Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]2[NH:7][C:8](C[N:5]2[C:3](=[O:4])[CH2:2]1)=[O:9].C(OC1NC(=O)CC1)C.C(=O)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:23]([O:22][C:8]([NH:7][CH:6]1[NH:5][C:3](=[O:4])[CH2:2][CH2:1]1)=[O:9])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: O=C1CN2C(=O)CCC2N1
Agent: CCOC1CCC(=O)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C1CCC(NC(=O)OCc2ccccc2)N1

Procedure:
WO 93/09120 describes a process for the preparation of dimiracetam (2,5-dioxohexa-hydro-1H-pyrrolo[1,2-a]imidazole) 1 and related compounds. 5-Ethoxy-2-pyrrolidone is reacted with benzyl carbamate with a catalytic amount of p-toluenesulfonic acid to give 5-benzyloxycarbonylamino-2-pyrrolidone. This compound is then deprotonated at the pyrrolidine nitrogen with sodium hydride in acetonitrile, and reacted with ethyl bromoacetate to give ethyl 5-benzyloxycarbonylamino-2-oxo-1-pyrrolidine-acetate 2. Cyclization can then be performed after cleavage of the ethyl ester and/or the benzyloxycarbonyl protecting group in the presence of a variety of cyclizing agents.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1.[C:19]([CH2:23][CH2:24][C:25](Cl)=[O:26])([O:21][CH3:22])=[O:20]>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:25](=[O:26])[CH2:24][CH2:23][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Fc1cc(Cl)ccc1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.9 %

Procedure:
To a stirred suspension of anhydrous aluminum chloride (1.451 g, 0.0109 mol) in dichloromethane (20 mL) under nitrogen at 5° C. was added dropwise a solution of 4-chloro-2-fluorobiphenyl (0.858 g, 0.00415 mol) in dichloromethane (13 mL) over 10 minutes followed by the dropwise addition of 3-carbomethoxypropionyl chloride (0.57 mL, 0.0046 mol) in dichloromethane (13 mL) over 25 minutes. The resulting mixture was stirred for 2.5 hours then allowed to warm slowly to room temperature. Stirred for 3 days, for convenience. Then the mixture was recooled and quenched with the dropwise addition of water (145 mL). The organic layer was washed with water, aqueous sodium bicarbonate, brine, and dried (MgSO4). The mixture was rotary evaporated to give 1.25 g of 4-(4′-chloro-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a pale yellow solid; mp 90.5-92.5° C.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([CH2:14][CH3:15])[C:11]([OH:13])=[O:12].[CH3:16][CH2:17]O>>[CH2:16]([O:13][C:11]([C:10]1[NH:7][C:1]2[C:6]([C:14]=1[CH3:15])=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:12])[CH3:17]
Reactant: CCO
Reactant: NNc1ccccc1
Reactant: CCC(=O)C(=O)O
Product: CCOC(=O)c1[nH]c2ccccc2c1C

Procedure:
A mixture of phenyl hydrazine (8.92 g), 2-oxo-butyric acid (10.11 g), TsOH mono hydrate (47.1 g) in EtOH (200 mL) was refluxed overnight, then cooled, the solids were filtered off and briefly washed with EtOH, all liquids were combined and concentrated to give a residue, which was subsequently partitioned between EtOAc and water, the organic phase was washed with sat. NaHCO3 solution, and sat. NaCl solution respectively, then dried over anhydrous sodium sulfate, filtered, concentrated and crystallized to give product (15.6 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=8.65 (br, s, 1H), 7.63 (d, 1H), 7.40-7.10 (m, 3H), 4.40 (q, 2H, J=7.1 Hz), 2.61 (s, 3H), 1.43 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH:1]1([C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:16])[C:7]([O:9][CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(OCC)C>C(#N)C.C(Cl)CCl>[Br-:23].[CH:1]1([C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:16])[C:7]([O:9][CH:10]2[CH2:14][CH2:13][N+:12]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH3:15])[CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: CN1CCC(OC(=O)C(O)(c2ccccc2)C2CCCC2)C1
Solvent: ClCCCl
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)C[N+]1(C)CCC(OC(=O)C(O)(c2ccccc2)C2CCCC2)C1
Product: [Br-]
Reaction time: 2 h

Procedure:
To compound 4 (0.369 g, 1.22 mmol) in 10 ml of dry acetonitrile, ethyl bromoacetate (0.377 g, 2.25 mmol) was added at room temperature. The mixture was stirred for 2 h. Evaporation of acetonitrile gave a crude product. The crude product was dissolved in a small volume of ethylene chloride and then poured into 50 ml of dry ethyl ether to precipitate. This procedure was repeated three times to obtain Compound (b) as pure product (0.45 g, 79%). White powder, m.p.: 192-194° C.
Reaction SMILES: C(OCC)(=O)C.[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=[O:22])[CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[C:15]=1[C:31](=[O:48])[NH:32][CH2:33][CH2:34][CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[N+]=[N-]>[H][H].[C].[Pd]>[NH2:7][CH2:10][CH2:11][O:12][CH2:13][C:14]1[N:19]=[C:18]([CH3:20])[C:17]([C:21]([OH:23])=[O:22])=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[C:15]=1[C:31](=[O:48])[NH:32][CH2:33][CH2:34][CH:35]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1.[NH2:7][CH2:10][CH2:11][O:12][CH2:13][C:14]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=[O:22])[CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[C:15]=1[C:31](=[O:48])[NH:32][CH2:33][CH2:34][CH:35]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: [H][H]
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCN=[N+]=[N-])N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCN)N1
Product: Cc1nc(COCCN)c(C(=O)NCCC(c2ccccc2)c2ccccc2)c(-c2cccc(Cl)c2)c1C(=O)O

Procedure:
3 ml of ethyl acetate and 10% palladium carbon were added to 0.100 g (0.170 mmol) of 6-(2-azidoethoxy) methyl-4-(3-chlorophenyl)-5-(3,3-diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid and stirred at room temperature in hydrogen atmosphere under normal pressure for 40 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue thus obtained by evaporating the solvent was subjected to Reversed-phase High-performance Liquid Chromatography using octadodecyl group bounded type silica gel as a filler. Then, the obtained substance was eluted with the mixed solvent of water and acetonitrile. The fraction of the object compound was freeze-dried to obtain the title compound as a by-product material of 6-(2-aminoethoxy) methyl-4-(3-chlorophenyl)-5-(3,3-diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].C1(C)C=CC=CC=1.[OH-:20].[Na+].OO>O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:9])[F:10])[C:3]=1[C:11]([OH:20])=[O:12]
Reactant: [OH-]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)F)c(C(=O)O)c1Cl
Temperature: 50 °C
Reaction time: 7 h
Yield: 49 %

Procedure:
In a 500 ml flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde are added to 30 ml of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6 ml of water is added to the reaction mixture, followed by 103 ml of a 30% solution of hydrogen peroxide in water, whilst keeping the temperature below 37° C. After the end of the addition, the reaction mixture is stirred at 50° C. for 7 hours. Once the reaction mixture is back to room temperature, the two phases are separated and the organic phase is extracted with 100 ml of water. The combined aqueous phases are acidified to pH 2 with aqueous hydrochloric acid. The resulting white precipitate is filtered, washed twice with 20 ml of water, and dried to yield 3.2 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.78 (s, 3H); 7.12 (t, 1H, JHF=53.60 Hz) 13.19 (s, 1H); IR (KBr): 1688 cm−1 (C═O); 2200-3200 cm−1 broad (hydrogen bond).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:18]([NH2:20])[CH3:19])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:22]1[C:27]([C:28]#[N:29])=[CH:26][N:25]=[CH:24][N:23]=1.CC[N:32](C(C)C)C(C)C>C(O)CCC.CCOC(C)=O>[NH2:32][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:20][CH:18]([C:10]2[N:9]([C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[C:17]3[C:12]([N:11]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)[CH3:19])[N:25]=[CH:24][N:23]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(N)c1nc2ncccc2n1-c1cc(F)cc(F)c1
Reactant: N#Cc1cncnc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ncccc2n1-c1cc(F)cc(F)c1
Temperature: 120 °C

Procedure:
To a solution of 1-[1-(3,5-difluorophenyl)-1H-imidazo[4,5-b]pyridin-2-yl]-ethylamine (200 mg, 0.729 mmol) and 4-chloro-pyrimidine 5-carbonitrile (112 mg, 0.729 mmol) in n-butanol (2.18 mL) was added DIEA (282 mg, 2.187 mmol) at rt. The reaction mixture was heated at 120° C. overnight. After completion, the reaction mixture was diluted with EtOAc and the resulting solid was collected by filtration to provide 4-amino-6-{1-[1-(3,5-difluorophenyl)-1H-imidazo[4,5-b]-pyridin-2-yl]ethylamino}-pyrimidine-5-carbonitrile: 1H NMR (400 MHz, DMSO-d6) δ 1.597 (d, J=6.8 Hz, 3H), 5.631-5.698 (m, 1H), 7.201 (br s, 2H), 7.255-7.287 (m, 1H), 7.363-7.409 (m, 3H), 7.663 (d, J=7.6 Hz, 1H), 7.759 (d, J=7.6 Hz, 1H), 7.882 (s, 1H), 8.462 (d, J=3.6 Hz, 1H); LC-MS (ESI) m/z 393.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:34][CH:33]=[CH:32][CH2:31]3)[N:26]=[C:25]([CH3:35])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O>O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:34][CH:33]=[CH:32][CH2:31]3)[N:26]=[C:25]([CH3:35])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CC=CC2)n1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CC=CC2)n1
Yield: 58.6 %

Procedure:
A solution of ((2R)-2-(cyclopentylmethyl)-3-{2-[6-(2,5-dihydro-1H-pyrrol-1-yl)-5-fluoro-2-methyl-4-pyrimidinyl]hydrazino}-3-oxopropyl)(tetrahydro-2H-pyran-2-yloxy)formamide (140 mg) in 4:1 AcOH:water (2 mL) was stirred at room temperature until deprotection was complete. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[6-(2,5-dihydro-1H-pyrrol-1-yl)-5-fluoro-2-methyl-4-pyrimidinyl]hydrazino}-3-oxopropyl)hydroxyformamide (68 mg, 58%). LCMS: (M+H)+: 407.3.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].CC(C)([O-])C.[K+].Br[CH2:35][C:36]#[N:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:35][C:36]#[N:37])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: N#CCBr
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(OCC#N)cccc4c3nc12
Temperature: 100 °C

Procedure:
To a suspension of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide: hydrobromide salt (230 mg) in dry N,N-dimethylformamide (3 mL) was added potassium tert-butoxide (175 mg) and then bromoacetonitrile (47 μL). The reaction mixture was heated to 100° C. for 1 hour. The reaction mixture was then cooled, diluted with ethyl acetate, washed with sodium carbonate solution and brine, dried (MgSO4) and the solvent removed in vacuo to provide crude product. This was purified using flash chromatography (silica, 25% MeOH in ethyl acetate) to yield the title compound as a yellow solid (74 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]([NH2:20])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]#[N:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#C[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of benzyl-(2S)-2-aminocarbonyl-4,4-difluoropyrrolidine-1-carboxylate and triethylamine (2.1 eq.) in dichloromethane was cooled to 0° C. and trifluoroacetic anhydride (1.1 eq.) was added dropwise under nitrogen. Stirring was continued for 1 hour allowing the mixture to reach room temperature. Volatiles removed in vacuo and residue taken up in ethyl acetate, washed with HCl 1N, brine and dried over Na2SO4. Evaporation gave title compound as brown oil.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]1[CH2:19][CH2:18][CH2:17][NH:16][C:15]2[C:14](=[O:20])[C:13](=[O:21])[C:12]1=2)(=[O:8])[O:5]CC)C.O>C(Cl)Cl>[O:20]=[C:14]1[C:13](=[O:21])[C:12]2[N:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH2:19][CH2:18][CH2:17][NH:16][C:15]1=2
Reactant: CCOP(=O)(CCN1CCCNc2c1c(=O)c2=O)OCC
Solvent: ClCCl
Solvent: O
Product: O=c1c2c(c1=O)N(CCP(=O)(O)O)CCCN2
Reaction time: 15 h
Yield: 64.7 %

Procedure:
Under N2 bromotrimethylsilane (83 mL, 96.3 g, 0.63 mole; Aldrich 19,440-9) was added dropwise at a fast rate to a solution of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid diethyl ester (37.6 g, 0.12 mole) in methylene chloride (350 mL). The reaction mixture was kept in a water bath at approximately 20° C. for 15 hr. The clear solution was concentrated in vacuo and the foamy residue was taken up in acetone (600 mL) with vigorous shaking to result in a thin suspension. Water (50 mL, 2.78 moles) was added to give a gummy precipitate which solidified instantly. The suspension was shaken vigorously for 10 minutes, filtered and washed with acetone to give a yellow solid compound. The solids were taken up in boiling water (450 mL) and the hot solution was filtered through a fluted filter paper to remove a small amount of insoluble material. The clear aqueous solution was cooled in ice and crystallization began at once. The thick crystalline mass was diluted by slow addition of acetone (800 mL), kept cold for 1 hr, filtered and washed with acetone and then hexane to give the title compound as a pale yellow solid (20.2 g). A second crop from the mother liquor (100% purity by LC) yielded an additional amount (6.5 g) for a total yield of 87%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21]Cl>CN(C)C=O>[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Cn1ccc2ccc(C=O)cc21
Yield: 89.3 %

Procedure:
To a solution of indole-6-carboxaldehyde (457 mg) in N,N-dimethylformamide (5 mL) were added potassium carbonate (936 mg) and 2,6-dimethylbenzyl chloride (752 mg) at room temperature, and then the reaction mixture was subjected to microwave irradiation at 160° C. for 30 minutes. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (740 mg) as a yellow solid.
Reaction SMILES: [Na].[N:2]1([C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH3:3].Cl[CH2:16][P:17](=[O:20])(C)[CH3:18].[CH3:21]N(C=O)C>>[CH3:7][N:6]1[C:8]2[N:9]=[CH:10][N:11]([CH3:21])[C:12]=2[C:13](=[O:14])[N:2]([CH2:3][P:17](=[O:20])([CH3:18])[CH3:16])[C:4]1=[O:5]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CP(C)(=O)CCl
Reactant: CN(C)C=O
Agent: [Na]
Product: Cn1cnc2c1c(=O)n(CP(C)(C)=O)c(=O)n2C

Procedure:
A solution of 20.2 g (0.1 mol) of theophylline sodium salt in 400 ml of DMF was heated at 130° C. for 3 hours with 12.7 g of chloromethyldimethyl-phosphine oxide. The solution was filtered, the solvent was evaporated and the residue was taken up in methanol. The precipitate was filtered off and dried to constant weight under reduced pressure.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C[Si]([C:27]#[N:28])(C)C>>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[C:27]#[N:28])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: C[Si](C)(C)C#N
Reactant: CCCOc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1
Product: CCCOc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-propoxybenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 80%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1N([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1)C.Cl.CN(C)CCCN=C=NCC.O[N:61]1[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=2[N:63]=N1.C(N(CC)CC)C>ClCCl>[N:63]1[CH:64]=[CH:69][CH:68]=[CH:67][C:66]=1[CH:65]([NH:61][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1
Reactant: CN(c1ccccn1)c1ccccn1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(c1ccccn1)c1ccccn1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (250 mg, 0.57 mmol) was combined with di-(2-pyridyl)-methylamine hydrochloride (126 mg, 0.57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (121 mg, 0.69 mmol), 1-hydroxybenzotriazole (85 mg, 0.63 mmol), and triethylamine (0.32 ml, 2.3 mmol) in 3 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 75 ml of dichloromethane, and the organic phase washed sequentially with water (2×40 ml), and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a yellow residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 3% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 112 mg of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[C:14](OC(Cl)(Cl)Cl)=[O:15].O>C(Cl)Cl.CCCCCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:14](=[O:15])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]nc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
To the suspension of 4-chlorobenzhydrazide (8.53 g, 0.05 mole) in methylene chloride (100 ml), equipped with a magnetic stirring bar, a nitrogen inlet, a dropping funnel, and an outlet connected to diluted base solution for trapping the HCl gas, was dropwise added trichloromethyl chloroformate (5.94 g, 0.03 mole). After addition, the reaction mixture was heated to reflux for 2 hr. The reaction was cooled down to room temperature and poured into a mixture of water (500 ml) and hexane (200 ml) and stirred for 10 to 20 min. The resultant precipitate was collected by suction-filtration and was washed with hexane to give a solid product. The product was dried in air at room temperature overnight yielding 5.5 g (60% yield) of 2-(4-chlorophenyl)-1,3,4-oxadiazolin-5-one as a solid, m.p.=225°-227° C. NMR and IR spectra showed the desired structure. Without further purification, this product was subjected to the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:12][O:13]S(OC)(=O)=O.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:3]([CH2:12][OH:13])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COS(=O)(=O)OC
Reactant: COc1c(C)c[n+]([O-])cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C)cnc(CO)c1C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
3.5-Dimethyl-4-methoxypyridine-N-oxide (61.2 g) obtained in Example 2 was dissolved in CH3OH (458 ml). Dimethylsulfate (38 ml 0.4 moles) was added dropwise during 15 minutes and pH adjusted to 5.0 using 10M NaOH. The mixture was stirred for 15 minutes and thereafter refluxed for 1 hour. An additional amount of dimethylsulfate (3.8 ml, 0.04 moles) was added dropwise and the mixture was refluxed for 1.5 hours. Stirring was continued overnight at room temperature. Thereafter the mixture was heated to reflux and (NH4)2S2O8 (91.2 g, 0.4 moles) dissolved in water (169 ml) was added during 1.75 hours, followed by refluxing for 1.5 hours and stirring at room temperature overnight. Thereafter CH3OH (452 ml) was added. Precipitated salts were filtered off and discarded. After evaporation of CH3OH, the remaining water phase (pH 0.6) was adjusted to pH 10.0 using 10M NaOH (145 ml). The water phase was extracted three times with CH2Cl2. The combined CH2Cl2 phases were dried over Na2SO4, evaporated and dried, yielding 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine (44.2 g). The identity of the product was confirmed with 1H and 13C NMR and the purity checked with gas chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[CH3:12].[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.Cl>O.C(O)C.O1CCCC1>[CH2:15]([O:14][C:13](=[O:17])[CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=1)=[O:11])[CH3:16]
Reactant: COc1ccc(C(C)=O)cc1C
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(OC)c(C)c1

Procedure:
At room temperature, to a mixture of 1-(4-methoxy-3-methylphenyl)-ethanone (described in Reference Preparation example 48) and tetrahydrofuran 200 ml was added diethyl carbonate 16.1 g, 55% sodium hydride 6.2 g, dibenzo-18-crown-6 0.05 g and ethanol 3 mL, and the resulting mixture was stirred with heating under reflux for eight hours. To the reaction mixture was added water, and the resulting mixture was acidified with 10% aqueous hydrochloric acid solution and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-3-methyl-phenyl)-3-oxo-propionic acid ethyl ester 14.8 g.