Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N:2]1([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)#[N:26]>ClCCl.C(OCC)(=O)C>[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:5]2[CH2:4][CH2:3][N:2]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:29][CH:28]=1)#[N:26]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C(NN1CCNCC1)c1ccc(F)cc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)N2CCN(NC(=O)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
To a stirred solution of N-piperazinyl-p-fluorobenzamide hydrobromide (300 mg) and triethylamine (0.41 ml) in dichloromethane (6 ml) was added 4-cyanobenzoyl chloride (196 mg) at 0° C. The mixture was stirred at ambient temperature for 3 hours, diluted with ethyl acetate and washed with water (×2). The organic layer was separated, dried over magnesium sulfate, and concentrated. The crystal residue was recrystallized from methanol, ethyl acetate and n-hexane to give N-[4-(4-cyanobenzoyl)-1-piperazinyl]-4-fluorobenzamide (199 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[S:22][C:23]([CH3:26])=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:23]1[S:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(OB([O-])[O-])s1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(C)s3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
In toluene/ethanol/water (10/1/1.2 ml) was dissolved methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (870 mg), and to the solution were added 5-methyl-2-thienyl borate (530 mg) and potassium carbonate (1.02 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (152 mg). The mixture was stirred at 100° C. for 16 hours, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-(5-methyl-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (210 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[OH:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[CH2:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCOc1ccc(C(=O)OCC)cc1
Yield: 33 %

Procedure:
A mixture of 50 parts of 4-bromo-1-butene, 58 parts of ethyl 4-hydroxybenzoate, 55.2 parts of potassium carbonate and 320 parts of 2-propanone was refluxed for 68 hours. The reaction mixture was evaporated and the residue was dissolved in methylbenzene. The organic solution was washed with a diluted sodium hydroxide solution. The separated organic layer was dried, filtered and evaporated, yielding 25 parts (33%) of ethyl 4-(3-butenyloxy)benzoate as an oily residue (interm. 14).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][C:12]3[C:8]4[C:9](=[N:23][CH:24]=[CH:25][C:7]=4[C:6]=2[CH:26]=1)[N:10]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=3.C([N-]C(C)C)(C)C.[Li+].[I:35]I>O1CCCC1.O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][C:12]3[C:8]4[C:9](=[N:23][CH:24]=[CH:25][C:7]=4[C:6]=2[CH:26]=1)[N:10]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=3[I:35]
Reactant: II
Reactant: C[Si](C)(C)CCOCn1cc2c3c(ccnc31)-c1cc(F)ccc1OC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: C[Si](C)(C)CCOCn1c(I)c2c3c(ccnc31)-c1cc(F)ccc1OC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Example 14G (310.0 mg, 0.837 mmol) in tetrahydrofuran (8 mL) at −78° C. was added 2M lithium diisopropylamide (1.255 mL, 2.51 mmol) in tetrahydrofuran/heptane/ethylbenzene dropwise. After 60 minutes, a solution of iodine (531 mg, 2.092 mmol) in tetrahydrofuran (3 mL) was cannulated into the reaction mixture and the mixture was stirred at −78° C. for 2 hours. The mixture was quenched with aqueous sodium thiosulfate and extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified on silica using the ISCO Companion flash system eluting with heptanes/ethyl acetate (9:1 to 8:2) to provide the title compound. MS (ESI+) m/z 496.8 (M+H)+.
Reaction SMILES: [C:1]12[C:10](=[O:11])[O:9][C:7](=O)[C:2]=1[CH2:3][CH2:4][CH2:5][CH2:6]2.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[O:20][CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>C(O)(=O)C>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[C:10](=[O:11])[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:7]2=[O:9])=[CH:15][C:14]=1[O:20][CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Cl)c(OC2CCCC2=O)c1
Solvent: CC(=O)O
Product: O=C1CCCC1Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Reaction time: 2.5 h

Procedure:
A mixture of 1.52 g. of cyclohexene-1,2-dicarboxylic anhydride, 2.26 g. of 4-chloro-3-(cyclopentanon-2-yloxy) aniline and 10 ml. of acetic acid was stirred at room temperature for 30 minutes and then was refluxed with stirring for 2.5 hours. The solvent was distilled off under a reduced pressure and then, ethyl acetate was added to the residue to extract the product. The extract was washed with water and dehydrated over sodium sulfate. The solvent was distilled off and the product was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 1:4) to obtain Compound No. 5 shown in Table 1.
Reaction SMILES: O(C1C=CC(NC2N=CN=C(N[C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27]C)=[O:26])C=2)=CC=1)C1C=CC=CC=1.[Li+].[OH-]>CO.C1COCC1.O>[C:25]([OH:27])(=[O:26])[C:24]1[CH:29]=[CH:30][CH:31]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 227.5 %

Procedure:
To a stirred solution of methyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoate (0.3 g, 0.72 mmol) in methanol/THF (2/2, 4 mL) was added LiOH (0.122 g, 2.9 mmol) in H2O (4 mL) and the reaction mixture was stirred at rt for 2 h. It was concentrated under reduced pressure. the residue was diluted with water (2 mL) and was extracted with dichloromethane (5 mL). The aqueous layer was separated and was acidified with 1.5 N HCl (pH ˜5-6) to get a white precipitate, which was collected by filtration and dried under vacuum to give 34644-phenoxyphenylamino)pyrimidin-4-ylamino)benzoic acid (0.2 g 69%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].ClC(OCC)=O.C(N(CC)CC)C.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C1COCC1.O>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:24][CH:23]=1
Reactant: CC(C)=CC(=O)O
Reactant: Nc1ccc(F)cc1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 10.0 g (0.1 mol) of 3-methyl-2-butenoic acid in 200 ml of THF is mixed with 9.4 ml (0.1 mol) of ethyl chloroformate and 14.1 ml (0.1 mol) of triethylamine at 0° C. After 10 minutes at room temperature, 10.6 ml (0.11 mol) of 4-fluoroaniline is added to it. The batch is stirred for 1 hour at room temperature, diluted with water and extracted with ethyl acetate (1 l). The organic phase is washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is purified by column chromatography on silica gel with hexane-ethyl acetate. Yield 18.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:17])[NH:12][C:13](=[S:16])[NH:14][CH:15]=2)=[CH:5][N:4]=1.Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1.C(NC(C)C)(C)C>C(Cl)Cl.CC(=O)OCC>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][S:16][C:13]3[NH:14][CH:15]=[C:10]([CH2:9][C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=4)[C:11](=[O:17])[N:12]=3)=[CH:21][CH:22]=2)=[CH:28][CH:29]=1
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: Fc1ccc(Oc2ccc(CCl)cc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 60 °C
Yield: 55.5 %

Procedure:
A mixture of 5-((2-methoxypyrimidin-5-yl)methyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (2.75 g, 10.99 mmol), 1-(chloromethyl)-4-(4-fluorophenoxy)benzene (2.6 g, 10.99 mmol) and diisopropylamine (3.34 g, 33.0 mmol) in DCM (50 mL) was heated at 60° C. overnight. After cooling to room temperature, the mixture was washed with brine, the organic phase was dried over Na2SO4, filtered and concentrated to leave the crude product, which was slurred in EA (20 mL) for 10 min, filtered, washed with EA and concentrated in vacuo to afford the title compound (2.75 g, 51.4% yield) as white solid. LCMS: rt=1.47 min, [M+H]=451.0
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]([NH:1][C:2]2[S:3][C:4]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)[N:6]=2)=[O:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2nc(-c3ccco3)c(N3CCOCC3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
2-Amino-4-(2-furyl)-5-morpholinothiazole (3.58 g, 14.3 mmol) obtained in Step 1 of Example 29, 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (3.27 g, 14.3 mmol) and PyBOP (8.16 g, 15.7 mmol) were dissolved in DMF (30 mL), and triethylamine (4.37 mL, 31.4 mmol) was added thereto, followed by stirring overnight at room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed successively with 1 mol/L hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 42 (4.52 g, 68%).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:5]=2[O:4]1.C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC#N>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH:3]([CH2:2][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:7][C:6]=2[CH:8]=1
Reactant: FC(F)(F)c1ccc2c(c1)CC(CI)O2
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccc2c(c1)CC(CN1CCNCC1)O2
Yield: 51.4 %

Procedure:
To a solution of 2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran (2.8 g, 8.5 mmol) in CH3CN (40 ml) was added potassium carbonate (2.36 g, 17.1 mmol, 2 eq) and piperazine (2.94 g, 34.1 mmol, 4 eq) at room temperature. The mixture was heated at reflux for 3 hours, the solids were filtered off, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel chromatography using 1-2.5% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine as light yellow oil (1.25 g, 51%); (ES, m/z): [M+H]+ 287; 1H NMR (300 MHz, CDCl3): δ 7.37 (d, J=9.0 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 5.00-5.10 (m, 1H), 3.26-3.35 (m, 1H), 2.96-3.04 (m, 1H), 2.88-2.95 (m, 4H), 2.78-2.80 (m, 1H), 2.54-2.69 (m, 4H).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][C:20]=1[F:21]>>[F:14][C:15]1[CH:16]=[C:17]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)[CH:18]=[CH:19][C:20]=1[F:21].[F:14][C:15]1[CH:16]=[C:17]([C:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH:3]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Product: COC(=O)c1cc2c([nH]1)CC=C2c1ccc(F)c(F)c1
Product: COC(=O)c1cc2c([nH]1)CCC2c1ccc(F)c(F)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.5 g, 2.79 mmol) was reacted with 3,4-difluorophenylmagnesium bromide (14 mL, 7.0 mmol, 0.5 M in THF) according to General Procedure 3 to give methyl 4-(3,4-difluorophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6 (with 5% Pd/C), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane affording the title compound. 0.333 g. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.16-2.27 (m, 1H), 2.70-2.98 (m, 3H), 3.75 (s, 3H), 4.22 (t, J=7.22 Hz, 1H), 6.53 (d, J=1.85 Hz, 1H), 7.02-7.07 (m, 1H), 7.11 (ddd, J=11.96, 7.86, 2.15 Hz, 1H), 7.21 (dt, J=10.68, 8.43 Hz, 1H), 10.68 (br. s, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH2:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:13]([N:9]1[CH2:10][CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: c1ccc(C2=NNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1cccnc1)N1CCC(c2ccccc2)=N1
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
3-Phenyl-2-pyrazoline (2.9 g) synthesized in Reference Example 2 was dissolved in chloroform (20 ml). Thereto were added nicotinic acid chloride hydrochloride (4 g) and triethylamine (6 ml) with ice-cooling. Stirring was conducted for 30 minutes at room temperature. The reaction mixture was washed with water and concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol:chloroform=1/100) to obtain 3.7 g of a title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[C:8]([O:10][CH3:11])[C:5]=1[CH2:6][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(O)cc(OC)c1C=O
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(O)cc(OC)c1CN1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.1 %

Procedure:
A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (0.30 g, 1.65 mmol), piperidine (0.20 mL, 1.98 mmol) and acetic acid (0.47 mL, 8.25 mmol) in methanol (20 mL) was stirred for 20 minutes before addition of sodium cyanoborohydride (0.27 g, 4.30 mmol). The reaction mixture was allowed to stir at ambient temperature for 4 h then loaded onto a 10 g SCX-2 cartridge which was then washed with methanol (30 mL) and then eluted with 2N ammonia in methanol (50 mL). Concentration of the combined basic fractions in vacuo afforded the title compound (220 mg, 53%) as a white solid. 1H NMR (DMSO-D6, 300 MHz): 9.39 (s, 1H), 6.03 (s, 2H), 3.66 (s, 6H), 3.30 (s, 2H), 2.32-2.24 (m, 4H), 1.42-1.35 (m, 4H), 1.34-1.26 (m, 2H). LCMS (Method B): RT=1.90 min, M+H+=252.
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].CN1CCNCC1[Al+]C1CNCCN1C.CCOCC>O1CCCC1>[C:1]([NH:8][C:9]([CH3:14])([CH3:13])[CH:10]=[O:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN1CCNCC1[Al+]C1CNCCN1C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
N-Boc-2-aminoisobutyric acid is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over NaSO4 and evaporated to yield N-Boc-2-amino-2-methylpropanal.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[CH3:14])([O-:3])=[O:2].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=O.[K+].[OH-:27].[Na+].[OH2:29]>>[N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH:11]([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[C:14]([OH:29])=[O:27])([O-:3])=[O:2]
Reactant: O
Reactant: [OH-]
Reactant: Cc1ccc(OC(F)F)cc1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(OC(F)F)cc1[N+](=O)[O-]
Reaction time: 7 h

Procedure:
72.1 g of 2-nitro-4-difluoromethoxytoluene and 300 ml of pyridine are refluxed. A solution of 336 g of potassium permanganate in 500 ml of water is then added in portions. The batch is subsequently held for a further 7 hours at 80° C. When cold, 500 ml of 2N sodium hydroxide solution are added, the mixture is extracted with ether, and the aqueous phase is acidified with concentrated hydrochloric acid. During this process, the product separates out as an oil which crystallizes on prolonged stirring. After filtration, washing with dilute hydrochloric acid and drying, 53.6 g of desired product are obtained in the form of white crystals (m.p. 136°-138° C.).
Reaction SMILES: [N:1]1([C:8]([NH2:10])=[NH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:9][C:8]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:10][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)N1CCCCCC1
Product: NCc1c(N)nc(N2CCCCCC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=366.0 (M+H+), was prepared from azepane-1-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: Cl.S(OS([O-])(=O)=O)([O-])(=O)=[O:3].[NH2:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](N)=[N:18][C:16]=2[N:17]=1>O>[NH2:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([OH:3])=[N:18][C:16]=2[N:17]=1
Reactant: Nc1ncc2cc(-c3ccccc3)c(N)nc2n1
Reactant: O=S(=O)([O-])OS(=O)(=O)[O-]
Agent: Cl
Solvent: O
Product: Nc1ncc2cc(-c3ccccc3)c(O)nc2n1
Reaction time: 8 h

Procedure:
To a solution of 2 L of concentrated HCl and 1 L of water is added 300 g of the disulfate salt of 2,7-diamino-6-phenylpyrido[2,3-d]pyrimidine and the resulting mixture refluxed with stirring overnight The reaction mixture is cooled in an ice bath, filtered, and the insoluble product washed with water, followed by ethanol to give 149 g of the title compound 2-amino-6-phenyl-pyrido[2,3-d]pyrimidin-7-ol, mp 390-395° C. (darkens slowly above 350° C.).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:4]=[CH:3]1.C(N(CC)CC)C.[C:19]1([C:25](Br)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[C:19]1([C:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:2]2[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:4]=[CH:3]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1c[nH]cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-imidazoleacetate hydrochloride, as described above in Step A, (4.30 g, 24.3 mmol) in dry DMF (50 mL) were added triethylamine (7.45 mL, 53.5 mmol), then triphenylmethyl bromide (8.64 g, 26.7 mmol). The mixture was stirred at ambient temperature for 18 hours, then partitioned between H2O (250 mL) and EtOAc (250 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica, eluting with EtOAc, to yield the product as a pale solid.
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:11]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([CH:27]=[CH:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CO.O1CCCC1>[C:11]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([CH:27]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:3]([C:2]([O:9][CH3:10])=[O:8])[C:4]([O:6][CH3:7])=[O:5])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COC(=O)C=Cc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC(c1ccc2c(c1)CCN2C(=O)OC(C)(C)C)C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of sodium (156 mg) in methanol (15 ml) was treated with dimethyl malonate (0.8 ml) and after stirring for 15 minutes the mixture was then treated with a solution of methyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)acrylate [1.0 g, reference Example 7(b)] in tetrahydrofuran (15 ml). The mixture was stirred at reflux for 3 hours, then cooled to room temperature, then treated with water (2 ml) and then evaporated. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with fresh ethyl acetate. The combined organic layer and extracts were washed with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (15:85, v/v) to give the title compound (530 mg) as a clear oil. MS (ES+) 458 (MNa+). MS (ES−) 434 (M−).