Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][CH2:28][C:29]([O:31]C)=[O:30])=[O:26])=[CH:20][C:19]=3[Cl:33])=[CH:14][CH:13]=2)[C:9]([CH3:34])=[N:8][C:7]=1[CH3:35])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:20][C:19]=3[Cl:33])=[CH:14][CH:13]=2)[C:9]([CH3:34])=[N:8][C:7]=1[CH3:35])(=[O:5])[NH2:4]
Reactant: COC(=O)CNC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)NCC(=O)O)cc3Cl)cc2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 19.9 %

Procedure:
Powdered potassium hydroxide (106 mg, 1.89 mmol) was added in one portion to methyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)acetate (Intermediate 20-1; 294 mg, 0.63 mmol) in tert-butanol (4062 μL) at 45° C. The resulting solution was stirred at 45° C. for 150 minutes, a thick white suspension slowly precipitate formed. 2M HCl (5 mL) was added and the mixture was evaporated to remove the organic solvent. The reaction mixture was diluted with EtOAc and water, the organic layer was collected, dried with MgSO4 and evaporated to afford crude product. This was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)acetic acid (56.8 mg, 19.92%) as a white solid.
Reaction SMILES: [N:1]1[C:2](=[O:13])[CH2:3][C:4](=[O:12])[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:21]([CH3:23])[CH3:22].O>CS(C)=O.C(OCC)(=O)C>[CH3:22][CH:21]([N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:12])[CH2:3][C:2]1=[O:13])[CH3:23]
Reactant: O=C1CC(=O)N=c2ccccc2=N1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)CC(=O)Nc2ccccc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 8.3 %

Procedure:
A solution of 1,5-benzodiazepine-2,4-dione (5.5 g, 0.031 mole) in DMSO (70 mL) was treated with cesium carbonate (10.17 g, 0.031 mole) and 2-iodopropane (5.27 g, 0.03 1 mole). The reaction was heated to 80° C. for two hours and then stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate (400 mL) and poured into water (500 mL). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (400 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 3:1 ethyl acetate:hexane to give 560 mg of product.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=3)=[CH:49][CH:48]=2)=[C:25]([CH2:27][CH2:28][NH:29][CH:30]2[CH2:39][CH2:38][CH2:37][C:36]3[N:35]=[C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:31]2=3)[CH:26]=1>C(#N)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)=[CH:49][CH:48]=2)=[C:25]([CH2:27][CH2:28][N:29]([CH2:2][CH2:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH:30]2[CH2:39][CH2:38][CH2:37][C:36]3[N:35]=[C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:31]2=3)[CH:26]=1
Reactant: COC(=O)c1ccc(CCI)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1cc(F)ccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
533 mg (1.84 mmol) of methyl 4-(2-iodoethyl)benzoate and 97 mg (0.92 mmol) of anhydrous sodium carbonate were added to a solution of 380 mg (0.61 mmol) of rac-ethyl 5-[(2-{5-fluoro-2-[(4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzyl)oxy]phenyl}ethyl)amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 159A) in 5 ml of dry acetonitrile, and the mixture was stirred in a microwave apparatus (Biotage Initiator) at 140° C. for 4 h. The reaction solution was then cooled and purified directly by preparative HPLC (mobile phase: acetonitrile/water 9:1). This gave 178 mg (0.23 mmol, 37% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=O.[CH:21]1([C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27])[CH2:23][CH2:22]1.C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:26]([CH3:27])[C:25]([C:24]([CH:21]1[CH2:23][CH2:22]1)=[O:29])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cc(Br)ccc2N)cc1
Solvent: CCCCCCC
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Reaction time: 16 h
Yield: 47 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-(4-methanesulfonyl-phenyl)-methanone [example A15] and 1-cyclopropyl-1,3-butanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 47%; MS: m/z=443 (M+H).
Reaction SMILES: CS(O)(=O)=O.[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15][OH:16])=[CH:12][CH:11]=1)[CH3:8].[NH2:17][CH2:18][CH2:19][CH2:20]O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:17][CH2:18][CH2:19][CH2:20][O:16][CH2:15][C:13]1[O:14][C:10]([CH2:9][N:7]([CH3:6])[CH3:8])=[CH:11][CH:12]=1
Reactant: NCCCO
Reactant: CN(C)Cc1ccc(CO)o1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1ccc(COCCCN)o1
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
To a stirred solution of methanesulphonic acid (18 ml) in dry tetrahydrofuran (40 ml) kept at room temperature was added, with stirring, a mixture of 5-[(dimethylamino)methyl]-2-furanmethanol (4.65 g) and 3-amino-1-propanol (6.75 g). After 3 days the suspension was heated on a steam bath for 30 mins. Excess anhydrous sodium carbonate and ethyl acetate (100 ml) were added and the heating continued for 20 mins. The hot suspension was filtered and the residue washed with hot ethyl acetate (3×50 ml). The combined filtrates were evaporated to dryness, water (150 ml) added and the solution extracted with ethyl acetate (3×50 ml). The aqueous fraction was acidified with oxalic acid (5 g) and the solution evaporated to low bulk. Ethyl acetate (100 ml) and excess anhydrous sodium carbonate were added and the suspension heated to boiling point for 30 mins. The hot suspension was filtered and the combined filtrates and washings evaporated to dryness. The oily residue was distilled (100°-110°/0.2 mm) to give the title compound (2.76 g).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:16]1([CH:8]([C:7]2[CH:6]=[C:5]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:4][C:3]=2[CH2:1][CH3:2])[OH:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCc1sc(C2CCOCC2)cc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1sc(C2CCOCC2)cc1C(O)C1CCCCC1
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 2-ethyl-5-(tetrahydro-2H-pyran-4-yl)thiophene-3-carbaldehyde (692 mg) synthesized above in tetrahydrofuran (10 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (4.64 mL) at 0° C., and the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7, volume ratio) to give the title compound (737 mg, 77%) as a white solid.
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)([O-:6])=[O:5].[CH2:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:17][CH3:18]>C(#N)C>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:19]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: CCCNc1ccc(Cl)cc1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CC#N
Product: CCCN(C(=O)Nc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1

Procedure:
1.09 g of 2-chlorobenzoylisocyanate was added to a solution of 2.00 g of N-(4-aminophenyl)-N'-(4-chlorophenyl)-N'-propylurea in 50 ml of acetonitrile while stirring at room temperature. After stirring for 1.5 hours at room temperature the formed precipate was sucked off, washed with diethyl ether, and dried. According to PMR the product had the desired structure; the product melted at 170° C. The starting aniline was obtained from the corresponding nitro compound by reduction with hydrogen under the influence of Raney nickel as a catalyst; in this reaction ethanol was used as a solvent. N-(4-nitrophenyl)-N'-(4-chlorophenyl)-N'-propylurea was prepared by a coupling of p-nitrophenylisocyanate with N-propyl-4-chloroaniline in acetonitrile as a solvent. In a corresponding manner, in which, if desired, instead of acetonitrile diethyl ether was used as a solvent for the first-mentioned reaction, the following compounds were prepared; the compound numbers correspond again with the number given before in the specification:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:27]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1.BrC1C=CC(F)=CC=1.CC(C)(C)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[S:8][C:7]=2[CH:27]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)csc2c1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CC(C)(C)C(=O)O
Agent: Fc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccc(C(F)(F)F)cc3)sc2c1
Yield: 84.6 %

Procedure:
To a 5 mL microwave vial, added a solution of (E)-tert-butyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (50 mg, 0.13 mmol) in anhydrous DMA (1.5 mL), followed by 1-bromo-4-(trifluoromethyl)benzene (35.3 mg, 0.16 mmol), 1-bromo-4-fluorobenzene (448 mg, 2.56 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos palladacycle 1st generation, 10.4 mg, 0.013 mmol), trimethylacetic acid (40.1 mg, 0.392 mmol) and potassium carbonate (54.2 mg, 0.392 mmol). The microwave vial was sealed, purged and back-filled with nitrogen. The reaction mixture subjected to microwave irradiation for 2 h at 150° C. Upon completion the reaction was diluted with EtOAc, and washed with water and brine. The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a red brown residue which was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-tert-butyl 3-(4-((6-methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3 yl)oxy)phenyl)acrylate (59.4 mg, 0.11 mmol, 86% yield). 1H NMR (400 MHz, CD3OD) δ ppm=1.42-1.61 (m, 9H), 3.77-3.98 (m, 3H), 6.31 (d, J=15.66 Hz, 1H), 6.87-7.04 (m, 3H), 7.28 (d, J=9.09 Hz, 1H), 7.46 (d, J=2.53 Hz, 1H), 7.47-7.57 (m, 3H), 7.65 (d, J=8.08 Hz, 2H), 7.89 (d, J=8.08 Hz, 2H). LC/MS (m/z, MH+): 471.40.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:32]2[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2ccc(C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 4-methylphenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in tetrahydrofuran (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.98 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([S:9][C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:24]([N:26]=[C:27]=[O:28])=[O:25]>O1CCOCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([S:9][C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:24](=[O:25])[NH:26][C:27](=[O:28])[N:19]([CH3:20])[C:17]4=[O:18])=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C=NC(=O)Cl
Reactant: CNC(=O)Nc1ccc(Sc2nc3ccc(Cl)cc3s2)cc1
Solvent: C1COCCO1
Product: Cn1c(=O)[nH]c(=O)n(-c2ccc(Sc3nc4ccc(Cl)cc4s3)cc2)c1=O
Yield: 77.6 %

Procedure:
Methyl isocyanate (0.41 g) was added to a solution of 4-(6-chlorobenzothiazol-2-ylthio)-aniline (2.0 g) in pyridine (20 ml), with stirring. The mixture was stirred at room temperature for 12 hours and evaporated to dryness. The residue was dissolved in a minimal volume of boiling ethanol and the solution was cooled in a refrigerator. The resulting solid substance was collected by filtration and dried to give N-[4-(6-chlorobenzothiazol-2-ylthio)phenyl]-N'-methylurea (1.5 g), which had a melting point of 289°-291° C. This urea (1.4 g) was dissolved in 1,4-dioxane (50 ml), and chlorocarbonyl isocyanate (0.47 g) was added. The mixture was heated at the boiling point for 5 hours and evaporated to dryness. The solid residue was dissolved in a minimal volume of boiling ethanol and the solution was cooled in a refrigerator. The resulting solid substance was collected by filtration and dried to give 1.3 g of 1-[4-(6-chlorobenzothiazol-2-ylthio)phenyl]-3-methyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione of melting point 232°-233° C.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:5]=1[NH:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([O:15][CH3:16])[N:8]=1)([O-])=O.[C:22](O)(=O)[CH3:23]>C(OC(=O)C)(=O)C.[Fe]>[Cl:21][C:19]1[CH:18]=[CH:17][C:5]2[N:6]([C:7]3[N:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([O:15][CH3:16])[N:8]=3)[C:22]([CH3:23])=[N:1][C:4]=2[CH:20]=1
Reactant: COc1nc(Nc2ccc(Cl)cc2[N+](=O)[O-])nc(OC)n1
Reactant: CC(=O)O
Agent: [Fe]
Solvent: CC(=O)OC(C)=O
Product: COc1nc(OC)nc(-n2c(C)nc3cc(Cl)ccc32)n1
Temperature: 25 °C

Procedure:
2-Nitro-4-chloro-N-(4,6-dimethoxy-[1,3,5]triazin-2-yl)aniline (0.5 g) and iron powder (0.3 g) were dissolved in acetic acid (10 ml) and acetic anhydride (5 ml), followed by reflux for 4 hours. The reaction mixture was cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, water was added to the residue, and the crystals were collected by filtration, washed with water and dried. Recrystallization from ethanol was carried out to obtain 0.39 g of the desired product as white feather-like crystals (m.p. 173-176° C.)
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:24])([F:23])[CH2:6][N:7]([C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)C>C(O)(=O)C.[Fe]>[Cl:22][C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:4](=[O:3])[C:5]([F:24])([F:23])[CH2:6][N:7]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:13]=2[N:14]=1
Reactant: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
To a solution of 6.16 g (0.016 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-difluoro-propanoic acid ethyl ester (IV-20) in 120 mL of acetic acid was added 6.0 g (0.11 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed successively with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Recrystallization of the residue with ethyl acetate and hexane gave 2.94 g of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CCN(CC)CC.Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+].Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl.CN(C=O)C.C1COCC1.O>[O:22]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][N:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: O=C(Cl)CCCCBr
Reactant: Nc1ccccc1O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCCN1c1ccccc1O
Reaction time: 2 h

Procedure:
To a solution of 2-aminophenol (1.09 g, 0.01 mol), Et3N (4.46 mL, 0.032 mol) and 4-dimethylaminopyridine (0.122 g, 0.001 mol) in CHCl3 (20 mL) in an ice-H2O bath was added dropwise 5-bromovaleryl chloride (2.95 mL, 0.022 mol) with stirring. After 2 hr, the reaction mixture was washed with 1N HCl until the aqueous layer was acidic, then washed with H2O, aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration to dryness gave a yellow oil which solidifed on standing. This bisacylated product was dissolved in DMF (20 mL) and heated at 80° C. with cesium carbonate (4.89 g, 0.015 mol) for 3 hr, then partitioned between EtOAc and ice water. The aqueous layer was extracted with EtOAc (3×), the organics combined, washed with H2O, aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration to dryness gave a crude product which was treated with 1N NaOH solution (12 mL, 0.012 mol) in THF (20 mL)—H2O (10 mL) with stirring at ambient temperature for 2 hr. The reaction mixture was neutralized with 1N HCl (12 mL, 0.012 mol), concentrated, and extracted with EtOAc (3×), the organics combined, washed with H2O, aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:20][C:21](=[O:24])[CH2:22][NH2:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][NH:23][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)CCCCCNC(=O)OC(C)(C)C
Yield: 127.8 %

Procedure:
By working analogously to what described in example 2, 6-(tert-butoxycarbonylamino)hexanoic acid (163 g) was directly condensed with glycine ethyl ester hydrochloride (118 g; 0.845 moles), obtaining thus N-[6-(tert-butoxycarbonylamino)hexanoyl]glycine ethyl ester (285 g) as a raw product which was used as such in the subsequent reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[N:22]1([C:28]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=2[NH2:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O>[N:22]1([C:28]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][C:29]=2[NH:30][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Methoxybenzoyl chloride (250 mg, 1.47 mmol, commercially available product) and triethylamine (254 μl, 1.83 mmol) were sequentially added at 0° C. to a dichloromethane (4 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (147 mg, 0.602 mmol), obtained as described in Referential Example 1-2. The resulting mixture was warmed to room temperature and stirred for 17 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=5/1). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]-4-methoxybenzamide (GIF-0615) (240 mg, quant.) was yielded as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH:9]([F:11])[F:10])=[N:6][CH:7]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH:9]([F:10])[F:11])=[N:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cn1)C(F)F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OC(c1ccc(Br)cn1)C(F)F

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)-2,2-difluoroethanone (1.0 g, 4.2 mmol) in methanol (10 mL) was added NaBH4 (180 mg, 4.6 mmol) at 0° C. The resulting solution was stirred at ambient temperature for 2 hours before the addition of saturated aqueous NH4Cl (5 mL) at 0° C. Methanol was removed in vacuo, and the resulting aqueous solution was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as an off-white solid, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.91 (d, J=6.0 Hz, 1H), 7.52 (d, J=6.0 Hz, 1H), 5.89 (td, J=54.4, 3.9 Hz, 1H), 4.92-4.84 (m, 1H), 4.52 (br, 1H).