Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:19])[CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1)(C)(C)C>O1CCOCC1>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:19])[CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1
Reactant: CC(CC#N)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(CC#N)N1CCC(N)CC1
Temperature: 45 °C
Reaction time: 3.5 h

Procedure:
A 4.0 M solution of HCl in 1,4-dioxane (100 ml) was added to a solution of [1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (50.0 mmol) in 1,4-dioxane (50 ml) at 25° C. The reaction mixture was stirred at 45° C. for 3.5 h, then was cooled to 25° C. and concentrated under reduced pressure to afford crude 3-(4-amino-piperidin-1-yl)-butyronitrile (hydrochloride salt) as a beige solid. 1H NMR (400 MHz, DMSO) δ 8.52 (s, 2H), 4.21 (s, 2H), 3.83-3.68 (m, 1H), 3.49-3.25 (m, 2H), 3.17 (dd, J=16.9, 8.0 Hz, 1H), 2.23-1.99 (m, 2H), 1.42 (d, J=6.7 Hz, 1H). This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:17]>[OH-].[Na+].O>[C:7]1([C:4]2[N:3]=[C:2]([S:1][NH2:17])[S:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: Sc1nc(-c2ccccc2)ns1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: NSc1nc(-c2ccccc2)ns1
Reaction time: 0.17 h

Procedure:
A solution of 30 g of 5-mercapto-3-phenyl-1,2,4-thiadiazole in 500 ml of 5% sodium hydroxide and a solution prepared by diluting 310 ml of 5.25% NaOCl to 500 ml with water were added dropwise simultaneously to 1325 ml of an ammonium hydroxide solution while maintaining the mixture at 0° with an ice/methanol bath. The resulting mixture was stirred for 10 minutes and the solids were collected, washed with water and dried under high vacuum (with P2O5) to give 18.5 g of powder. Recrystallization of 8.2 g of this material from benzene (300 ml) gave 4.8 g of crystals, m.p. >142° dec.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:7]=2[N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:23][C:24]([CH2:32][CH3:33])([CH2:30][CH3:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[C:24]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:13])([CH2:32][CH3:33])[CH2:30][CH3:31])[CH3:29]
Reactant: O=C(O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1
Reactant: CCOC(=O)C(N)(CC)CC
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid (Example 234 b) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=432.3 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[OH:30]C(CCO)CC(O)=O>>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:30])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4]
Reactant: O=C(O)CC(O)CCO
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21

Procedure:
For example, lovastatin (Ia) is prepared by lactonisation of the 3,5-dihydroxy pentanoic acid derivative (II) to (Ia) either by heating in an organic solvent or in the presence of an acid catalyst. The former, viz. mevinolinic acid, is obtained from a fermentation broth containing Asperigillus Terreus.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl:14]Cl>C(O)(=O)C>[Cl:14][C:7]1[CH:8]=[C:3]([S:2]([F:10])([F:11])([F:12])([F:13])[F:1])[CH:4]=[CH:5][C:6]=1[OH:9]
Reactant: Oc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: ClCl
Solvent: CC(=O)O
Product: Oc1ccc(S(F)(F)(F)(F)F)cc1Cl
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
5.00 g of 4-pentafluorosulfanylphenol (prepared in example 11a) were dissolved in 100 ml of acetic acid and a chlorine gas stream was passed through at 0° C. for 10 minutes. This warmed the solution to 30° C. which was subsequently stirred at RT for a further 90 minutes. Argon was used to drive the chlorine out of the solution and the solvent was subsequently removed under reduced pressure. 5.50 g of a pale yellow oil were obtained.
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[C:6](#[N:10])[C:7]([CH3:9])=[CH2:8].CC(N=NC(C#N)(C)C)(C#N)C>C(O)(=O)C>[CH2:1]([P:3]([CH2:8][CH:7]([C:6]#[N:10])[CH3:9])(=[O:5])[OH:4])[CH3:2]
Reactant: C=C(C)C#N
Reactant: CCP(O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Product: CCP(=O)(O)CC(C)C#N
Yield: 72.6 %

Procedure:
94 g (1 mol) of ethylphosphonous acid (produced as in Example 1) and 67 g (1 mol) of methacrylonitrile are initially charged in 200 ml of glacial acetic acid in a four-neck round-bottom flask equipped with stirrer, reflux condenser, thermometer and nitrogen inlet and heated. At about 100° C., 98.4 g of a 5% solution of AIBN in glacial acetic acid are added dropwise over 1 h. Thereafter, the solvent was distilled off in vacuo to leave 117 g (80% of theory) of ethyl(2-cyano-2-methylethyl)phosphinic acid.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][C:9]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].Cl.[CH3:21]OC(OC)(C)C>CO.C(Cl)Cl>[CH3:21][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:9]1[NH:10][C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=1
Reactant: COC(C)(C)OC
Reactant: Cn1c(=O)c2[nH]c(CCCC(=O)O)nc2n(C)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCc1nc2c([nH]1)c(=O)n(C)c(=O)n2C

Procedure:
10 g of theophylline-8-butyric acid are suspended in 50 ml of methanol. For one hour HCl-gas is fed into the suspension. While further feeding HCl-gas into the suspension, heating for one hour under reflux is effected. The feed of HCl-gas is interrupted, and 13.5 ml of 2,2-dimethoxypropane are added to the suspension. Afterwards, for a further 20 minutes HCl-gas is fed into the suspension. After standing over night at room temperature, the suspension is brought to dryness in vacuo. The residue is dissolved in 300 ml of methylenechloride. After having extracted the methylenechloride phase twice with 100 ml of saturated aqueous soda solution and twice with 100 ml of water, it is dried over annealed sodium sulfate and brought to dryness in vacuo. The residue is recrystallized from methanol. In this way 5.15 g (48.4 percent of the theoretically-calculated amount) of the title compound of melting point 200° to 204° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:5])[CH3:2].[CH3:23][NH:24][C@H:25]1[C@H:29]([S:30][CH3:31])[CH2:28][NH:27][CH2:26]1>>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:27]3[CH2:28][C@@H:29]([S:30][CH3:31])[C@H:25]([NH:24][CH3:23])[CH2:26]3)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CN[C@@H]1CNC[C@H]1SC
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@@H](NC)[C@H](SC)C3)ccc2c1=O

Procedure:
With use of 7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester obtained in Example A-1 (4) and trans-3-methylamino-4-methylthiopyrrolidine, there was obtained 1,4-dihydro-7-(trans-3-methylamino-4-methylthio-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester in the same manner as in Example C-1 (1).
Reaction SMILES: [CH2:1]([O:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:6]=[CH:5]1)[CH3:2].ClC(Cl)(Cl)C([N:22]=C=O)=O.CO>ClCCl>[CH2:1]([O:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:22])[C:7]=2[N:6]=[CH:5]1)[CH3:2]
Reactant: CCOn1cnc2c[n+]([O-])c3ccccc3c21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCOn1cnc2c(N)nc3ccccc3c21
Temperature: 0 °C
Yield: 22.5 %

Procedure:
A solution of 1-ethoxy-5-oxido-1H-imidazo[4,5-c]quinoline (2.4 g, 10.5 mmol) in dichloromethane (75 mL) was cooled to 0° C., and trichloroacetyl isocyanate (1.9 mL, 16 mmol) was added. The reaction was stirred for ten minutes at 0° C. and then stirred overnight at room temperature. Methanol (15 mL) was added, and the mixture was stirred for 15 minutes and concentrated under reduced pressure. The residue was dissolved in methanol (15 mL), and sodium methoxide (0.5 mL of a 25% w/w solution in methanol) was added. The mixture was stirred at room temperature for three hours and concentrated under reduced pressure. The residue was stirred with methanol (15 mL) and water (15 mL), and a solid formed. The solid was collected by filtration, recrystallized from methanol/water, and purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 2 mL of aqueous ammonium hydroxide per liter of eluent). The resulting solid was recrystallized from methanol/water and dried overnight under vacuum to provide 0.54 g of 1-ethoxy-1H-imidazo[4,5-c]quinolin-4-amine as brown crystals, mp 179-181° C.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([OH:22])([C:18]([O:20][CH3:21])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[OH:22][C:16]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][NH:14][CH2:15]1
Reactant: COC(=O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1(O)CNC1
Reaction time: 3 h

Procedure:
A reactor was charged with methyl 1-benzhydryl-3-hydroxyazetidine-3-carboxylate (1.6 g, 5.4 mmol), 10% Pd/C (0.300 g, 2.8 mmol), and glacial acetic acid (0.300 mL, 5.2 mmol) in MeOH (30 mL). The mixture was allowed to stir for 3 h under 50 psig of H2. The crude was filtered through Celite and rinsed with MeOH. After evaporation, the solid was rinsed with Et2O to give methyl 3-hydroxyazetidine-3-carboxylate as the acetic acid salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.74 (d, J=9.1 Hz, 2H), 3.69 (s, 3H), 3.44 (d, J=8.9 Hz, 2H), 1.88 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[CH3:43][N:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[C:49](O)=[O:50]>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([C@@H:45]3[CH2:46][CH2:47][CH2:48][N:44]3[CH3:43])=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: CN1CCC[C@H]1C(=O)O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)[C@@H]2CCCN2C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and (S)-1-methylpyrrolidine-2-carboxylic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.03 minutes; C31H39ClN6O3 (579.15); mass spectrum: (M−H)−=578.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]C(C)(C)C.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1.CCOC(C)=O>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[OH:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1cscn1
Reactant: O=CCCCCCCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(CCCCCCc1ccccc1)c1nccs1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
Thiazole (21 μL, 0.29 mmol) in anhydrous THF (1.9 mL) was cooled to −78° C. and treated dropwise with 1.4 M t-BuLi (273 μL, 0.38 mmol). The reaction mixture was stirred at −78° C. for 0.5 h before a solution of 7-phenylheptanal (73 mg, 0.38 mmol) in THF (1.3 mL) was added. The reaction mixture was stirred at −78° C. for 0.5 h before being warmed to room temperature. The reaction mixture was diluted with EtOAc, and washed with H2O, saturated aqueous NaHCO3 and saturated aqueous NaCl before the organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 1.5×6.5 cm, 15-25% EtOAc-hexanes) afforded the title compound (50 mg, 62%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.68 (d, 1H, J=3.2 Hz), 7.24 (m, 3H), 7.14 (m, 3H), 4.96 (dd, 1H, J=4.8, 7.6 Hz), 3.09 (br s, 1H), 2.56 (t, 2H, J=7.8 Hz), 1.87 (m, 2H), 1.58 (m, 2H), 1.44 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[C:21]([CH3:25])[C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: Cc1[nH]nc(N)c1C#N
Product: Cc1nn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc2c1C#N
Yield: 65.9 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg) 1.0 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (222 mg, 66%). MS (ISP) 337.1 [(M+H)+]; mp 238° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH3:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CCc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylamine (95 μL, 0.68 mmol) in methylene chloride (20 mL) was added dropwise 4-ethylbenzoyl chloride (81 mg, 0.48 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (66%) of the title compound as white crystals: mp 177-178° C.; [α]21D -43° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 377 (27, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].[C:24]1(=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[NH:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:25]2[C:26](=[O:33])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]2=[O:34])[CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(O)c1ccc(F)c(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(c1ccc(F)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 301 (0.0754 g, 0.219 mmol), isoindoline-1,3-dione (0.0387 g, 0.263 mmol) and PPh3 (0.127 g, 0.482 mmol) in THF cooled to 0° C. was added DEAD (0.0760 mL, 0.482 mmol) and the reaction warmed to RT and stirred overnight. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4) filtered and concentrated to an oil. The crude oil was purified by SiO2 chromatography to afford 0.0507 g (49%) of (2R)-tert-butyl 2-(2-(3-chloro-4-fluorophenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)pyrrolidine-1-carboxylate (303) as a clear oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[CH3:6][N:7]1[C:11]([CH:12]=O)=[CH:10][N:9]=[C:8]1[N+:14]([O-:16])=[O:15]>CO>[OH:1][CH2:2][CH2:3][NH:4][N:5]=[CH:12][C:11]1[N:7]([CH3:6])[C:8]([N+:14]([O-:16])=[O:15])=[N:9][CH:10]=1
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Reactant: NNCCO
Solvent: CO
Product: Cn1c(C=NNCCO)cnc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
A solution of 0.300 g. of 2-hydroxyethylhydrazine and 0.4 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 20 ml. of methanol is allowed to stand for two days. The solid which precipitates is recovered on the filter and washed with water. Yield: 0.245 g., m.p. 138°-140° C.
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)[C:4](=[NH:8])[O:5]CC.[O:22]1CCC[CH2:23]1>C1(C)C=CC=CC=1>[O:15]([C:11]1[CH:10]=[C:9]([CH:3]2[O:2][C:23](=[O:22])[NH:5][C:4]2=[O:8])[CH:14]=[CH:13][CH:12]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2cccc(Oc3ccccc3)c2)O1

Procedure:
By the procedure of Example 3, ethyl 1-hydroxy-1-(3-phenoxyphenyl)methanecarboximidate hydrochloride (13 g.) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(3-phenoxyphenyl)oxazolidine-2,4-dione (7.5 g., 66%; m.p. 104°-106° C.; m/e 269).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[NH:19][C:15]=4[N:14]=[CH:13]3)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.[C:23](=O)(O)[O-].[Na+]>CO.S(=O)(=O)(O)O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4[CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[NH:19][C:15]=4[N:14]=[CH:13]3)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1
Reactant: O=C(O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a stirred solution of 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylic acid (200 mg, 0.65 mmol, prepared as described in the procedure for example 6) in methanol (10 mL) was added concentrated sulfuric acid (5 drops). The solution was heated at reflux for 36 h then cooled to room temperature, basified with aqueous sodium bicarbonate (40 mL) and extracted with CH2Cl2 (2×40 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified twice by silica gel chromatography eluting with MeOH:CH2Cl2 0%→1%) to yield 63.4 mg (30.3%) of methyl 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate EXAMPLE 10. 1H NMR (400 MHz, CDCl3): δ=10.11 (br s, 1H), 8.08 (s, 1H), 7.76-7.74 (m, 1H), 7.58-7.51 (m, 3H), 7.47-7.42 (m, 3H), 6.99 (d, J=1.6 Hz, 1H), 3.93 (s, 3H). MS (ES+): m/z 324.23 (100) [MH+].
Reaction SMILES: [O:1]([CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[O:1]([CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[CH:15][CH:14]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Oc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Oc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4.4 g of methyl α-(phenoxy)-α-[p-(p-chlorophenoxy)phenyl]acetate, 27 g of 20% KOH, and 20 ml of methanol is refluxed overnight. After cooling to room temperature, the methanol is removed at reduced pressure. The residue is dissolved in 100 ml of H2O and extracted with 100 ml of ether. The aqueous layer is acidified with concentrated HCl and a yellow oil separates. The mixture is extracted with two 50 ml portions of chloroform. The combined extracts are washed with 50 ml of water and saturated brine and dried over MgSO4. Evaporation of the solvent at reduced pressure affords the product as a white solid, mp 114°-115.5° C., after trituration with petroleum ether.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([S:13](Cl)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1>>[NH:28]1[C:24]([C:20]2[CH:19]=[C:18]([NH:17][S:13]([C:9]3[CH:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:12]=[CH:11][CH:10]=3)(=[O:15])=[O:14])[CH:23]=[CH:22][CH:21]=2)=[N:25][N:26]=[N:27]1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(-c2ccccc2)c1
Yield: 30.2 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 3-phenylbenzenesulfonylchloride (14 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 5.7 mg (30%) of the title compound. 1H NMR (400 MHz, MeOH-d4) δ ppm 5.46-5.50 (m, 1 H) 7.24-7.43 (m, 5 H) 7.44-7.56 (m, 3 H) 7.70-7.79 (m, 4 H) 7.95-8.00 (m, 1 H). MS (ESI+) calcd for C19 H15N5O2S 377.0946, found 377.0946.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=1
Reactant: O=C(CBr)c1cccs1
Reactant: O=c1ncc(F)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(F)cnc1=O)c1cccs1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
A mixture of 5-fluoropyrimidin-2-one (456 mg) and 2-bromoacetylthiophene (820 mg) in triethylamine (1.33 ml) and ethanol (25 ml) was stirred at room temperature. After 2.5 h. the reaction mixture was concentrated to ca. 5 ml, diluted with ethyl acetate (300 ml) washed with water (3×50 ml), dried (MgSO4) and evaporated to a foam. This was crystallised from acetone to give the title pyrimidinone (225 mg), m.p. 183°-190° C. (dec) λmax (EtOH) 260 nm (ε10,308), 285.5 nm (ε 8,430).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11]C)=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].C[O:14][C:15]1[CH:23]=[CH:22][C:18](C(Cl)=O)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]2[O:9][C:10]([C:18]3[CH:22]=[CH:23][C:15]([OH:14])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:8]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cc(OC)c(Cl)cc1N
Product: Oc1ccc(-c2nc3cc(Cl)c(O)cc3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 16, from 5-chloro-2,4-dimethoxyaniline, and 4-methoxybenzoyl chloride and was obtained as an off-white solid, m.p. 254–256° C.; MS m/e 262 (M+H)+.