Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>CO.[Pd](Cl)Cl.[Li]>[CH3:23][O:22][C:18](/[CH:19]=[CH:20]/[C:16]1[C:14]([NH2:15])=[N:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])=[O:21]
Reactant: C=CC(=O)OC
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: Cl[Pd]Cl
Agent: [Li]
Solvent: CO
Product: COC(=O)/C=C/c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)nc1N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of 19.1 g of 5-chloromercuriccytidine (b) in 150 ml of methanol was prepared and then 210 ml of a methanol solution of 0.1 M lithium palladium chloride (Li2PdCl4), 40 ml of methyl acrylate, and 4.12 g of cupric chloride were added to above suspension and the mixture was stirred at room temperature for 14 hours. The palladium precipitate was removed by filtration and hydrogen sulfide was bubbled into the filtrate and the formed precipitate was removed by Celite filtration. The filtrate was neutralized with a saturated sodium bicarbonate solution and evaporated to dryness under reduced pressure. The residue was recrystallized from aqueous solution to give 4.62 g of (E)-5-(2-methoxycarbonyl ethenyl) cytidine (c).
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(O)(=O)C>[C:28]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:13][CH2:12]2)=[CH:20][CH:19]=1)(=[O:30])[CH3:29]
Reactant: Nc1ccc(CN2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CN2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 8 parts of 4-{[4-(diphenylmethyl)-1-piperidinyl]methyl}benzenamine in 50 parts of acetic acid is added 5 parts of acetic anhydride. The resultant mixture is heated to the boiling point under reflux and maintained thereat for 10 minutes, then stripped of solvents by vacuum distillation. The residue is combined with 10 volumes of water. The resultant mixture is made alkaline with concentrated ammonium hydroxide. The mixture thus obtained is extracted with dichloromethane. The dichloromethane extract is dried over anhydrous potassium carbonate and then stripped of solvent by vacuum distillation. The residue, recrystallized from benzene, affords N-acetyl-4-{[4-(diphenylmethyl)-1-piperidinyl]methyl}benzenamine melting at approximately 182°-183°. The product has the formula ##STR5##
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.CCO.[NH2:19][NH2:20]>>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[O:2][CH:1]=[N:19][N:20]=1
Reactant: NN
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Solvent: CCO
Product: FC(F)(F)c1cccc(Cc2nnco2)c1
Temperature: 135 °C

Procedure:
(3-Trifluoromethyl-phenyl)-acetic acid methyl ester (0.720 g, 3.30 mmol) was dissolved in hydrazine (7 mL) and EtOH (15 mL) and heated to 90° C. overnight. Analytical LCMS indicated complete reaction so the mixture was concentrated and azeotroped twice with toluene. The crude material was dissolved in triethylorthoformate and heated to 135° C. for 20 hours then allowed to cool. The reaction mixture was concentrated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17]O)[N:3]=1.C(N(S(F)(F)[F:25])CC)C>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17][F:25])[N:3]=1
Reactant: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(CO)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(CF)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a stirred suspension of 2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxymethylpyrimidine (185 mg; 1 mmol) in dry dichloromethane (25 ml), under nitrogen at -70° C., was added dropwise diethylaminosulphur trifluoride (263 μl; 2 mmol). The mixture was allowed to warm to 0° C. and kept at this temperature for 4 hours. After cooling to -70° C. the mixture was quenched with aqueous sodium bicarbonate, extracted with dichloromethane (2×50 ml), washed with saturated brine and dried (MgSO4). Concentration gave a colourless gum (0.2 g). Chromatography on silica gel, eluting with 0.01:1:19 Et3N:MeOH:CH2Cl2 gave the desired product which was triturated with CCl4 and dried in vacuo. 111 mg, mp. 224°-6° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:14][C:15]3[CH:16]=[C:17]([NH:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[C:10]2=[O:13])=[CH:5][CH:4]=1.[OH-].[Na+]>Br.C(O)(=O)C.O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:14][C:15]3[CH:16]=[C:17]([NH:21][S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C(Cc1cccc(NS(=O)(=O)C(F)(F)F)c1)CC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cc(O)ccc2CCC1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 439 mg (1.06 mmol) of the product of Example 30 in 8 mL 48% HBr and 8 mL acetic acid was heated to reflux for 75 minutes under N2. The reaction mixture was cooled to room temperature, diluted with 300 mL H2O, pH adjusted to 3-4 using 2N NaOH, and extracted with twice with 150 mL ethyl acetate. The ethyl acetate extracts were combined and washed once with brine and then dried over Na2SO4. Filtration, concentration and drying yielded 0.42 g of tan solid, which was purified by silica gel chromatography (4% methanol-CH2Cl2) to yield 357 mg of pure product, an off-white powder. (84% yield) m.p.: 191°-194° C.; MS (LSIMS): 400 M+H, Base; 1H NMR (AC 300, dimethylsulfoxide-d6): δ9.58 (br s, 1H, phenol OH); IR (cm31 1): 3330, 3280, 1670. Analysis calculated: C 54.13, H 4.04, N 3.51%; C 53.99, H 3.95, N 3.49%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([O:21][CH2:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=1[O:3][CH2:1][CH3:2])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[O:32]
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccc(Cl)cc1Cl

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b)
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]1[CH:16]=[C:17]([C:21]2[N:30]=[C:29]([NH:31][C:32]([C:34]3([C:37]4[CH:47]=[CH:46][C:40]5[O:41][C:42]([F:45])([F:44])[O:43][C:39]=5[CH:38]=4)[CH2:36][CH2:35]3)=[O:33])[CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][CH:20]=1)=[O:14])(C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:45][C:42]1([F:44])[O:41][C:40]2[CH:46]=[CH:47][C:37]([C:34]3([C:32]([NH:31][C:29]4[N:30]=[C:21]([C:17]5[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=5)[C:13]([OH:14])=[O:12])[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=4)=[O:33])[CH2:36][CH2:35]3)=[CH:38][C:39]=2[O:43]1
Reactant: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
TFA (1 mL) was added to a solution of methyl 2-(3-(tert-butoxycarbonyl)-phenyl)-6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)nicotinate (290 mg, 0.50 mmol) in CH2Cl2 (2.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with CH2Cl2 and neutralized with saturated aqueous NaHCO3. A white precipitate formed which was filtered, washed with H2O and air-dried to yield the product as a white solid (240 mg, 91%). ESI-MS m/z calc. 496.1. found 497.5 (M+1)+. Retention time 1.91 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.98-7.96 (m, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, 2H), 7.40-7.33 (m, 2H), 3.62 (s, 3H), 1.55-1.52 (m, 2H), 1.22-1.19 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[C:41]([O:46][CH3:47])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[C:41]([O:46][CH3:47])=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4OC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4OC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methoxy-3-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.48 g) in methylene chloride (14.4 ml) was added dropwise a solution of m-chloroperbenzoic acid (187 g) in methylene chloride (9.6 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, and recrystallized from ethanol, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methoxy-3-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 249) (267 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17](O)=[O:18])[CH2:14][N:15]=1)=[CH:7]2.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:18])[CH2:14][N:15]=1)=[CH:7]2
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N4CCOCC4)S3)[nH]c12
Reaction time: 15 h
Yield: 83 %

Procedure:
To a solution of [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg) and morpholine (0.088 mL) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole (137 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio), and the obtained pale-yellow oil was crystallized from ethyl acetate-diethyl ether to give the title compound (286 mg, yield 83%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[N:17][NH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CO.CCOCC>[ClH:32].[C:26]1([S:23]([C:16]2[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[NH:18][N:17]=2)(=[O:25])=[O:24])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(S(=O)(=O)c4ccccc4)c23)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)c1n[nH]c2cccc(N3CCNCC3)c12
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]-3-(phenylsulfonyl)-1H-indazole (0.022 g, 0.050 mmol) in methanol is treated with a 2 M solution of HCl in ether (0.4 mL), heated at reflux temperature for 1 h, cooled to room temperature and evaporated to dryness. The residue is re-dissolved in methanol and concentrated. Repeating this procedure three more times affords the title product as a white solid, 0.009 g (40% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:19])[CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:19])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)CCC(=O)c1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl 4-(2,6-difluorophenyl)-4-oxobutyrate (Step A, 9.52 g, 35.2 mmol) in dichloromethane (30 ml) was treated with trifluoroacetic acid (20 ml). The mixture was stirred at ambient temperature for 3 hours and concentrated. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to provide the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:23][CH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[C:27](=[O:43])[N:28]([CH:35]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][C:36]1=[O:42])[C:29]2=[O:34].C(N(CC)CC)C>CN(C=O)C>[O:42]=[C:36]1[CH:35]([N:28]2[C:27](=[O:43])[C:26]3[C:30](=[CH:31][CH:32]=[CH:33][C:25]=3[CH2:24][NH:23][C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[O:9])[C:29]2=[O:34])[CH2:40][CH2:39][C:38](=[O:41])[NH:37]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1cncnc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cncnc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
A mixture of pyrimidine-5-carboxylic acid (0.25 g, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in DMF (25 mL) was stirred at ambient temperature under nitrogen for 2 hours. 4-Aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were added, and the mixture was allowed to stir for 16 hours. The solvent was evaporated under vacuum, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting with 95:5 methylene chloride-methanol, providing 0.39 g of the product in 50% yield: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.53-2.65 (m, 2H), 2.83-2.91 (m, 1H), 4.98 (d, J=5.7 Hz, 2H), 5.18 (dd, J=12.4 Hz, d=5.4 Hz, 1H), 7.84 (s, 3H), 9.24 (s, 2H), 9.35 (s, 1H), 9.52 (t, J=5.7 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.3, 48.9, 122.1, 127.3, 127.5, 131.6, 133.4, 134.9, 138.4, 156.0, 160.1, 163.5, 167.0, 167.5, 169.8, 172.8; Anal. calcd for C19H15N5O5.0.3H2O: C, 57.23; H, 3.94; N, 17.56. Found: C, 57.27; H, 3.71; N, 17.27.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:19][CH2:20][CH3:21])[C:17]#[N:18])=[CH:11][C:10]=1[N+:22]([O-])=O)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[NH2:22][C:10]1[CH:11]=[C:12]([CH2:15][CH:16]([O:19][CH2:20][CH3:21])[C:17]#[N:18])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CCOC(C#N)Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(C#N)Cc1ccc(O)c(N)c1
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 3-(4-benzyloxy-3-nitrophenyl)-2-ethoxypropanenitrile (0.54 g, 1.7 mmol) in ethanol (25 ml) and acetic acid (75 ml) containing 10% palladium on carbon (0.40 g) was hydrogenated at 45 psi for 1 hour. The catalyst was filtered and the solution concentrated. The residue was treated with 5% sodium bicarbonate (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (2×100 ml) and brine (100 ml), dried over sodium sulfate and concentrated. The product was isolated by column chromatography (silica gel, 2% methanol in chloroform) as a solid (0.20 g, m.p. 114°-115° C.)
Reaction SMILES: CN(C)C1C=CC=CC=1.Cl[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12].[Br:26][C:27]1[CH:36]=[C:35]([CH3:37])[C:34]([CH3:38])=[CH:33][C:28]=1[NH:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[Br:26][C:27]1[CH:36]=[C:35]([CH3:37])[C:34]([CH3:38])=[CH:33][C:28]=1[N:29]([CH:30]([CH3:32])[CH3:31])[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12]
Reactant: Cc1cc(Br)c(NC(C)C)cc1C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1cc(Br)c(N(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C(C)C)cc1C
Temperature: 25 °C

Procedure:
N,N-dimethylaniline (7.12 mL, 56.2 mmol) followed by tert-butyl 4-(chlorocarbonyl)piperidine-1-carboxylate 1-11 (42.1 mL of a 1 M solution in methylene chloride, 42.1 mmol) were added to a neat stirred mixture of 2-bromo-N-isopropyl-4,5-dimethylaniline 1-9 (6.80 g, 28.1 mmol) and N,N-dimethylamino-pyridine (172 mg, 1.40 mmol) at approximately 0° C. The resulting mixture was heated to reflux for 30 min, cooled to ambient temperature and partitioned between diethyl ether and aqueous 1 N hydrochloric acid. The organic phase was separated and washed successively with aqueous 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-40% ethyl acetate/hexanes as eluent) afforded 1-12 as a white solid.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[O:15]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH:17]2[CH2:18][CH2:19][O:15][CH2:16]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: OC1CCOC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OC2CCOC2)cccc1[N+](=O)[O-]
Yield: 50 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and tetrahydrofuran-3-ol in 50% yield as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 1H), 2.32 (m, 1H), 3.81 (td, J=8.3, 4.6 Hz, 1H), 3.89 (m, 2H), 3.98 (dd, J=10.8, 4.5 Hz, 1H), 5.36 (m, 1H), 7.75 (dd, J=8.1, 1.5 Hz, 1H), 7.91 (t, J=8.2 Hz, 1H), 7.95 (dd, J=8.2, 1.6 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1([CH2:6]Cl)[CH2:5][O:4]1.[NH:8]1[CH:12]=[N:11][CH:10]=[N:9]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:8]1([CH2:2][C:3]([OH:4])([CH2:6][N:11]2[CH:10]=[N:9][N:8]=[CH:12]2)[CH2:5][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: c1nc[nH]n1
Reactant: ClCC1(CCl)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OC(Cn1cnnc1)(Cn1cncn1)Cn1cncn1
Yield: 10.7 %

Procedure:
28.2 g (0.2 mole) of 2,2-di(chloromethyl)-oxirane are added dropwise to a mixture of 82.5 g (1.2 moles) of 1,2,4-triazole and 82.5 g (0.6 mole) of potassium carbonate in 400 ml of acetone, while stirring. The reaction mixture is stirred under reflux for 50 hours and filtered and the filtrate is concentrated in vacuo. The oily residue is chromatographed (silica gel 60, Merck, chloroform/methanol=20/1). 5.9 g (10.7% of theory) of 1,3-di(1,2,4-triazol-1-yl)-2-hydroxy-2-(1,2,4-triazol-4-yl-methyl)-propane of melting point 220° C. are obtained.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH:19]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])([CH3:21])[CH3:20]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([O:22][CH:19]([CH3:21])[CH3:20])[CH:24]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC(C)Oc1cccc(N)c1
Agent: [Na+]
Product: CC(C)Oc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 64 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 572 mg of 3-isopropoxyaniline in place of the 2,4-difluoroaniline. 228 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[3-(propan-2-yloxy)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][C:21]1[CH:22]=[C:17]([Cl:16])[N:18]=[CH:19][N:20]=1
Reactant: Cc1ccc(O)c(Br)c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2cc(Cl)ncn2)c(Br)c1
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
To a solution of 2-bromo-4-methylphenol (500 mg), in dimethyl sulphoxide (2 ml), was added freshly ground potassium carbonate (407 mg). The mixture was stirred for 20 minutes, and 4,6-dichloropyrimidine (432 mg) was added. The mixture was stirred at ambient temperature for 2 hours, and the reaction mixture preadsorbed onto silica gel (1 g) and purified by column chromatography (eluting with 10% ethyl acetate/dichloromethane) to yield a gum (571 mg, 71%). NMR: 2.35 (3H, s), 7.25 (2H, s), 7.5 (1H, s), 7.55 (1H, s), 8.7 (1H, s); MS; (electrospray) 451 (MH)+.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:3]=[C:2]([CH2:4][C:5](=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:1]([OH:7])=[O:8]
Reactant: C=C1CC(=O)OC1=O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: C=C(CC(=O)c1ccccc1)C(=O)O
Yield: 70 %

Procedure:
From itaconic anhydride treated with a large excess of benzene in the presence of aluminum chloride, there is recovered with a yield of about 70% the derivative of the formula: ##STR8##