Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:11](Cl)Cl>S(Cl)(Cl)=O>[CH3:11][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-isonicotinic acid (10 g, 63.5 mmol)) was refluxed in thionylchloride (40 mL) under argon for 6 hr. The SOCl2 was evaporated under reduced pressure, twice toluene (30 mL) was added and evaporated. The residue was dried under high vacuum and set under argon. MeOH (50 mL) was added and the mixture was heated to reflux for 1 hr. and stirred overnight at r.t. The solvent was evaporated. To the residue were added saturated NaHCO3 and ether. The etheral phase was separated, washed with water, brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography using CH2Cl2 as eluent to give 9.1 g (84%) of the white and crystalline product. Rf (CH2Cl2)=0.51. 1H NMR (599 MHz, CDCl3) δ 8.52 (d, 1H, J=5.26 Hz, pyridine), 7.87 (d, 1H, J=1.31 Hz, pyridine) 7.75 (dd, 1H, J=5.26, 1.31 Hz, pyridine), 3.95 (s, 3H, methyl ester). 13C NMR (150 MHz, CDCl3) δ 164.5, 152.7, 150.8, 140.4, 124.3, 121.8, 53.2. HRMS (MALDI-FTMS): MH+ calculated: 172.016; found: 172.0161
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH:11][C:12]([NH:14][C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)=[NH:13])[O:4][CH2:3][CH2:2]1.[Cl:21]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:21][C:16]1[S:17][CH:18]=[C:19]([CH3:20])[C:15]=1[NH:14][C:12]([NH:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[O:1][CH2:2][CH2:3][O:4]2)=[NH:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cscc1NC(=N)NC1CCCCC12OCCO2
Solvent: CC(=O)O
Product: Cc1csc(Cl)c1NC(=N)NC1CCCCC12OCCO2
Yield: 47.9 %

Procedure:
N-(1,4-Dioxaspiro[4.5]dec-6-yl)-N′-(4-methylthiophen-3-yl)guanidine (49 mg) was dissolved in glacial acetic acid (3 ml), and a solution of N-chlorosuccinimide (20.3 mg) in glacial acetic acid (5 ml) was added slowly. The mixture was stirred for a number of hours and then allowed to stand at room temperature over the weekend, after which the glacial acetic acid was removed under reduced pressure, the residue was taken up in water and the mixture was adjusted to pH 10 using 2N sodium hydroxide solution. The basic phase was extracted three times with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. Removal of the solvent under reduced pressure gave 24 mg of the desired product which was used directly for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)=[C:4]([F:16])[CH:3]=1.[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH2:13][CH2:14][CH3:15])[C:9]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([C:18]#[N:17])=[CH:20][CH:21]=2)=[O:11])=[C:4]([F:16])[CH:3]=1
Reactant: CCCOC(C(=O)O)c1ccc(Br)cc1F
Reactant: N#Cc1ccc(CN)cc1
Product: CCCOC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F

Procedure:
(RS)-(4-Bromo-2-fluoro-phenyl)-propoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-propoxy-acetamide. Colorless oil. MS 405.3 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21]>>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:9][CH:10]=1
Reactant: CCOC(=O)NCCCl
Reactant: Oc1ccc(OCC(F)(F)F)cc1
Product: CCOC(=O)NCCOc1ccc(OCC(F)(F)F)cc1

Procedure:
Following the procedure of Example 1, 4-(2,2,2-trifluoroethoxy)phenol (0.42 g, 2.2 mmol) and ethyl N-(2-chloroethyl)carbamate (0.40 g, 2.6 mmol) are reacted together to give ethyl N-{2-[4-(2,2,2-trifluoroethoxy)phenoxy]ethyl}carbamate (compound 28, Table A).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.C[C:13](=O)[C:14](=[O:16])C.O=O>C(O)(=O)C>[C:14]([C:7]12[CH2:9][CH:3]3[CH2:4][CH:5]([CH2:10][CH:1]([C:2]3=[O:11])[CH2:8]1)[CH2:6]2)(=[O:16])[CH3:13]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CC(=O)C(C)=O
Agent: O=O
Solvent: CC(=O)O
Product: CC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In a flask were placed 2-adamantanone (100 mmol), acetylacetonatocobalt [Co(acac)2] (50 mmol), 2,3-butanedione (600 mmol), and acetic acid (100 g). A condenser and an oxygen balloon were attached to the flask, and the mixture in the flask was vigorously stirred at 80° C. for 4 hours. After the completion of the reaction, the reaction mixture was concentrated, was diluted with toluene and washing with water. The resulting organic layer was concentrated, the concentrate was subjected to silica gel column chromatography and thereby yielded the title compound 1-acetyladamantan-4-one in a yield of 21%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH3:3].[BH4-].[Na+]>CCO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccc(CO)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Crude 4-(propyloxy)-3-methoxybenzaldehyde (2.55 g) was dissolved in EtOH (30 mL) and cooled to 0° C. NaBH4 (0.499 g, 13.2 mmol) was added portionwise. After the addition was completed, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added and the resulting mixture was extracted with diethyl ether (3×100 mL). The combined organic layers were dried over anhydrous MgSO4. Removal of the solvent gave a pale yellow oil which was purified by silica gel column chromatography (hexanes/EtOAc, 4:1) to give 4-(propyloxy)-3-methoxybenzyl alcohol (2.38 g, 92% over two steps) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: N#Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
3-Cyanophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 min, the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1N HCl (30 mL) for 30 minutes and filtered. The solid was slurried with hot methanol (15 mL) to give 1-(3-cyano-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.33 g, 38%) as a white solid: mp 330-333° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.37-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.37-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 6.92 (t, J=5.5 Hz, 1H, NH), 7.32-7.65 (m, 6H, Ar), 7.93 (s, 1H, Ar), 9.00 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.55, 31.17, 39.67, 46.18, 51.57, 111.41, 118.91, 120.24, 121.59, 122.36, 124.64, 128.30, 130.02, 130.35, 131.63, 135.27, 139.92, 141.21, 154.98, 168.05, 171.00, 172.82; Anal. calcd. for C22H19N5O4+0.1H2O: C, 63.03; H, 4.62; N, 16.71. Found: C, 62.69, H, 4.48; N, 16.41.
Reaction SMILES: [ClH:1].[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:24])=[C:12]([C:15]4[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH2:22]O)[CH:16]=4)[CH:13]=3)[C:8](=[O:25])[C:7]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6]2)[CH2:4][CH2:3]1>S(Cl)(Cl)=O>[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:24])=[C:12]([C:15]4[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH2:22][Cl:1])[CH:16]=4)[CH:13]=3)[C:8](=[O:25])[C:7]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6]2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(CO)c3)c(F)cc2c1=O
Reactant: Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(CCl)c3)c(F)cc2c1=O
Yield: 85.9 %

Procedure:
Ethyl 1-cyclopropyl-6-fluoro-7-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylate hydrochloride (6.68 g) in 40 ml thionyl chloride was heated at reflux for two hours. The excess thionyl chloride was removed in vacuo and by repeatedly adding ethanol and concentrating. The residue was crystallized from ethanol to give 5.50 g ethyl 1-cyclopropyl-7-[2-(chloromethyl)-6-methyl-4-pyridinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate as its hydrochloride salt.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:38])[CH:11]([CH2:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:12][CH2:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[OH:8][NH:9][C:10](=[O:38])[CH:11]([CH2:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)(=[O:29])=[O:28])[CH2:12][CH2:13][CH2:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: COc1ccc(S(=O)(=O)CCCC(CS(=O)(=O)c2ccc(OC)cc2)C(=O)NOCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)CCCC(CS(=O)(=O)c2ccc(OC)cc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-benzyloxy-2-[(4-methoxybenzenesulfonyl)methyl]-5-(4-methoxybenzenesulfonyl)-pentanamide (0.3 g, 0.5 mmol), Pearlman's catalyst (0.11 g), and absolute ethyl alcohol is agitated under hydrogen (15 psig) overnight at room temperature. The mitue is filtered and the filtrate is concentrated in vacuo. The concentrate is chromatographed over silica gel with chloroform/ethyl acetate/methyl alcohol/acetic acid (50/40/10/1) and the eluate concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29]C(=O)C2C=CC=CC=2)[C@@H:16]([O:17]C(=O)C2C=CC=CC=2)[C@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=O)C.[OH:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH2:41][CH2:42][CH2:43][C:44]2=[O:49].B(F)(F)F>ClCCl>[O:38]([C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH2:41][CH2:42][CH2:43][C:44]2=[O:49])[C@@H:5]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:16]([OH:17])[C@H:6]1[OH:7]
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=C1CCCc2c(O)cccc21
Agent: FB(F)F
Solvent: ClCCl
Product: O=C1CCCc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cccc21
Yield: 139.5 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (426 mg, 0.84 mmol), 5-hydroxy-1-tetralone (122 mg, 0.75 mmol) and boron trifluoride diethyletherate (120 mg, 0.84 mmol, 106 μl) in dichloromethane (4 ml) was stirred at room temperature, under argon for 19 hours. Work-up as for Stage 1 in Example 1 then flash chromatography on silica gel (eluting with 2% acetone in toluene) gave the title compound as a colourless oil (308 mg of approx. 51% purity).
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:37]=[CH:36][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26]C)=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34]C)[CH:29]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=3)=[CH:36][CH:37]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Oc1cccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution was prepared of 1.5 g (2.9 mmol) of 1-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-methoxyphenyl)-6-methoxynaphthalene hydrochloride in 30 mL of CH2Cl2 and the solution was cooled to 0° C. under a nitrogen atmosphere. To this solution was added 1.09 mL (2.89 g, 11.5 mmol) of BBr3 and the reaction was allowed to proceed for two hours at 0° C. The reaction was quenched by the addition of aqueous NaHCO3 solution (50 mL). The reaction mixture was extracted with CHCl3. The organic layer was washed with brine, dried with Na2SO4, and evaporated to dryness. The residue was suspended in THF and filtered. To the filtrate was added 1 mL of 5N HCl and the solvents were removed by evaporation. This yielded 0.99 g of the title compound as a tan amorphous powder.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:28])[CH:15]([NH:16][C:17](=[O:27])[CH2:18][S:19]([CH2:22][C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:20])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:29]([S:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1)[CH2:30][CH2:31][S:32](=[O:35])(=[O:34])[NH2:33])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(#N)C>[F:26][C:23]([F:24])([F:25])[CH2:22][S:19]([CH2:18][C:17]([NH:16][CH:15]1[C:14](=[O:28])[N:13]2[C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH:29]([S:36][C:37]3[NH:41][N:40]=[N:39][N:38]=3)[CH2:30][CH2:31][S:32](=[O:34])(=[O:35])[NH2:33])[CH2:10][S:11][C@H:12]12)=[O:27])(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NS(=O)(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 3 h

Procedure:
The ester is dissolved in acetonitrile and trifluoroacetic acid is added. The solution is stirred for 3 hours, then evaporated to dryness to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32](Cl)=[O:33])=[CH:31][C:26]=2[O:25][CH2:24]1>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH:20][C:32]([C:30]3[CH:29]=[CH:28][C:27]4[O:23][CH2:24][O:25][C:26]=4[CH:31]=3)=[O:33])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C2c3c(C)c(NC(=O)c4ccc5c(c4)OCO5)c(C)c(C)c3OC2(C)C)cc1
Yield: 65 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 1,3-benzodioxol-5-carbonyl chloride, the title compound was synthesized according to Example 1b. Yield: 65%. Melting point: 164-165° C. (Ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30]>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([NH:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: COCCCN
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: COCCCNc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and 3-methoxy-propylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (t, J=5.8 Hz, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.47-7.50 (m, 2H), 7.24 (t, J=5.4 Hz, 1H), 6.82 (d, J=9.2 Hz, 1H), 3.39-3.42 (m, 4H), 3.20-3.22 (m, 5H), 2.01-2.03 (m, 2H), 1.73-1.85 (m, 7H), 1.22-1.31 (m, 2H). m/z: 426.0 [M+H]+
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl>[C:17]1([C:15]2[N:4]3[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]3[N:2]=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3ccccc3)ccnc12
Yield: 43.9 %

Procedure:
A stirred mixture of 11.0 g of 4-amino-5-imidazolecarboxamide hydrochloride and 15.0 g of 3-dimethylaminoacrylophenone (prepared as described in Example 1) in 120 ml of glacial acetic acid was heated at reflux for 4 hours. The solvent was evaporated in vacuo to give a dark oil which was dissolved in dichloromethane, then treated by stirring with saturated sodium bicarbonate. The organic solvent was evaporated and the remaining mixture was filtered and the solid was washed with water, dried, and then was recrystallized from ethanol to give 7.08 g of the desired product as a yellow solid, mp 226°-228° C.
Reaction SMILES: [Na].[Br-].[CH3:3][C:4]1([CH3:10])[NH:8][C:7]([NH2:9])=[N:6][CH2:5]1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([O-])=[O:14]>CO>[OH:16][C:11]1[N:9]=[C:7]2[NH:8][C:4]([CH3:10])([CH3:3])[CH2:5][N:6]2[C:13](=[O:14])[CH:12]=1
Reactant: CC1(C)CN=C(N)N1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Br-]
Agent: [Na]
Solvent: CO
Product: CC1(C)Cn2c(nc(O)cc2=O)N1
Yield: 99.2 %

Procedure:
To 250 mL of methanol under nitrogen, 5.21 g of sodium are added. Once dissolution is total and after returning to RT, 20 g of 5,5-dimethyl-4,5-dihydro-imidazol-2-amine bromide and 31.2 g of ethyl malonate are added. The medium is heated with reflux for 16 h. The reaction medium is dry concentrated, and then taken up in 40 mL of ice water. The expected product is precipitated by adding 1N HCl. The obtained precipitate is filtered, washed with water and then dried in the oven at 50° C. 18.62 g (yield=97%) of 7-hydroxy-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained as a white solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[O:5][CH2:4]1)=[O:26])=[CH:19]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@H]1COc2ccccc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1COc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
Alternatively, to a mixture of (S)-3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt (54 mg) (prepared in Itoh, et al., Chem. Pharm. Bull. 1986, 34, 1128–1147), tetrahydrofuran (10 mL), 5-chloroindole-2-carboxylic acid (39 mg), 1-hydroxy-7-azabenzotriazole (31 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57 mg) stirring at room temperature under argon was added diisopropylethylamine (65 mg). The resulting yellow suspension was stirred for 30 min, during which a solution formed. After evaporation under vacuum, the residue was redissolved in ethyl acetate (50 mL) and the resulting solution was washed sequentially with 1.0 M aqueous hydrochloric acid (25 mL), 1.0 M aqueous sodium hydroxide (25 mL), water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting solid crude product was triturated with diethyl ether (20 mL three times), followed by drying under vacuum to provide the title compound (63 mg).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].Cl[CH:16]=[C:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:18]=O.O>CN(C)C=O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([C:9]([F:10])([F:11])[F:12])=[N:1][CH:18]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: O=CC(=CCl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)cnc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
Ethyl 3-amino-4,4,4-trifluorocrotonate (1.55 g; prepared by the method of Swarts, Bull. Sci. acad. roy. Belg., 1926, 12 (5), 679) in dry dimethylformamide (2 ml) was added dropwise to a suspension of sodium hydride (0.20 g) in dimethylformamide (20 ml). The mixture was then stirred for 30 minutes and 3-chloro-2-(p-chlorophenyl)prop-2-enal (1.7 g) was added dropwise. The mixture was stirred for 2 hours, allowed to stand overnight and poured into water. The resulting mixture was twice extracted with diethyl ether and the combined extracts washed with water, dried and filtered through charcoal. The filtrate was concentrated and the residue recrystallised from aqueous ethanol to give the title compound (1.1 g), m.p. 84°-5°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/B(O)O)=[CH:5][CH:4]=1.[CH3:16][C:17]([CH3:38])([CH3:37])[CH2:18][C:19]([NH:21][C:22]1[C:30](C2C=NC=CC=2)=[C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:24]2[N:23]=1)=[O:20]>>[CH3:16][C:17]([CH3:38])([CH3:37])[CH2:18][C:19]([NH:21][C:22]1[C:30](/[CH:10]=[CH:9]/[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=2)=[C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:24]2[N:23]=1)=[O:20]
Reactant: OB(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1cccnc1
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
Trans-2-[4-(trifluoromethyl)phenyl]vinylboronic acid and the product from Example 110B were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.27-10.28 (bs, 1H), 9.11 (dd, J=6.9, 1.7 Hz, 1H), 8.69 (dd, J=4.1, 1.7 Hz, 1H), 7.63-7.73 (m, 5H), 7.34 (d, J=16.5 Hz, 1H), 7.15 (dd, J=6.9, 4.1 Hz, 1H), 2.35 (s, 2H), 1.09 (s, 9H); MS (ESI) m/z 403 (M+H)+.
Reaction SMILES: [C:1]1(=O)O[C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[C:13]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1CBr)#[N:14].C(N(CC)CC)C>C(#N)C>[O:6]=[C:5]1[C:4]2[C:3](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]2[CH2:1][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:13]=2[NH:14]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: N#Cc1ccccc1CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1[nH]c2c(c3ccccc13)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of homophthalic anhydride (324 mg, 2.0 mmol) in acetonitrile (15 mL) was added 2-cyanobenzyl bromide (431 mg, 2.0 mmol, 1.0 eq) and triethylamine (5 mL). The reaction was stirred under inert atmosphere at room temperature for 30 minutes, after which time a yellow precipitate appeared. The reaction mixture was then heated at reflux for 18 h and the resulting white precipitate was filtered, washed using acetonitrile (3×8 mL) and dried under vacuum to provide Compound 13a as a white crystalline solid. Yield=150 mg (32%).