Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:27][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([OH:23])=O)[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.Cl.CN.C[CH2:32][N:33](C(C)C)C(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][C:2]1[S:27][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([NH:33][CH3:32])=[O:23])[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoic acid (118 mg, 0.29 mmol) was heated in 3 mL of thionylchloride at 80° C. for 3 h. The reaction was cooled to room temperature and the thionylchloride was removed under reduced pressure. The residue obtained was dissolved in 25 mL of DCM followed by addition of methylamine hydrochloride (60 mg, 0.88 mmol) and DIEA (227 mg, 1.76 mmol). The reaction was allowed to stir at room temperature for 16 h and washed with 25 mL of water. The DCM layer was dried over Na2SO4 and evaporated under reduced pressure; the crude product was purified by silica chromatography in 5% MeOH-DCM to obtain 58 mg of product in 48% yield. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.76 (s, 1H), 7.65 (d, 1H), 7.45 (d, 1H), 7.39 (t, 1H), 7.02 (s, 1H), 6.22 (bs, 1H), 4.96 (bs, 1H), 4.18 (m, 1H), 3.57 (s, 2H), 3.03 (d, 3H), 2.87 (d, 2H), 2.23 (t, 2H), 2.08 (d, 2H), 1.59 (m, 2H); MS (ESI) m/z: Calculated for C20H23ClN5OS, 416.13; Observed: 416.2 (M++1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12]([OH:14])=[O:13])(=[O:8])=[O:7]>S(=O)(=O)(O)O>[CH3:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:1]([O-:4])=[O:2])[C:17]=1[Cl:18])[C:12]([OH:14])=[O:13])(=[O:8])=[O:7]
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Temperature: 15 °C

Procedure:
To a stirred mixture of concentrated sulfuric acid (75 ml.) and concentrated nitric acid (48 ml.), cooled to 15° C., is added a solution of 3-methylsulfonyl-4-chlorobenzoic acid (31.5 g.; 0.134 mole) in concentrated sulfuric acid (185 ml.). The reaction mixture is heated on a steam bath for 21/2 hours then poured into ice. There is collected 34 g. (91%) of 3-methylsulfonyl-4-chloro-5-nitrobenzoic acid, m.p. 197° C. after recrystallization from ethanol.
Reaction SMILES: CC(C(CCCCN1C(C(C)C)=C(C(NC2C=CC=CC=2)=O)C(C2C=CC=CC=2)=C1C1C=CC(F)=CC=1)C(O)(O)C([O-])=O)(C)C.[OH-].[Na+].C([O-])(=O)C.[Ca+2:52].C([O-])(=O)C.[CH3:57][CH:58]([C:60]1[N:64]([CH2:65][CH2:66][C@@H:67]([OH:75])[CH2:68][C@@H:69]([OH:74])[CH2:70][C:71]([OH:73])=[O:72])[C:63]([C:76]2[CH:77]=[CH:78][C:79]([F:82])=[CH:80][CH:81]=2)=[C:62]([C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)[C:61]=1[C:89]([NH:91][C:92]1[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=1)=[O:90])[CH3:59]>C(#N)C.O.C1CCCCC1.C(OCC)(=O)C>[CH3:59][CH:58]([C:60]1[N:64]([CH2:65][CH2:66][C@@H:67]([OH:75])[CH2:68][C@@H:69]([OH:74])[CH2:70][C:71]([O-:73])=[O:72])[C:63]([C:76]2[CH:81]=[CH:80][C:79]([F:82])=[CH:78][CH:77]=2)=[C:62]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:61]=1[C:89]([NH:91][C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1)=[O:90])[CH3:57].[CH3:59][CH:58]([C:60]1[N:64]([CH2:65][CH2:66][C@@H:67]([OH:75])[CH2:68][C@@H:69]([OH:74])[CH2:70][C:71]([O-:73])=[O:72])[C:63]([C:76]2[CH:81]=[CH:80][C:79]([F:82])=[CH:78][CH:77]=2)=[C:62]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:61]=1[C:89]([NH:91][C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1)=[O:90])[CH3:57].[Ca+2:52]
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Agent: CC(=O)[O-]
Agent: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCCCC(C(C)(C)C)C(O)(O)C(=O)[O-]
Agent: [Ca+2]
Solvent: C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)[O-]
Reaction time: 0.5 h

Procedure:
20 gm of R—(R*,R*)]-1,1-dimethylethyl-2-(4-fluorophenyl)-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoate was taken in 400 mL of acetonitrile to obtain clear solution at 40° C. to 45° C. The reaction mixture was cooled to 25° C. to 30° C. and 2.60 gm of NaOH solution in 100 mL of water was added within 15 min and stirred for 30 min. Acetonitrile was distilled under vacuum to obtain white slurry or solid. The compound thus obtained was further cooled at 10° C. to 15° C. 400 mL of water was added followed by slow addition of 400 mL of ethyl acetate to dissolve the solution. 10.46 gm of calcium acetate solution in 244 mL of water was added to obtain hazzy solution at 10° C. to 15° C. The reaction mixture was stirred for 2 hrs at 35° C. to 40° C. and cooled to 30° C. to 35° C. The organic layer was separated and washed with water and filtered through hyflow bed followed by washing with ethyl acetate. The organic layer was treated with butylated hydroxy toluene. The organic phase was then distilled to remove ethyl acetate completely till powder or lump of material was obtained. The solid thus obtained was treated with 100 mL of cyclohexane and stirred for 30 min. The product was filtered, washed with cyclohexane and dried at 30° C. to 35° C. The partially dried wet cake was treated with diethyl ether to obtain slurry. The slurry was filtered and dried to get stabilized atorvastatin amorphous.
Reaction SMILES: C([O:4][C:5](=[O:73])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:72])[NH:24][CH2:25][CH2:26][C@H:27]([NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:38][C@@H:39]([CH2:43][S:44][C:45]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]([NH2:42])=[O:41])=[O:37])=[O:29])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C=C.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[NH2:42][C:40](=[O:41])[C@@H:39]([NH:38][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:28](=[O:29])[C@@H:27]([NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:26][CH2:25][NH:24][C:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C@@H:6]([C:5]([OH:73])=[O:4])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:21][CH:20]=1)=[O:72])[CH2:43][S:44][C:45]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCCCC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCCCC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
250 mg (0.24 mmol) of the compound from example 22A was dissolved in approx. 5 ml tetrahydrofuran. 170 μl (1.22 mmol) Triethylamine, 48 μl (1.22 mmol) formic acid and 28 mg (0.024 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 20 ml water and twice extracted with approx. 20 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water/methanol gradient to yield 167 mg (65% of theory) product.
Reaction SMILES: [NH2:1]C(OCC)=O.[F-].[Cs+].[CH3:9][O:10][CH2:11][C@H:12]1[CH2:16][O:15][C:14](=O)[O:13]1>CN(C)C=O>[CH3:9][O:10][CH2:11][C@@H:12]1[O:13][C:14](=[O:15])[NH:1][CH2:16]1
Reactant: COC[C@H]1COC(=O)O1
Reactant: CCOC(N)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COC[C@H]1CNC(=O)O1
Temperature: 140 °C
Reaction time: 72 h
Yield: 63731.8 %

Procedure:
Urethane (37.4 g, 0.420 mmol) was dissolved in N,N-dimethylformamide (200 mL), and thereto were added cesium fluoride (5.80 g, 38.2 mmol) and (S)-4-methoxymethyl-1,3-dioxolan-2-one (50 g, 0.382 mol, optical purity 97.7%ee), in order. The mixture was stirred for 72 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by distillation to give the subject (R)-5-methoxymethyloxazolidin-2-one (35.1 g, yield 69.6 %, optical purity 97.3%ee).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:27][CH:28]([F:31])[CH2:29]I.C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH2:29][CH:28]([F:31])[F:27])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: FC(F)CI
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1CC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (100 mg, 0.271 mmol) was suspended in acetonitrile (5 ml). 1,1-Difluoro-2-iodoethane (0.053 ml, 116 mg) and cesium carbonate (124 mg, 0.380 mmol) were added and the resulting mixture was stirred overnight at RT. Next day 2 ml of THF and 50 μl of 1,1-difluoro-2-iodoethane was added and the stirring was continued for three more nights. Another 0.2 ml of 1,1-difluoro-2-iodoethane was added and the reaction mixture was stirred overnight. The reaction mixture was evaporated. 3 ml of N,N-dimethyl formamide was added and the mixture filtered. Filtrate was purified with LC/MS-trigger. Yield 27.4%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 2.44 (s, 3H), 4.19-4.33 (m, 3H), 4.39 (dd, 1H), 4.51-4.62 (m, 1H), 5.82-6.13 (m, 1H), 6.61 (d, 1H), 7.49 (d, 1H), 7.52 (s, 1H), 7.64-7.71 (m, 2H), 7.85 (dd, 1H), 8.00 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:15][C:16]1[N:21]=[C:20]([C:22](O)=[O:23])[CH:19]=[C:18]([CH3:25])[N:17]=1>>[CH3:15][C:16]1[N:21]=[C:20]([C:22]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]3[CH3:11])=[CH:4][CH:3]=2)=[O:23])[CH:19]=[C:18]([CH3:25])[N:17]=1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: Cc1cc(C(=O)O)nc(C)n1
Product: Cc1cc(C(=O)Nc2ccc3c(c2)N(C)C(=O)C3(C)C)nc(C)n1

Procedure:
Prepared in analogy to example 1b from 6-amino-1,3,3-trimethylindolin-2-one and 2,6-dimethylpyrimidine-4-carboxylic acid. The title compound was obtained as white foam.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][C@H:13]1[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14]1.C([O-])(O)=O.[Na+].O>CCOCC>[CH2:5]([O:4][C:2]([N:16]1[CH2:17][C@H:13]([OH:12])[CH2:14][C@H:15]1[C:18]([OH:20])=[O:19])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
A solution of benzyl chloroformate (50 mL, 0.35 mol) in Et2O (160 mL) was added dropwise, during 10 min, to a rapidly stirred mixture of trans-4-hydroxy-L-proline (39.8 g, 0.308 mol), NaHCO3 (63.7 g, 0.758 mol) and H2O (660 mL). The reaction mixture was stirred at room temperature for 20 h. The layers were separated, and the aqueous layer was washed with Et2O (4×200 mL), cooled, and then acidified to pH 1-2 with concentrated hydrochloric acid. The resulting emulsion was extracted with EtOAc (5×200 mL). Combined EtOAc extracts were washed in succession with H2O (3×500 mL) and brine (3×500 mL), dried over MgSO4, and then concentrated in vacuo to give intermediate (4) as a colorless foam (62.7 g, 78%). Additional reactions were carried out to give a total of 284 g of product suitable for further transformation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1(CC(O)=O)CCCCC1>C1C=CC=CC=1>[CH2:19]([O:18][C:12](=[O:17])[C:13]([C:14](=[O:15])[CH3:16])=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:20]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOC(=O)CC(C)=O
Agent: O=C(O)CN1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccc(O)c(OC)c1)C(C)=O

Procedure:
Condensation of 3-methoxy-4-hydroxy benzaldehyde (vanillin) with ethyl acetoacetate in the presence of piperidine-acetic acid and benzene as the reaction medium at reflux temperature yields the title product. The reaction takes about 3.5 hours for completion.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[F:28][CH:29]([F:32])[CH2:30]I>CN(C)C=O>[F:28][CH:29]([F:32])[CH2:30][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1
Reactant: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1
Reactant: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(NCC2CN(CC(F)F)CCO2)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
To a solution of EXAMPLE 415B (633 mg) in anhydrous N,N-dimethylformamide (10 mL) was added sodium carbonate (254 mg) and 2,2-difluoroethyl iodide (422 mg). After stirring at 110° C. for 48 hours, the mixture was concentrated. The residue was mixed with water (20 mL) and extracted with ethyl acetate. The crude product was purified on a silica gel column eluting with 10% methanol in methylene chloride to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(Cl)Cl.[C:13]1([CH3:21])[C:14]([S:19]Cl)=[CH:15][CH:16]=[CH:17][CH:18]=1.C(Cl)(Cl)Cl>CCOCC>[CH3:21][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: Cc1ccccc1SCl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1c[nH]c(Sc2ccccc2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
Under a nitrogen atmosphere, methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was dissolved in 50 ml. of methylene chloride. The stirred solution was cooled in an ice-water bath and o-toluenesulfenyl chloride (3.16 g., 20 mmoles) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. Thin layer chromatography (silica gel, chloroform eluant) indicated virtually complete reaction at this time. An equal volume of ether was added and a small amount of insolubles removed by filtration. Crude product (5 g.) was obtained by evaporation in vacuo to a gum. The latter was chromatographed on 150 g. of silica gel with 75 ml. fractions of the chloroform eluant collected. Fractions 10 to 13 were combined and evaporated in vacuo to yield partially purified product (1.69 g., m.p. 114°-119° C.). Recrystallization from methylene chloride/hexane gave purified methyl 5-(2-methylphenylthio)pyrrole-3-carboxylate (1.1 g., m.p. 126°-128° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][C:10]([CH2:18]CS([O-])(=O)=O)([CH2:12]CS([O-])(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[NH:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)[C:26]=1[C:43]#[N:44].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[CH2:9][C:10]2([CH2:12][N:29]3[N:28]=[C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:32][CH:31]=4)[C:26]([C:43]#[N:44])=[C:25]3[NH:24][CH2:18]2)[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])CCC1(CCS(=O)(=O)[O-])CN(Cc2ccccc2)C1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC1(CN(Cc3ccccc3)C1)C2
Temperature: 80 °C
Reaction time: 16 h
Yield: 8.1 %

Procedure:
To a solution of (1-benzylazetidine-3,3-diyl)bis(methylene)dimethanesulfonate (300 mg, 0.83 mmol) in DMF (10 mL) was added 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (230 mg, 0.83 mmol) and K2CO3 (230 mg, 1.66 mmol). The mixture was stirred at 80° C. under N2 for 16 hr. The mixture was concentrated. The residue was washed with H2O (100 mL×2), dried and purified by pre-TLC (DCM/CH3OH=10/1) to afford 30 mg (10%) of desired product as a yellow liquid. MS (ESI) m/e [M+1]+ 447.9.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=2)[C:4]1=[O:30])[CH3:2].OO.NC(N)=[O:35].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[N+:7]([O-:35])[CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([CH:21]([CH3:22])[CH3:23])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:29])[CH3:28])=[CH:15][CH:14]=2)[C:4]1=[O:30])[CH3:2]
Reactant: NC(N)=O
Reactant: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(C)c21
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2c1c(C)cc[n+]2[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.3 %

Procedure:
To a stirred mixture of 1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5 g) and urea hydrogen peroxide (2.32 g) in CH2Cl2 (50 mL) was added trifluoroacetic anhydride (3.32 mL) at 0° C. The mixture was stirred at room temperature for 12 h, and treated with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with AcOEt. The organic layer was combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, AcOEt) to give the title compound (1.0 g).
Reaction SMILES: O[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>P(Cl)(Cl)(Cl)=O>[Cl:15][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]#[N:8])=[CH:4][N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: NC(=O)c1cnc(O)c([N+](=O)[O-])c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(Cl)c([N+](=O)[O-])c1
Temperature: 130 °C
Yield: 108.8 %

Procedure:
A mixture of 6-hydroxy-5-nitronicotinamide (343 g), phosphorus oxychloride (40 ml) and phosphorus pentachloride (1287 g) was heated at 130° C. for 3.5 hours. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and an aqueous saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and evaporated to afford 6-chloro-5-nitronicotinonitrile (374 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11]Br)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[N:20].[CH3:21][NH2:22]>C1COCC1>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][NH:22][CH3:21])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[N:20]
Reactant: N#Cc1ccccc1-c1oc2ccc(CBr)cc2c1Br
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1ccc2oc(-c3ccccc3C#N)c(Br)c2c1
Temperature: 25 °C

Procedure:
3.1 g (7.9 mmol) 3-Bromo-5-(bromomethyl)-2-(2-cyanophenyl)benzofuran (prepared according to EP 434 249) were dissolved in 50 ml THF, and 25 ml of a 40% aqueous solution of methylamine was added via a dropping funnel. The mixture was stirred at room temperature over night and warmed for 2 h at 40° C. The solvent was removed in vacuo, the residue stirred with water, filtrated by suction, and washed with water. The title compound was purified by column chromatography (silica gel, dichloromethane / ethanol 99:1 to 90:10) and obtained as a colorless powder after evaporation to dryness, m.p. 114° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.N(O[C:34](C)([CH3:36])[CH3:35])=O>C(#N)C.[Cu](Cl)Cl>[C:19]([C:15]1[CH:14]=[C:13]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][CH2:35][CH2:34][CH3:36])[S:3][C:4]=3[CH:10]=2)[C:16]=1[O:17][CH3:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)ON=O
Reactant: COc1c(-c2ccc3nc(N)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: Cl[Cu]Cl
Solvent: CC#N
Product: CCCNc1nc2ccc(-c3cc(-n4ccc(=O)[nH]c4=O)cc(C(C)(C)C)c3OC)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a mixture of the product from Example 53 (50 mg, 0.118 mmol) and copper(II) chloride (24 mg, 0.178 mmol) in acetonitrile (3 mL) at 0° C. was added tert-butyl nitrite (21 μL, 0.178 mmol). The mixture was stirred at 0° C. for 1 h, and then warmed to 65° C. and stirred for 2 h. The mixture was concentrated in vacuo and purified by column chromatography on silica gel using 5% MeOH in CH2Cl2 to give the title compound as an off-white solid (43 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25].CN(C)C=O>O>[CH3:17][C:15]([CH3:16])([CH3:18])[CH2:14][C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[O:19]
Reactant: CC(C)(C)CC(=O)Nc1ccc2ncnc(N)c2c1
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CNc1ncnc2ccc(NC(=O)CC(C)(C)C)cc12)C(=O)OC
Temperature: 100 °C
Yield: 82.7 %

Procedure:
A mixture of 4-amino-6-(3,3-dimethylbutyramido)quinazoline (8.5 g), dimethyl methoxymethylenepropanedioate (12.75 g) and N,N-dimethylformamide (34 g) was stirred for an hour at 100° C. After cooling to ambient temperature, to the resultant mixture was added water to give precipitates, which were separated by filtration, washed with water and dried to give crystalline dimethyl [{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate (10.9 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([Br:17])[CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[C:7]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[Br:17][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[C:13]2[C:8]=1[C:7]([CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14]2
Reactant: COC(=O)C1Cc2c(OC)ccc(Br)c2C(CC2CCCC2)=N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Br)c2c(CC3CCCC3)nc(C(=O)O)cc12
Yield: 99.4 %

Procedure:
To a stirring solution of 0.4 g (1.05 mmol) of the above ester in 2.5 ml of THF, 0.6 ml of MeOH was added along with 0.6 ml of 2N LiOH at rt. Usual work up as described in general procedure C gave 0.38 g of title compound as a light yellow solid.