Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:26][C:27]1([CH3:40])[C:31]([CH3:33])([CH3:32])[O:30][B:29]([C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)[O:28]1.[C:41]([O:45][C:46](=[O:52])[CH2:47][CH2:48][C:49](O)=[O:50])([CH3:44])([CH3:43])[CH3:42].C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[O:50]=[C:49]([N:37]1[CH2:36][CH:35]=[C:34]([B:29]2[O:28][C:27]([CH3:40])([CH3:26])[C:31]([CH3:32])([CH3:33])[O:30]2)[CH2:39][CH2:38]1)[CH2:48][CH2:47][C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:52]
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.5 %

Procedure:
HATU (3.68 g) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (1.98 g), 4-tert-butoxy-4-oxobutanoic acid (1.686 g), N,N-diisopropylethylamine (3.38 mL), and DMF (20 mL) at 0 C, and the obtained mixture was stirred at room temperature for 3 days. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to obtain the title compound (1.84 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[H-].[Na+].CS(O[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26][CH2:25]3)[C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc([N+](=O)[O-])cc32)CC1
Yield: 98 %

Procedure:
6-Nitro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 83) (776 mg, 4 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (5.6 mmol) as described for Intermediate 2. The product precipitated upon quenching of the reaction mixture with water and was isolated by filtration in 98% yield, yellow solid.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOCC1.O.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>CCOC(C)=O.C/C(/O)=C/C(C)=O.C=C.C=C.[Rh].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([CH:19]2[CH2:20][CH2:21][CH2:22][C:17](=[O:23])[CH2:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1C=CCCC1
Agent: [Rh]
Agent: C=C
Agent: CC(=O)/C=C(/C)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCCC(c2ccccc2)C1
Temperature: 120 °C
Yield: 33.4 %

Procedure:
To a solution of phenylboronic acid (0.630 g, 5.17 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.0193 g, 0.0310 mmol) in 10:1 dioxane/water (2.5 ml) was added acetylacetonatobis(ethylene)rhodium(I) (0.00800 g, 0.0310 mmol), and the reaction was degassed with argon. To this was added cyclohex-2-enone (0.100 ml, 1.03 mmol), and the reaction was heated to 120° C. for 16 hours in a screw-top vial. The reaction was allowed to cool to ambient temperature, diluted with EtOAc, and washed with twice with saturated sodium bicarbonate and once with saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system eluting with a linear gradient of 5-50% EtOAc in hexanes to yield 60 mg of the title compound (33.3% yield).
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH2:17][CH:18]([Cl:20])Cl)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[CH:21]1([N:24]2[CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=[N:25]2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:20]/[CH:18]=[CH:17]/[O:16][C:3]1[C:2]([C:27]2[CH:26]=[N:25][N:24]([CH:21]3[CH2:23][CH2:22]3)[CH:28]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([CH3:15])[N:8]2[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)N1c2ccc(Br)c(OCC(Cl)Cl)c2CC[C@@H]1C
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(O/C=C/Cl)c2CC[C@@H]1C
Temperature: 100 °C
Reaction time: 15 h
Yield: 29.3 %

Procedure:
A 50-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen and charged with 1-[(2S)-6-bromo-5-(2,2-dichloroethoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (43 mg, 0.11 mmol), 1-cyclopropyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 mg, 0.17 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol), potassium carbonate (31 mg, 0.22 mmol), 1,4-dioxane (24 mL), and water (4 mL). The resulting mixture stirred for 15 h at 100° C. in an oil bath. After cooling to room temperature, the reaction mixture was passed a short pad of celite and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with dichloromethane/methanol, 50:1 then 20:1) to afford (S,E)-1-(5-(2-chlorovinyloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (12 mg, 26%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.05-1.15 (m, 7H), 1.35-1.58 (m, 1H), 2.21 (s, 3H), 2.25-2.50 (m, 2H), 2.80-2.93 (m, 1H), 3.65-3.75 (m, 1H), 4.61 (s, 1H), 4.70-4.85 (m, 1H), 5.52 (d, J=4.20 Hz, 1H), 6.52 (d, J=4.20 Hz, 1H), 7.15-7.25 (m, 1H), 7.54 (d, J=8.40 Hz, 1H), 7.89 (s, 1H), 8.07 (s, 1H). MS (ESI, pos. ion) m/z 372 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:57]=[CH:56][C:6]([C:7]([O:22][CH2:23][C@@:24]2([CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][N:53]=[N+]=[N-])[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][SiH2:39][C:40]([CH3:45])([CH3:44])[CH:41]([CH3:43])[CH3:42])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:65][C:66]([F:73])([F:72])[C:67](OCC)=[O:68]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:57]=[CH:56][C:6]([C:7]([O:22][CH2:23][C@@:24]2([CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:67](=[O:68])[C:66]([F:73])([F:72])[F:65])[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][SiH2:39][C:40]([CH3:45])([CH3:44])[CH:41]([CH3:43])[CH3:42])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(C(OC[C@@]2(C=CCCCCCN=[N+]=[N-])O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(OC[C@@]2(C=CCCCCCNC(=O)C(F)(F)F)O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 76.5 %

Procedure:
To Compound (5) (450 mg, 0.56 mmole) in dry methanol (7.5 mL) was added under stirring 1,3-propanedithiol (0.284 mL, 2.82 mmole) followed by triethylamine (0.394 mL, 2.82 mmole). The mixture was stirred at room temperature for 5 days. The mixture was diluted with methanol (7 mL) and ethyl trifluoroacetate (0.675 mL, 5.6 mole) and triethylamine (0.237 mL, 1.7 mole) was added. Stirring at room temperature was continued for 24 hours. The resulting suspension was diluted with dichloromethane (5 mL) and the solvent was removed under reduced pressure. Column chromatography on silica gel with ethyl acetate/hexane mixtures gave 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-(7-trifluoroacetamido-1-hepten-1-yl)-thymidine (6) (371 mg, 76%), m.p. 75°-76° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1.O>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:14]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a 0° C. suspension of NaH (60% in mineral oil, 658 mg, 16.5 mmol) in THF (20 mL) under nitrogen was slowly added a solution of imidazole (1.03 g, 15.1 mmol) in THF (20 mL). The resulting suspension was stirred at 0° C. for 15 minutes, then ethyl bromoacetate (2.2 mL, 20 mmol) was added. The reaction was stirred at room temperature for 4.5 hours, then was diluted with H2O (25 mL). The THF was evaporated under reduced pressure and the remaining aqueous solution was extracted with CH2Cl2 (25 mL×3). The combined organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH2Cl2/MeOH, 19:1) gave the ester as a yellow liquid (1.52 g, 9.87 mmol, 65%). 1H NMR (CDCl3) δ 1.28 (t, 3H, J=7.1 Hz), 4.24 (q, 2H, J=7.1 Hz), 4.68 (s, 2H), 6.95 (s, 1H), 7.09 (s, 1H), 7.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:14]([O:16]CC)=[O:15])=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)Oc1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(OC(CCCCCc2ccc(Cl)cc2)C(=O)O)cc1
Temperature: 40 °C

Procedure:
A mixture of 3.25 g (9 mmol) of ethyl 7-(4-chlorophenyl)-2-(4-methylphenoxy)heptanoate, 15 ml of 1N caustic potash solution and 45 ml of methanol is heated for 3 h, with stirring, at 40° C. Then the methanol is evaporated in vacuo, the aqueous solution is washed with ether and acidified with dilute hydrochloric acid. The precipitated oil is taken up in ether and the ether solution is dried and concentrated by evaporation. The residue is ground with ligroin. 2.7 g (86% of theory) is obtained of 7-(4-chlorophenyl)-2-(4-methylphenoxy)heptanoic acid, M.P. 74°-76° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[CH:25]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(OC(C)C)cc3)c1)N2
Temperature: 120 °C
Yield: 61.5 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.43 g, 1.1 mmol), 4-isopropoxy benzeneboronic acid (0.40 g, 2.2 mmol), bis(triphenylphosphine)palladium (II) chloride (77 mg, 0.11 mmol) and 2 M sodium carbonate (1.6 mL, 3.2 mmol) in dioxane (10 mL) was heated for 3 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.30 g, 62%) as a white solid: LC/MS m/e calcd for C29H33NO3 (M+H)+: 444.6, observed: 444.1.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[CH:33]=[CH:32][C:16]3[N:17]([CH3:31])[C:18]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=5[N:25]=4)=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.[BH-](OC(C)=O)(OC(C)=O)[O:35][C:36]([CH3:38])=O.[Na+]>C(Cl)Cl>[OH:35][CH2:36][CH2:38][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[CH:33]=[CH:32][C:16]3[N:17]([CH3:31])[C:18]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=5[N:25]=4)=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCNCC3)ccc21
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(CCO)CC3)ccc21
Yield: 27.4 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [1-(2-hydroxy-ethyl)piperidin-4-ylmethyl]-amide (35 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (piperidin-4-ylmethyl)-amide dihydrochloride (135 mg), [1,4]dioxane-2,5-dio (65 mg), and Na(OAc)3BH (95 mg) in DCM (2 mL). LC/MS: m/z 498.5.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1>CO>[N:17]1([C:2]2[CH:16]=[CH:15][C:5]([C:6]([C:8]3[NH:9][C:10](=[O:14])[NH:11][C:12]=3[CH3:13])=[O:7])=[CH:4][CH:3]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Reactant: c1ccc2[nH]cnc2c1
Solvent: CO
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 185 °C

Procedure:
1,3-Dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one (4.4 g, 20 mmol) is combined with 1H-benzimidazole (30 g, 254 mmol) in a sealed flask with stirring, and the mixture heated at about 185° C. for about 7 hr. The mixture is cooled, 120 mL of methanol is added and the mixture stirred in an ice bath. The suspension is filtered and the filter cake washed with water and acetone. The remainder of the process is carried out as in Example IV to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([N+:19]([O-])=O)=[CH:13][C:12]=1[O:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH2:19])=[CH:13][C:12]=1[O:22][CH3:23])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1CCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCNC(=O)OC(C)(C)C)c(OC)cc1N
Yield: 90.7 %

Procedure:
27 g (83 mmol) N-t-butoxycarbonyl-4-nitro-2,5-dimethoxyphenethylamine J3 was dissolved in 300 ml methanol, and 1.5 g 10% palladium on carbon black was added. This suspension was hydrogenated at 2.2 atm. for 18 hours till no further hydrogen uptake was observed. The catalyst was filtered off and the solvent was evaporated to afford 22.3 g white powder (yield: 98%). 1H-NMR (CDCl3), δ (ppm): 1.40 (s, 9H), 1.55 (s, 2H), 2.65 (t, 2H), 3.25 (t, 2H), 3.70 (s, 3H), 3.80 (s, 31H), 6.30 (s, 1H), 6.58 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(=O)c2ccc(N3CCCCC3)cc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 3.73 g of 1-acetyl-4-(4-fluorobenzoyl)piperidine and 3.0 ml of piperidine was stirred at 100° C. for 24 hours and the reaction mixture was then dissolved in 100 ml of ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and the organic Layer was dried over anhydrous magnesium sulfate. The solvent was then removed and the residue was recrystallized from ethyl acetatehexane to give 3.7 g of the title compound as colorless crystals melting at 122°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([Cl:16])[N:10]=[C:9]([Cl:17])[N:8]=1.[C:23](=O)([O-])O.[Na+].CI.C(OC(C)C)(C)C>C(Cl)Cl.CCCCCC.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:23])=[O:14])=[C:11]([Cl:16])[N:10]=[C:9]([Cl:17])[N:8]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(CNc2nc(Cl)nc(Cl)c2C(=O)O)cc1Cl
Agent: [Na+]
Solvent: CI
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: COC(=O)c1c(Cl)nc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2,6-dichloropyrimidine (prepared in the above (1)) 17.55 g, sodium hydrogen carbonate 4.07 g, methyl iodide 5.48 ml and dimethylformamide 50 ml is stirred overnight at room temperature. The reaction mixture is diluted an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give a pale yellow solid. The solid is suspended in a mixture of methylene chloride, isopropyl ether and hexane, and filtered. The precipitate is washed with a mixture of isopropyl ether and hexane to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-2,6-dichloropyrimidine as a colorless crystalline powder 8.64 g. mp 118-119° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:8][N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)CNC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)c1ccncc1

Procedure:
17 g (113 mmol) of 4-chloropyridine, 17 g (111 mmol) of ethyl (methylamino)acetate and 47 ml (333 mmol) of triethylamine were stirred in 350 ml of xylene at 130° C. for 24 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10]N(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[C:4]([Cl:9])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: COc1ccc(Br)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-chlorophenol (7.0 g, 33.0 mmol, 1 eq), N,N-dimethylformamide (50 mL) and cesium carbonate (8.5 g, 42.0 mmol, 1.2 eq) was stirred at room temperature then iodomethane (2.5 mL, 1.2 eq) was added. The mixture was heated to 50° C. overnight, cooled to room temperature and treated with water (500 mL). The reaction was extracted with dichloromethane, dried (sodium sulfate) and concentrated in vacuo. The crude was purified by flash chromatography eluting with cyclohexane. 7.5 g of clean product in a quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][Sn](C)(C)C.[F-].[K+].O>CN(C)P(N(C)C)(N(C)C)=O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:4]([C:3]1[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:11]
Reactant: C[Sn](C)(C)C
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: N#Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.5 %

Procedure:
A mixture of 2-chloronicotinic acid chloride (8.8 g, 49.5 mmol), tetramethyltin (5.5 mL, 40 mmol) and bis(benzonitrile)palladium(II) chloride (0.385 g) in 20 mL of hexamethylphosphoramide was stirred at room temperature for 20 hours. The mixture was stirred with 50 mL of 10% potassium fluoride and then poured into 50 mL of water. The mixture was extracted with diethyl ether (4×50 mL) and the combined extracts were washed with water, saturated sodium bicarbonate and sodium chloride, dried (Na2SO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (3:1) to give 3-acetyl-2-chloropyridine (4.2 g, 27 mmol).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH:19]1([Mg]Br)[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH:19]1([CH:15]([C:12]2[CH:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][CH:7]=3)=[N:10][CH:11]=2)[OH:16])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCC1
Reactant: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Solvent: C1CCOC1
Product: OC(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a −78° C. solution of 2-(4-(trifluoromethyl)phenyl)pyrimidine-5-carbaldehyde (1.0 g, 3.96 mmol) in THF (6 mL) was added cyclopentylmagnesium bromide (2.97 mL of a 2.0M solution in THF, 5.95 mmol). The solution was stirred at 0° C. for two hours. The mixture was quenched with saturated aqueous NH4Cl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methanol (1.0 g) as a red oil.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[C:11]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:38])=[C:24]([NH:26][C:27](=[O:37])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[NH2:36])[CH:25]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C>C(O)(=O)C>[C:11]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:38])=[C:24]([N:26]2[C:27](=[O:37])[C:28]3[C:29](=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[N:36]=[CH:1]2)[CH:25]=1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)c(N)c1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(=O)n(-c3cc(NC(=O)c4ccccc4)ccc3Cl)cnc2c1

Procedure:
Triethyl orthoformate (0.189 ml) was added to a stirred mixture of N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide (0.15 g), ethanol (10 ml) and glacial acetic acid (0.022 ml) and the resultant mixture was heated to 70° C. for 16 hours. The mixture was evaporated. The residue was partitioned between methylene chloride and a saturated aqueous solution of sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated and the residue was triturated under a mixture of ethyl acetate and diethyl ether. The material so obtained was further purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.054 g); NMR Spectrum: (DMSOd6) 3.92 (s, 3H), 7.12-7.22 (m, 2H), 7.48-7.6 (m, 3H), 7.68 (d, 1H), 7.88-8.0 (m, 3H), 8.04-8.12 (m, 2H), 8.28 (m, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 406 and 408.