Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.Cl.C([O:13][C@@H:14]1[C@@H:55]([O:56]C(=O)C)[C@H:54]([O:60]C(=O)C)[C@@H:53]([CH2:64][O:65]C(=O)C)[O:52][C@H:15]1[O:16][C:17]1[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:43][CH2:42][N:41]([C:44](=[O:47])[CH2:45][NH2:46])[CH2:40][CH2:39]4)[CH2:34]3)=[CH:25][C:24]=2[CH3:48])=[C:20]([CH:49]([CH3:51])[CH3:50])[NH:19][N:18]=1)(=O)C.C(N(C(C)C)CC)(C)C>ClCCl>[C@@H:15]1([O:16][C:17]2[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][C:35]5([CH2:43][CH2:42][N:41]([C:44](=[O:47])[CH2:45][NH:46][C:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:40][CH2:39]5)[CH2:34]4)=[CH:25][C:24]=3[CH3:48])=[C:20]([CH:49]([CH3:51])[CH3:50])[NH:19][N:18]=2)[O:52][C@H:53]([CH2:64][OH:65])[C@@H:54]([OH:60])[C@H:55]([OH:56])[C@H:14]1[OH:13]
Reactant: CC(C)CN=C=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)CN)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(/C=C/CCN2CCCC3(CCN(C(=O)CNC(=O)NCC(C)C)CC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
Add isobutyl isocyanate (77 mg, 0.78 mmol) to a solution of 4-(4-{(1E)-4-[9-(aminoacetyl)-2,9-diazaspiro[5.5]undec-2-yl]but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (350 mg, 0.39 mmol) and diisopropylethylamine (302 mg, 2.34 mmol) in dichloromethane (1.0 mL). After 30 min at room temperature, concentrate to dryness under the reduced pressure. Treat the residue with 2.0 M NH3/methanol (1.0 mL) for 3 hours at room temperature, remove the solvent under the reduced pressure. Purify the resulting residue by preparative HPLC method: high pH, 29% B for 4 min, 29-44% B for 5 min @ 85 mL/min using a 30×75 mm, 5 um C18XBridge ODB column, solvent A—H2O w NH4HCO3 @ pH 10, solvent B—acetonitrile to yield the title compound as solid (134 mg, 0.18 mmol). MS (m/z): 755.2 (M+1), 753.2 (M−1).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.S(Cl)(Cl)=O.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[O:7]=[C:5]([C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1)[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:8]
Reactant: Brc1ccccc1
Reactant: CC(C)CCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: CC(C)CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 82 h

Procedure:
A mixture of 25 g (.215 mol) of 4-methyl valeric acid and 9.35 g (0.247 mol) of thionyl chloride was heated at reflux for 1.5 hour. The excess thionyl chloride was removed under reduced pressure using a cryogenic trap. The residue was taken up with 120 g (0.764 mol) of bromobenzene (Compound 27) and the mixture was cooled in an ice-bath and then treated with 23 g (0.172 mol) of anhydrous aluminum chloride through a powder addition funnel The mixture was stirred at room temperature for 82 h and then quenched by the addition of 50 ml of an ice/water mixture, followed by 30 ml of conc. HCl. The organic layer was separated and the aqueous layer extracted with 2×50 ml of ether. The organic extracts were combined and washed successively with water and saturated NaCl solution and then dried (MGSO4) The solvent was then removed in-vacuo and the residue purified by distillation (~80 degrees C./0.01 mm) to give the title compound as a colorless solid. PMR (CDCl3): & 0.94 (6 H, d, J~6.0 Hz), 1.53-1.68 (3H, m), 2.85-2.97 (2H, m)., 7.60 (2H, d, J~8.4 Hz), 7.83 (2H, d, J~8.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][OH:13].N1C=CC=CC=1.[C:20](Cl)(=[O:22])[CH3:21].Cl>C1(C)C=CC=CC=1>[C:20]([O:13][CH2:12][C:3]1[C:4]([CH3:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1CO
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OCc1c(C)ccc([N+](=O)[O-])c1C
Temperature: 0 °C
Yield: 75.2 %

Procedure:
A stirred solution of 2,6-dimethyl-3-nitrobenzene-1-methanol (51.3 g, 0.283 mole) and 25 ml of pyridine in 350 ml of toluene was warmed to 70°. During a ten minute period, acetyl chloride (22.2 g, 0.283 mole) was added to the reaction mixture. The reaction mixture was heated at 85° for 21/2 hours, then poured over 300 g of ice, and 100 ml of a 4 N hydrochloric acid solution was added thereto. The organic phase was separated and washed with 100 ml of aqueous 2 N hydrochloric acid, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to give (2,6-dimethyl-3-nitrophenyl)methyl acetate (47.5 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[Cl:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[CH2:50][NH:49][CH2:48][CH2:47]2.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[Cl:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[CH2:50][N:49]([C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]1=[O:17])[CH2:48][CH2:47]2
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Reactant: Clc1ccc2c(c1)CCNC2
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1CCc2cc(Cl)ccc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 216A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 6-chloro-1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.11 (m, 4H), 7.03 (ddd, J=6.1, 10.3, 12.6, 3H), 4.65 (d, J=24.0, 2H), 4.33 (d, 1H), 4.21-4.04 (m, 1H), 3.89-3.44 (m, 5H), 2.87 (dt, J=5.9, 11.7, 2H), 2.66-2.44 (m, 1H), 2.23-2.04 (m, 1H); MS (DCI) m/z 387.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([OH:28])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH:9]1[CH3:31])=O)(C)(C)C.Br[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:44])([F:43])[F:42])[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([N:11]3[CH2:10][CH:9]([CH3:31])[NH:8][CH:13]([CH3:14])[CH2:12]3)=[O:30])=[CH:21][CH:20]=2)=[CH:27][C:26]=1[O:28][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:42])([F:43])[F:44])[CH3:34]
Reactant: CC(Br)c1ccccc1C(F)(F)F
Reactant: CC1CN(C(=O)c2ccc(-c3cnc(N)c(O)c3)cc2)CC(C)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C(=O)c2ccc(-c3cnc(N)c(OC(C)c4ccccc4C(F)(F)F)c3)cc2)CC(C)N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70° C. for 8 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TFA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (20 mg, yield 34.2%).
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5](=O)[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17]>CC(O)C>[C:20]([O:19][C:15]([NH:16]/[N:17]=[C:5](\[C:4]#[C:3][Si:2]([CH3:14])([CH3:13])[CH3:1])/[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C[Si](C)(C)C#CC(=O)CCCC(=O)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N/N=C(\C#C[Si](C)(C)C)CCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 54.0 g (254 mmol) of 7-(trimethylsilyl)-5-oxohept-6-ynoic acid from step A above in 750 mL of IPA under an atmosphere of nitrogen was added 33.6 g (254 mmol) of tert-butyl carbazate. The reaction mixture was stirred for 4 h at ambient temperature then evaporated in vacuo to remove all volatiles. This afforded the title compound as a yellow gum which was used without further purification (77 g, 93%). LC-MS: m/z (ES) 327 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[CH3:26]I.Cl>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:26]
Reactant: CI
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (0.351 gm., 0.001 mole) in dimethylformamide (7 ml.) is cooled in an ice bath then treated with sodium hydride (0.084 g. of a 57% oil dispersion, 0.002 moles) and stirred for two hours. Methyl iodide (1 ml.) is added and the reaction mixture is stirred at 25° C. for two hours, poured into ice water, and acidified with dilute aqueous hydrochloric acid affording (1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 168°-169° C.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20]>CO>[CH3:18][S:19]([NH:22][C:14](=[NH:17])[CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: CS(N)(=O)=O
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Solvent: CO
Product: CS(=O)(=O)NC(=N)CCSCc1csc(NC(=N)N)n1
Reaction time: 48 h
Yield: 92.1 %

Procedure:
In 10.2 ml of methanol were dissolved 1.27 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and 0.86 g of methanesulfonamide and after reacting for 48 hours at room temperature, the solvent was distilled off under reduced pressure. Then, the residue formed was purified by a silica gel column chromatography using a mixture of chloroform and methanol (20:1→10:1) to provide 1.44 g amorphous N-methanesulfonyl-3-[(2-guanidinothiazol-4-yl)-methylthio]propionamidine. The product shows the following physicochemical properties:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+].O>CO>[CH3:5][O:4][C:2]([N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]1)=[O:3]
Reactant: COC(=O)Cl
Reactant: c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)N1C=CC=CC1
Reaction time: 2 h

Procedure:
Methyl chloroformate (30.9 mL/400 mmol) was added via syringe to a mixture of pyridine (31.6 g/400 mmol) and sodium borohydride (16.0 g/420 mmol) in methanol (150 mL) at -78° C. Stirred for two hours then poured in to water then extracted with diethyl ether (3×300 mL). The extracts were dried over NaCl/Na2SO4 then evaporated. The residue was purified by preparative chromatography using silica gel eluting with ethyl acetate/hexanes to yield the 1-(methoxycarbonyl)-1,2-dihydropyridine, 1A (20.2 g/130 mmol).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[OH:12].[Br:13][CH2:14][CH2:15]Br>O.C(O)C>[Br:13][CH2:14][CH2:15][O:12][C:5]1[C:4]([Cl:3])=[CH:9][C:8]([Cl:10])=[CH:7][C:6]=1[Cl:11]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1cc(Cl)c(OCCBr)c(Cl)c1
Yield: 67.4 %

Procedure:
A solution of sodium hydroxide (7.8 g, 0.195 mol) in water (20 ml) was added to a solution of 2,4,6-trichlorophenol (38.0 g, 0.192 mol) in ethanol (200 ml). 1,2-dibromoethane (47 g, 0.25 mol) was then added and the resultant mixture was refluxed overnight. On cooling, the solid was filtered off and the filtrate concentrated under reduced pressure. Ether was added to the residue and the solution was then washed with dilute sodium hydroxide solution and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation, the residue was recrystallised from ethanol to give 1-bromo-2-(2,4,6-trichlorophenoxy)ethane as a white solid (39.4 g). A mixture of the 1-bromo-2-(2,4,6-trichlorophenoxy) ethane (20.0 g, 0.066 mol), triethylamine (6.7 g, 0.066 mol) and propylamine (3.9 g, 0.066 mol) in ethanol (500 ml) was then refluxed overnight. After removal of the solvent by evaporation, the residue was dissolved in ether, washed with water and dried (MgSO4). Evaporation of the solvent left an oil which, after flash chromatography on silica gel using chloroform as the eluant, yielded N-propyl-N-2-(2,4,6-trichlorophenoxy)ethylamine as an oil (12.6 g).
Reaction SMILES: N#N.Br[C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[N:10][C:6]=2[CH:5]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:8]1[C:7]2[CH:17]=[CH:18][C:4]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:5][C:6]=2[N:10]=[N:9]1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc2c(c1)nnn2C1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)nnn2C1CCCCO1
Temperature: 80 °C
Yield: 97 %

Procedure:
A 100-mL round-bottom flask equipped with a magnetic stir bar, a rubber septum and N2 inlet was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d][1,2,3]triazole (3.5 g, 12.4 mmol), Pd(Ph3P)2Cl2 (0.87 g, 1.24 mmol), CuI (0.47 g, 0.48 mmol), and triethylamine (62 mL). This mixture was degassed with three vacuum/N2 cycles. Trimethylsilylacetylene (3.5 mL, 24.8 mmol) was added, and the mixture was heated at 80° C. for 4 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was cooled down to room temperature, filtered through Celite, washed with ethyl acetate (100 mL), and concentrated. The crude product was purified on a silica gel column eluting with 5% ethyl acetate in hexanes to afford the title compound as a pale yellow oil (3.6 g). LCMS: 216 [(M-THP+H)+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[C:4](=[O:18])[C:3]=1[C:19](OCC)=[O:20].Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[C:4](=[O:18])[C:3]=1[C:19]([NH:32][CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])=[O:20]
Reactant: CCOC(=O)C1=C(O)c2cc(C(F)(F)F)ccc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(C(F)(F)F)ccc2C(C)(C)C1=O
Temperature: 23 °C
Reaction time: 14 h
Yield: 61.5 %

Procedure:
A solution of crude ethyl 4-hydroxy-1,1-dimethyl-2-oxo-6-(trifluoromethyl)-naphthalene-3-carboxylate (562 mg, 1712 μmol), glycine tert-butyl ester hydrochloride (316 mg, 1883 μmol) and DIPEA (447 μL, 2568 μmol) in 1,4-dioxane (20 mL) was heated to 120° C. in a sealed vessel. After 14 hours, the reaction was cooled to 23° C., and the solvent was removed under vacuum. The residue was diluted with EtOAc (100 mL), washed with water (75 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 4-8% EtOAc/hexane) affording 435 mg of the title compound. MS m/e=358.1 (M-C4H8+H)+.
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:2]=[O:3].[CH3:27][NH:28][CH3:29]>O1CCCC1.O>[CH3:27][N:28]([CH3:29])[C:2](=[O:3])[NH:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2
Reactant: CCc1c(C)c2c(c(N=C=O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2

Procedure:
A solution of 0.65 g (1.8 mmol) of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate in 10 ml of tetrahydrofuran is treated with 5 ml of a solution of 40% dimethylamine in water. After 1 hour the reaction is partitioned between water and ethyl acetate. The organic phase is washed with water three times, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate.
Reaction SMILES: CC(OC(C)=O)=O.CCN(CC)CC.[N+:15]1([O-])[C:16](=[CH:20][CH:21]=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])C(O)=O.OC1C=CC(C(O)=O)=CN=1.C(Cl)[Cl:39]>>[Cl:39][C:16]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][N:15]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(C(=O)O)[n+]([O-])c1
Agent: O=C(O)c1ccc(O)nc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(Cl)nc1
Yield: 53.8 %

Procedure:
This example proceeded as in Example 1, but the reaction was carried out at 0° to 5° C. the bath used had 25.5 g of Ac2O, 20 g of Et3N, 350 g of CH2Cl2 and 18.3 of isocinchomeronic acid-N-oxide. The yield was 53.8 percent of 6-chloronicotinic acid (2-chloro-5-pyridine carboxylic acid), and 39.0 percent of 6-hydroxynicotinic acid (2-hydroxy-5-pyridine-carboxylic acid).
Reaction SMILES: Br[C:2](=[CH:5]OC(C)C)[CH:3]=[O:4].[S:10]1[CH2:14][C:13](=[NH:15])[NH:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[N:15]1[C:2]([CH:3]=[O:4])=[CH:5][N:12]2[C:13]=1[CH2:14][S:10][CH2:11]2
Reactant: CC(C)OC=C(Br)C=O
Reactant: N=C1CSCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1cn2c(n1)CSC2
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 36.9 %

Procedure:
The solution of 2-bromo-3-isopropoxypropenal (6.9 g) in dry acetonitrile (326 mL) was added to the solution of crude thiazolidin-4-ylideneamine (3.3 g) in dry acetonitrile (326 mL) at room temperature. The reaction mixture was stirred at room temperature for 19.5 h, added triethylamine (4.9 mL) and then refluxed for 2 h. The reaction mixture was cooled to room temperature and then evaporated under reduce pressure. The residue was dissolved in dichloromethane (300 mL) and washed with 50% potassium carbonate aqueous solution (20 g). After filtration and separation, the aqueous layer was extracted with dichloromethane (50 mL×4). The organic layers were combined, dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with CHCl3-MeOH (100:3) to obtain crude 7H-Imidazo[1,2-c]thiazole-2-carbaldehyde as a brown solid. The crude product was re-crystallized twice from CHCl3-n-hexane (1st: 30:5, 2nd: 30:60) at 0° C. to give the required aldehyde as pale brown crystals (Yield: 1.84 g, 15%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc([N+](=O)[O-])cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13](CCNC1C=CC=CN=1)[C:12]2=O)=[O:8].[OH-:40].[Na+]>CO>[CH2:14]1[C:15]2[C:11](=[CH:10][C:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:28][C:29]([O:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[C:3]([OH:2])=[O:39])=[O:8])=[CH:17][CH:16]=2)[CH2:12][NH:13]1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2)NC(=O)OCc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@@H](CNC(=O)c1ccc2c(c1)CNC2)C(=O)O)OC(=O)c1ccccc1

Procedure:
A methanol solution (25 mL) of 5-2 (328 mg, 0.61 mmol) and 1N NaOH (5 mL, 5 mmol) was stirred under ambient conditions overnight. The reaction was concentrated to dryness and the residue dissolved in H2O and the solution acidified with 6 N HCl to provide 5-3 as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]1=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]4[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]5[CH2:21][CH2:20]5)=[O:18])[N:15]=4)[CH:12]=3)=[C:4]([F:24])[CH:3]=2)=[O:41])[C:34]1=[O:43]
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
A mixture of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.459 mmol), 1-(2-bromo-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (146 mg, 0.448 mmol), HATU (262 mg, 0.689 mmol), N,N-diisopropylethylamine (160 μl, 0.919 mmol) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 3 days. After dilution with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 30 g, ethyl acetate/hexane=2/98→100/0) and preparative HPLC (acetonitrile/water=40/60→50/50, containing 0.1% trifluoroacetic acid) to give the title compound (152 mg, 52%) as a white solid.