Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=O)#[N:8].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[S:29].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>O1CCCC1.O>[NH2:8][C:7]1[C:9]2[C:10]3[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=3[C:12](=[O:14])[N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[C:28]=2[S:29][C:31]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: S=C=Nc1ccccc1Cl
Reactant: COC(=O)CBr
Reactant: COC(=O)c1ccccc1CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc2c(c1N)c1ccccc1c(=O)n2-c1ccccc1Cl
Yield: 78.3 %

Procedure:
To a solution of 1.85 g of potassium t-butoxide in 32.3 ml of a dry tetrahydrofuran was added 2.83 g of methyl 2-cyanomethylbenzoate with stirring under an ice-cooling in a stream of nitrogen, and then to the mixture was added 3.02 g of 2-chlorophenyl isothiocyanate for 10 minutes. The mixture was stirred under an ice-cooling for 10 minutes. To the reaction mixture was added 2.72 g of methyl bromoacetate for 10 minutes, and the mixture was stirred for 80 minutes at room temperature. The reaction mixture was cooled under an ice-bath, and 363 mg of potassium t-butoxide was added to the cold mixture. The mixture was stirred for 1 hour under an ice-cooling. To the reaction mixture was added 70 ml of water for 2 minutes, and the mixture was stirred for 15 minutes. Precipitates were collected by a filtration, and successively washed with water, methanol and hexane, and dried under reduced pressure to obtain 4.87 g of the desired product as white colorless crystals.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([O:11]C)=[O:10])=[N:5]1.[OH-].[Li+]>C1COCC1.CO.O>[F:14][C:2]([F:1])([F:13])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[N:5]1
Reactant: COC(=O)c1ccn(CC(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccn(CC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
Methyl 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylate (Intermediate 204, 0.312 g, 1.5 mmol) was dissolved in a mixture of THF (2 mL), MeOH (2 mL) and water (1 mL); lithium hydroxide (0.188 g, 4.5 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was concentrated, the residue dissolved in water (1 mL) and the mixture was neutralised. This was extracted with EtOAc (2×10 mL), the organic extracts were dried over sodium sulfate and concentrated under vacuum. The crude material was washed with pentane (2×10 mL) to afford 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid (0.200 g, 69%). 2-N-methyl-2-N-phenyl-6-{5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-1,3,5-triazine-2,4-diamine was then prepared from 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid (0.159 g, 0.820 mmol) and 4-amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1, 0.125 g, 0.483 mmol) according to the method described for Example 251 to afford the title compound (0.110 g, 55%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@@H:5]([O:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=1)[CH3:2].[CH2:24]([OH:27])[C:25]#[CH:26].C(N(CC)CC)C>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:23])[C@@H:5]([O:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:26]#[C:25][CH2:24][OH:27])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)OC
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(C#CCO)cc1)OC
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A solution of (2S)-2-methoxy-3-(4-trifluoromethane-sulfonyloxy-phenyl)-propionic acid ethyl ester (0.861 g, 2.53 mmol), propargyl alcohol (0.88 mL, 15.18 mmol), triethylamine (1.41 mL, 10.12 mmol) and dichlorobis(triphenylphosphine)palladium (II) in 10 mL of dry DMF was heated to 90° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with 50 mL of water, and extracted with diethyl ether (3×30 mL). The combined organic layers were washed with 0.5 N HCl (2×20 mL) and brine (20 mL), dried (MgSO4), and concentrated. The residue purified by column chromatography (silica gel, hexanes/ethyl acetate 2:1, Rf0.17) to give a yellow-brown oil (0.211 g, 32%). 1H-NMR (200.15 MHz, CDCl3): δ 7.35 (d, 2H, J=8.1), 7.18 (d, 2H, J=8.1), 4.48 (s, 2H), 4.17 (q, 2H, J=7.3), 3.93 (dd, 1H, J=7.3, 5.7), 3.34 (s, 3H), 3.02 (s, 1H), 2.99 (d, 1H, J=2.2), 1.8 (s, 1H), 1.22 (t, 3H, J=7.3).
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+]>CO.O1CCCC1>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(CCl)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone (75 g, 0.2 mol) in a mixture of 800 mL of methanol and 800 mL of tetrahydrofuran was added sodium borohydride (13.17 g, 0.348 mol, 1.54 equiv.) over 100 min. The solution was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in 1000 mL of ethyl acetate and washed with 1N KHSO4, saturated aqueous NaHCO3, saturated aqueous NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give an oil. The crude product was dissolved in 1000 mL of hexanes at 60° C. and allowed to cool to room temperature where upon crystals formed that were isolated by filtration and washed with copious amounts of hexanes. This solid was then recrystallized from hot ethyl acetate and hexanes to provide 32.3 g 43% of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150–151° C., FAB MS: MLi+=340.
Reaction SMILES: [CH3:1][S:2]/[C:3](=[N:16]\[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)/[N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([C:13]([OH:15])=O)[S:12][C:6]=2[CH2:5]1.[C:23]([O:27][C:28](=[O:39])[NH:29][C:30]1[CH:35]=[CH:34][C:33](OC)=[CH:32][C:31]=1[NH2:38])([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN([CH:64]=[O:65])C>C(N(CC)CC)C>[C:23]([O:27][C:28]([NH:29][C:30]1[CH:35]=[C:34]([O:65][CH3:64])[CH:33]=[CH:32][C:31]=1[NH:38][C:13]([C:11]1[S:12][C:6]2[CH2:5][N:4]([C:3]([S:2][CH3:1])=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][CH2:8][C:7]=2[N:10]=1)=[O:15])=[O:39])([CH3:24])([CH3:25])[CH3:26]
Reactant: CS/C(=N\c1ccccc1)N1CCc2nc(C(=O)O)sc2C1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2nc3c(s2)CN(C(=Nc2ccccc2)SC)CC3)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of 5-[(Z)-(methylthio)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid obtained from step III of example 116 (1 eq), (2-amino-4-methoxy-phenyl)-carbamic acid tert-butyl ester (1.2 eq), EDCI (1.2 eq), HOBt (1.2 eq) and triethylamine in DMF were stirred at room temperature for 15 h. Solvent was evaporated and the residue was purified by either column chromatography or preparative HPLC to afford methyl 2-({2-[(tert-butoxycarbonyl)amino]-4-methoxyphenyl}carbamoyl)-N-phenyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbimidothioate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:18][CH:19]([CH3:22])[CH2:20]I.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:22])[CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(N2CCN(CC(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 68.7 %

Procedure:
A solution of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (2.09 g, 8.44 mmol), 2-methyl-iodopropane (2.1 g, 11.39 mmol), and potassium carbonate (4.7 g, 34 mmol) in acetonitrile (80 mL) was heated in a pressure vessel at 80° C. for 24 hours. The reaction was cooled and the acetonitrile was removed under reduced pressure. The solids were dissolved in methylene chloride/water. The organic layer was dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The resultant residue was purified by chromatography on SiO2 (10% MeOH/CH2CL2 with 0.2% NH3) to give 1-[3-(methyloxy)-4-nitrophenyl]-4-(2-methylpropyl)piperazine as a pale yellow solid (1.70 g, 5.8 mmol, 69% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (d, J=6.59 Hz, 6 H), 1.80 (ddd, J=13.69, 7.05, 6.91 Hz, 1 H), 2.13 (d, J=6.04 Hz, 2 H), 2.52 (s, 4 H), 3.38 (s, 4 H), 3.93 (s, 3 H), 6.29 (d, J=2.38 Hz, 1 H), 6.40 (dd, J=9.43, 2.47 Hz, 1 H), 7.98 (d, J=9.52 Hz, 1 H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:3][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH3:7])[CH2:5]1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide (60 mg, 0.11 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL, 13.0 mmol). The bright yellow-orange reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylene diamine (0.4 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with CH2Cl2. A very fine precipitate formed which was collected via filtration. This solid was taken up in MeOH/CH2Cl2 (200 mL) and filtered again, rinsing with MeOH/CH2Cl2. The filtrate was concentrated and triturated with EtOAc/MeOH to afford 28 mg (62%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide as a light yellow solid. MS: (M+H)+=409; 1H NMR (DMSO-d6,300 MHz): δ (ppm) 9.08 (s, 1H), 8.37-8.48 (m, 2H), 7.96 (d, J=8.7 Hz, 1H), 7.70 (dd, J=9.8, 1.9 Hz, 1H), 7.18 (td, J=9.1, 2.3 Hz, 1H), 4.92 (br. s., 1H), 4.14 (s, 3H), 4.04-4.13 (m, 1H), 3.87 (br. s., 1H), 2.14-2.34 (m, 2H), 1.78-1.93 (m, 1H), 1.58 (quin, J=9.8 Hz, 2H), 1.19 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:17]([CH3:18])[CH:16]=[CH:15][C:9]3=[N:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH2:3]1.[Cl:20][C:21]1[C:22]([NH2:29])=[N:23][C:24]([NH2:28])=[N:25][C:26]=1Cl.CCN(CC)CC>CN(C=O)C>[Cl:20][C:21]1[C:26]([NH:14][CH:12]([C:11]2[N:10]=[C:9]3[CH:15]=[CH:16][N:17]([CH3:18])[C:8]3=[CH:7][C:6]=2[N:4]2[CH2:5][C:2]([F:1])([F:19])[CH2:3]2)[CH3:13])=[N:25][C:24]([NH2:28])=[N:23][C:22]=1[NH2:29]
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC(F)(F)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1N1CC(F)(F)C1
Temperature: 90 °C
Reaction time: 48 h
Yield: 5.3 %

Procedure:
To a 10 mL vial were added 1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (61 mg, 0.23 mmol), 5,6-dichloropyrimidine-2,4-diamine (41.0 mg, 0.229 mmol) and Et3N (0.064 mL, 0.46 mmol) in DMF (2 mL). The resulting yellow solution was heated to 90° C. and stirred for 48 hours. The crude product was purified by preparative HPLC eluting with 30-55% ACN in water (with ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as a pale yellow solid (5 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.41 (m, 3 H), 3.73-3.86 (m, 3 H), 4.17-4.35 (m, 2 H), 4.43-4.58 (m, 2 H), 5.33-5.48 (m, 1 H), 5.69-5.80 (m, 2 H), 5.89-6.01 (m, 2 H), 6.32-6.43 (m, 1 H), 6.45-6.54 (m, 1 H), 7.37-7.43 (m, 1 H), 7.45-7.51 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C17H19ClF2N8, 409; found 409.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=O)=[CH:5][CH:4]=1.C[O:19][CH:20](OC)[N:21]([CH3:23])C.CN[C:28](=O)[CH2:29][C:30]1[S:31][CH:32]=[C:33]([CH3:35])[N:34]=1.[H-].[Na+]>O1CCCC1.O.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:28]=[C:29]([C:30]3[S:31][CH:32]=[C:33]([CH3:35])[N:34]=3)[C:20](=[O:19])[N:21]([CH3:23])[C:10]=2[C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: CNC(=O)Cc1nc(C)cs1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(CC(=O)c2cnccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc(-c3nc(C)cs3)c(=O)n(C)c2-c2cnccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
A solution of 2-(4-methoxyphenyl)-1-(pyrazine-2-yl)ethanone (1.0 g) and dimethylformamide-dimethylacetal (10 cm3) were stirred at room temperature for 18 h. The excess reagent was evaporated under reduced pressure to give an oil. The oil was dissolved in tetrahydrofuran (60 cm3). N-methyl 2-(4-methylthiazol-2-yl)acetamide (0.74 g) and methanol (0.36 cm3) were added followed by sodium hydride (0.42 g). The reaction mixture was stirred at room temperature under nitrogen for 18 h then poured into water (500 cm3) and extracted with diethyl ether (3×150 cm3). The ether extracts were combined, washed with brine dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by chromatography using dichloromethane (500 cm3), dichloromethane/methanol (99:1, 500 cm3) dichloromethane/methanol (98:2) as eluant. The appropriate fractions were combined and evaporated under reduced pressure to give a foam, which on tritiation with ether gave a solid. The solid was recrystallised from ethyl acetate to give 5-(4-methoxyphenyl)-1-methyl -3-(4-methylthiazol-2-yl)-6-(pyrazin-2-yl)-1H-pyridin-2-one (0.15 g 8%) as a greenish-yellow solid m.p. 168-170° C. (Found: C, 64.48; H, 4.45; N, 14.22. C21H18N4O2S requires C, 64.60; H, 4.65; N, 14.35%); δH (360 MHz; CDCl3) 2.52 (3H, s, ArCH3) 3.53 (3H, s, NMe), 3.74 (3H, s, OCH3) 6.70(2H, d, J 9, methoxyphenyl H-2), 6.92(2H, d, J 9, methoxyphenyl H-2), 7.05 (1H, s, thiazolyl H-4) 8.25 (1H, d, J pyrazine H-), 8.52 (1H, d, J pyrazine H-) 8.72 (2H d J pyrazine H- and 1H, s, pyridone H-4); m/z (ESP+) 391 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C(OCC)(=O)C.ClCCl>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:44]3[CH2:43][CH2:42][C:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=4)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccn2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(N)=O)(c4ccccn4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (2.85 g, 5.2 mmol) and 4-(pyridin-2-yl)-piperidine-4-carboxylic acid amide (1.4 g, 6.8 mmol). Chromatograph on silica gel eluting sequentially with ethyl acetate, dichloromethane, 2% methanol/dichloromethane, 4% methanol/dichloromethane, and then 6% methanol/dichloromethane to give the title compound: Rf =0.24 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:33][S:34]([CH2:37][C:38]#[N:39])(=[O:36])=[O:35].C(O)(=O)C.N1CCCCC1>C(O)C>[CH3:33][S:34]([C:37](=[CH:21][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:13]2[N:14]=[C:15]3[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:10]3=[N:11][CH:12]=2)=[CH:24][CH:23]=1)[C:38]#[N:39])(=[O:36])=[O:35]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: CS(=O)(=O)CC#N
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)S(C)(=O)=O)cc3)nc12
Yield: 64 %

Procedure:
To a 10 ml seal tube, 4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.1 g, 0.00022 mol) and 2-(methylsulfonyl)acetonitrile (0.105 g, 0.00088 mol) were taken in ethanol (5 ml). Piperidine acetate (3.3 M solution in water) (1.0 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed for 24 hr. After completion of the reaction, ethanol was distilled out to obtain crude product. The crude product was purified by column chromatography using 30% ethyl acetate in hexanes to yield 0.078 g of 2-(methylsulfonyl)-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylonitrile which was converted to the title compound as described above.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][NH2:20]>C(OC(=O)C)C>[CH2:1]([NH:8][CH2:9][C:10]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][NH:20][C:10](=[O:12])[CH2:9][NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCNCCN
Reactant: O=C(O)CNCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CNCc1ccccc1)NCCCNCCNC(=O)CNCc1ccccc1
Reaction time: 1 h

Procedure:
The p-nitrophenyl ester of N-benzylglycine (2 g) and N-(2-aminoethyl)-1,3-propanediamine (0.18 g) are dissolved in ethylacetate (30 ml). After standing for 1 hour, the mixture is filtered, evaporated and resulting solid triturated with diethyl ether. Recrystallisation of the product from ethanol yields N-[2-(benzylaminoacetamido)-ethyl]-3-(benzylaminoacetamido)-propylamine as a solid, νmax (nujol) 1680, 1630, 1540 cm-1 ; δ(d6DMSO) 1.5 (quintet, 2H), 2.5 (m, 4H), 3.1 (q, 4H), 3.6 (d, 4H), 5.0 (s, 4H), 7.3 (s, 10H), 7.4 (m, 2H), 7.7 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[CH:5]=[CH:6][CH:7]=1.C(O[C:15](=O)[CH2:16][CH2:17][C:18]1[N:19]([CH:31]2[CH2:33][CH2:32]2)[C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:21][CH:22]=1)C.CC(C)([O-])C.[Na+].CCO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:15]([CH2:16][CH2:17][C:18]3[N:19]([CH:31]4[CH2:33][CH2:32]4)[C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[O:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=NO)c1cccc(Cl)c1
Reactant: CCOC(=O)CCc1cnc(-c2ccc(OC)cc2)n1C1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ncc(CCc3nc(-c4cccc(Cl)c4)no3)n2C2CC2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
3-chloro-N′-hydroxybenzenecarboximidamide (54.3 mg, 0.32 mmol), 3-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-propionic acidethyl ester (100 mg, 0.32 mmol) and sodium-tert-butoxide (30.6 mg, 0.32 mmol) were mixed with EtOH (1 ml) and toluene (1 ml), followed by stirring at 100° C. for 24 h. The mixture was then concentrated, in-vacuo, and the residue was purified via column chromatography using 50% EA in hex. and then triturated with Et2O to isolate the title compound (27 mg). 1H-NMR: 8.1 (m, 1H), 7.97 (dd, 1H), 7.64 (d, 2H), 7.47 (m, 2H), 6.96 (d, 2H), 6.88 (s, 1H), 3.87 (s, 3H), 3.37 (m, 4H), 3.24 (m, 1H), 1.06 (m 2H), 0.68 (m, 2H).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH2:11](Cl)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][C:4]=2[O:5]1
Reactant: ClCC=Cc1ccccc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C(=Cc1ccccc1)COc1ccc2c(c1)OCO2

Procedure:
A mixture of sesamol (27.6 g.), cinnamyl chloride (30.4 g.), anhydrous potassium carbonate (50.0 g.), potassium iodide (2.0 g.) in anhydrous acetone (100 ml.) was heated under reflux for 1.5 hrs. The acetone was removed by evaporation, and the residue was treated with excess water and cooled to give an oil, which subsequently solidified. The crude product was collected by filtration and recrystallized from methanol to give MDCB as colorless prisms, m.p. 83° C., yield 15.0 g. (Found: C, 75.4; H, 5.67. Calculated for C16H14O3 : C, 75.6; H, 5.55.) The nuclear magnetic resonance (NMR) spectrum of MDCB at 100 MHz in deuterated chloroform (CDCl3) exhibited absorbances as follows: a doublet (2 protons) at δ 4.59 (coupling constant J = 6.0 Hz), a singlet (2 protons) at δ 5.89 a multiplet (5 protons) at δ 6.22-6.80, and a multiplet (5 protons) at δ 7.18-7.48.
Reaction SMILES: C(CC([O-])=O)#N.C(O[CH:10]=[C:11]([C:17]#[N:18])[C:12](OCC)=[O:13])C.NC(=N)S.S(O)(O)(=O)=O.[CH3:28][S:29][C:30](=[NH:32])[NH2:31]>>[C:17]([C:11]1[C:12]([OH:13])=[N:31][C:30]([S:29][CH3:28])=[N:32][CH:10]=1)#[N:18]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CSC(=N)N
Agent: N#CCC(=O)[O-]
Agent: N=C(N)S
Agent: O=S(=O)(O)O
Product: CSc1ncc(C#N)c(O)n1

Procedure:
Scheme I describes a typical method for preparing the pyrido[2,3-d]pyrimidin-7(8H)-ones and the 7-(8H)-imides, compounds wherein X is O or NH. The synthesis starts by reacting a cyanoacetate such as ethyl ethoxymethylenecyanoacetate with a thiopseudourea such as 2-methyl-2-thiopseudourea sulfate to provide 5-cyano-4-hydroxy-2-(methylsulfanyl)pyrimidine. This reaction is described more fully in Helv. Chim. Acta., 42:763-772 (1959). The 4-hydroxypyrimidine is next reacted with a halogenating agent such as phosphorous oxychloride or thionyl chloride to provide a 4-halo pyrimidine, for example, 5-cyano-4-chloro-2-(methylsulfanyl)pyrimidine. The halopyrimidine next is reacted with an amine R2NH2 to provide a 5-cyano-4-substituted amino-2-(methylsulfanyl)pyrimidine. The amine utilized can have R2 be the group desired in the final product, for example, alkyl such as methyl, or R2 can be a group that can be later removed, for example, benzyl or the like, to generate compounds wherein R2 is hydrogen. Compounds where R2 is hydrogen can be alkylated and acylated by standard methods.