Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH:3]([CH2:18][CH3:19])[C:4](=O)[C:5]([NH:7][CH2:8][C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)=[O:6].C(#[N:22])C>>[CH3:2][CH:3]([C:4]1[C:5](=[O:6])[NH:7][CH:8]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:22]=1)[CH2:18][CH3:19]
Reactant: CC#N
Reactant: CCC(C)C(=O)C(=O)NCC(=O)c1cccnc1
Agent: Cl
Product: CCC(C)c1nc(-c2cccnc2)c[nH]c1=O

Procedure:
In a manner analogous to Example 1, by condensing 3-(2-amino-1,1-diethoxyethyl)pyridine with 3-methyl-2-oxopentanoic acid there is obtained rac-N-[2,2-diethoxy-2-(3-pyridyl)ethyl]-3-methyl-2-oxovaleramide as an amorphous, colorless solid. Subsequent acidic hydrolysis to rac-3-methyl-2-oxo-N-[(3-pyridylcarbonyl)methyl]valeramide hydrochloride (beige, crystalline solid, melting point 158°-159°) and ring closure gives rac-3-(1-methylpropyl)-5-(3-pyridyl)-2(1H)-pyrazinone as a yellow solid, melting point 146°-148° (from acetonitrile). The conversion into rac-2-chloro-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine is also effected analogously to Example 1. Hydrazinolysis to rac-2-hydrazino-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine in the form of beige crystals, melting point 166°-167° (from ethanol/water) and subsequent condensation with diethyl malonate gives ethyl rac-8-(1-methylpropyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 335 (M)+, which is converted by saponification into the above acid, MS: 267 (M-CO 2)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:17][O:15][C:14]([C:9]1([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 25 °C
Yield: 103.7 %

Procedure:
In a 150 mL round-bottomed flask 1-tert-butoxycarbonylamino-cyclopentanecarboxylic acid (1.00 g, 4.36 mmol) was dissolved in acetone (30 mL). Potassium carbonate (1.51 g, 10.9 mmol) was added followed by iodomethane (0.41 mL, 6.54 mmol). The reaction mixture was heated at reflux overnight then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between diethyl ether and H2O. The aqueous layer was extracted with diethyl ether. The combined organics were washed with H2O and brine then dried over Na2SO4, filtered and concentrated to afford 1.1 g (99%) of 1-tert-butoxycarbonylamino-cyclopentanecarboxylic acid methyl ester as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:7]=1[Cl:23].CC(C)=O>CO>[CH3:3][O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:7]=1[Cl:23]
Reactant: COC(=O)c1ccc(C(=O)/C=C/c2cccc(O)c2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
Sodium borohydride (25 mg, 0.66 mmol) was added to a solution of (E)-2-chloro-4-[3-(3-hydroxyphenyl)-1-oxoprop-2-en-1-yl]benzoic acid methyl ester (Example 91; 316 mg, 1 mmol) in methanol (3 mL). The solution was stirred at room temperature for 3 h, then acetone (1 mL) was added and the solution was stirred for a further 10 min. The solvent was evaporated, ethyl acetate (15 mL) was added and the solution was washed with 0.5N hydrochloric acid solution (10 mL) and brine. Each of the aqueous layers was extracted in turn with ethyl acetate (10 mL). The combined organic layers were dried (MgSO4), filtered, evaporated and the resulting solid was triturated with diethyl ether to furnish rac.-(E)-2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoic acid methyl ester (310 mg, 97% yield) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>Cl>[CH3:13][C:12]([NH:6][C:5]1[CH:4]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of 161.0 g of α, α, α-trifluoro-m-toluidine in 500 ml of 2N hydrochloric acid, at room temperature, with vigorous agitation, is added rapidly 102.0 g of acetic anhydride. An exothermic reaction occurs and the temperature is allowed to rise spontaneously to about 50°. Subsequently, the mixture is allowed to cool to room temperature, and then cooled in ice. The crystalline solid is filtered to give 189.3 g of α,α,α-trifluoro-m-acetotoluidide.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>C1COCC1>[CH3:21][O:20][C:18]([C:13]1([CH2:26][CH2:25][CH2:24][CH2:23][Br:22])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: COC(=O)C1CCCC1
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CCCCBr)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of diisopropylamine (150 mmol, 21 mL) in THF (100 mL) at −10° C. was added dropwise a 2.5M solution of n-butyl lithium in hexanes (145 mmol, 58 mL) while maintaining the temperature below 0° C. After the addition was complete, the solution was stirred for 30 min at 0° C., then it was cooled to −70° C. using a dry ice/acetone bath. A solution of methyl cyclopentanecarboxylate (100 mmol, 13.1 g) in THF (20 mL) was added dropwise at −70° C. maintaining the reaction temperature between −60 to −70° C. The mixture was then stirred for 1 h at −50 to −60° C. and a solution of 1,4-dibromobutane (100 mmol, 21.59 g) in THF (20 mL) was added dropwise and the light brown suspension was stirred for 1 h at −60 to −70° C. The cooling bath was removed and the reaction was allowed to equilibrate to room temperature and stirred overnight. The reaction mixture then was poured into a saturated solution of ammonium chloride (200 mL) and the mixture was extracted with diethyl ether (2×100 mL). The combined extracts were washed with brine (150 mL), dried (MgSO4), filtered and the solution was concentrated under reduced pressure. The resulting residue was distilled at 120-133° C./2.5 mm Hg to obtain 12.8 g (48%) of 1-(4-bromobutyl)cyclopentanecarboxylic acid methyl ester as a colorless oil. HR MS: Obs. mass, 262.0565. Calcd. mass, 262.0568, (M+).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:34][CH2:33][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25]1>>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([CH:25]2[CH2:26][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:33][CH2:34][NH:24]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1CCNC(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
Following the procedure set out in Example 1, 3.0 parts of 3,3,3-triphenylpropionyl chloride and 2.0 parts of ethyl isonipecotate are reacted to provide 2-(3,3,3-triphenylpropionyl)-4-ethoxycarbonyl piperidine. Reduction of 5.0 parts of this material with 3.0 parts of lithium aluminum hydride in tetrahydrofuran provides 1-(3,3,3-triphenylpropyl)-4-hydroxymethylpiperidine, melting at 142.5°-144°. This compound has the following structural formula. ##STR47##
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH:3](OC(C)(C)C)N(C)C.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:14][CH2:15][CH3:16]>>[CH3:1][N:2](/[CH:12]=[C:14](\[CH2:15][CH3:16])/[C:13]([O:18][CH2:19][CH3:20])=[O:17])[CH3:3]
Reactant: CCCC(=O)OCC
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CCOC(=O)/C(=C/N(C)C)CC

Procedure:
The title compound was prepared from N,N,N′,N′-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine and ethyl butanoate according to the procedure for the preparation of Example 84, part A. [M+H] Calc'd for C9H17NO2, 172. Found, 172.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)C1Cc2ccccc2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1Cc2ccccc2N1C(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of indoline-2-carboxilic acid (6.52 g, 40 mmol) and triethyl amine (11 mL, 78 mmol) in anhydrous CH2Cl2 (100 mL) was added dropwise a solution of benzoyl chloride (5.62 g, 40 mmol) in CH2Cl2 (25 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min and then at room temperature for additional 2.5 hours. The reaction mixture was washed successively with 5% aqueous KHSO4 solution (2×20 mL), brine (25 mL), dried over Na2SO4, and evaporated under reduced pressure to dryness. The residue was chromatographed on a silica gel column (3×35 cm) using CHCl3/MeOH (100:1) as the eluent. The main fractions containing the desired product was combined, evaporated under reduced pressure to dryness and the solid residue was recrystallized from MeOH to give the known 1-benzoyl-2,3-dihydro-1H-indole-2-carboxylic acid, 10.66 g (81%): mp 209-210° C. (191-193° C.)19; 1H NMR (DMSO-d6) δ 3.09 (1H, d, J=16.3 Hz, CH), 3.61-3.63 (1H, m, N—CH), 4.97 (1H, brs, CH), 7.06 (1H, m, ArH), 7.25-7.26 (2H, m, 2×ArH), 7.49 (5H, m, 5×ArH), 8.14-8.17 (1H, m, ArH), 13.01 (1H, brs, exchangeable, OH). MS: m/z 268.0 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].C([Li])CCC.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH2:20][CH2:21][CH2:22][CH3:23])[CH3:19])=[O:17].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH2:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:3]#[C:2][CH2:1][OH:4])[CH2:21][CH2:22][CH3:23]
Reactant: C#CCO
Reactant: CCCCN(C)C(=O)CCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)CCCCCC#CCO
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
A solution of 1.77 ml of propargyl alcohol, 30 ml of tetrahydrofuran and 7.5 ml of hexamethyl phosphotriamide cooled to −60° C. was admixed with 37.5 ml of a 1.6M solution of butyl-lithium in hexane and after stirring for 45 minutes at −30° C., 7 g of the product of Step A in solution in 7 ml of tetrahydrofuran were added. The mixture was stirred for 16 hours at ambient temperature and then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with 2N hydrochloric acid and with a saturated solution of sodium bicarbonate, dried and evaporated to dryness. The 5.78 g of residue were chromatographed on silica (eluant: methylene chloride—ethyl acetate 70-30, then methylene chloride—isopropanol 95-5) to obtain 1.65 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Br[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13]>C(O)C>[Br:1][C:2]1[N:7]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CCO
Product: FC(F)(F)c1cn2c(Br)cccc2n1
Yield: 84.6 %

Procedure:
6-Bromopyridin-2-amine (20.0 g, 116 mmol) and 3-bromo-1,1,1-trifluoroacetone (24.0 mL, 231 mmol) were dissolved in ethanol (200 mL), and the mixture was heated under reflux for 4 days. The precipitated solid was collected by filtration and dissolved in dichloromethane. The solution was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (26.0 g, yield 85%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.S(=O)(=O)(O)O.[Br:10][C:11]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:12]=1[NH2:13].[BH4-].[Na+]>O1CCCC1>[Br:10][C:11]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:12]=1[NH:13][CH:2]([CH3:4])[CH3:1]
Reactant: Cc1cc(N)c(Br)cc1C
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)c(NC(C)C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of acetone (5.60 mL, 76.3 mmol) and aqueous 4 M sulfuric acid (5.20 mL, 20.8 mmol) in tetrahydrofuran (15 mL) was added dropwise to a stirred solution of 2-bromo-4,5-dimethylaniline 1-8 (13.9 g, 69.3 mmol) in tetrahydrofuran (40 mL) at approximately 0° C. Sodium borohydride (2.62 g, 69.3 mmol) was added cautiously and the resulting mixture allowed to warm to ambient temperature. After 30 min, the reaction was quenched by the careful sequential addition of water (25 mL) and sodium hydroxide pellets (until strongly alkaline). The reaction mixture was extracted with tert-butyl methyl ether (150 mL) and the organic phase was washed with brine, dried (sodium sulfate) and concentrated in vacuo to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-20% ethyl acetate/hexanes as eluent) afforded 1-9 as a clear, pale orange oil.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Reactant: Cc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C)c2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (1.0 g, 3.89 mM), 3-methylbenzyl bromide (0.54 ml, 3.97 mM), and potassium carbonate (1.07 g, 7.78 mM) in 20 mL DMF was stirred at room temperature for 19 hours. The mixture was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous layer extracted with EtOAc. The combined EtOAc layers were extracted with 1N HCl, water, then brine. After drying (NaSO4), evaporation in vacuo afforded 1.41 g (100%) of 9-[(3-methylphenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ 7.4-7.05 (m, 6H), 6.8 (m, 1H), 5.3 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.7-2.3 (m, 4H), 2.3 (s, 1H), 1.2 (d, J=7 Hz, 3H). MS (ES) m/e 362.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH2:20]([N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1)[CH3:21]>>[CH2:20]([N:22]([CH3:30])[C:23]1[N:24]=[CH:25][C:26]([NH:29][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[O:9][C:10]=2[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:27][CH:28]=1)[CH3:21]
Reactant: CCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2Br)oc1C(F)(F)F
Product: CCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3Br)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-ethyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C19H16BrF3N4O2 (m/e) 469, obsd 470 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:21])[CH3:2].[CH3:22][O:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:25][CH2:24][O:23][CH3:22])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:21])[CH3:2]
Reactant: CCn1c(=O)ccc2cnc(Nc3ccc(O)cc3)nc21
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(OCCOC)cc3)nc21
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 8-ethyl-2-(4-hydroxyphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (92 mg, 0.33 mmol), 2-methoxyethyl bromide (55 mg, 0.40 mmol) and potassium carbonate (360 mg, 2.61 mmol) in 5 mL of dimethylformamide was heated at reflux for 5 minutes. After cooling to room temperature, water was added, and the resultant solid collected by filtration. The solid was dissolved in ethyl acetate and the solution dried over magnesium sulfate, filtered, concentrated, and purified by flash chromatography eluting with ethyl acetate to provide 92 mg (56%) of 8-ethyl-2-[4-(2-methoxyethoxy)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one, mp 169-171° C.
Reaction SMILES: [F:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[F:1][C@H:2]1[C@H:7]([O:8][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)[C@H](F)C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 10.1 %

Procedure:
A solution of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (52.76 g, 241 mmol) dissolved in anhydrous methylene chloride (1 L) was cooled to 0° C. and treated with triethylamine (43.6 mL, 313 mmol) followed by methanesulfonyl chloride (20.5 mL, 265 mmol). The solution was allowed to warm slowly to ambient temperature and stirred for 14 hours. The mixture was partitioned between saturated NaHCO3 (400 mL) and methylene chloride (400 mL). The aqueous layer was extracted with methylene chloride. The combined organic phases were washed with 1N HCl and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexanes:EtOAc to provide the desired product (7.24 g).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c2ccccc12
Reaction time: 5 h

Procedure:
4-Fluoro-1-nitro-naphthalene (1 g) was dissolved in EtOAc (20 mL) and placed into a hydrogenating flask containing Palladium on activated charcoal (10%, 0.3 g). The reaction mixture was hydrogenated at 50 psi for 5 hr. During the reaction, the pressure of the hydrogen dropped due to the consuming of the hydrogen, and it was brought back to 50 psi a few times. Finally, the reaction stopped when all the starting material was used. The resulting solution was 5 filtered through a pad of celite and washed with EtOAc (20 mL). The clear filtrate was concentrated and dried under vacuum to yield 4-Fluoro-1-aminonaphthalene.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[N:11]([O-])=[O:12].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[N:11]=[O:12]
Reactant: O=N[O-]
Reactant: Cn1c(=O)cc(N)[nH]c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(N)c(N=O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione (6 g, 42.6 mmol) in acetic acid (50 mL) was added a solution of sodium nitrite (6.8 g, 98.6 mmol) in water (20 mL) dropwise, then the mixture was stirred at room temperature for 1 h. The mixture was filtered, the filter cake was washed with water and ethanol and dried under vacuum to give 6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione as violet solid, which was used directly in the next step.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[K].Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-])=O>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[NH:19][C:13]=2[CH:14]=1
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [K]
Product: O=C1Nc2cc(Cl)ccc2Oc2ccccc21

Procedure:
The title compound was prepared according to the procedures reported in Coyne et al (J. Med. Chem., 1967, 10:541). Briefly, this entailed coupling potassium salicylaldehyde with 2, 5-dichloronitrobenzene, followed by oxidation to the carboxylic acid, reduction of nitro, and finally ring closure, to yield the desired 8-chloro starting material.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+].O>CS(C)=O>[CH3:10][O:11][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccnc1OC
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-3-methoxy-pyridine (110 g) in DMSO (1 L) was added sodium methoxide (124 g). The reaction mixture was heated to 80° C. overnight. The reaction mixture was poured into 3 L water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:31])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([CH:16]=[CH:17][C:18]([NH:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)=[O:19])[CH:7]=[CH:6][C:5]1=2.I[CH3:33].O>CN(C=O)C>[CH3:33][N:20]([C:18](=[O:19])[CH:17]=[CH:16][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([CH3:31])([CH3:3])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:9]=1)[C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(NC(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)C(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
300 mg (10 mmol) of sodium hydride (80% in oil) and 30 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. A solution of 1.8 g (4.8 mmol) of methyl 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acryloylamino]benzoate (prepared in Example 2 (a)) in 50 ml of DMF is added dropwise and the mixture is stirred until the evolution of gas has ceased. 750 μl (12 mmol) of iodomethane are then added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The solid obtained is triturated from hexane, filtered off and dried. 1.6 g (83%) of the expected methyl ester, with a melting point of 167-8° C., are collected.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:26])[CH2:23][C:24]#[N:25])[CH2:5][CH2:4]1.Cl[Sn]Cl>CCOC(C)=O>[F:1][C:2]([F:28])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:26])[CH2:23][C:24]#[N:25])[CH2:5][CH2:4]1
Reactant: CNc1cc(N(C)CC#N)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: CNc1cc(N(C)CC#N)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-cyanomethyl-amino]-4-methylamino-5-nitro-benzoic acid amide (50 mg, 0.12 mmol), SnCl2 (134 mg 0.59 mmol and 5 mL EtOAc is stirred at reflux for 4 h. The mixture is diluted with EtOAc, washed with sat aq NaHCO3, filtered through a pad of celite and the celite pad is washed with EtOAc. The combined organic phases are dried with Na2SO4, filtered and concentrated.