Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18]CC)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[CH:25]([NH2:27])=[NH:26]>>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2=[N:27][CH:25]=[N:26][C:16](=[O:18])[CH:11]2[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: N=CN
Agent: Cl
Solvent: CC(=O)O
Product: O=C1N=CN=C2CCN(Cc3ccccc3)CC12

Procedure:
Various N-substituted-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine derivatives are prepared using a general procedure described below. Accordingly, ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride is reacted with formamidine acetate to yield 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(4aH)-one, which, in turn, is reacted with POCl3 to afford the 4-chloro derivative. The intermediate chloro derivative is then condensed with substituted aniline or amine to give the desired N-substituted-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine. Debenzylation using standard procedures known in the art followed by nucleophilic displacement of an appropriate 2-halo-pyridine yields the appropriate N-substituted-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine. As a representative example, synthesis of N-(4-tert-butylphenyl)-6-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine is depicted in Scheme 1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:29][CH3:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][C:16]=2[O:17][CH2:18][C:19](O)=[O:20])(=[O:11])=[O:10])[CH:8]=1)#[N:2].Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:29][CH3:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][C:16]=2[O:17][CH2:18][C:19]([NH:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38])=[O:20])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: CCOC(=O)CN
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.9 %

Procedure:
To a stirred solution of 0.3 g of [2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetic acid, 0.107 g of glycine ethyl ester hydrochloride and 0.103 g of 1-hydroxybenzotriazole monohydrate in N,N-dimethylformamide were added 0.106 mL of triethylamine and 0.146 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride under ice-cooling, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.33 g of ethyl [2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]-acetylamino]acetate
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH2:14])[C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:14][O:23]2)[C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc(F)c2c(c1C)COC2=O
Solvent: ClCCl
Product: Cc1c(C2CO2)cc(F)c2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-fluoro-4-methyl-5-vinyl-3H-isobenzofuran-1-one (420 mg, 1.71 mmol) in 10 mL of DCM was slowly added mCPBA (741 mg, 85% purity, 3.43 mmol) in 10 mL of DCM at 0° C. After warming to room temperature, the mixture was stirred overnight. The mixture was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers was washed with brine and then concentrated. The residue was purified by column chromatography to give product 7-fluoro-4-methyl-5-oxiranyl-3H-isobenzofuran-1-one. The enantiomers of the product were resolved via SFC (Column Chiralpak AD-H 250*4.6 mm I.D., 5 μm; Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.35 mL/min; Wavelength: 220 nm). MS m/z 209 (M+1)+.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:20][C@H:21]([C:26]([N:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32][CH3:33])=[O:31])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)C(C)C>C(Cl)Cl>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:20][C@H:21]([C:26]([N:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32][CH3:33])=[O:31])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Z-Leu-OH (1 equivalent), H-Leu-Pro-OMe (1 equivalent) synthesized in (a) and TEA (1 equivalent) were dissolved in dry methylene chloride, and WSCD (1 equivalent) was added under cooling with ice. Thereafter, the mixture was stirred at room temperature for 20 hours, and the reaction mixture was washed successively with IN HCl, water, saturated aqueous sodium bicarbonate, water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under vacuum. The resulting crude product was purified by medium-pressure liquid column chromatography to obtain the end compound. Z-Leu-Leu-Pro-OMe (1 equivalent) thus obtained was dissolved in ethanol, and boron trifluoride-ether complex (1 equivalent) and palladium on carbon (a small amount) were added. The mixture was subjected to catalytic reduction in a hydrogen atmosphere to remove the Z group, and the solvent was distilled off under vacuum to obtain the end compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[NH2:9].[OH-].[Na+].[CH:12](O)=O>>[Br:8][C:4]1[C:3]2[N:9]=[CH:12][NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)c1N
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Product: Brc1cccc2[nH]cnc12

Procedure:
A solution of 1,2-diamino-3-bromobenzene (2.00 g, 10.7 mmol) in formic acid (10 mL) was stirred at 100° C. for 1 hour. The pH of the mixture was adjusted to 14 by the addition of 4 M sodium hydroxide solution, precipitating the product as a solid. This was separated by filtration, washed with water and air-dried affording the product as an off-white solid. A further crop of equally pure material precipitated from the filtrate upon standing at room temperature for a few days. Total yield=1.98 g, 94%. 1H NMR (500 MHz, d6-DMSO): δ 12.83 (1H, s), 8.30 (1H, s), 7.58 (1H, d, J=7.9 Hz), 7.41 (1H, d, J=7.1 Hz), 7.14 (1H, t, J=7.8 Hz); m/z (ES+) 197, 199 [MH+].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[CH2:22]([N:24]=[C:25]=[S:26])[CH3:23]>>[CH2:22]([NH:24][C:25]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[CH:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[CH:14]=1)=[O:19])=[S:26])[CH3:23]
Reactant: CCN=C=S
Reactant: CSc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Product: CCNC(=S)NNC(=O)c1ccc2ncn(-c3ccc(SC)cc3)c2c1
Yield: 90 %

Procedure:
In the same manner as in Reference Example 115 and using 1-[4-(methylthio)phenyl]-1H-benzimidazole-6-carbohydrazide instead of 3-[4-(methylthio)phenyl]-1-benzofuran-5-carbohydrazide and ethyl isothiocyanate instead of methyl isothiocyanate, the title compound (yield 90%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH3:12]OC(OC)N(C)C.N1CCCC1>CN(C)C=O.CO.O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:12][NH:9]2)=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCNC1
Solvent: CO
Solvent: CN(C)C=O
Product: Clc1ccc2cc[nH]c2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A mixture of 4-chloro-2-nitrotoluene (34 g, 0.2 mole), dimethylformamide dimethyl acetal (28 mL, 0.2 mole) and pyrrolidine (25 mL 0.3 mole) in dimethylformamide (DMF) is heated at 100° C. for 72 h, cooled to room temperature and concentrated in vacuo to give a deep red residue. The residue is taken up in methanol/tetrahydro-furan (1:1), treated with about 2 mL of a Raney nickel slurry and hydrogenated at atmospheric pressure. The reaction is monitored by GC, TLC and H2 uptake. After 2 hours, the hydrogenation is continued at 20 psi-40 psi for a total hydrogenation time of 24 hours. The resultant reaction mixture is filtered through diatomaceous earth. The filtercake is washed with methylene chloride and the combined filtrate is washed sequentially with 1 N HCl and saturated NaHCO3, dried over MgSO4 and concentrated in vacuo to give a brown oil residue. The residue is crystallized in hexanes to give the title product as a brown solid, 22 g (72.6 % yield), identified by IR, 1HNMR, 13CNMR and mass spectral analyses.
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:17]=1)=[O:10])=O)([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH:1]([NH:4][C:5]1[O:10][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:8][N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Nc1nnc(NCCCOc2cccc(CN3CCCCC3)c2)o1

Procedure:
The compound is prepared by a method analogous to that of Example 40 from N-isopropyl-N'-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1,2-hydrazine dicarboxamide and phosphorus oxychloride. The analytical values are summarized in Table III.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[C:24]3[C:23]4[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=4[N:17]=[C:16]([NH2:26])[C:15]=3[N:14]=[C:13]2[CH2:27][O:28][CH2:29][CH3:30])=[CH:5][CH:4]=1.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1>>[CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[C:24]3[C:23]4[CH:22]=[CH:21][C:20]([C:39]5[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=5)=[CH:19][C:18]=4[N:17]=[C:16]([NH2:26])[C:15]=3[N:14]=[C:13]2[CH2:27][O:28][CH2:29][CH3:30])=[CH:5][CH:4]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(Cc1ccc(OC)cc1)S(N)(=O)=O
Reactant: OB(O)c1cccnc1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCC(Cc1ccc(OC)cc1)S(N)(=O)=O
Yield: 53.9 %

Procedure:
4-Methoxybenzyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (1.16 g, 2.0 mmol) and pyridine-3-boronic acid (0.30 g, 2.4 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, at which time additional pyridine-3-boronic acid (0.3 equivalent) was added and the reaction was heated for an additional five hours. The work-up procedure used in Part F of Examples 125–135 was followed. The crude product was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) and then triturated with methanol, isolated by filtration, and dried for 20 hours under high vacuum at 140° C. to provide 0.62 g of 4-methoxybenzyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as a beige powder, mp 230–231.5° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2.[N+:16]([O-])([OH:18])=[O:17]>FC(F)(F)C(O)=O>[N+:16]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][C:2]1([CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)[CH2:1]2)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCC2(CC1)Cc1ccccc1C2
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC2(CC1)Cc1ccc([N+](=O)[O-])cc1C2

Procedure:
A spiro(cyclohexane-1,2'-indan)-4-one [11] [prepared as above in step (10) of the first process for producing the compounds of Process B] in the cold (at about 0° C.) in trifluoroacetic acid, has nitric acid added thereto and the low temperature maintained for from about 1 to about 4 hours, to yield a corresponding 5'-nitrospiro(cyclohexane-1,2'-indan)-4-one [29].
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2C(OC(C)(C)C)=O)=[N:4][CH:3]=1.[ClH:19].O1CCOCC1>>[ClH:19].[Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: Brc1cnc([C@@H]2CCCN2)[nH]1
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of Example 126E (5.0 g, 15.8 mmol) in 4M HCl/Dioxane (40 mL) was allowed to stir for one hour. The mixture was concentrated to afford 3.99 g (100%) of the title compound. MS (ESI) m/z 217 (M+H)+.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])[CH:15]=[CH:14]3)=[N:3][CH:2]=1.Br[CH2:34][C:35]([NH2:37])=[O:36]>CN(C=O)C>[F:32][C:29]([F:31])([F:30])[C:25]1[CH:24]=[C:23]([NH:22][C:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:4]4[C:5]5[CH2:9][N:8]([CH2:34][C:35](=[O:36])[NH2:37])[CH2:7][C:6]=5[N:1]=[CH:2][N:3]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:21])[CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)CBr
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CNC4)ccc21
Solvent: CN(C)C=O
Product: NC(=O)CN1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2C1
Reaction time: 1 h

Procedure:
5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (217 mg, 0.494 mmol) is dissolved in DMF (5 mL) and TEA (160 μl, 1.15 mmol) is added followed by 2-bromoacetamide (250 mg, 1.81 mmol). The solution is stirred at it for 1 h. The reaction is concentrated and the residue absorbed onto silica gel and separated via FCC (0-10%, 10% NH4 in MeOH:DCM) to obtain 5-(6-carbamoylmethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 497.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 10.38 (br. S., 1 H) 8.58 (s, 1 H) 8.27 (d, J=8.84 Hz, 1 H) 8.09-8.13 (m, 2 H) 7.96 (s, 1 H) 7.65 (t, J=8.08 Hz, 1 H) 7.48-7.51 (m, 2 H) 7.38 (br. S., 1 H) 7.09-7.17 (m, 2 H) 6.80 (d, J=3.03 Hz, 1 H) 4.12 (dd, J=10.61, 2.02 Hz, 4 H) 3.38 (s, 2 H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:3][OH:4].[OH-].[K+].[C:17](Cl)(Cl)=[O:18]>C1(C)C=CC=CC=1.O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@H:2]2[CH2:3][O:4][C:17](=[O:18])[NH:1]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)Cl
Reactant: N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1N[C@@H](Cc2ccc([N+](=O)[O-])cc2)CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from step (b) (4.9 g) was suspended in toluene, the suspension cooled to 0° C. and a solution of potassium hydroxide (7.0 g) in water (56 ml) added dropwise. A solution of phosgene (62.5 ml of a 12% w/v solution in toluene) was added dropwise to the resulting solution over 30 minutes and stirring continued for 1 hour. The mixture was extracted with ethyl acetate and the extracts washed with brine, dried and evaporated in vacuo to give a yellow oil. Crystallisation from ethyl acetate gave the desired product as pale yellow crystals (2.3 g).
Reaction SMILES: [Br-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13].[Li]CCCC.[CH:38]([C:41]1[CH:42]=[C:43]([CH:47]([CH3:51])[CH2:48][CH:49]=O)[CH:44]=[CH:45][CH:46]=1)([CH3:40])[CH3:39].O>C1COCC1>[CH:38]([C:41]1[CH:42]=[C:43]([CH:47]([CH3:51])[CH2:48][CH:49]=[C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=2)[CH3:13])[CH:44]=[CH:45][CH:46]=1)([CH3:40])[CH3:39]
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Reactant: CC(c1ccc2ccccc2c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=CCC(C)c1cccc(C(C)C)c1)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.6 %

Procedure:
A solution of 1-(2-naphthyl)ethyltriphenylphosphonium bromide (2.30 g, 4.62 mmol, 1.0 equiv.) in THF (16 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 2.9 mL, 4.62 mmol, 1.0 equiv.) at 0° C., the red-brown suspension was stirred at 0° C. for 15 min. 3-(3-Isopropylphenyl)butanal (1.32 g, 6.94 mmol, 1.5 equiv.) in THF (2 mL) was added, and the mixture was stirred at 0° C.→70° C. for 18 h. After addition of H2O, the aqueous layer was extracted with hexanes (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3) to yield 0.57 g (38%) of the title compound as a colorless viscous oil.
Reaction SMILES: C(OC(=O)C)C.Cl.C(OCC)(=O)C.C(O[C:19](=O)[N:20](C)[CH2:21][CH2:22][N:23]([CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=[CH:38]2)[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)(C)(C)C>CO>[CH3:45][N:41]1[C:42]2[C:37](=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:23]([CH2:22][CH2:21][NH:20][CH3:19])[CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:44][CH:43]=2)[CH:38]=[CH:39][C:40]1=[O:46]
Reactant: CN(CCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
A 4N-hydrogen chloride ethyl acetate solution(48 ml) was added to an ethyl acetate solution (300 ml) of methyl-(2-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (11.5 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. PL-HCO3(40 g) was added to the methanol solution of the residue and followed by celite filtration. The filtrate was condensed under reduced pressure to give the title compound(9.96 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([N+:15]([O-])=O)[CH:8]=1)[CH3:6]>CO.[Pd]>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])=[CH:8][C:9]=1[NH2:15]
Reactant: COCCN(C)c1ccc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COCCN(C)c1ccc(OC)c(N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2.50 g (10.4 mmol) (2-methoxy-ethyl)-(4-methoxy-3-nitro-phenyl)-methyl-amine in 100 ml methanol was added a spatula end of 10% palladium on charcoal and the mixture was then stirred for 16 hours at room temperature under an atmosphere of hydrogen. The mixture was then filtered and the filtrate concentrated in vacuo to afford 1.90 g (87 (ho) 4-methoxy-N1-(2-methoxy-ethyl)-N1-methyl-benzene-1,3-diamine as an off-white crystalline solid. ES-MS m/e (%): 211 (M+H+, 100).
Reaction SMILES: [ClH:1].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[CH2:10]([OH:12])[CH3:11]>C(OCC)C>[ClH:1].[CH2:10]([O:12][C:2](=[NH:3])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:11]
Reactant: CCOC(=O)CC#N
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)CC(=O)OCC
Reaction time: 72 h
Yield: 88 %

Procedure:
Hydrogen chloride gas was bubbled through a stirred solution of ethyl cyanoacetate (900 g. 7.96 moles), ethanol (410 ml, 7.0 moles) and diethyl ether (2.4 liters). The temperature was kept below 15° C. by use of a cooling bath. After 3.5 hours 395 g (10.8 moles) of hydrogen chloride had been absorbed. The mixture was kept in a cold room for 72 hours. Then the resulting white, crystalline product was filtered off, washed first with diethyl ether, then with petroleum-ether (b.p. 60°-80° C.) and dried under vacuum. The product weighed 1210 g (88% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:6]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:4]([NH:5][C:33]([C:24]2[CH:25]=[CH:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=2)=[O:34])[C:3]=1[O:21][CH3:22]
Reactant: COc1c(Cl)cc(F)c(N2C(=O)c3ccccc3C2=O)c1N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(Cl)cc(F)c(N2C(=O)c3ccccc3C2=O)c1NC(=O)c1ccc2ccccc2c1

Procedure:
3-Chloro-5-fluoro-2-methoxy-6-(phthalimido)aniline (0.32 g, 1 mmol), 2-naphthoyl chloride (0.23 g, 1.2 mmol), and triethyl amine (0.12 g, 1.2 mmol) were dissolved in tetrahydrofuran (20 ml) and solution refluxed for 3 hr. Solvent was then removed under reduced pressure and the residue subjected to column chromatography on silica gel. Title compound was eluted with hexane-ethyl acetate (7:3; 0.12 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:34])(=[O:33])[N:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH3:24])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([N:23]([CH3:24])[S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][N:7]4[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]4)=[CH:11][CH:12]=3)=[CH:21][CH:20]=2)(=[O:33])=[O:34])[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C1CN(Cc2ccc(-c3ccc(S(=O)(=O)N(C)c4cccc(OC)c4)cc3)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(-c3ccc(CN4CC(C(=O)O)C4)cc3)cc2)c1
Reaction time: 0.5 h
Yield: 4.3 %

Procedure:
To a stirred solution of the product of Step D (0.06 g, 0.13 mmol) in THF (3 ml) a solution of LiOH (0.006 g, 0.25 mmol) in H2O (1 ml) was added at 80° C. The mixture was stirred for 0.5 h and solvents were evaporated to dryness. The residue was purified by FCC(SiO2) to give the title compound (0.0026 g, 43%) as creamy solid. 1H-NMR (CDCl3:CD3OD) 7.58 (s, 4H); 7.58 (d, 2H, J=8 Hz); 7.56 (d, 2H, J=7.23 Hz); 7.49 (d, 2H, J=8.25 Hz); 7.13 (t, 1H, J=8.14 Hz); 6.76 (dd, 1H, J=8.33, 2.05 Hz); 6.68 (t, 1H, J=2.15 Hz); 6.58 (dd, 1H, J=7.94, 1.32 Hz); 4.25 (s, 2H); 4.21-4.02 (m, 4H); 3.70 (s, 3H); 3.38-3.32 (m, 3H); 3.13 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH2:20][CH2:21][C:22]#[N:23]>>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:21]([CH2:20][C:14]3[C:13]([O:12][CH3:11])=[CH:18][CH:17]=[CH:16][C:15]=3[F:19])[C:22]([NH2:23])=[N:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(F)ccc1C=O
Reactant: COc1cccc(F)c1CCC#N
Product: COc1cccc(F)c1Cc1cc2ccc(F)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-fluorobenzaldehyde and 3-(2-methoxy-6-fluorophenyl)propionitrile.