Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][C:25]=1[O:32][CH3:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:6]2[CH:7]=[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]([O:3][CH2:1][CH3:2])=[N:5]2)=[CH:26][C:25]=1[O:32][CH3:33])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: COc1cc(CCl)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (1.59 g), 4-benzyloxy-3-methoxybenzyl chloride (1.97 g), and N,N-dimethylformamide (30 ml), sodium hydride (60%, oily, 0.30 g) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-(4-benzyloxy-3-methoxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionate (2.93 g, yield: 89%) was obtained as a colorless oily substance from the fractions eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.OS([O-])(=O)=O.[K+].[CH2:17]([OH:19])[CH3:18]>>[C:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCO
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
p-Hydroxyacetophenone was converted to 1-(p-acetoxyphenl) ethanol and then dehydrated using liquid phase dehydration in the presence of potassium acid sulfate to produce p-acetoxystyrene, according to the method of Corson et al. (J. Org. Chem., 1958, 23, 544). p-Acetoxystyrene (1.6 g) was added to a stirred solution of potassium hydroxide (1.4 g) in water (14 ml) at 5 degrees Centigrade. Stirring was continued at 0.5 degrees Centigrade for 2 h. The mixture was then washed with ether, and the aqueous phase neutralized with saturated sodium hydrogen carbonate solution. The product was extracted into dichloromethane, the solution was dried over anhydrous calcium chloride and the solvent removed, to yield a cloudy oil (0.7 g) which solidified on standing to a waxy solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH3:36])=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:35][CH3:36])=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OC)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OC)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-methyl-7-methoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]3[C:11](=[CH:12][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]3)[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1.CSC.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[N+:13]([O-:25])=[CH:12][C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2ncc3c(c2c1)CCCC3
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Product: COc1ccc2c(c1)c1c(c[n+]2[O-])CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of Compound 273 (91.80 g, 430 mmol) in dichloromethane (500 mL) cooled at zero degrees C. was added a solution of mCPBA (55 percent, 161.7 g, 516 mmol) in dichloromethane (900 mL), and the resulting mixture was stirred at 25° C. for 1 hour. Dimethyl sulfide (6.95 mL, 94.6 mmol) was added and stirring was continued for 15 minutes followed by addition of saturated aqueous sodium bicarbonate solution (1000 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were dried (MgSO4), filtered through a 3 cm×3 cm plug of silica, and evaporated in vacuo. The residue was purified by recrystallization from benzene-cyclohexane to give a total of 88.34 g (90 percent) of the N-oxide Compound 280a: off-white crystalline solid; mp 167°-169° C.; Rf =0.31 (silica, 20 percent methanol in ethyl acetate); IR (CHCl3) νmax 2943, 1617, 1512, 1459, 1428, 1379, 1108 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=9.5 Hz, 1 H, H4), 8.18 (s, 1 H, H 6), 7.30 (dd, J=9.5, 2.6 Hz, 1 H, H3), 7.10 (d, J=2.6 Hz, 1 H, H1), 2.95 (t, J=6.2 Hz, 2 H, H10), 2.77 (t, J=6.2 Hz, 2 H, H7), 1.99-1.94 and 1.89-1.85 (m, 2 H each, H8 and H9); 13C NMR (125 MHz, CDCl3 ) δ 159.1, 134.8, 134.3, 131.4, 130.8, 121.7, 120.3, 101.8, 55.5, 27.0, 24.7, 22.1, 21.8; MS (FAB+) m/e (rel intensity) 230 (M+H, 100), 213 (10); HRMS for C 14 H16NO2 (M+H), calcd 230.1181, found 230.1194.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C(O[C:20](=[O:22])[CH3:21])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:7][CH:6]1[O:8][C@H:9]([CH2:14][O:15][C:20](=[O:22])[CH3:21])[C@@H:10]([O:13][C:9](=[O:8])[CH3:10])[C@H:11]([O:12][C:6](=[O:7])[CH3:5])[C@@H:5]1[NH:4][C:1](=[O:3])[CH3:2])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1C(OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 187.1 %

Procedure:
A solution of N-acetylmannosamine (100 mg, 0.420 mmol) in pyridine (5 mL) was stirred at 0° C. To this solution was added acetic anhydride (5.0 mL, 53 mmol) and a catalytic amount of DMAP. The mixture was stirred overnight and allowed to warm to rt. Concentration and co-evaporation with toluene (6×10 mL) afforded the crude product which was purified via silica gel chromatography eluting with a gradient of 1:4 to 1:1 EtOAc/hexanes, yielding 153 mg (94%) of a viscous oil. IR (thin film): 3368, 2965, 2255, 1750, 1665, 1536 cm−1. 1H NMR (500 MHz, CDCl3): δ 2.05 (app s, 6H), 2.051 (app s, 6H), 2.08 (app s, 9H), 2.08 (s, 3H), 2.085 (s, 3H), 2.09 (s, 3H), 3.79 (ddd, 1H, J=2.5, 5.3, 9.6), 4.02-4.05 (m, 2H), 4.08 (dd, 1H, J=2.4, 12.4), 4.27 (dd, 1H, J=3.8, 5.5), 4.29 (dd, 1H, J=3.2, 5.5), 4.62 (ddd, 1H, J=1.8, 4.5, 9.2), 4.76 (ddd, 1H, J=1.7, 4.0, 9.1), 5.04 (dd, 1H, J=4.0, 9.9), 5.11 (app t, 1H, J=9.7), 5.15 (app t, 1H, J=10.0), 5.32 (dd, 1H, J=4.5, 10.2), 5.84 (d, 1H, J=1.7), 5.92 (d, 1H, J=9.1), 6.00 (d, 1H, J=1.7), 6.01 (d, 1H, J=9.1). 13C NMR (125 MHz, CDCl3): δ 20.5, 20.6, 20.7, 20.8, 23.1, 23.3, 49.3, 49.5, 50.7, 61.9, 62.1, 65.3, 65.5, 68.8, 70.1, 71.3, 73.4, 76.7, 77.0, 77.2, 90.6, 91.7, 169.6, 169.7, 169.9, 170.0, 170.2, 170.5. HRMS (FAB) m/z 412.1227 (MNa+C16H23NNaO10 requires 412.1220).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:5]1[N:9]2[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21][C:20]3=[O:25])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=[O:4].[CH:28](=O)[CH2:29][CH2:30][CH3:31].N1CCCCC1>C(O)C>[CH:28](=[C:22]1[S:21][C:20](=[O:25])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][S:14][C:10]2[N:9]3[C:5]([C:3](=[O:4])[C:2]([F:26])([F:1])[F:27])=[CH:6][N:7]=[C:8]3[CH:13]=[CH:12][CH:11]=2)[C:23]1=[O:24])[CH2:29][CH2:30][CH3:31]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2ncc(C(=O)C(F)(F)F)n12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3ncc(C(=O)C(F)(F)F)n23)C1=O

Procedure:
To a solution of 250 mg (0.6 mmol) of 3-[4-(3-trifluoroacetylimidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 54 μl (0.6 mmol) of n-butyraldehyde in 5 ml of ethanol, 6 μl (0.06 mmol) of piperidine was added, followed by refluxing for 1 hour. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1) to yield 200 mg (70.0%, light yellow oily substance) of the desired product.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1>ClCCl>[C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]([Cl:34])([Cl:35])[Cl:36])=[O:30])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(CCCCCCCCCCCO)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCCCC(=O)OCC(Cl)(Cl)Cl
Yield: 29.9 %

Procedure:
This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (2.0 g; 8.6 mmol), the product of 14a (3.0 g; 8.6 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 2.1 g; 10.0 mmol), and pyridine (4.0 mL) in dichloromethane (75 mL) using Procedure E. The crude product was purified on a 90×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:3), collecting 13×50 mL fractions. Following evaporation of fractions 6-11, 1.44 g (30%) product was obtained (yellowish oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: Clc1ccc(OC2CCNCC2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of 2-chloro-5-(piperidin-4-yloxy)-pyridine (4.55 g, 21.39 mmol) and Et3N (5.92 mL, 42.8 mmol) in DCM (50 mL) was treated with methanesulfonyl chloride (2.48 mL, 32.09 mmol) and stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-70% EtOAc in cyclohexane) gave 2-chloro-5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine (3.19 g, 51%). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=2.9 Hz, 1H), 7.28-7.16 (m, 2H), 4.58-4.49 (m, 1H), 3.44-3.28 (m, 4H), 2.83 (s, 3H), 2.13-1.92 (m, 4H). LCMS (m/z, Method A) ES+ 290.9 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11]N(C)C.[OH-].[Na+].[N+:17]([CH:20]([CH3:22])[CH3:21])([O-:19])=[O:18]>C(O)(=O)C>[CH3:21][C:20]([CH3:22])([N+:17]([O-:19])=[O:18])[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(Cc1c[nH]c2ccc(Cl)cc12)[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 20 h
Yield: 105.1 %

Procedure:
5-Chloro-3-(dimethylaminomethyl)-1H-indole (10.6 g, 50.5 mmol), prepared as in Example 2, Step (a) and powdered sodium hydroxide (3.0 g, 75.0 mmol) were combined in 2-nitropropane (80 mL, 890.8 mmol) and the mixture was stirred at 120° C. and under nitrogen for 20 hours. The mixture was cooled, acidified with 10% acetic acid (80 mL), stirred at room temperature for 1 hour, and then extracted into ether. The organic phase was separated, washed with water and then brine, dried over magnesium sulfate, and evaporated. Filtration of the residue through a short column of silica gel gave 3-(2,2-dimethyl-2-nitroethyl)-5-chloro-1H-indole (13.5 g, 53.1 mmol) as a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH2:14])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C[Al](C)C.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH:35][C:36](=O)[O:37]C)[N:29]=1>C(Cl)Cl>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH:35][C:36]([NH:14][S:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:12])=[O:13])=[O:37])[N:29]=1
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Reactant: NS(=O)(=O)c1cccc2cccnc12
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3cccnc23)n1
Reaction time: 0.75 h
Yield: 47.8 %

Procedure:
To a stirred mixture of 8-quinolinesulfonamide (4.2 g) in 100 ml methylene chloride is added a 2 M toluene solution of trimethylaluminum (15 ml). The resulting solution is stirred under N2 for 45 min. Solid methyl (4-methoxy-6-methylpyrimidin-2-yl)carbamate (4.0 g) is added and the mixture is heated at reflux for 60 hrs. The reaction is quenched sequentially with acetic acid (2 ml) 6 N HCl (5 ml) and water (25 ml). The organic solution is retained, dried with MgSO4, filtered, and is concentrated in vacuo to a crude solid. Washing with methyl acetate afforded 3.6 g of a pale yellow powder m.p. 181°-185° C. The infrared spectrum showed characteristic absorption bands at 3100 and 1700 cm-1.
Reaction SMILES: [Na].[NH:2]([C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](OC)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>[C:20]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1[CH:18]=[CH:19][C:9]([NH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10][CH:11]=1)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OCCCOc1ccc(Nc2ccccc2)cc1
Reactant: CCCCCC(=O)OC
Agent: CC(C)[O-]
Agent: [Al+3]
Agent: [Na]
Product: CCCCCC(=O)OCCCOc1ccc(Nc2ccccc2)cc1

Procedure:
Following the method of Example 1 using a mixture of sodium metal and aluminum isopropylate catalysts, the reaction of 24.3 g. of 3-(p-anilinophenoxy)propanol with 13 g. of methyl hexanoate was carried out at 140°-145° C. for several hours. The reaction mixture was dissolved in petroleum ether, washed with sodium bicarbonate solution and then with water and dried. After removal of solvent, the residue was recrystallized from isooctane to isolate the ester, 3-(p-anilinophenoxy)propyl hexanoate as a crystalline solid, m.p. 50°-51° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:4]([CH2:16][CH3:17])[N:3]=1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=2)=[C:4]([CH2:16][CH3:17])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1nc(N)nc(N)c1-c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
In this method, commercially available 2,4-diamino-6-ethyl-5-(4-chlorophenyl)pyrimidine is nitrated with 70% nitric acid and concentrated sulfuric acid, yielding the corresponding 2,4-diamino-6-ethyl-5-(4-chloro-3-nitrophenyl)pyrimidine. The thus-prepared nitrophenylpyrimidine is in turn reduced with stannous chloride dihydrate in 10M hydrochloric acid, yielding the corresponding 2,4-diamino-6-ethyl-5-(3-amino-4-chlorophenyl)pyrimidine. The aminophenylpyrimidine may then be treated with an appropriate acid chloride in the presence of a base in tetrahydrofuran, yielding the desired 2,4-diamino-6-ethyl-5-[3-(substituted-carbonylamino)-4-chlorophenyl]pyrimidine (wherein W is --NHC(O)R4). These compounds may optionally be reduced with 1M boron-tetrahydrofuran complex in tetrahydrofuran, affording 2,4-diamino-6-ethyl-5-[3-(substituted-amino )-4-chlorophenyl]pyrimidine (wherein W is --NHR5).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Yield: 77.6 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 2-methoxybenzoyl chloride (102 μl, 0.685 mmol), 62.6 mg (78%) of the title compound were recovered.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>O1CCCC1>[CH3:32][S:33]([N:3]1[CH:4]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[C:5]2[C:20](=[O:21])[CH2:19][CH2:18][C:6]=2[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:2]1=[O:1])(=[O:35])=[O:34]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(2,5-Dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 1, 255 mg, 0.64 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 72 mg, 1.8 mmol) in dry tetrahydrofuran (15 mL) and the mixture is stirred at room temperature for 10 min. Methanesulfonyl chloride (104 μL, 1.35 mmol) is added and the mixture is stirred at 50° C. for 2 h. Water (1 mL) is added and the mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 230 mg; ESI mass spectrum [M+H]+=476; Retention time HPLC: 0.91 min (Z018_S04).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:31][CH2:32][CH3:33]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([N:17]([CH2:31][CH2:32][CH3:33])[C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N(NC(=O)C(F)(F)F)c1cccc(C#N)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)C(F)(F)F)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
5.0 g (15.19 mmol) of the crude product 402 are treated with 7.42 g (22.77 mmol) of cesium carbonate in 100 ml of DMF under a nitrogen atmosphere. After 30 min, 3.87 ml (22.77 mmol) of 1-iodopropane are slowly added dropwise and the mixture is then stirred at RT for 18 h. After customary work-up, 5.64 g (100%) of 403 are thus obtained as an oil, which is employed directly in stage 4.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1.O>C(O)CO.Cl>[N+:20]([C:5]1[CH:6]=[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[NH:1][C:2]2=[N:3][CH:4]=1)([O-:22])=[O:21]
Reactant: Nc1ncc([N+](=O)[O-])cc1NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: OCCO
Product: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1
Temperature: 160 °C
Yield: 92.1 %

Procedure:
To a stirred suspension of N-(2-Amino-5-nitropyridin-3-yl)-4-nitrobenzamide (6) (1.15 g, 3.8 mmol) in ethylene glycol (75 mL) was added HCl (Conc., 3 drops) and the mixture heated at 160° C. for 6 h. The solution was cooled to room temperature and poured into H2O (200 mL) and the resulting solid collected by filtration, rinsed with H2O, and dried in vacuo at 80° C. to give 4 as a pale yellow solid (1 g, 3.5 mmol, 92%). 1H NMR (500 MHz, DMSO-d6) δ14.58 (br s, 1H), 9.28 (apparent d, 1H), 8.88 (br s, 1H), 8.51 (d, J=8.39 Hz, 2H), 8.45 (d, J=8.28 Hz, 2H). EIMS M−1 284.3. Rf=0.55 (silica, 19:1 DCM/MeOH)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N+:11]([O-:23])[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CCc2ccc[n+]([O-])c21
Temperature: 0 °C

Procedure:
To a mixture of 25.1 grams (0.103 mole) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 175 ml of dry CH2Cl2 at 0° C. under an argon atmosphere was added dropwise over 70 minutes a solution of 24.12 grams of 3-chloroperoxy-benzoic acid in 150 ml of CH2Cl2. After the addition the solution was stirred for 1/2 hour after which the ice bath was removed. After two days the reaction was poured into 1.0N aqueous NaOH and extracted with CH2Cl2. The organic portions were combined, washed once with water, dried over MgSO4, filtered and concentrated in vacuo. The resultant product was triturated with isopropyl ether and filtered to provide 25.8 grams (96%) yield of the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]([C:10](O)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].S(Cl)([Cl:17])=O>>[F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]([C:10]([Cl:17])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CC(C)[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)[C@H](NC(=O)C(F)(F)F)C(=O)Cl
Reaction time: 0.25 h

Procedure:
A solution of 1 g. of N-trifluoroacetyl-L-valine in 5 ml. of thionyl chloride was cooled to 5° C. and stirred for 15 minutes. The excess thionyl chloride was removed under reduced pressure under a stream of dry nitrogen gas, affording N-trifluoroacetyl-L-valyl chloride as an oil.
Reaction SMILES: C(N(CC1C=CC=CC=1)C1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)C=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)C=2)CCOC1)C1C=CC=CC=1.[NH2:47][CH2:48][CH2:49][OH:50]>>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:23]=[C:22]([NH:47][CH2:48][CH2:49][OH:50])[C:21]3[C:20](=[CH:25][CH:16]=[N:15][CH:14]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: NCCO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Product: O=S1(=O)CCN(c2cc(NCCO)c3cnccc3n2)Cc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-naphthyridine) and 2-aminoethanol. MS obsd. (ESI+) [(M+H)+] 385, 1H NMR (400 MHz, CD3OD) δ ppm 9.66 (s, 1 H), 8.66-8.64 (d, J=6.8 Hz, 1 H), 8.26-8.24 (d, J=6.8 Hz, 1 H), 8.05-8.03 (d, J=7.6 Hz, 1 H), 7.97-7.95 (d, J=7.2 Hz, 1 H), 7.71-7.69 (d, J=7.2 Hz, 1 H), 7.56-7.54 (d, J=7.6 Hz, 1 H), 6.30 (s, 1 H), 5.38 (s, 1 H), 4.72-4.60 (m, 2 H), 3.87-3.86 (m, 2 H), 3.71-3.67 (m, 4 H).