Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:14])=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH:2]=[CH:3][CH3:4].[CH2:16](Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O.O>[CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:16][CH3:17])=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH:2]=[CH:3][CH3:4]
Reactant: CCBr
Reactant: CC=CCC1Cc2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)=O
Product: CC=CCC1Cc2ccc(OCC)cc2C1=O
Yield: 98 %

Procedure:
A solution of 5.0 g of (RS)-2-(2-buten-1-yl)-6-hydroxy-1-indanone, 4.1 ml of ethyl bromide, 6.83 g of potassium carbonate and 10 ml of N,N-dimethyl-formamide in 70 ml of acetone was heated to 35° for 35 hours. After cooling, the solution was poured into 100 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. 5.6 g (98%) of (RS)-2-(2-buten-1-yl)-6-ethoxy-1-indanone were obtained as a red-brown oil which was used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[CH2:14]SCCC(OCC)=O)=[O:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[CH2:14][OH:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCSCc1nnsc1SCCC(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CCSc1snnc1CO
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(2-ethoxycarbonylethyl)thio]-4-[(2-ethoxycarbonylethyl)thiomethyl]-1,2,3-thiadiazole (1.0 g, 3.0 mmol) in dichloromethane (40 mL) was added m-chloroperoxybenzoic acid in several portions at 0° C. until the starting material was disappeared. The mixture was then sequentially washed with saturated aqueous sodium thiosulfate, cold aqueous 1% sodium hydroxide and brine, and was concentrated to dryness. The oxidized product was treated with trifluoroacetic anhydride (2 mL) for 30 min at room temperature. After removal of trifluoroacetic anhydride under the reduced pressure, the mixture was stirred in ethyl acetate/1% sodium hydroxide (30 ml/30 mL) for 30 min. The ethyl acetate layer was concentrated to a volume of 5 mL and methanol (10 mL) was added. Excess sodium borohydride (200 mg) was added in portions at 0° C. while stirring. After 30 min, the reaction was quenched with diluted hydrochloric acid. The mixture was extracted with ethyl acetate and concentrated. The residue was purified by silica gel chromatography (1% methanol/dichloromethane) to provide 225 mg of 5-[(2-ethoxycarbonylethyl)thio]-4-hydroxymethyl-1,2,3-thiadiazole. 1H NMR (CDCl3) δ 1.27 (t, 3H, J=8), 2.71 (t, 2H, J=7), 3.27 (t, 2H, J=7), 4.16 (q, 2H, J=8), 5.03 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:38])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH2:32][O:33][CH2:34][CH3:35])=[CH:26][C:25]=2[O:36][CH3:37])=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])C.[Li+].[OH-]>C1COCC1.O>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[C:7]([NH:6][C@H:5]([C:4]([OH:38])=[O:3])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([O:36][CH3:37])=[CH:26][C:27]([CH2:32][O:33][CH2:34][CH3:35])=[CH:28][C:29]=2[O:30][CH3:31])=[CH:20][CH:19]=1)=[O:16]
Reactant: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OCC)cc2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(OC)c1
Temperature: 5 °C
Reaction time: 20 h
Yield: 74.8 %

Procedure:
To a solution of the compound of Example 1 (207 mg) in THF/H2O (8 ml/2 ml) was added LiOH (30 mg) at 5° C. The mixture was stirred at 5° C. for 20 hours, quenched with 6N HCl (1 ml) and extracted with AcOEt. The organic layer was washed with H2O and brine, dried (MgSO4) and evaporated. The residue was recrystallized from a mixture of MeOH, diethyl ether and hexane to yield the title compound (147 mg). The compound of Example 2 (301 mg) was also hydrolyzed in a similar manner to give the title compound (238 mg) mp. 196-198° C.; IR (Nujol) 3300, 3270, 1705, 1651, 1462, 1126 cm−1; MS (ESI−Q1MS) m/z 530 (M−H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24][CH2:23]2>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][N:25]([C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)[CH2:24][CH2:23]2
Reactant: Brc1ccc2c(c1)CCNC2
Reactant: Clc1ncnc(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc(N2CCc3cc(Br)ccc3C2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
2,4-Dichloro-1,3,5-triazine (2.01 g, 12.7 mmol) was dissolved in 10 mL of dry DMF and the solution was cooled to 0° C. To this solution was added N,N-diisopropylethylamine, (6.65 mL, 38.2 mmol) and 6-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.26 g, 12.7 mmol). The resulting reaction mixture was stirred at 0° C. to RT for 1.5 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc. The organics were dried with MgSO4, filtered and concentrated under reduced pressure. The crude material obtained was purified with medium pressure silica gel chromatography using gradient eluent, 0-40% EtOAc in hexanes to afford 6-bromo-2-(4-chloro-1,3,5-triazin-2-yl)-1,2,3,4-tetrahydroisoquinoline (1.90 g, 46% yield) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]#[N:9]
Reactant: CS(=O)(=O)c1ccc2c(Cl)c(C(N)=O)sc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(Cl)c(C#N)sc2c1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A stirring 0° C. slurry of 3-chloro-6-methanesulfonyl-benzo[b]thiophene-2-carboxylic acid amide 7 (2.8 g, 9.7 mmol) in CH2Cl2 (50 mL) was treated by sequential addition of TFAA (4.0 mL, 5.9 g, 28 mmol) then pyridine (4.0 mL, 3.9 g, 49 mmol). After 2 h, the resulting solution was washed with 0.1 M HCl, dried (Na2SO4), filtered, and evaporated. Chromatography gave 2.1 g (81%) of 3-chloro-6-methanesulfonyl-benzo[b]thiophene-2-carbonitrile 8; 1H NMR δ 3.15 (s, 3H), 8.09 (dd, 1H, J=1.5, 8.6), 8.15 (dd, 1H, J=0.7, 8.6), 8.52 (dd, 1H, J=0.7, 1.5).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:13]C1CC(C(C)C)CCC1=O>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([Br:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: CCOC(=O)C1CCC(=O)CC1
Product: CCOC(=O)C1CCC(=O)C(Br)C1

Procedure:
The bromination of 4-oxo-cyclohexane carboxylic acid ethyl ester takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:10]=[C:11](Br)[C:12](=[O:21])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:8].[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B1OC(C([O-])=O)C=CO1)#[N:24].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:11]1[C:12](=[O:21])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=[C:9]([C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:8])[CH:10]=1)#[N:24]
Reactant: N#Cc1ccccc1B1OC=CC(C(=O)[O-])O1
Reactant: O=C(c1cc(Br)c(=O)n(-c2ccccc2)c1)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cc(C(=O)c2ccccn2)cn(-c2ccccc2)c1=O
Temperature: 130 °C
Reaction time: 5 h
Yield: 21.2 %

Procedure:
To a mixed liquid of 200 mg of 5-(2-pyridinecarbonyl)-1-phenyl-3-bromo-1,2-dihydropyridin-2-one, 130 mg of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 400 mg of cesium carbonate and 6 ml of dimethylformamide was added 60 mg of tetrakistriphenylphosphine palladium, followed by stirring at 130° C. for 5 hours in nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added thereto. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 45 mg of the title compound as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][O:5][N:6]=1.O.[NH2:10][NH2:11]>C(#N)C>[NH2:1][C:2]1[C:3]([C:7]([NH:10][NH2:11])=[NH:8])=[N:4][O:5][N:6]=1
Reactant: NN
Reactant: N#Cc1nonc1N
Solvent: CC#N
Solvent: O
Product: N=C(NN)c1nonc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of 4-amino-furazan-3-carbonitrile (0.50 g, 4.50 mmol) in acetonitrile (7.0 mL) was added hydrazine monohydrate (0.28 mL) dropwise. The solution was stirred at ambient temperature for 3 hours after which time a white solid precipitated. The solid was washed with acetonitrile and dried in vacuo to afford the title compound (0.60 g, 94%) as a white, fluffy solid. HPLC Method A Rt 0.18 min, m/z (ES+) (M+H)+ 143.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH3:9].O.[C:19](O)(=O)C>>[C:8]([NH:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][CH:13]=1)[CH:19]=[CH:6][C:5]([OH:4])=[O:7])(=[O:10])[CH3:9]
Reactant: CC(=O)O
Reactant: CC(=O)Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cccc(C=CC(=O)O)c1
Reaction time: 8 h
Yield: 89 %

Procedure:
Tin II chloride dihydrate (170 g, 0.75 mol) was dissolved in concentrated HCl (200 mL). Warming was necessary to obtain a clear solution. 3-Nitrocinnamic acid (35 g, 0.181 mol) was added portionwise with stirring. After about 20% of the 3-nitrocinnamic acid had been added, the mixture was warmed with a heat gun to 45° C. to initiate reaction. The rate of addition was controlled to maintain a temperature of 65-75° C. The reaction was exothermic, but not vigorous on this scale. After the addition was complete, and the reaction started to subside, the flask was transferred to an oil bath at 65° C. for 1 h. The mixture was then cooled to room temperature. The solid was filtered, washed with 2 N HCl, (100 mL) and sucked dry. The filter cake was dried in a vacuum oven for 1 h, then in air overnight, to give about 65 g of the crude amine. This material was suspended in acetic acid (300 mL) and acetic anhydride (150 mL, 1.6 mol) was added gradually with stirring. After the initial exotherm subsided, the mixture was stirred in an oil bath at 110° C. for 2 h, resulting in a clear solution. LCMS showed complete conversion to the desired acetanilide. The solution was cooled and water (50 mL) was added. After standing overnight the solution was concentrated to about 300 mL. More water (100 mL) and 2 N HCl (50 mL) were added. The precipitate was filtered, washed with water and dried to give 3-acetamido cinnamic acid (33.2 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[NH:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=2)[N:29]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[N:16]([CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=3)[N:29]=2)[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Clc1ccc2ccc(CBr)nc2c1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(Cc3ccc4ccc(Cl)cc4n3)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a mixture of the methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (312 mg, 0.92 mmol) (J. Med. Chem. 1990, 33, 1781-1790) and 2-bromomethyl-7-chloroquinoline (225 mg, 0.88 mmol) in DMF (3 ml) at 0° C. was added 50% NaH (48 mg, 1.04 mmol). After stirring at 0° C. for 1 hr, ice was added to the reaction mixture. When the ice had melted the resultant solid was filtered, dried and swished with Et2O to afford the title compound (311 mg).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.[OH-].[Na+].[CH3:16][Si:17]([CH3:22])([CH3:21])[CH2:18]CO>C(OC(C)C)(C)C>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5](=[CH:12][CH:13]=1)[C:6]([O:7][CH2:8][CH2:16][Si:17]([CH3:22])([CH3:21])[CH3:18])=[O:11]
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: C[Si](C)(C)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Product: C[Si](C)(C)CCOC(=O)c1ccc(F)cc1N

Procedure:
7-Fluoro-1H-3,1-benzoxazine-2,4-dione (2.0 g), sodium hydroxide (0.05 g) and 2-(trimethylsilyl)ethanol (1.31 g) were heated together at 100° for 30 minutes until effervescence ceased. After cooling, the residue was suspended in diisopropyl ether, then filtered and evaporated. The residue was recrystallised from petroleum ether to give 2-(trimethylsilyl)ethyl 4-fluoroanthranilate, mp 43°-44°. (Compound 20).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:14]#[N:15])[C:12]#[N:13])=[CH:7][C:6]=1[CH3:16]>C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:14]([NH2:15])=[N:2][NH:3][C:12]=2[NH2:13])=[CH:7][C:6]=1[CH3:16]
Reactant: Cc1cc(C(C#N)C#N)ccc1Cl
Reactant: NN
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2c(N)n[nH]c2N)ccc1Cl
Temperature: 70 °C

Procedure:
Hydrazine monohydrate (0.312 mL, 6.4 mmol) was added to a solution of the product from Example 47A (512 mg, 2.69 mmol) in CHCl3 (25 mL). The reaction flask was evacuated and purged with nitrogen (3 cycles) and the mixture was heated at 70° C. under nitrogen for 22 hours, then cooled to room temperature. The mixture was concentrated under vacuum to provide the title compound as a beige solid. MS (DCI/NH3) m/z 223/225 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16]1[CH:21]2[C:22]3[C:27]([CH2:28][CH2:29][N:20]2[C:19](=[O:30])[CH2:18][NH:17]1)=[CH:26][CH:25]=[CH:24][CH:23]=3.C(N(CC)CC)C>CN(C)C=O>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=[C:2]1[N:17]1[CH2:18][C:19](=[O:30])[N:20]2[CH2:29][CH2:28][C:27]3[C:22]([CH:21]2[CH2:16]1)=[CH:23][CH:24]=[CH:25][CH:26]=3
Reactant: O=C1CNCC2c3ccccc3CCN12
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CC(=O)N3CCc4ccccc4C3C2)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
2-Chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (332 mg, 1.5 mmol) was added to the solution of 1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (313 mg, 1.55 mmol), triethylamine (0.223 ml, 1.6 mmol) in N,N-dimethylformamide (8 ml) and the mixture was stirred for 4 hour and stood overnight. Ice-water was added to the solution and resulting precipitate was collected by filtration and washed with water and then dried to afford 2-(1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl)-1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (555 mg, 96%). Treatment with 4N hydrogen chloride in ethyl acetate yielded corresponding hydrogen chloride salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH:25]=[C:24]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:29][CH2:28]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOC(=O)c1cnc2cc(Br)ccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccn12
Temperature: 160 °C

Procedure:
To a solution of 5-ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (24g) (300 mg, 1.11 mmol) in DMF (9 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (414 mg, 1.34 mmol), K2CO3 (1.8M, 1.85 mL, 3.33 mmol) and Pd(PPh3)4(87 mg, 0.11 mmol). The reaction was evacuated and backfilled with nitrogen twice then heated at 160° C. for 10 minutes via microwave. After the reaction mixture was filtered through a pad of Celite, the mixture was diluted with a saturated solution of NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude ethyl 7-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (89) (MS (m/z) 372.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[O:16].Cl>O.C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][CH:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(CC(=O)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A solution of Meldrum's acid (5.0 g, 35 mmol) in anhyd THF (25 mL) was added cautiously to a stirred suspension of sodium hydride (95%, 960 mg, 38 mmol) in anhyd THF (25 mL). The resulting solution was stirred at room temperature for 1 h. A solution of 2,4′-dibromoacetophenone (11.6 g, 42 mmol) in anhyd THF (25 mL) was added dropwise, and the resultant solution was stirred at room temperature for 16-24 h (TLC control). The reaction mixture was poured into water (50 mL), acidified to pH 2-3 with 0.5 N hydrochloric acid and extracted with ethyl acetate (3×50 mL). The combined extract was washed with water, sat'd aq NaCl, dried over anhyd MgSO4, filtered and concentrated in vacuo. Trituration and filtration from MeOH afforded the title compound as a white solid (6.56 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[C:13]([CH:17]=1)[C:14]([O:16][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (19.17 g, 51.35 mmol) in DMF (150 mL) was added potassium bicarbonate (6.16 g, 61.62 mmol) followed by benzyl bromide (6.2 mL, 51.41 mmol). The mixture was stirred for 5 h at room temperature and water was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v), the corresponding product was obtained as white solid (21.42 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.51 (dd, J=8.5, 2.1 Hz, 1H), 7.41 (m, 10H), 7.09 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.85 (m, 1H), 5.33 (s, 2H), 5.15 (s, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][CH:6]([CH2:13][CH2:14][O:15][CH3:16])[CH2:7][NH:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:17]O>>[ClH:3].[OH:5][CH:6]([CH2:13][CH2:14][O:15][CH3:16])[CH2:7][NH:8][CH2:9][C:10]([O:12][CH3:17])=[O:11]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: COCCC(O)CNCC(=O)O
Product: COCCC(O)CNCC(=O)OC
Product: Cl
Reaction time: 8 h

Procedure:
11.94 ml of thionylchloride are added dropwise, within 20 minutes, to a suspension of 5.80 g of (2-hydroxy-4-methoxy-butylamino)-acetic acid in 200 ml methanol while cooling with an ice bath. The reaction mixture is allowed to come up to ambient temperature overnight. For working up, the cloudy solution is evaporated to dryness. The residue is stirred several times with 100 ml aliquots of methanol, which is then distilled off in vacuo using the rotary evaporator. The viscous crude product is reacted further without any additional purification.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])[C:29](O)=O)=[CH:24][CH:23]=1.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:53][NH2:54]>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:29]2[NH:54][N:53]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([N:6]4[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]4)=[C:9]([O:19][CH3:20])[CH:10]=3)[N:16]=2)[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])=[CH:24][CH:23]=1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: NN
Reactant: O=C(O)C(CCCCCl)c1ccc(Br)cc1
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(Br)cc3)n2)ccc1-n1cnc(Cl)c1
Yield: 46.9 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (4.0 g, 9.42 mmol, from preparation A) and 2-(4-bromophenyl)-6-chlorohexanoic acid (3.60 g, 11.77 mmol, from preparation AT) were coupled [N-methylmorpholine (5.18 mL, 47.1 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (1.48 mL, 47.1 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, crude 5-(1-(4-bromophenyl)-5-chloropentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (2.43 g, 4.42 mmol, 46.9% yield) was obtained as a brown foamy solid The crude product was used in next step without purification. LC-MS (M+H)+ 551.2.
Reaction SMILES: [CH3:1][CH:2](C[AlH]CC(C)C)C.[C@H:10](O)([C:16]([O-:18])=[O:17])[C@@H:11](O)[C:12]([O-:14])=O.[Na+].[K+].[CH3:22]COCC>C1COCC1>[CH3:22][C:16]1([CH2:10][CH2:11][CH:12]=[O:14])[O:18][CH2:2][CH2:1][O:17]1
Reactant: CCOCC
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(CCC=O)OCCO1
Reaction time: 1 h

Procedure:
To a solution of 5-2 (44.74 g, 0.22 mol) in 400 mL THF at −78° C. was added DIBAL (264 mL 1 M in hexanes, 0.264 mol) over 10 minutes. After stirring for 1 h, 350 ml of 1.0 M Rochelle's salt and 300 ml ether was added followed by the removal of the cooling bath. After stirring for 1 h, the organic portion was separated and dried over Na2SO4. Evaporative removal of the solvent gave 4-3 as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:9].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:2]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:15][CH:14]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCOc1ccc(C(=O)OC)cc1

Procedure:
A slurry of 4-bromo-1-butene (1.4 g), methyl p-hydroxybenzoate (1.5 g) and K2CO3 (1.8 g) in acetone was heated to reflux for 18 hours. The reaction was cooled, filtered, and concentrated to a yellow oil. The oil was chromatographed with 20% ethyl acetate/hexanes to give the titled compound.