Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.C(#N)C.O>[Cl:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]([CH3:14])[C:9](=[O:13])[CH:10]=1
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C(=O)O)c(Cl)cc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.2 %

Procedure:
4-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (2.65 g, 12.3 mmol) was dissolved in a mixture of tetrahydrofuran (16 mL), acetonitrile (16 mL) and water (8 mL). Sodium hydroxide (1.23 g, 30.8 mmol) was added and the reaction mixture was allowed to stir at ambient temperature for 24 h. The reaction mixture was diluted with water (50 mL) and was acidified to pH 2 with 1 M hydrochloric acid and was extracted many times with ethyl acetate (about 1 L). The extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to afford an orange-tinged solid. Crystallization from methanol-ethyl acetate afforded 4-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0.859 g, 37% yield) as an off-white solid: 1H NMR (DMSO-d6, 400 MHz) δ 13.02 (br s, 1H), 8.58 (s, 1H), 6.58 (s, 1H), 3.48 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]([C:18]#[N:19])([CH:15]([CH3:17])[CH3:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH:2]=[CH2:3].N(C(C)(C)C#N)=NC(C)(C)C#N.[BrH:32].C(=O)([O-])[O-].[K+].[K+]>C1CCCCC1.CCCCCC>[Br:32][CH2:3][CH2:2][CH2:1][C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)([CH:15]([CH3:17])[CH3:16])[C:18]#[N:19]
Reactant: C=CCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C
Reactant: Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Yield: 94 %

Procedure:
To a solution of 50 g of α-allyl-α-isopropyl-3,4-dimethoxy- benzyl cyanide and 2 g of azobisisobutyronitrile in 400 ml of cyclohexane (or n-hexane) gaseous hydrogen bromide was introduced for 70 minutes, when, according to GLC, the reaction mixture did not contain the starting allyl derivative. During the introduction of the hydrogen bromide, the reaction temperature raised to 40° C. The reaction mixture was neutralized with 200 ml of 30% solution of potassium carbonate. The separated cyclohexane solution of the product was washed with water until neutral pH. After drying and evaporating the solvent under diminished pressure, the crude product (61.7 g, 94%) was obtained, which could be used without purification in further reaction step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Mg:12].II.[Cl-:15]>CCOCC>[C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][Mg:12][Cl:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCCCCc1ccccc1
Reactant: [Cl-]
Reactant: [Mg]
Agent: II
Solvent: CCOCC
Product: Cl[Mg]CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
220 ml. of a solution of (4-chlorobutyl)benzene (1083 g., 6.42 mole) in 1280 ml. of ether is added to a flask containing magnesium (241.6 g., 0.9 mole) in 834 ml. of ether. The mixture is refluxed and a few crystals of iodine are added. The reaction initiates after about 30 minutes. When the initial reaction subsides, the remaining chloride solution is added at a rate sufficient to maintain reflux (addition time about 1.5 hours). Reflux is maintained an additional 2.5 hours and the mixture is cooled and allowed to stir overnight under argon at room temperature to give the Grignard solution, (4-phenylbutyl)magnesium chloride.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16](OC)[O:17]C)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C(O)=O>O>[CH2:1]([N:4]([CH2:15][CH:16]=[O:17])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC(OC)OC)C(=O)OCc1ccccc1
Solvent: O=CO
Solvent: O
Product: C=CCN(CC=O)C(=O)OCc1ccccc1
Yield: 100.2 %

Procedure:
A solution of benzyl N-allyl-N-(2,2-dimethoxyethyl)carbamate (30 g, 107 mmol) in formic acid (36.8 mL, 860 mmol) and water (4.84 mL) is stirred at room temperature overnight. The mixture is concentrated and diluted with hexanes/ethyl acetate (1:2) and water. The organic layer is separated, washed with brine solution until pH=6, and dried over sodium sulfate. The solvent is evaporated to give the title compound (25 g, 99%). ES/MS (m/e): 234 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:29])([CH3:28])[CH:21]([NH2:27])[C:22]1[S:23][CH:24]=[CH:25][N:26]=1>>[CH3:19][C:20]([CH3:29])([CH3:28])[CH:21]([NH:27][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:22]1[S:23][CH:24]=[CH:25][N:26]=1
Reactant: CC(C)(C)C(N)c1nccs1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2,2-Dimethyl-1-thiazol-2-yl-propylamine (CAN 1247122-26-4) as starting materials and isolated (15 mg, 32%) as a white solid; MS (ESI, m/z): 414.5 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6](CCC(C)C)[C:7]([CH2:9][OH:10])=[N:8][C:4]=2[CH:3]=1.BrC1C(N)=C(N)C=CC=1>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:9][OH:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)CCn1c(CO)nc2cc(Br)ccc21
Agent: Nc1cccc(Br)c1N
Product: OCc1nc2cc(Br)ccc2[nH]1

Procedure:
(5-Bromo-1H-benzoimidazol-2-yl)-methanol was prepared by the same procedure as [5-bromo-1-(3-methyl-butyl)-1H-benzoimidazol-2-yl]-methanol, starting with 3-bromophenylenediamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.C(ON=O)CC(C)C.[Si:17]([O:24][CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:28]2[O:27][C:26]([CH2:25][O:24][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])=[CH:30][CH:29]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccco1
Reactant: Nc1cccc(Br)c1
Agent: CC(C)CCON=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2cccc(Br)c2)o1
Temperature: 50 °C
Yield: 26 %

Procedure:
To a stirred solution of m-bromoaniline (6.88 g; 0.04M) in 42.2 g (0.2M) of 2-(t-butyldimethylsilyloxymethyl)furan at 0° was added isoamylnitrite (10.75 mL: 0.08M) dropwise over a period of 0.5 hr. The resulting mixture was then heated 16 hours at 50° C. The reaction mixture was cooled and diluted with 150 mL of ether and washed with 2×100 mL of ice cold water. The organic phase was dried over anhydrous magnesium sulfate, and the residue was distilled after filtering through 50 G of silica gel bed, to give 26% of the desired 2-(3'-bromophenyl)-5-(t-butyldimethylsilyloxymethyl)-furan as a colorless liquid boiling at 163°-7°/~0.5 mm.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([Cl:26])=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[ClH:26].[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH:16][C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)nc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: Cl
Product: O=C(Nc1ccc(N2CCN3CCC2CC3)nc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Was prepared according to Method G from 6-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-pyridin-3-ylamine and 4-nitrobenzoyl chloride. Mp. >310° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20]Br>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16]([CH:15]=[C:14]([Br:20])[CH2:13][CH2:12]2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([OH:19])[CH:14]([Br:20])[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2cc(OCc3ccccc3)ccc21
Reactant: BrBr
Solvent: CCOCC
Product: BrC1=Cc2ccc(OCc3ccccc3)cc2CC1
Product: OC1c2ccc(OCc3ccccc3)cc2CCC1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized by referring to J. Org. Chem., 1984, 49 (22), 4226. To a suspension of 6-benzyloxy-3,4-dihydro-2H-naphthalen-1-one (200 g) in diethyl ether (2 l) was added dropwise bromine (60 ml) on an ice bath, and the solution was stirred overnight at room temperature. The reaction mixture was poured into ice water, extracted with diethyl ether, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, then filtered through NH silica gel, the solvent was evaporated in vacuo. To the resulting 6-benzyloxy-2-bromo-3,4-dihydro-2H-naphthalen-1-one (250 g) was added ethanol (2.5 l), the solution was stirred, sodium borohydride (25 g) was added thereto on an ice bath followed by stirring overnight at room temperature. The reaction mixture was poured into ice water, and the resulting solid was washed with water to provide 6-benzyloxy-2-bromo-1,2,3,4-tetrahydronaphthalen-1-ol (290 g). To a suspension of this compound (260 g) in toluene (800 ml) was added p-toluenesulfonic acid monohydrate (6.0 g), and the solution was refluxed for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then filtered through NH silica gel, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (34 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([NH2:13])=[S:12].[C:14]([O:19][CH2:20][Br:21])(=[O:18])[CH:15]([CH3:17])[CH3:16]>CC(C)=O>[BrH:21].[C:14]([O:19][CH2:20][S:12]/[C:11](=[N:10]/[C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH3:1])/[NH2:13])(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: COc1ccc(NC(N)=S)c(C)c1
Reactant: CC(C)C(=O)OCBr
Solvent: CC(C)=O
Product: Br
Product: COc1ccc(/N=C(\N)SCOC(=O)C(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
2-Methyl-4-methoxyphenyl thiourea (0.5 grams (g), 2.55 millimoles (mmol)) and bromomethyl isobutyrate were combined in 5 mL of acetone at ambient temperature, and the solution was allowed to stir for 18 hours (h). The solution was then cooled to 0° C. and the resulting solid was filtered and air-dried to give (E)-(N′-(4-methoxy-2-methylphenyl)carbamimidoylthio)methyl isobutyrate HBr (B1) (0.83 g, 82%): mp 127-130° C.; 1H NMR (CDCl3) δ 11.34 (s, 1H), 10.29 (s, 1H), 8.32 (s, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.79 (d, J=2.8 Hz, 1H), 6.74 (dd, J=8.7, 2.8 Hz, 1H), 3.81 (s, 3H), 2.69 (heptet, J=7.0 Hz, 1H), 2.31 (s, 3H), 1.22 (d, J=7.0 Hz, 6H); ESIMS m/z 297 ([M+H]+).
Reaction SMILES: [CH3:1][OH:2].[F-].C([N+](C[CH2:18][CH2:19][CH3:20])(CCCC)CCCC)CCC.[CH2:21]1[CH2:25][O:24]CC1.C1C[O:29]CC1>>[C:1]([O:24][CH2:25][CH2:21][OH:29])(=[O:2])[C:19]([CH3:18])=[CH2:20]
Reactant: CO
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Agent: [F-]
Product: C=C(C)C(=O)OCCO

Procedure:
To a stirred solution of 1.74 g (2 ml, 10 mmoles) of MTS and 1 ml of 1 M tris(dimethylamino)-sulfonium difluorotrimethylsilicate/acetonitrile in 20 ml of anhydrous THF under argon was added dropwise a mixture of 5 g (50 mmoles) of MMA and 10.1 g (50 mmoles) of 2-trimethylsiloxyethyl methacrylate (prepared by the reaction of chlorotrimethylsilane with 2-hydroxyethyl methacrylate in the presence of triethylamine). Exothermic copolymerization occurred. After stirring for 1 h at ambient temperature, 10 ml of methanol was added, and the solution was refluxed for 1 h. Evaporation in vacuo gave 12.79 g of copolymer, the NMR spectrum of which showed it to contain 11% of the residual trimethylsilyl protecting group due to incomplete methanolysis. To complete methanolysis, 6 g of the copolymer was stirred at reflux for 1 h with 20 ml of methanol, 20 ml of THF and 1 ml of 1 M tetrabutylammonium fluoride/THF. Evaporation of the solution in vacuo gave 5.6 g of poly(MMA/2-hydroxyethyl methacrylate) copolymer. GPC: Mn 1400, Mw 1500, D 1.07 (theor. M.W. 1150). 220 MHz NMR: 1:1 mole ratio of MMA and hydroxyethyl methacrylate. Hydroxyl number: 233, 246 (equivalent to 49 mole % hydroxyethyl methacrylate polymer repeat units and 51 mole % MMA polymer repeat units.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:17]([C:18]#[CH:19])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.[CH2:20]([O:22][C:23](=[O:42])[C@H:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)[CH3:21].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.[Pd](Cl)Cl.O>[CH2:20]([O:22][C:23](=[O:42])[C@H:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:25][C:26](=[O:34])[C:27]1[CH:28]=[CH:29][C:30]([C:19]#[C:18][C:17]2[C:3]3[C:2]([OH:1])=[N:7][C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][C:4]=3[NH:15][CH:16]=2)=[CH:31][CH:32]=1)[CH3:21]
Reactant: C#Cc1c[nH]c2nc(NC(=O)C(C)(C)C)nc(O)c12
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(I)cc1)C(=O)OCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2c[nH]c3nc(NC(=O)C(C)(C)C)nc(O)c23)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a suspension of 3.33 g (12.9 mmol) of N-(4-hydroxy-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropionamide in 64 mL of acetonitrile stirred under nitrogen was added 5.77 g (28.4 mmol) of BSA and the resulting mixture was stirred at 40° C. for 2 hours, then cooled to ambient temperature. To the resulting solution was added sequentially 5.58 g (12.9 mmol) of N-4-iodobenzoyl-L-glutamic acid diethyl ester, 2.6 g (25.8 mmol) of triethylamine, and a mixture of 0.114 g (0.65 mmol) of palladium(II) chloride and 0.338 g (1.29 mmol) of triphenylphosphine in 16 mL of acetonitrile. The resulting mixture was heated under reflux overnight (18 hours), after which time HPLC analysis of an aliquot indicated complete conversion of the (acetylenic) starting material. The mixture was cooled to ambient temperature and 2 mL of water was added. The resulting suspension was stirred for 30 minutes, filtered, and the precipitate washed with acetonitrile and dried, affording 6.15 g (85%) of N-[4-[2-[2-(2,2-dimethylpropionyl)amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl ]ethynyl]benzoyl]-L-glutamic acid diethyl ester as a tan solid. The melting point and NMR spectral data for the product were in agreement with data obtained on an authentic sample prepared by the procedure of Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][CH2:7][N:8]([CH2:10][CH2:11][OH:12])[CH3:9].[H-].[Na+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([N+:30]([O-:32])=[O:31])[CH:22]=1>CS(C)=O>[ClH:20].[N+:27]([C:24]1[CH:25]=[C:26]([CH:21]=[CH:22][C:23]=1[N+:30]([O-:32])=[O:31])[O:12][CH2:11][CH2:10][N:8]([CH2:7][CH2:6][C:5]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:9])([O-:29])=[O:28]
Reactant: COc1ccc(CCN(C)CCO)cc1OC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
A portion (0.50 g, 2.1 mmol) of the 2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethanol produced in (1) above was dissolved in dimethyl sulfoxide (6 ml) and 60% sodium hydride (0.12 g, 3 mmol) was added to the resulting solution. The reaction mixture was stirred at room temperature for 1 h and 1-chloro-3,4-dinitrobenzene (0.48 ml, 4 mmol) was added on a water bath. The mixture was stirred at room temperature for 2 h and after adding a saturated aqueous solution of sodium bicarbonate, three extractions were conducted with chloroform. The organic layers were combined, dried with sodium sulfate and concentrated under vacuum. The residue was purified by being subjected to column chromatography on silica gel using a 15:1 solvent system of chloroform and methanol as an eluent and the fractions containing the end compound were collected and the solvent was evaporated under vacuum, with the residue being recrystallized from ethanol to yield the titled compound 1-(3,4-dinitrophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride (0.31 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[O:13][C:14]([CH3:35])=[C:15]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]4)[N:16]=2)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[O:13][C:14]([CH3:35])=[C:15]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]4)[N:16]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4cccc(N)c4)oc3C)ccc21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4cccc(NC(C)=O)c4)oc3C)ccc21
Reaction time: 16 h
Yield: 55.1 %

Procedure:
To a solution of DMAP (1.0 mg) and acetyl chloride (9.3 mg, 0.12 mmol) in 1 mL dichloromethane was added a solution of ethyl ((1S)-5-{2-[2-(3-aminophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (25 mg, 0.06 mmol) in dichloromethane (1 mL). Then, triethylamine (0.5 mL) was added and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and redissolved in acetonitrile/methanol. The solution was filtered through a C8-Silica plug before preparative HPLC purification using 10 to 80% acetonitrile in water gradient to afford 15.3 mg (55.6%) of the desired product. 1H NMR (300 MHz/CDCl3) δ 7.97 (s, 1H), 7.70 (d, 2H), 7.49 (s, 1H), 7.37 (t, 1H), 7.03 (d, 1H), 6.76 (s, 1H), 6.69 (d, 1H), 4.11-4.22 (m, 4H), 3.48 (qr, 1H), 2.92 (t, 2H), 2.72-2.88 (m, 2H), 2.68 (dd, 1H), 2.27-2.40 (m, 5H), 2.16 (s, 3H), 1.64-1.76 (m, 1H), 1.24 (t, 3H). EI-LCMS(rel abundance), m/z 463.4 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:24])=[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:38]([CH2:40][CH2:41][CH2:42]Cl)[CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.CCOCC>[CH3:1][O:2][C:3]1[N:4]([CH2:42][CH2:41][CH2:40][N:38]([CH3:39])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:5]([CH3:24])[C:6]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1
Reactant: CN(CCCCl)Cc1ccccc1
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC1=NC(c2cccc([N+](=O)[O-])c2)=C(C(=O)OC(C)C)C(C)N1CCCN(C)Cc1ccccc1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methyethyl ester (2.0 g, 6.0 mmol) in dimethylformamide (7.0 ml) was treated with finely ground potassium carbonate (1.7 g, 12.0 mmoles), N-benzyl-3-chloro-N-methylpropylamine (2.37 g, 12.0 mmol) and a catalytic amount of 18-crown-6. The reaction was heated at 70°-75° C. under argon overnight. The reaction was allowed to cool down to room temperature and was diluted with ether. It was filtered, and the filtrate was washed with water, brine and was dried over anhydrous magnesium sulfate. Evaporation of solvent provided a brown oil which was purified by flash chromatography (20% acetone in hexanes) to yield the title compound (1.51 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]2)=[N:32][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:40]([CH:37]3[CH2:38][CH2:39][N:34]([C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:44])([F:26])[F:43])=[CH:33][N:32]=4)[CH2:35][CH2:36]3)=[O:41])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(F)(F)F)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 125 mg (0.456 mmol) rac-[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester, 198 mg (0.547 mmol) 1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylic acid, 208 mg (0.547 mmol) HATU and 353 mg (2.73 mmol) DIPEA in 10 mL DMF and stirred for 1 h ar room temperature. The mixture was concentrated and DMF and DIPEA was added and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 187 mg (66%) of the title compound as light brown viscous oil. MS m/e: 619.4 [M+H]+.
Reaction SMILES: C[C:2]1[NH:3][C:4]([CH2:27][CH:28]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1C(OCC)=O.Cl.[NH2:31]O.[C:33]([O-:36])(=[O:35])[CH3:34].[Na+].[C:38]([O-])(=O)[CH3:39]>C(OC(=O)C)(=O)C>[CH3:7][C:2]1[NH:3][C:4]([CH2:27][C:28]#[N:31])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:34]=1[C:33]([O:36][CH2:38][CH3:39])=[O:35]
Reactant: CCOC(=O)C1=C(C)NC(CC=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: NO
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1=C(C)NC(CC#N)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]

Procedure:
Starting from a mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formylmethyl-1,4-dihydropyridine-3,5-dicarboxylate, hydroxylamine hydrochloride and sodium acetate in acetate acid and acetic anhydride, was obtained an oil of diethyl 2-methyl-4-(2-nitrophenyl)-6-cyanomethyl-1,4-dihydropyridine-3,5-dicarboxylate, by applying an essentially similar manner to that of Example 4-2).