mL), dried (Na2SO4), filtered, concentrated under reduced pressure, and purified by chromatography (75% diethyl ether/Hexanes to 100% diethyl ether) to provide the title compound. 1H-NMR (DMSO-d6) δ 8.81 (s, 1H), 8.04 (s, 1H), 7.64 (d, 1H), 7.60 (s, 1H), 7.55 (m, 2H), 7.25 (t, 1H), 7.14 (d, 1H), 6.81 (t, 1H), 4.49 (d, 2H), 3.99 (s, 3H), 3.30 (m, 1H), 1.25 (d, 6H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[C:9]([O:16]C)[CH:10]=[CH:11][C:12]=2[O:14]C)[N:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[N+]([O-])([O-])=O.[NH4+].[Ce]>CC#N>[N+:1]([C:4]1[C:13]2[C:12](=[O:14])[CH:11]=[CH:10][C:9](=[O:16])[C:8]=2[N:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(OC)c2c([N+](=O)[O-])ccnc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1C=CC(=O)c2c([N+](=O)[O-])ccnc21
Reaction time: 0.25 h

Procedure:
400 mg (1.71 mmol) of 4-nitro-5,8-dimethoxyquinoline are dissolved in 10 mL of CH3CN and 5 mL of water at room temperature. 2.8 g (5.2 mmol) of cerium ammonium nitrate are added and the reaction medium is stirred for 15 min. After evaporating off the CH3CN on a rotary evaporator, 10 mL of water are added and the medium is extracted with CH2Cl2 (3 times 20 mL). After drying the organic phases and evaporating off the solvent on a rotary evaporator, 290 mg of 4-nitroquinoline-5,8-dione are obtained in the form of an orange powder.
Reaction SMILES: [C:1]1([CH3:37])[C:2]([NH:7][C:8]2[O:9][C:10]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].C[Sn+](C)C>ClCCCl.C(Cl)Cl>[C:1]1([CH3:37])[C:2]([NH:7][C:8]2[O:9][C:10]([C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:26][CH2:25]4)=[CH:22][CH:23]=3)=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(Nc2ccccc2C)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccccc1Nc1nc(C(=O)O)c(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)o1
Temperature: 80 °C
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(4-(2-(o-toluidino)-4-(ethoxycarbonyl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.042 g, 0.08 mmol) in DCE (2 ml) was added trimethyltin hydroxide (0.140 g, 0.77 mmol) and the resulting mixture was heated at 80° C. overnight. The reaction was cooled to room temperature and diluted with DCM. The organic phase was washed with water. The combined aqueous phase was extracted with DCM and the combined organic phase dried over MgSO4 and the solvent removed in vacuo to afford 2-(o-toluidino)-5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)oxazole-4-carboxylic acid (0.038 g, 0.08 mmol, 96%). LCMS (1) Rt: 1.89 min; m/z (ES+) 479.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([CH:20]=[CH2:21])=[CH2:19]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[O:15][C:18]([O:17][CH3:16])([CH3:19])[CH2:20][CH2:21]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: C=CC(=C)OC
Solvent: c1ccccc1
Product: COC1(C)CCc2cc(OCc3ccccc3)ccc2O1

Procedure:
A mixture of 40g. of p-(benzyloxy)phenol, 33.6 g. of 2-methoxybutadiene, and 30 ml. of benzene was sealed in a glass tube under N2. The tube was heated at 160°-165° for 20 hours, cooled and opened. The yellow solution was chromatographed on silica gel with 97.5:2.5 benzene-ethyl acetate to give (±)-6-benzyloxy-2-methoxy-2-methylchroman, identical with the material prepared as described in Example 44, as 34.5 g. of pale yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:15]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[CH:34]=3)(=[O:32])=[O:31])([CH:17]3[CH2:29][C:20]4[NH:21][C:22]5[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][C:27]=5[C:19]=4[CH2:18]3)[F:16])=[N:13][N:14]=2)=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[Br:39][C:35]1[CH:34]=[C:33]([S:30]([C:15]([CH:17]2[CH2:29][C:20]3[NH:21][C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][C:27]=4[C:19]=3[CH2:18]2)([F:16])[C:12]2[O:11][C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=3)=[N:14][N:13]=2)(=[O:32])=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(-c2nnc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3cccc(Br)c3)o2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc(Br)c1)C(F)(c1nnc(-c2ccc(CO)cc2)o1)C1Cc2[nH]c3ccc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 12 mg (0.02 mmol) of (RS, SR) 4-[5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,3,4]oxadiazol-2-yl}-benzoic acid methyl ester in 0.5 mL of THF was treated with 3 mg (0.08 mmol) of lithium aluminiumhydride and stirred at RT for one hour. The mixture was treated with a mixture of ice cubes and water and extracted twice with dichlormothane. Drying of the combined organic phases over Na2SO4, filtration and evaporation gave 10 mg (86%) of (RS, SR) (4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,3,4]oxadiazol-2-yl}-phenyl)-methanol as a yellow solid, MS: 618 (MH+, 1Br).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.[CH3:13][C@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].S1C=CC=C1>C1(C)C=CC=CC=1.[Rh]>[C:15]1([CH:14]([NH:21][CH:5]2[CH:6]3[CH2:11][C:2]4([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]2[CH2:3]4)[CH2:7]3)[CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: [Rh]
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: c1ccsc1
Solvent: Cc1ccccc1
Product: CC(NC1C2CC3CC1CC(O)(C3)C2)c1ccccc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Commercially available 5-hydroxyadamantan-2-one (0.1 mol), L(-)-Alpha-methyl-benzyl amine (0.105 mol), aluminium isopropoxide (0.1 mol) and Rhodium on active carbon (20 mol %) were suspended in 500 ml of toluene, 20 ml of the 4% thiophene solution were added. The reaction mixture was stirred at 50° C. for 24 h.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25][C:26]1[C:27]([N+:37]([O-:39])=[O:38])=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29](O)=[O:30].ClCCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:26]([OH:25])[C:27]=1[N+:37]([O-:39])=[O:38]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 73.7 %

Procedure:
6.5 g of L-proline methyl ester and 10.5 g of N,N'-dicyclohexylcarbodiimide were successively added to an ice-cooled and constantly stirred solution of 10.7 g of 3-hydroxy-4-methoxy-2-nitrobenzoic acid dissolved in a mixture consisting of 180 ml of dichloromethane and 15 ml of N,N'-dimethylformamide, and then the same treatment as in Example 1 was carried out. Thus, there was obtained 12 g of 1-(3-hydroxy-4-methoxy-2-nitrobenzoyl)-L-proline methyl ester as a yellow-colored prismatic crystal having melting point of 108° to 110° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH3:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate (798 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromopropane (301 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (161 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.Cl.Cl.[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:24]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: N[C@@H]1CCN(Cc2ccc(F)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccc(F)cc3)C2)cn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
A mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg, 1.41 mmol), (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (565 mg, 2.11 mmol) and triethylamine (928 mg, 9.17 mmol) was stirred at 100° C. for 6 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (35% EtOAc/hexane˜50% EtOAc/hexane) to give ethyl (2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (245 mg, 47%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH:22]1[CH2:25][CH:24]([C:26]#[N:27])[CH2:23]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:22]3[CH2:25][CH:24]([C:26]#[N:27])[CH2:23]3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: N#CC1CNC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 31.1 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), azetidine-3-carbonitrile (2.7 mg, 0.032 mmol), 4-methylmorpholine (4.93 mg, 0.049 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a semi-solid (3.7 mg, 30.6%). 1H NMR (400 MHz, CD3OD) δ 0.94 (t, J=6.32 Hz, 3 H) 1.07 (dd, J=18.19, 6.32 Hz, 3 H) 2.44-2.59 (m, 1 H) 3.47-3.79 (m, 1 H) 4.15-4.40 (m, 2 H) 4.57 (dt, J=9.73, 4.99 Hz, 1 H) 4.63-4.78 (m, 1 H) 4.84 (d, J=19.71 Hz, 1 H) 5.06-5.30 (m, 2 H) 7.82 (d, J=11.37 Hz, 1 H) 8.25 (d, J=5.56 Hz, 1 H). [M+H] calc'd for C18H18ClN5O2, 372; found, 372.4.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC(=O)C=Cc1cc(C)ccc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: Cc1ccc(F)c(C2CC(=O)CC(=O)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (1.4 g) was added at room temperature diethyl malonate (3.3 g) and then was added little by little 4-(2-fluoro-5-methylphenyl)-3-buten-2-one (3.5 g), and the reaction mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (11 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (11 ml) for 5 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered, washed with water and isopropylether to give 5-(2-fluoro-5-methylphenyl)cyclohexane-1,3-dione (1.6 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].[N:12]1[CH:17]=CC=NN=1>CCO.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[NH:12][CH:17]=[N:11]2
Reactant: c1cnnnc1
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=c1[nH]cnc2cccc(Cl)c12
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of 6-chloro anthranilic acid (2.12 g, 12.3 mmol) and triazine (1.0 g, 12.3 mmol) in EtOH (40 mL) containing piperidine (3 drops) was heated under reflux with stirring for 8 h. On cooling crystals formed, which were filtered to yield 5-chloroquinazolin-4-one (1.55 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:17]([F:19])[F:18])=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12]C(C)(C)C)=[O:11])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:17]([F:18])[F:19])=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Cl)ccc1C(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1cc(Cl)ccc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of Intermediate 14B (232 mg, 0.804 mmol) in DCM (2.0 mL) was added TFA (2.0 mL, 26.0 mmol). The reaction was stirred under argon at rt. After 1 h, the solvent was removed and residue was dried to give Intermediate 14 (191 mg, 100%) as tan solid. 1H NMR (400 MHz, MeOD) δ 7.99 (dt, J=15.8, 1.5 Hz, 1H), 7.83 (s, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.55-7.48 (m, 1H), 7.01 (t, J=54.6 Hz, 1H), 6.51 (d, J=15.8 Hz, 1H). 19F NMR (376 MHz, MEOD) δ −111.67 (s, 2F) ppm. MS (ESI) m/z: 233.1 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(OCC)(=O)C>C(Cl)Cl>[CH2:9]([O:8][C:6]([NH:4][CH2:3][CH2:1][OH:2])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To ethanolamine (9.0 ml, 149 mmol) in methylene chloride (100 ml) at 0° C. was added benzyl chlorformate (10.0 ml, 70 mmol). The mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2M HCl, saturated NaHCO3 solution, and brine, then dried over Na2SO4 and evaporated to provide 12.91 g (94%) of the desired compound as a white solid. 1H-NMR (CDCl3,TMS) 7.47 (m,5H), 5.11 (s,2H), 3.73 (m,2H), 3.38 (m,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9](=[CH:18][N:19](C)C)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.O.[NH2:24]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:10](=[O:11])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:18][NH:19][N:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1)C(=O)c1cccc(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C(c1ccccc1)c1c[nH]nc1-c1cccc(Cl)c1

Procedure:
1-(3-Chlorophenyl)-2-(N,N-dimethylaminomethylene)-3-phenyl-1,3-propanedione (11.25 g) synthesized in accordance with Example 1 was dissolved in ethanol (150 ml) and added with hydrazine hydrate (1.98 g). After heating at reflux temperature for 3 hours, the solvent was distilled off, and then the resulting residue was added with diisopropyl ether and stirred. The resulting solid was then filtered off, recrystallized from acetonitrile to give the compound of interest (3.0 g). M.P.: 161.3-164.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=3[Cl:18])[NH2:14])=[N:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([NH:14][C:26](=[O:27])[O:28][CH:29]([CH3:31])[CH3:30])[CH:15]=[CH:16][C:17]=3[Cl:18])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)OC(=O)Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-[6-bromo-1H-imidazo[4,5-b]pyridin-2-yl]-4-chloroaniline (I-2b) (1 g, 3.08 mmol, 1.00 equiv) in DMF (10 mL) at 0° C. was added 0.5 ml of pyridine followed by isopropyl chloroformate (solution 1M in toluene) (3.85 ml, 3.85 mmol, 1.25 equiv). The reaction mixture was stirred overnight at room temperature and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (0 to 100% Ethyl acetate/Hexanes) to afford the title compound I-11. 1H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 7.63 (s, 1H), 7.57 (d, J=8.8, 1H), 4.97 4.80 (m, 1H), 1.26 (d, J=6.2, 6H); MS M/Z=409.0 (M+1). RT=1.77: Method B.
Reaction SMILES: [C:1]([Si:5]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]3[NH:19][CH:20]=[N:21][C:16]3=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(=O)OC(=O)CC1.[CH3:47][N:48]([CH3:53])[CH2:49]N(C)C>C(Cl)Cl>[C:1]([Si:5]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]3[N:19]([CH2:47][N:48]([CH3:53])[CH3:49])[CH:20]=[N:21][C:16]3=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CN(C)C
Reactant: CC(C)(C)[Si](OC1CCN(c2ccc3nc[nH]c3n2)CC1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)O1
Agent: [K+]
Solvent: ClCCl
Product: CN(C)Cn1cnc2ccc(N3CCC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)nc21
Temperature: 23 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of 5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-3H-imidazo[4,5-b]pyridine (4.65 g, 10.2 mmol) in CH2Cl2 (50 mL) was added potassium carbonate (1.60 g, 11.6 mmol, 1.1 eq), succinic anhydride (1.15 g, 11.5 mmol, 1.1 eq) and, N,N,N′,N′-tetramethylmethanediamine (1.6 mL, 11.7 mmol, 1.1 eq) and the resulting suspension stirred for 16 hr at 23° C. The reaction was diluted with CH2Cl2 and washed with 20% NaOH (50 mL), water, dried over Na2SO4, and concentrated to afford {5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-imidazo[4,5-b]pyridin-3-ylmethyl}-dimethyl-amine orange oil (5.13 g, 9.89 mmol, 97%). 1H NMR (400 MHz, CDCl3) δ: 7.81 (s, 1H), 7.72 (d, J=6.0 Hz), 4H), 7.42 (m, 6H), 6.67 (d, J=8.6 Hz, 1H), 4.99 (s, 2H), 4.01 (sept, 1H), 3.91 (m, 2H), 3.38 (m, 2H), 2.38 (s, 6H), 1.68-1.78 (m, 4H), 1.10 (s, 9H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:17]([F:18])=[C:16](F)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1.Cl.[OH:35][NH:36][CH:37]1[CH2:40][NH:39][CH2:38]1.CN1CCCC1>C(OCC)C>[NH2:7][C:8]1[C:17]([F:18])=[C:16]([N:39]2[CH2:40][CH:37]([NH:36][OH:35])[CH2:38]2)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: ONC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(N4CC(NO)C4)c(Cl)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 0.05 h
Yield: 45.6 %

Procedure:
To 300 mg of pyridine were added 120 mg of 5-amino-1- (6-amino-3, 5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-hydroxyaminoazetidine hydrochloride, and 250 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 3 minutes. After adding 5 ml of diethylether, the mixture was allowed to stand for 1 hour and decanted. 2 ml of ethanol was added and the mixture was stirred. The precipitate was collected by filtration and washed with ethanol and diethylether successively to obtain 64 mg of the title compound as a yellow powder.