Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:19][CH2:18][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)([OH:20])[CH2:16][CH2:15]3)=[O:13])[CH2:7][C:6]=2[CH:31]=1.[N+:32]([C:35]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:36]=1[NH2:37])([O-:34])=[O:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:37][C:36]1[CH:38]=[CH:39][C:40]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]([C:12]([N:14]4[CH2:19][CH2:18][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=5)([OH:20])[CH2:16][CH2:15]4)=[O:13])[CH2:7][C:6]=3[CH:31]=2)=[CH:41][C:35]=1[N+:32]([O-:34])=[O:33]
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: O=C(N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)N1CCOc2ccc(Br)cc2C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2ccc3c(c2)CN(C(=O)N2CCC(O)(c4cccc(C(F)(F)F)c4)CC2)CCO3)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 26 %

Procedure:
To a solution of 1-[(7-bromo-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl)carbonyl]-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol (0.688 g, 1.38 mmol) and 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.365 g, 1.38 mmol) in dioxane (24 mL) and water (3.00 ml) was added tribasic potassium phosphate (0.413 g, 1.79 mmol). The solution was sparged with N2(g) for ten minutes before the addition of dichloro[1,1-bis-(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.023 g, 10 mol %). The resulting suspension was heated at 90° C. for 2 hours in a sealed tube vessel. On cooling to room temperature the mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL) and then dried over anhydrous sodium sulfate. Filtration and concentration afforded a crude orange oil that was purified by silica gel chromatography (7:3 hexanes/ethyl acetate) to provide 1-{[7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol (0.200 g, 26% yield) as an orange oil. MS (EI) for C28H27F3N4O5: 557 (MH+).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C=O)C>[N+:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[NH:22][C:21]1[CH:23]=[CH:24][C:18]([O:17][C:16]([F:15])([F:25])[F:26])=[CH:19][CH:20]=1)[C:6]([O:8][CH3:9])=[O:7])([O-:14])=[O:13]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Nc2ccc(OC(F)(F)F)cc2)c([N+](=O)[O-])c1

Procedure:
A stirred solution of methyl 4-fluoro-3-nitrobenzoate (853 mg, 4.28 mmol), 4-trifluoromethoxyaniline (759 mg, 4.28 mmol) and triethylamine (1.79 mL, 12.9 mmol) in DMF (5.00 mL) was heated to 70° C. for 24 h. The reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-10% methanol/DCM as eluent) afforded the title compound i-3a. m/z (ES) 357 (MH)+. 1H NMR (500 MHz, CDCl3): δ 9.77 (s, 1H), 8.96 (s, 1H), 8.03 (d, 1H, J=8.5 Hz), 7.34 (m, 4H), 7.16 (d, 1H, J=8.5 Hz), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][CH:15]=[CH2:16])[C:7]([OH:9])=[O:8])C=C>C(Cl)Cl.CCOC(C)=O.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:18][O:17][C:11]1[C:12]2[O:13][CH2:14][CH:15]=[CH:16][CH2:1][C:4]=2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=1
Reactant: C=CCOc1c(CC=C)cc(C(=O)O)cc1OC
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)cc2c1OCC=CC2
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a stirred solution of 3-allyl-4-allyloxy-5-methoxybenzoic acid (200 mg, 0.81 mmol) in CH2Cl2 (20 mL) at room temperature was added benzylidene-bis-(tricyclohexylphosphine)dichlororuthenium (Grubb's catalyst, 35 mg, 0.04 mmol, 0.05 eq.). After stirring for 2 h the reaction was diluted with EtOAc (150 mL) then extracted with 2.0 N NaOH (100 mL). Aqueous layer was treated with brine (100 mL) then acidified to pH 5 using 1.0 N HCl. The aqueous layer was then extracted with EtOAc (2×200 mL). The organic layer was dried over MgSO4 and then concentrated in vacuo to afford 9-methoxy-2,5-dihydrobenzo[b]oxepine-7-carboxylic acid (179 mg, 100%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C=CC=CC=1>CN(C=O)C.C(OC(C)C)(C)C>[CH3:25][C:19](=[CH:5][C:4]1[CH:3]=[C:2]([F:1])[C:9]([F:10])=[C:8]([F:11])[CH:7]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1cc(F)c(F)c(F)c1

Procedure:
1.0 eq. of 3,4,5-trifluorobenzaldehyde is dissolved in DMF and stirred at room temperature with 1.1 eq. of ethyl 2-(triphenylphosphanylidene)propionate until complete conversion can be determined by means of thin-layer chromatography. The mixture is freed from the solvent and the residue is stirred in diisopropyl ether. The insoluble residue is filtered off, the filtrate is concentrated in vacuo and the residue is chromatographed on silica gel (EA/heptane 1:1), the title compound being obtained in the form of a colorless solid. (M.p.: 66-68° C.).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[O:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1>>[O:30]1[CH:34]=[CH:33][C:32]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]=2[CH3:29])=[CH:31]1
Reactant: OB(O)c1ccoc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccoc1)OCC2c1ccc(C(C)C)cc1
Yield: 51 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and 3-furylboronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 51%. Melting point: 183-185° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=1)[C:9]([OH:11])=O.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH2:36])=[N:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH:36][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=[C:6]([O:5][C:4]3[CH:21]=[CH:22][C:23]([F:24])=[C:2]([F:1])[CH:3]=3)[CH:7]=2)=[N:33][CH:32]=1)[CH3:26]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(F)c(F)c2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(F)c(F)c3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-(3,4-Difluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[C:5]([CH3:22])[CH:4]=1.[H-].[Na+].I[CH2:26][CH2:27][CH3:28]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:26][CH2:27][CH3:28])[N:10]=2)=[C:5]([CH3:22])[CH:4]=1
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(C)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2C)c2cccc(C(F)(F)F)c21
Yield: 57.4 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxy-2-methylphenyl)-7-(trifluoromethyl)-1H-indazole (0.150 g, 0.49 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and iodopropane (0.07 mL, 0.7 mmol) to give the title compound (0.098 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[C:9]([O:12]C(=O)C)(=[O:11])[CH3:10]>CCOC(C)=O>[C:9]([O:12][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc[n+]1[O-]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccccn1

Procedure:
A solution of the 2-methyl pyridine N-oxide (1.0 mmol) in acetic anhydride (5 mmol) was heated to reflux for 0.5 h. Work-up (EtOAc), drying (MgSO4), evaporation and purification by preparative TLC or flash chromatography afforded the 2-(acetoxymethyl)pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[O:25].[CH3:37][NH2:38].C1COCC1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14]([NH:38][CH3:37])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[O:25]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cccc(C(F)(F)F)c4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cccc(C(F)(F)F)c4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 31.1 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (0.092 g, 0.18 mmol) and 2.00M MeNH2/THF (0.89 ml, 1.8 mmol) were combined to afford 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (28 mg, 31% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.61 (s, 1H), 8.12-8.09 (m, 2H), 8.04 (s, 1H), 7.68 s, 1H), 7.64 (brd, J=10.0 Hz, 1H), 7.50 (dd, J=7.6 and 16.0 Hz, 1H), 7.31 (brd, J=7.6 Hz, 1H), 7.06 (d, J=12.4 Hz, 1H), 6.82 (brs, 1H), 3.59 (s, 3H), 3.08 (brd, J=4.4 Hz, 3H), 2.16 (s, 3H); MS (ESI) m/z: 501.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N+:15]([O-])=[CH:14][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si]([C:24]#[N:25])(C)C.CN(C)C(Cl)=O>CN(C)C=O.O1CCOCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:24]#[N:25])[C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)C#N
Reactant: O=[N+]([O-])c1ccc(-n2cnc3c[n+]([O-])ccc32)cc1
Agent: CN(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 14 h
Yield: 75.4 %

Procedure:
In a mixed solvent of 1 mL of dimethylformamide and 2 mL of dioxane, 100 mg (0.39 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine 5-oxide prepared in Step A of Example 90 was dissolved, and 310 μL (0.78 mmol) of tri-methylsilylcyanide and 144 μL (0.78 mmol) of N,N-dimethylcarbamoyl chloride were added thereto and the mixture solution was stirred at 90° C. for 14 hours. The solvent was distilled, and the residue was partitioned between ethyl acetate (10 mL×2) and a sodium hydrogencarbonate aqueous solution (10 mL). The combined organic layers was washed with a saturated sodium chloride solution, dried on anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was triturated with ethyl acetate to obtain 78 mg (75%) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4]1.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C.C(OCC)(=O)C.O>[OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][N:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=3)[CH2:10][C@@H:5]2[CH2:4]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OC[C@H]1C[C@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCN3C[C@@H](CO)C[C@H]3C2)nc1
Temperature: 25 °C

Procedure:
A solution of 1.0 g (6.4 mmol) of (7S,8aS)-7-hydroxymethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 13, Step A), 1.77 g (12.8 mmol) of 2-chloro-5-cyanopyridine and 2.71 g (25.6 mmol) of sodium carbonate in 50 mL of isoamyl alcohol was heated at reflux for 18 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and water, the pH was adjusted to 11 with sodium carbonate, the layers were separated, and the aqueous layer extracted with ethyl acetate. The combined organic phase was dried (magnesium sulfate), filtered and evaporated to give (7S,8aS)-7-hydroxymethyl-2-(5-cyanopyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])(C)(C)[CH3:2].ClC(OCC)=O>C(Cl)Cl>[CH2:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)NCCCN
Yield: 141.5 %

Procedure:
To a solution of 0.5 g (2.9 mmol) of 3-tert-butyloxycarbonylaminopropylamine in 8 ml of DCM and 0.37 g (2.9 mmol) of NEM was added a solution of 0.32 g (0.29 mmol) of ethyl chloroformate in 2 ml of DCM. After 24 h at RT the mixture was washed with water and dried. The solvent was evaporated and the residue was stirred with 5 ml of TFA (90%). After 1 h the solvent was evaporated to give 0.6 g of the title compound. MS=147.0 (M+1)+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].C(N(CC)CC)C.[C:14]([O:18][C:19]([N:21]1[CH2:26][C@H:25]([CH2:27][CH3:28])[N:24]([CH2:29][C:30]([OH:32])=[O:31])[CH2:23][C@H:22]1[CH3:33])=[O:20])([CH3:17])([CH3:16])[CH3:15].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][C@H:25]([CH2:27][CH3:28])[N:24]([CH2:29][C:30]([O:32][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:31])[CH2:23][C@H:22]1[CH3:33])=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: BrCc1ccccc1
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
Cs2CO3 (3.4 g, 10.5 mmol) was added to a solution of (2R,5S)-4-carboxymethyl-5-ethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester triethylamine salt (3.9 g, 9.6 mmol) in DMF (20 mL). After stirring for 2 h at room temperature, a solution of benzyl bromide (1.25 mL, 10.5 mmol) in DMF (10 mL) was added over 30 minutes. The reaction mixture was stirred overnight at room temperature and the resulting solid was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in EtOAc and washed with water. The organic phase was dried (MgSO4), filtered and concentrated and the residue was purified by SiO2 chromatography (EtOAc:Petrol 1:1) to give (2R,5S)-4-benzyloxycarbonylmethyl-5-ethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.8 g) as a pale yellow oil. 1H NMR (CDCl3): 7.45-7.29 (5H, m), 5.26-5.08 (2H, m), 4.27-4.08 (1H, m), 3.89 (1H, d), 3.52-3.22 (3H, m), 2.75 (1H, dd), 2.68-2.40 (2H, m), 1.47 (11H, d), 1.26 (3H, d), 0.90 (3H, t).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[CH:18]=[CH:17][N:16]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:14]=2[N:15]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[C:18]([C:5](=[O:7])[CH3:6])=[CH:17][N:16]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:14]=2[N:15]=1
Reactant: Clc1ncc2ccn(C3CCCC3)c2n1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cn(C2CCCC2)c2nc(Cl)ncc12
Yield: 96.7 %

Procedure:
To a solution of aluminium chloride (400 mg, 2.99 mmol) and acetyl chloride (711 uL, 10 mmol) in dichloromethane (2 mL) is added 2-chloro-7-(cyclopentyl)-7H-pyrrolo[2,3-d]pyrimidine (221 mg, 1.0 mmol) in dichloromethane (5 mL), dropwise. After 20 minutes saturated aqueous sodium bicarbonate is added to pH 9-10 and the solution is extracted with dichloromethane. The organic phase is dried, anhydrous Na2SO4 and concentrated to obtain 1-(2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethanone (255 mg, 97%) as an off-white amorphous solid (97%). 1H-NMR and LCMS.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:12]=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33].O>CN(C=O)C>[F:33][C:32]([F:34])([F:35])[C:23]1[CH:24]=[C:25]([C:28]([F:31])([F:29])[F:30])[CH:26]=[CH:27][C:22]=1[CH2:21][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:12]=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=CC1=Cc2ccc(O)cc2OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC1=Cc2ccc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc2OC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
7-Hydroxy-2H-chromene-3-carbaldehyde (200 mg) was dissolved in DMF (5 mL), and K2CO3 (235 mg) and 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (0.234 mL) were added thereto, followed by stirring at 80° C. for 30 minutes. The reaction liquid was poured into water, and the resulting powder was collected by filtration and dried under reduced pressure to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-2H-chromene-3-carbaldehyde (455 mg) as a pale yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=C)[CH:7]=1)[CH3:5].[Mn]([O-])(=O)(=O)=[O:22].[K+].S(=O)(=O)(O)O.S([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.O>[C:12]([C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:2])=[O:20])[CH:11]=[CH:10][CH:9]=1)(=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=C(c1ccccc1)c1cccc(C(C)C(=O)OC)c1
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 18 h

Procedure:
α-(3-(1-Phenylethenyl)phenyl)propionic acid methyl ester (36 g) obtained in Example 4 was dissolved in 250 ml of benzene and 250 ml of water was further added thereto with vigorous stirring to prepare a suspension. Then, 2 liter of 2% aqueous solution of potassium permanganate was dropped little by little over 1.5 hours. After the dropping, stirring was continued for 18 hours at room temperature. After the reaction, it was acidified by adding concentrated sulfuric acid and was treated by adding 35 g of sodium sulfite. After that, 500 ml of water was added and extraction was carried out three times with 150 ml of ether. The ether solution was washed with water and it was added to 5% aqueous solution of sodium hydroxide. The aqueous solution was hydrolyzed at the refluxing temperature for 5 hours. After cooling, the solution was extracted with ether. The aqueous layer was acidified by adding hydrochloric acid and extracted again with ether, which was a followed by washing with water, drying with anhydrous magnesium sulfate, and filtration. The ether was then removed by reduced-pressure evaporation. Finally, 20 g of α-(3-benzoylphenyl)propionic acid (ketoprofen) was obtained by re-crystallization from benzene/petroleum either mixture. The melting point and spectrum were the same as those of an authentic sample.
Reaction SMILES: [Br:1][C:2]1[C:12]([Br:13])=[C:11]([Br:14])[C:10]([Br:15])=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].[OH-].[NH4+:17]>O>[Br:1][C:2]1[C:12]([Br:13])=[C:11]([Br:14])[C:10]([Br:15])=[C:4]2[C:5]([NH:17][C:8](=[O:7])[C:3]=12)=[O:6]
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21

Procedure:
3,4,5,6-Tetrabromophthalic anhydride (100 grams; 0.217 mole) was charged into a glass reaction vessel. Concentrated ammonium hydroxide (300 ml) was incrementally added at room temperature with stirring. After the addition was completed the reaction slurry was heated with stirring for a period of about 2 hours resulting in the evaporation of most of the water present and leaving a yellow powder. The powder was further dried in a forced air oven and was then recrystallized from benzyl alcohol. The crystalline product was then washed with acetone, filtered and dried to yield the desired product 3,4,5,6-tetrabromophthalimide.
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.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[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]([N:38]4[CH2:39][CH2:40][C@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

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, DIPEA and (S)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.36 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 451 [M+H]
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:24])[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([Cl:16])[N:8]=1>C(O)(=O)C.[Fe]>[CH2:17]([N:6]1[CH2:5][CH:4]([CH3:24])[C:3](=[O:2])[NH:13][C:12]2[CH:11]=[N:10][C:9]([Cl:16])=[N:8][C:7]1=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C(C)CN(Cc1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1CN(Cc2ccccc2)c2nc(Cl)ncc2NC1=O
Yield: 28.8 %

Procedure:
To a solution of 2.55 g (0.007 mole) of (rac)-3-[benzyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-2-methyl-propanoic acid methyl ester in 50 mL of acetic acid, was added 2.550 g (0.0457 g-atom) of iron powder. The mixture was heated at 80 degrees for 2 hours, then filtered through Celite while still hot. The filtercake was washed with 200 mL of ethyl acetate, and the combined filtrate washed successively with 200 mL of water, 200 mL of 7.4 M ammonium hydroxide, 200 mL of water and 200 mL of brine. The aqueous layers were extracted with 200 mL of ethyl acetate, and the combined ethyl acetate layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane—hexanes to give 0.61 g of (rac)-9-benzyl-2-chloro-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-42) as off-white crystalline solid.