Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]2)=[CH:25][CH:24]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[O:4].C(N(CC)C(C)C)(C)C.[CH3:46][O:47][C:48](=[O:60])[C@@H:49]([N:57]=[C:58]=[O:59])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C)C=O>[CH2:50]([C@@H:49]([C:48](=[O:60])[O:47][CH3:46])[NH:57][C:58](=[O:59])[NH:1][C@@H:2]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]2)=[CH:27][CH:28]=1)[C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C=O
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a solution of methyl 2-[4-({(2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoyl}amino)butoxy]-6-hydroxybenzoate (8.0 mg, 0.015 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.008 mL, 0.045 mmol) and (S)-2-isocyanato-3-phenyl-propionic acid methyl ester (3.5 mg, 0.017 mmol) and stirred overnight at room temperature. The product was purified by preparative LCMS to afford the desired product (1.9 mg, 17%). LCMS found for C35H41N4O11S (M+H)+: m/z=725.1
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[C@@H:48]([CH3:59])[CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][NH:49][C@@H:48]([CH3:59])[CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-[(3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}-carbonyl)amino]methyl}-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (33 mg), TFA (0.2 mL) and DCM (1.0 mL) was stirred at room temperature overnight. Then TEA (0.4 mL) was added at −78° C. and the solution was then concentrated. Dilution with MeOH (0.5 mL) followed by separation via a Gilson HPLC (basic conditions) afforded the desired product (13 mg). LC-MS m/z 729 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[Li+].[CH3:9][CH:10]([N-]C(C)C)[CH3:11].C(Br)C=C>C1COCC1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:11][CH:10]=[CH2:9].[CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: CC(=O)CC(C)=O
Product: C=CCCCCCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2,4-pentanedione (4.11 mL, 39.9 mmol) was dissolved in anhydrous THF (120 mL) and cooled to 0° C. using an ice-water bath. To the stirred THF solution, 2.2 equivalent of 2.0 M LDA (44 mL, 87.8 mmol) was slowly added. After addition was complete, the mixture was stirred at 0° C. for 20 min under argon atmosphere. Allyl bromide (3.46 mL, 39.9 mmol) was then added to the resulting pale red solution at 0° C. under argon. After removing of ice-water bath, the resulting reaction was allowed to stir for 20 min at room temperature before being quenched by saturated aqueous 1 M of HCl (aq). The reaction mixture was extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed with brine, water (3×50 mL), dried over MgSO4. After filtration, the solution was concentrated, and the residue was purified by chromatography using 9:1 ratio of n-hexane:EtOAc. The product, 3, was isolated as a pale yellow oil, 1.21 g (22% yield).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[O:4][N:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:14])([F:16])[F:15])[O:4][N:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2ccccc2C(F)(F)F)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2C(F)(F)F)on1
Yield: 73.9 %

Procedure:
3-Hydroxy-5-(2-trifluoromethylphenyl)isoxazole (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.23 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.36 g, 74%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[C:16]([OH:18])=[S:17])=[CH:5][CH:4]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[C:16]([O:18][CH3:19])=[S:17])=[CH:7][CH:8]=1
Reactant: COc1ccc(Cc2cnccc2C(O)=S)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=S)c1ccncc1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.8 %

Procedure:
A solution of 4.9 g (17.8 mmol) of 3-(4-methoxyphenyl)methylthiopyridine-4-carboxylic acid and 4.9 g (30 mmol) of carbonyldiimidazole in 50 mL of dry N,N-dimethylformamide was stirred at 0° C. for 10 minutes and then allowed to warm to room temperature. After 2 hours the solution was cooled to 10° C. and quenched with 20 mL of methanol. The mixture was stirred for 2 hours and then the solvent was concentrated. The residue was partitioned between ether and water and the aqueous layer was extracted with three portions of ether. The ether extracts were dried (MgSO4) and concentrated to afford 5.1 g (93%) of a crystalline solid, m.p. 99°-100° C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[S:23]1[CH:27]2[NH:28][C:29](=O)[CH:30]=[CH:31][N:26]2[CH:25]=[CH:24]1>CC#N>[S:23]1[CH:27]2[NH:28][C:29](=[S:10])[CH:30]=[CH:31][N:26]2[CH:25]=[CH:24]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1C=CN2C=CSC2N1
Solvent: CC#N
Product: S=C1C=CN2C=CSC2N1
Reaction time: 1.5 h
Yield: 121.9 %

Procedure:
Lawesson's reagent (5.26 g.) was added to a boiling solution of 8H-thiazolo[3,2-a]pyrimidin-7-one (4.0 g.) in CH3CN(200 ml.) and the mixture was heated under reflux with stirring for 1.5 h. On cooling silica gel (70-230 mesh, 15 g.) was added and the mixture was evaporated to dryness. The residue was applied to a column of silica gel (300 g.) and eluted with MeOH/CH2Cl2 (5-10% to give 8H-thiazolo[3,2-a]-pyrimidin-7-thione (2.7 g.). Trimethyloxonium tetrafluoroborate (2.0 g.) was added to a stirred suspension of 8H-thiazolo[3,2-a]pyrimidin-7-thione (1.5 g.) in dry CH3CN (50 ml.). After stirring for 2 h, the solution was concentrated to about 20 ml., and with vigorous stirring anhydrous ether (100 ml.) was added to precipitate 7-methylthiothiazolo[3,2-a]-pyrimidinium tetrafluoroborate (1.3 g.), having nmr in d6DMSO:
Reaction SMILES: [F:1][C:2]1[CH:3]=C([CH:7]=[C:8]([F:19])[C:9]=1[N:10]([CH2:15][CH:16]([OH:18])[CH3:17])[CH2:11][CH:12]([OH:14])[CH3:13])C#N.[OH-:20].[Na+].[CH2:22]([OH:24])[CH3:23]>>[F:1][C:2]1[CH:3]=[C:23]([CH:7]=[C:8]([F:19])[C:9]=1[N:10]([CH2:15][CH:16]([OH:18])[CH3:17])[CH2:11][CH:12]([OH:14])[CH3:13])[C:22]([OH:20])=[O:24]
Reactant: CC(O)CN(CC(C)O)c1c(F)cc(C#N)cc1F
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: CC(O)CN(CC(C)O)c1c(F)cc(C(=O)O)cc1F

Procedure:
A solution of the 3,5-difluoro-4-[bis(2-hydroxypropyl)amino]benzonitrile and NaOH (8 g, 0.2 mol) in aqueous ethanol (100 ml, 50%) was refluxed for 2.5 hours. The solution was partitioned between EtOAc (1.2 1) and HCl (500 ml, 0.4 M), the aqueous layer washed with EtOAc (3×240 ml), the combined organic layers dried (MgSO4) and evaporated to dryness. The residue was chromatographed using CH2Cl2-EtOH-ACOH as eluent.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:21])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9]1([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10]2=[O:15].O1CC1COC1C=CC=C2C=1CC1(CCCCC1)C2=O.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>O1CCOCC1>[C:42]([NH:46][CH2:2][CH:3]([OH:21])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9]1([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10]2=[O:15])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)N
Reactant: O=C1c2cccc(OCC(O)CCl)c2CC12CCCCC2
Agent: O=C1c2cccc(OCC3CO3)c2CC12CCCCC2
Solvent: C1COCCO1
Product: CC(C)(C)NCC(O)COc1cccc2c1CC1(CCCCC1)C2=O

Procedure:
7.5 g of a mixture of mainly 4'-(3-chloro-2-hydroxypropoxy)-spiro(cyclohexane-1,2'-indan)-1'-one and of 4'-(2,3-epoxypropoxy)-spiro(cyclohexane-1,2'-indan)-1'-one in 50 ml dioxane and 30 ml tert.-butylamine are heated at 130° for 20 hours in an autoclave, then cooled and partitioned between 2 N tartaric acid and ether. The aqueous phase is made alkaline and extracted with ether. The organic phases are evaporated to yield the title compound in free base form (M.Pt. 87°-88°) which is converted into the hydrogen maleate; M.Pt. 180°-181°, and hydrogen malonate M.Pt. 143°-145°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.C(COC)OC.[C:31]1(OB(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:7][N:6]4[CH:8]=3)[CH2:13][CH2:14]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccc(N2CCN(Cc3cn4cc(-c5ccccc5)ccc4n3)CC2)cc1

Procedure:
A mixture of 6-bromo-2-[[4-(4-chlorophenyl)-1-piperazinyl]methyl]imidazo[1,2-a]pyridine. (Example 23; 0.091 g), tetrakis(triphenylphosphine)palladium (0) (Aldrich; 0.0078 g), and dimethoxyethane (2 mL) is stirred at room temperature for 10 min, at which time phenylboric acid (Aldrich; 0.0306 g) is added, followed by sodium bicarbonate (0.0565 g) in water (1 mL). The mixture is stirred at reflux for 3 h and then allowed to cool. Dimethoxyethane is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel using acetone/dichloromethane/methanol (50/200/1) to give 0.027 g of the title compound. MS m/z 402; 1H NMR (CDCl3) δ2.76, 3.21, 3.80, 6.84, 7.19, 7.37-7.58, 7.61, 7.64, 8.26.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([NH:17][CH:18]1[C:31](=[O:32])[N:20]2[C:21]([C:27]([O:29][CH3:30])=[O:28])=[C:22]([CH3:26])[CH2:23][S:24](=[O:25])[C@H:19]12)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl.C(O)(=O)C.[W]>[C:9]([NH:17][CH:18]1[C:31](=[O:32])[N:20]2[C:21]([C:27]([O:29][CH3:30])=[O:28])=[C:22]([CH2:26][Br:1])[CH2:23][S:24](=[O:25])[C@H:19]12)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C1=C(C)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 0 °C
Yield: 58.5 %

Procedure:
1.2 g (6.8 mmoles) of N-bromosuccinimide were added to an ice-cooled solution of 1.4 g (4 mmoles) of methyl 7-benzamido-3-methyl-3-cephem-4-carboxylate-1-oxide in a mixture of 25 ml of dichloromethane and 50 ml of acetic acid. The mixture was stirred and irradiated with a 150 W tungsten lamp for 1.5 hours. The reaction mixture was poured into water and dichloromethane and the organic layer was separated and washed three times with 500 ml of water. After treatment with activated charcoal, it was dried over magnesium sulfate and filtered. The filtrate was concentrated to about 20 ml in vacuo and the product was precipiated by addition of 150 ml of diethyl ether. The mixture was filtered and the product was washed with diethyl ether. It was crystallized by dissolving it in 100 ml of refluxing dichloromethane and precipitation by addition of 100 ml of diethyl ether to obtain 1.0 g pure methyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide (yield 58.8%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].C(O)C.[CH3:13][C:14]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:15]=1[CH2:16]Cl>O>[CH3:13][C:14]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Reactant: Cc1ccc(C)c(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C)c(CSc2ccccn2)c1
Temperature: 40 °C

Procedure:
A mixture of 5.6 g (0.05 mole) of 2-mercaptopyridine, 3.3 g (0.05 mole) of potassium hydroxide (85% pellets), 35 ml of ethanol and 5 ml of water was prepared. To this mixture was added 7.8 g (0.05 mole) of 2,5-dimethyl-benzylchloride, while maintaining good stirring. The mixture was stirred and heated to 40° C. for 45 minutes, cooled to room temperature, and then added to 150 ml of water. The aqueous mixture was extracted with 150 ml of diethyl ether; the ether phase washed with 150 ml of water. Finally, the ether phase was dried with anhydrous sodium sulfate. Removal of the ether left a green oil. An infrared spectrum was consistent with the structure of 2-((2,5-dimethylphenyl)methylthio) pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[S:7])=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[S:7])=[CH:21][CH:22]=1
Reactant: Cc1ccc(C(=S)c2cc(CC(=O)O)cc3c2OCC3)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(C(=S)c2cc(CC(=O)O)cc3ccoc23)cc1

Procedure:
7-(4-Methylthiobenzoyl)-2,3-dihydrobenzofuran-5-ylacetic acid (1.0 g) was heated at reflux in carbon tetrachloride (100 ml) containing n-bromosuccinimide (0.54 g) and a catalytic quantity of benzoyl peroxide. After approximately 2 hours the reaction mixture was cooled and extracted with dilute aqueous sodium carbonate. The aqueous extract was acidified with hydrochloric acid, extracted with ethyl acetate, dried and evaporated to yield a residue which was crystallized from acetone/hexane to give (7-(4-methylthiobenzoyl)benzofuran-5-ylacetic acid, m.p.--151°-153° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[N:27][CH:26]=[CH:25][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[N:27][CH:26]=[CH:25][C:10]=1[C:11]1[O:12][C:15]2[CH:16]=[CH:17][C:18]([C:20]([F:21])([F:23])[F:22])=[CH:19][C:14]=2[N:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a mixture of 1.78 g of 3-tert-butoxycarbonylamino-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 20 ml of tetrahydrofuran and 1.29 g of triphenylphosphine, 2.15 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred at room temperature for one hour and then stirred while heating at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.69 g of 2-(3-tert-butoxycarbonylamino pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 36”).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: CN(C)CCN
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)NCCN(C)C)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-(dimethylamino)ethyl)-3-methylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and N1,N1-dimethylethane-1,2-diamine following the procedures described for Example 117. 1H NMR (methanol-d4): δ 8.60 (s, 1H), 8.39 (s, 1H), 8.08 (d, 1H), 7.68 (s, 1H), 7.57-7.59 (m, 2H), 7.19-7.22 (m, 2H), 3.57-3.61 (m, 2H), 3.07-3.16 (m, 4H), 2.64-2.67 (m, 2H), 2.52 (s, 3H), 2.38 (s, 6H), 2.35 (s, 3H). LRMS [M+H]=442.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=O)[C:11](=[CH:20]N(C)C)[CH2:10][N:9]=1.[ClH:24].[C:25]([NH2:30])(=[NH:29])[CH:26]([CH3:28])[CH3:27].CO.C[O-].[Na+]>O>[Cl:24][C:16]1[CH:17]=[CH:18][C:13]2[C:12]3[N:30]=[C:25]([CH:26]([CH3:28])[CH3:27])[N:29]=[CH:20][C:11]=3[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: CC(C)C(=N)N
Reactant: Cl
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2ccccc2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)c1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.5 g (10 mmole) of 1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one, 4.8 g (40 mmole) of isobutyramidine hydrochloride, 10 ml (41 mmole) of a 4.12M methanol solution of sodium methoxide and 100 ml of methanol was stirred at room temperature for 2 hr. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. Crystallization of the oil with ether gave a light yellow solid, mp 127°-129° C. Recrystallization from a mixture of ether and petroleum ether gave colorless rods, mp 127°-129° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].[N+](=[CH2:14])=[N-]>C(OCC)C>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([N+:9]([O-:11])=[O:10])=[N:4][CH:5]=1)(=[O:8])[CH3:14]
Reactant: C=[N+]=[N-]
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Solvent: CCOCC
Product: CC(=O)c1cnc([N+](=O)[O-])n1C
Temperature: 0 °C
Reaction time: 168 h

Procedure:
To a solution of 0.70 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 180 ml. of diethyl ether, a solution of 0.43 g. of diazomethane in 86 ml. of diethyl ether is added under cooling at about 0° C. After standing at room temperature for 7 days, the reaction mixture is filtered and then evaporated to dryness. The residue (0.60 g.), dissolved, in 6 ml. of chloroform, is chromatographed on 6 plates of silica gel, eluting with a 9:1 (v/v) chloroform:methanol mixture, and TLC spots are visualized under U.V. light. The silica gel, which corresponds to an Rf value from 0.64 up to 0.76 is collected and extracted with methanol. From this solution, after filtration and concentration, 0.065 g. of 5-acetyl-1-methyl-2-nitroimidazole is obtained, m.p. 81°-83° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH2:22][CH2:23][CH2:24][C@@H:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]#[CH:33])[CH2:27][C@@H:26]1[CH2:34][C:35]([O:37][CH3:38])=[O:36]>C(N(CC)CC)C.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH2:22][CH2:23][CH2:24][C@@H:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]#[C:33][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[CH2:27][C@@H:26]1[CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C#CCN1CC[C@@H](CCCc2ccnc3ccc(OC)cc23)[C@@H](CC(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C[C@H]1CN(CC#Cc2cc(F)cc(F)c2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
0.35 cm3 of 1-bromo-3,5-difluorobenzene and then 0.112 g of tetrakis(triphenylphosphine)palladium and 0.037 g of cuprous iodide were added at a temperature in the region of 20° C., under an inert atmosphere, to a stirred mixture of 0.77 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-acetate in 7.7 cm3 of triethylamine. The suspension obtained was heated at a temperature in the region of 80° C. for 3 hours and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 50 cm3 of ethyl acetate in 20 cm3 of water. After stirring the mixture for 15 minutes, the remaining insoluble material was filtered through clarcel and then the filtrate was separated by settling: the organic phase was separated off, then washed with 3 times 3 cm3 of water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The oily residue obtained was purified by. chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 40-63μ; diameter 3 cm; 45 g), elution was carried out with a dichloromethane/methanol (97/3 by volume) mixture. The fractions comprising the expected product were collected. These fractions were concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.345 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetate was obtained in the form of an oil with a pale yellow color. Mass spectrum (El): m/z=506 M+.