Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][C:18]1[CH:23]=[C:22]([C:24]([NH:16][CH:13]2[CH2:12][CH2:11][N:10]([C:4]3[N:3]=[CH:2][NH:1][C:6]4=[N:7][CH:8]=[CH:9][C:5]=34)[CH2:15][CH2:14]2)=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NC2CCN(c3nc[nH]c4nccc3-4)CC2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 2-methyl-4-pyridinecarboxylic acid (63.1 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E12 (72 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 8.55 (2H, m), 8.17 (1H, s), 7.62 (1H, s), 7.53 (1H, d), 7.18 (1H, d), 6.60 (1H, d), 4.70 (2H, dt), 4.15 (1H, m), 3.35 (3H, s), 3.25 (2H, dt), 1.90 (2H, m), 1.53 (2H, m), MS(ES+) 337 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:55]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])(=[O:58])[CH:56]=[CH2:57]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:60]([O:59][C:55](=[O:58])/[CH:56]=[CH:57]/[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1)([CH3:63])([CH3:62])[CH3:61]
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccc(/C=C/C(=O)OC(C)(C)C)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a solution of 6-(5-bromo-2-n-propoxyphenyl)-3-methyl-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 11; 2.14 g, 0.0053 mol) and triethylamine (0.81 g, 0.008 mol) in acetonitrile (4 ml), was added palladium(II) acetate (0.06 g, 0.00027 mol), tri-o-tolylphosphine (0.16 g, 0.00053 mol) and t-butyl acrylate (1.03 g, 0.008 mol). The mixture was heated under reflux for 4 hours, cooled to room temperature and then partitioned between water (30 ml) and dichloromethane (30 ml). The organic phase was removed and the aqueous phase extracted with dichloromethane (2×30 ml). The combined organic solutions were dried (Na2SO4) and the solvent removed by evaporation under vacuum to give a greenish brown solid. Purification by column chromatography (SiO2, CH2Cl2 then 2% MeOH in CH2Cl2) and crystallisation from ethyl acetate-hexane afforded the title compound as white crystals (1.48 g, 58%), m.p. 181-182° C. Found: C, 66.50; H, 6.75; N, 12.27. C25H32N4O4 requires C, 66.35; H, 7.12; N, 12.38%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][CH:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:21]([O:23][C:24]([C@@H:26]([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C@@H:26]([NH:35][C@H:36]([C:38]([N:11]1[N:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[S:13][C@H:12]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:39])[CH3:37])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Reactant: CSc1ccc(C2=NNC(C(=O)OC(C)(C)C)S2)cc1
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccc(SC)cc2)S[C@H]1C(=O)OC(C)(C)C

Procedure:
Prepared from the product of step e) and N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine by similar processes to those of Example 1, steps b and c as a yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:15](O)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:15]([Cl:2])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)C=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(Cl)C=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.164 g of phosphorus pentachloride were added to 90 ml of a methylene chloride solution containing 4.485 g of 3,3-diphenylacrylic acid, which had previously been cooled at 0°-5° C. The reaction mixture was then stirred for one hour at room temperature, after which the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 50 ml of toluene, and then the solvent was once again distilled off under reduced pressure. This procedure comprising dissolution and distillation was repeated once more. 3,3-Diphenylacryloyl chloride was obtained as a white solid. This crude product was immediately used in the next reaction.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[OH:24][CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27](=O)[O:26]1.CN(C)C=O>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH:27]4[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25](=[O:24])[O:26]4)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: O=C1OC(O)c2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C4OC(=O)c5ccccc54)CC3)cc21
Yield: 99 %

Procedure:
A mixture of 1-ethyl-1,4-dihydro-6-fluoro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid 0.5 g, 3-hydroxyphthalide 0.24 g and dimethylformamide 5 ml was heated at 100°-110° C. for 3 hours under stirring. After cooling, ethanol was added, and the insoluble matters were collected by filtration. The precipitates obtained were washed with ethanol and dried. 0.70 g (99%) of 1-ethyl-1,4-dihydro-6-fluoro-4-oxo-7-(4-phthalidyl-1-piperazinyl)quinoline-3-carboxylic acid was obtained as colorless powders.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24])[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[NH2:38][C:13]1[C:12]2[N:11]=[C:10]([CH2:22][CH2:23][CH3:24])[N:9]([CH2:8][CH2:7][CH2:6][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:25])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: [NH4+]
Reactant: CCCNC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCNC(=O)CCCn1c(CCC)nc2c(N)nc3ccccc3c21

Procedure:
N-Propyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide (5.6 g, 15 mmol) was treated with mCPBA (8.5 g, 38 mmol), concentrated ammonium hydroxide (100 mL), and p-toluenesulfonyl chloride (4.9 g, 26 mmol) according to the method described in Part F of Example 1. The crude product was dissolved in hot toluene (25 mL) and dichloromethane. A precipitate slowly formed, was isolated by filtration, and was washed with toluene (15 mL). The solid was recrystallized twice from 4:1 methanol:water (25 mL), and the crystals were heated at reflux in chloroform in the presence of charcoal (1 g). The mixture was filtered through a layer of CELITE filter agent, and the filtrate was concentrated under reduced pressure. The residue was recrystallized twice from methanol:water and twice from toluene (15 mL) and dried overnight in a vacuum even to provide 0.74 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylbutanamide as a grey solid, mp 161-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[CH:15]=[C:16]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28](C)[C:29](=O)OC(C)(C)C)[CH2:22][CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[N:12]=[C:11]([C:37]([F:40])([F:39])[F:38])[CH:10]=1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:44]=[CH:43][CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH:28][CH3:29])[CH2:22][CH2:21]3)[CH:15]=2)[N:12]=[C:11]([C:37]([F:38])([F:39])[F:40])[CH:10]=1)=[O:8]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCN1CCC(c2cccc(-n3nc(C(F)(F)F)cc3C(=O)NCc3ccccc3OC)c2)CC1
Temperature: 21 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a stirred solution of 70 (20 mg, 0.032 mmol) in CH2Cl2 (650 μl) was added TFA (50 μl, 0.650 mmol). The resulting solution was allowed to stir at 21° C. for 1.5 h. After the usual work-up, the residue was purified by preparative TLC using 10% MeOH/CH2Cl2. The title product 71 (16 mg, 79% yield) was isolated as a white solid. 1H NMR (CD3OD) δ(ppm): 7.38-7.36 (m, 3H), 7.27-7.24 (m, 2H), 7.14 (s, 1H), 7.12 (s, 1H), 6.94 (d, 1H, J=8.0 Hz), 6.87 (t, 1H, J=7.2 HZ), 4.44 (s, 2H), 3.81 (s, 3H), 3.13 (t, 2H, J=5.6 Hz), 3.05 (d, 2H, J=11.6 Hz), 2.72 (s, 3H), 2.67 (t, 2H, J=6.0 Hz), 2.61-2.59 (m, 1H), 2.22 (td, 2H, J=2.8, 12.0 Hz), 1.83-1.77 (m, 4H). LRMS (ESI): calc. 515.6; found 516.8 (MH)+.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[CH:16]=2)=[C:7]([NH:37][C:38]([NH:40][C:41]2[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][CH:44]=[CH:43][C:42]=2[CH:50]([CH3:52])[CH3:51])=[O:39])[C:6]1=[O:53])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:16]=2)=[C:7]([NH:37][C:38]([NH:40][C:41]2[C:42]([CH:50]([CH3:51])[CH3:52])=[CH:43][CH:44]=[CH:45][C:46]=2[CH:47]([CH3:49])[CH3:48])=[O:39])[C:6]1=[O:53])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCN3CCN(C(=O)OC(C)(C)C)CC3)c2)c2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCN3CCNCC3)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 571.4 %

Procedure:
To a solution of N-[1-butyl-4-[3-{2-(4-tert-butoxycarbonyl-1-piperazinyl)-ethoxy}phenyl]-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (26 mg, 0.035 mmol) in methylene chloride (5 ml) was added trifluoroacetic acid (1 ml, 13 mmol), and the mixture was stirred at room temperature for two hours. The mixture was concentrated under reduced pressure to remove the solvent, and to the residue was added 5% aqueous ammonia (50 ml), and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (20% methanol in chloroform) to give the title compound (13 mg, 0.20 mmol).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:11]=[C:10]([CH:12]=[O:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=2)[CH:4]=1.[CH3:24][Mg]Br>O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:11]=[C:10]([CH:12]([OH:13])[CH3:24])[C:9]2[C:5](=[CH:6][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[N:8]=2)[CH:4]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(C(F)(F)F)cc(C=O)c2n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C

Procedure:
To a solution of 5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carbaldehyde (0.5 g, 1.45 mmol) in tetrahydrofuran (10 mL) at −78° C. was added methyl magnesiumbromide (3 M in diethyl ether, 0.97 mL, 2.90 mmol). The reaction was allowed to gradually warm in the ice bath (ca. 1 h) to 0° C. The reaction which had been a suspension became a solution. The reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 444 mg (85%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 8.23 (s, 1H), 7.93 (s, 1H), 7.39 (s, 1H), 5.73 (s, 2H), 5.38 (q, J=6.4 Hz, 1H), 3.65 (m, 2H), 3.52 (bs, 1H), 1.71 (d, J=6.7 Hz, 3H), 0.94 (m, 2H), −0.03 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 147.3, 136.6, 128.0, 124.8, 124.7 (q, J=273 Hz), 124.7 (q, J=32 Hz), 121.3, 118.4 (q, J=4.8 Hz), 117.4 (q, J=2.9 Hz), 82.1, 68.2, 68.0, 23.4, 17.9, −1.4.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[N:22]=[C:23]([CH3:26])[S:24][CH:25]=1>>[CH3:26][C:23]1[S:24][CH:25]=[C:21]([NH:20][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[N:22]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1ccnn1C
Reactant: Cc1nc(N)cs1
Product: Cc1ccc(Nc2ccnn2C)c(C(=O)Nc2csc(C)n2)n1

Procedure:
The title compound, was prepared from 6-Methyl-3-(2-methyl-2H-pyrazol-3-ylamino)-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 75, step 2 using 4-Amino-2-methylthiazole instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a light brown solid, MS (ISP): m/e=329.1 (M+H+).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]([C@@H:11]([C@H:13]([C:15]([O:17]CC)=O)[OH:14])[OH:12])([O:8]CC)=O.O>CO>[CH2:1]([NH:5][C:6](=[O:8])[C@@H:11]([C@H:13]([C:15]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:17])[OH:14])[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: CCCCN
Solvent: CO
Solvent: O
Product: CCCCNC(=O)[C@H](O)[C@@H](O)C(=O)NCCCC
Reaction time: 0.5 h
Yield: 56 %

Procedure:
N,N′-Di-n-butyl L-tartaramide was prepared by the reaction of n-butyl amine with diethyl L-tartrate. Diethyl L-tartrate (20.010 g, 1.0 eq) and HPLC grade methanol (40 mL) were weighed into a 250 mL round-bottomed flask equipped with a teflon coated magnetic stir bar. n-Butyl amine (14.906 g, 2.0 eq) was slowly poured into the stirring diethyl L-tartrate solution. Some fuming and a color change from water-white to pale yellow were observed. Additional methanol (10 mL) was used to rinse all of the amine into the reaction flask. After stirring the solution for 30 min, the flask was stoppered and refrigerated at approximately 45° F. (7° C.). The product crystallized out after 30 min of refrigeration; however, it was allowed to remain in the refrigerator for 3 days. The white needle-like crystals were filtered, washed with methanol (˜150 mL), washed with diethyl ether (2×30 mL), and dried under vacuum. The product was obtained in 56% yield (14.275 g, 54.8 mmole).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1)#[N:18]>C1(C)C=CC=CC=1>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17](=[NH:18])[C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][CH:20]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: Cc1cncc(C#N)c1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cncc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (10.5 g, 0.051 mol) in toluene (500 mL) was added trimethylaluminum (2M solution in toluene, 75.0 mL, 0.150 mol) over 15 minutes at 0° C. The reaction mixture was warmed up to room temperature and stirred for 2 hours. A solution of 3-cyano-5-methylpyridine from step 3 in 90 mL of toluene was added over 10 minutes and the mixture was stirred at 85-90° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered through a slurry of silica gel. After filtration, the residue was washed with methanol (800 mL). The combined filtrate was concentrated under reduced pressure and the residue was treated with a mixture of ether and hexane (2/1, 1000 mL). The brownish solid was filtered and washed with more ether and hexane to give 11.8 g of N-[4-(methylsulfonyl)phenyl]-5-methylnicotinamidine (80%). To a mixture of the above crude amidine (11.3 g, 0.039 mol) and sodium bicarbonate (9.83 g, 0.12 mol) in isopropanol (400 mL) was added 3-bromo-1,1,1-trifluoroacetone (11.2 g, 0.059 mol) quickly at room temperature. After hearing the reaction mixture at 75-80° C. for 16 hours, the solvent was removed and the residue was partitioned between water and methylene chloride. The organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (ethyl acetate/acetone, 98:2) to give pure 3-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine as a yellow solid (3.85 g, 25%): mp (DSC) 237-239° C.; Anal. Calc'd. for C17H16F3N3O3S: C, 51.12, H, 4.04, N, 10.52, S, 8.03. Found: C, 51.02, H, 3.94, N, 10.19, S, 8.11.
Reaction SMILES: [C:1]([C:4]1[C:5](Cl)=[N:6][C:7]([S:33][CH3:34])=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[S:30]([CH3:32])=[O:31])(=[O:3])[NH2:2].[NH3:36]>O1CCOCC1>[NH2:36][C:5]1[C:4]([C:1](=[O:3])[NH2:2])=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:19][CH2:18]3)=[CH:13][C:12]=2[S:30]([CH3:32])=[O:31])[CH:8]=[C:7]([S:33][CH3:34])[N:6]=1
Reactant: CSc1cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)=O)c(C(N)=O)c(Cl)n1
Reactant: N
Solvent: C1COCCO1
Product: CSc1cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)=O)c(C(N)=O)c(N)n1
Temperature: 80 °C

Procedure:
A mixture of the product of Example 14E (637 mg, 1.18 mmol) and 25% aqueous ammonia (2 mL) in 1,4-dioxane (3 mL) was heated in a seated tube at 80° C. for 24 hours. After cooling to ambient temperature, the mixture was concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 25/1 dichloromethane/methanol to give the title compound. MS: 521 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[CH3:6][S:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11].[OH-].[Na+]>O.O1CCCC1>[CH3:6][S:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:5][CH2:4][C:3]#[N:2])=[O:11]
Reactant: CSc1ncccc1C(=O)Cl
Reactant: N#CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncccc1C(=O)NCC#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a stirred solution of aminoacetonitrile hydrochloride (5.95 g) in a mixture of water (100 ml) and tetrahydrofuran (100 ml) was added slowly 2 -(methylthio)nicotinoyl chloride (10 g) at 0° C. while adjusting pH to 8-9 with 4N-aqueous sodium hydroxide. After stirring for 30 minutes at 0° C., the solvent was evaporated to give a residue, which was chromatographed on silica gel (350 ml) eluting with ethyl acetate to give [2-(methylthio)nicotinoyl]aminoacetonitrile (9.9 g).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([CH:22]=1)[NH:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:7].[N:28]1([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:1][N:2]([CH3:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([CH:22]=1)[NH:14][C:15]1[CH:20]=[C:19]([NH:36][CH2:35][CH2:34][CH2:33][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[N:18]=[CH:17][N:16]=1)=[O:7]
Reactant: NCCCN1CCCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1cc(NCCCN2CCCC2)ncn1

Procedure:
A mixture of 4-[5-(3-dimethylaminobenzamido)-2-methylanilino]-6-chloropyrimidine (0.114 g), 3-pyrrolidin-1-ylpropylamine (0.95 ml), N,N-di-isopropylethylamine (0.063 ml) and n-butanol (2 ml) was stirred and heated to reflux for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 10:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained the title compound (0.124 g); NMR Spectrum: (DMSOd6) 1.59 (m, 6H), 2.15 (s, 3H), 2.34 (m, 6H), 2.93 (s, 6H), 3.14 (m, 2H), 6.72 (m, 1H), 6.89 (m, 1H), 7.2 (m, 4H), 7.3 (m, 1H), 7.5 (m, 1H), 7.72 (m, 1H), 7.96 (m, 1H), 8.16 (s, 1H), 10.02 (s, 1H); Mass Spectrum: M+H+ 474.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].[O:37]1[CH2:49][CH:38]1[CH2:39][O:40][C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[C:43]#[N:44]>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][NH:27][CH2:49][CH:38]([OH:37])[CH2:39][O:40][C:41]3[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=3[C:43]#[N:44])=[CH:23][CH:24]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(CCN)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(CCNCC(O)COc3ccccc3C#N)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 4.1 g (8.3 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-aminoethyl)-phenoxy]-ethyl}-ester 5-methyl ester and 1.6 g of 2-(2,3-epoxypropoxy)-benzonitrile in 20 ml of isopropanol is heated under reflux for 2 hours and then concentrated to dryness by evaporation under reduced pressure. The residue is dissolved in 20 ml of 1N methanesulphonic acid and extracted with 40 ml of ethyl acetate. The aqueous phase is separated off and rendered alkaline with 2N sodium hydroxide solution. The crude product obtained by extraction with ethyl acetate is "flash" chromatographed over silica gel using toluene/isopropanol/concentrated ammonia (170:30:3) as eluant. 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{{{2-{{p-{2-[3-(o-cyanophenoxy)-2-hydroxypropylamino]-ethyl}-phenoxy}}-ethyl}}}-ester 5-methyl ester is obtained in the form of an amorphous foam.