Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[C@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:18]([OH:20])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C(=O)=O>O1CCOCC1>[CH2:2]([N:9]1[CH:10]2[CH2:11][CH2:12][CH2:13][CH:14]1[C:15](=[O:17])[N:28]([C:27]1[CH:29]=[CH:30][C:24]([O:23][C:22]([F:21])([F:31])[F:32])=[CH:25][CH:26]=1)[C:18]2=[O:20])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)[C@H]1CCC[C@@H](C(=O)O)N1Cc1ccccc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C=O
Solvent: C1COCCO1
Product: O=C1C2CCCC(C(=O)N1c1ccc(OC(F)(F)F)cc1)N2Cc1ccccc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
1,1-Carbonyl diimidazole (CDI; 1.2 g, 7.4 mmol) was added to a mixture of cis-1-benzyl-piperidine-2,6-dicarboxylic acid hydrochloride (1.0 g, 3.34 mmol) and dioxane (10 mL) at rt under N2. The mixture was heated at 100° C. After 15 min, a solution of 4-trifluoromethoxyaniline (600 mg, 3.39 mmol) and dioxane (2 mL) was added. After an additional 2 h, CDI (500 mg, 3.08 mmol) was added (Caution: CO2 evolution). After an additional 1 h, the reaction was allowed to cool to rt, concentrated, diluted with ethyl acetate (120 mL) and washed with 0.5N HCl (100 mL×2). The organic extract was dried, filtered, concentrated, and purified by silica gel chromatography (1:0→4:1; hexanes:ethyl acetate) to give 9-benzyl-3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione: MS (ESI): 405.4 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].Br[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[C:15]([O:17][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CCBr
Reactant: CCCCOc1c(O)c2ccc(O)cc2oc1=O
Product: CCCCOc1c(O)c2ccc(OCCC(=O)OCC)cc2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-butoxy-4,7-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-butoxy-4-hydroxy-7-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:20][N:19]1[C:15]([C:14]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:16][N:17]=[CH:18]1
Reactant: COC(=O)c1cc2ccccc2cc1-c1cncn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cncc1-c1cc2ccccc2cc1C(=O)O
Reaction time: 20 h
Yield: 74.3 %

Procedure:
A solution of methyl-3-(1-methyl-imidazol-5-yl)-2-naphthoate (Preparation 14) (8.5 g, 32 mmol) in THF/MeOH (3/2,120 mL) was treated with aqueous NaOH (1.0 N, 48 mL). After 20 hours at RT, it was neutralized with aqueous HCl (1.0 N, 20 mL). The solvent was evaporated in vacuo. The solid residue was treated with MeOH (5 mL), then evaporated again. The resulting crude material was purified by flash chromatography (5% MeOH/EtOAc) affording the title compound as a pale-yellow solid (6.0 g, 74%). 1H NMR (CDCl3): 8.34 (s, 1H), 7.95 (d, J=8.1, 1H), 7.90 (d, J=8.1, 1H), 7.72 (s, 1H), 7.53 (s, 1H), 7.52 (m, 1H), 7.50 (m, 1H), 6.83 (s, 1H), 3.16 (s, 3H). (ESI) m/z (M+H)+=253.10.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]([F:34])([F:33])[C:28]1[CH:32]=[CH:31][NH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:30]1[CH:31]=[CH:32][C:28]([C:27]([F:34])([F:33])[F:26])=[N:29]1)[C:11]([C@@H:12]([N:14]1[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]1=[O:23])[CH3:13])=[CH:10]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](c1cc2cccc(Cl)c2nc1-n1ccc(C(F)(F)F)n1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (0.2000 g, 0.539 mmol), 3-(trifluoromethyl)pyrazole (0.0733 g, 0.539 mmol), cesium carbonate (0.351 g, 1.08 mmol) and in DMF (1.80 mL, 0.539 mmol) was stirred at 100° C. After 2 h, The mixture was cooled to room temperature. To the cooled mixture was added water (30 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL×1), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 10 min, then 10 to 50% gradient of EtOAc in hexane over 20 min, then 50% isocratic of EtOAc for 10 min as eluent to give 2-((S)-1-(8-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (1 H, s), 8.51 (1 H, d, J=2.2 Hz), 8.25 (1 H, dd, J=8.4, 1.0 Hz), 8.08 (1 H, dd, J=7.7, 0.9 Hz), 7.63-7.85 (5 H, m), 6.92 (1 H, d, J=2.7 Hz), 5.94-6.05 (1 H, m), 1.83 (3 H, d, J=7.0 Hz); LC-MS (ESI) m/z 471.1 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:21]([O:22][CH3:23])=[CH:20][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[NH:14][CH:13]=[C:12]([C:17]#[N:18])[C:11]3=O.[Cl:24]CCOC1C(OC)=CC2C=C3C(C(=O)C(C#N)=CN3)=CC=2C=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:24][C:11]1[C:10]2[C:15](=[CH:16][C:7]3[CH:6]=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[C:21]([O:22][CH3:23])=[CH:20][C:8]=3[CH:9]=2)[N:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: COc1cc2cc3[nH]cc(C#N)c(=O)c3cc2cc1OCCCl
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCCl
Yield: 87 %

Procedure:
To a slurry of 1.11 g of 8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile (1:1 mixture) and 5 mL of phosphorus oxychloride is added 0.15 mL of anhydrous dimethylformamide. This is stirred and heated to reflux for 20 minutes using an oil bath, followed concentration in vacuo. The dark residue is quenched with 30 mL of cold water. The solid formed is collected, washed with water and dried to give 1.02 g (87%) of 4-chloro-7-methoxy-8(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-chloro-8-methoxy-7(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture) as a greenish yellow solid, m.p. 195-209° C. dec.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8])[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]([NH2:18])=[O:17].[CH2:19]1[O:27][C:26]2[CH:25]=[CH:24][C:23]([CH2:28][C:29](OC)=O)=[CH:22][C:21]=2[O:20]1.CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:19]1[O:27][C:26]2[CH:25]=[CH:24][C:23]([CH2:28][C:29]3[NH:18][C:16](=[O:17])[C:3]4[C:4]([CH3:15])=[N:5][N:6]([CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8])[C:2]=4[N:1]=3)=[CH:22][C:21]=2[O:20]1
Reactant: CCCCCCC(C)n1nc(C)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(C)n1nc(C)c2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 13.6 %

Procedure:
10 mg (0.037 mmol) of 5-amino-3-methyl-1-(2-octyl)-1H-pyrazole-4-carboxamide and 30 mg (0.129 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 2 mg (16%) of a solid, Rf=0.67 (dichloromethane/methanol=15:1).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].CN1CCNCC1.C([O:24][C:25]([C:27]1[O:28][C:29]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:30]=2[C:31]=1[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=O)C>C1(C)C=CC=CC=1>[CH3:42][O:41][C:39]1[CH:38]=[CH:37][C:30]2[C:31]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:27]([CH:25]=[O:24])[O:28][C:29]=2[CH:40]=1
Reactant: CCCCCc1c(C(=O)OCC)oc2cc(OC)ccc12
Agent: CN1CCNCC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCCc1c(C=O)oc2cc(OC)ccc12
Yield: 94.7 %

Procedure:
As in Example 152, sodium bis(2-methoxyethoxy)aluminum hydride in toluene (3.4M; 33.6 mL) and toluene (30 mL) pretreated with N-methypiperazine (13.5 mL) in toluene (20 mL) was reacted with 6-methoxy-3-pentyl-2-benzofurancarboxylic acid ethyl ester (6 g) in toluene (90 mL) for 30 minutes at -45° C. The previously described work up yielded 4.82 g of 6-methoxy-3-pentyl-2-benzofurancarboxaldehyde as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([OH:13])[C:9]1=[O:14])=[O:6])[CH3:3].Br[C@@H:17]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([O:13][CH:17]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:18]([O:20][CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:9]1=[O:14])=[O:6])[CH3:3]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Reactant: O=C(OC(c1ccccc1)c1ccccc1)[C@@H](Br)COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OC(COCc1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a solution of (3S-trans)-[[(1,1-dimethylethoxy)carbonyl]amino]-4-methyl-1-hydroxy-2azetidinone (55 mg, 0.26 mmol) and (S)-2-bromo-3-(phenylmethoxy)propanoic acid, diphenylmethyl ester (110 mg, 0.26 mmol) in dimethylformamide (1 ml) was added potassium carbonate (100 mg, 1 mmol). The resulting slurry was stirred for three hours at room temperature, quenched with hydrochloric acid (1N, 10 ml) and extracted with ether (20 ml). The organic layer was washed twice with dilute hydrochloric acid (1N, 2×10 ml), with saturated sodium chloride solution (20 ml), dried over magnesium sulfate and evaporated at reduced pressure. Purification of the product by preparative thin layer chromatography afforded the title compound (108 mg) as a mixture of diastereomers.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=O)=[CH:12][CH:11]=1.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:8][O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][CH:16]2[N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:12][CH:11]=1
Reactant: C1CNCCNC1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: COc1ccc2c(c1)C(N1CCCNCC1)CC2
Yield: 70.4 %

Procedure:
Homopiperazine (30.6 g, 0.306 mol), 6-methoxy-indan-1-one (4.95 g, 30.56 mmol), titanium(IV) isopropoxide (17.9 ml, 60 mmol) and sodium borohydride (2.7 g, 71 mmol) were reacted by Method A to give the product (5.3 g, 70.5%). The crude product was used without purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:6].[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.O1CCCC1.O>C(OCC)(=O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:13]=3)=[CH:21][CH:20]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)CCCCl)c2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCCCl)Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1

Procedure:
4-{[2-(4-Chlorobutyrylamino)-4-pyridyl]oxy}aniline (100 mg), p-fluorophenyl isocyanate (0.037 ml) and tetrahydrofuran (3 ml) were stirred at room temperature for 25 minutes. Water and ethyl acetate were added to the reaction solution for extraction, NH type silica gel was added to the extract, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=1:1, followed by ethyl acetate and ethyl acetate:methanol=10:1). The solvent was distilled off under reduced pressure to obtain 56 mg of the target substance as a white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(O)(=O)C.[Si]([O:41][CH2:42][CH2:43][CH:44]([C:53]1[C:57]([CH:58]2[CH2:60][CH2:59]2)=[C:56]([CH:61]2[CH2:64][CH:63]([CH2:65][CH:66]([CH2:69][CH3:70])[CH2:67][CH3:68])[CH2:62]2)[O:55][N:54]=1)[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[CH:58]1([C:57]2[C:53]([CH:44]([CH2:43][CH2:42][OH:41])[CH2:45][C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])=[N:54][O:55][C:56]=2[CH:61]2[CH2:62][CH:63]([CH2:65][CH:66]([CH2:69][CH3:70])[CH2:67][CH3:68])[CH2:64]2)[CH2:59][CH2:60]1
Reactant: CCC(CC)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)CC1CC(c2onc(C(CCO)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To tetrabutylammonium fluoride (1 M in tetrahydrofuran) (6.26 mL) were added water (0.0725 mL), acetic acid (0.29 mL) and a solution of tert-butyl 5-(tert-butyldiphenylsilanyloxy)-3-{4-cyclopropyl-5-[3-(2-ethylbutyl)cyclobutyl]isoxazol-3-yl}valerate (2.76 g) in tetrahydrofuran (20 mL) at ice temperature. The mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/6→1/4→1/2) to give the title compound (1.72 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].C(Cl)(Cl)Cl>CN(C)C=O.[Cl-].[Na+].O>[CH2:30]([NH:2][CH:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCNC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A suspension of 3-amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride (65 mg) obtained in Example 1 and potassium carbonate (148 mg, Wako Pure Chemical Industries) in N,N-dimethylformamide (5 ml) is added with allyl bromide (0.453 ml, Tokyo Kasei Kogyo), and the mixture is stirred at 50° C. for 12 hours. The reaction mixture is cooled to room temperature, and then added with saturated brine (10 ml) and chloroform (10 ml), and the organic layer is separated. The aqueous layer is extracted 3 times with chloroform (10 ml for each time), and the combined organic layer is washed twice with saturated brine (20 ml for each time). The organic layer is dried over anhydrous magnesium sulfate, and then the solvent is evaporated under reduced pressure. The residue is purified by silica gel chromatography (chloroform:methanol=30:1) to obtain the title compound (30 mg (predictive yield)).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.C[O:21][C:22](=O)[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[C:31]([O:30][C:28]([N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[C:22]([C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1)=[O:21])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cc(Br)c2cccc(C(F)(F)F)c2n1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Yield: 29 %

Procedure:
This was prepared from 4-bromo-2,8-bis(trifluoromethyl)quinoline by the method of example 31 using (S)-N-tert-butoxycarbonylproline methyl ester in place of N-diphenylmethyl-3-azetidinone and the product (1.32 g, 29%) isolated as a cream solid: IR νmax (Nujol)/cm−1 2979, 2883, 1748, 1698, 1401, 1368, 1312, 1160 and 1110; NMR δH (400 CDCl3) (mixture of 2 rotamers) 1.41 and 1.45 (9H, 2×s), 1.79-2.13 (3H, m), 2.11-2.31 (1H, m), 3.32-3.70 (2H, m), 5.09 and 5.16 (1H, 2×dd, J 8.8, 4.3 and J 9.0, 5.5 Hz), 7.78-7.83 (1H, m), 8.03 and 8.04 (1H, 2×s), 8.18-8.29 (1H, m), 8.41 and 8.51 (1H, 2×d, J 8.5 and J 8.5 Hz).
Reaction SMILES: [C:1]([C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:20](OC(=O)C)(=[O:22])[CH3:21]>S(=O)(=O)(O)O>[C:20]([O:19][C:13]1[CH:12]=[CH:11][C:10]([C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCCCCCCC(=O)c1ccc(OC(C)=O)c(C(=O)O)c1
Temperature: 100 °C
Yield: 85 %

Procedure:
1 g of 5-n-octanoylsalicylic acid is suspended in 15 ml of acetic anhydride. After addition of 2 drops of concentrated sulphuric acid the solution is heated to 100° C. for 15 minutes. The solution is poured onto 150 ml of crushed ice. After extracting with ether, washing the organic phase with the water, drying over sodium sulphate and evaporating, 1 g of a white crystalline product is obtained. The yield is 85%. The recrystallization is done from a 50/50 mixture of toluene and petroleum ether. The melting point is 130° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[C@H:12]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14](=[O:22])[C@@H:13]1[CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)C=C.N1CCOCC1>O1CCCC1.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>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([C@H:12]2[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[C@@H:13]2[CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:36])[CH3:35])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[C:5]([OH:4])[CH:10]=1
Reactant: C=CCOc1cc(Br)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(Br)cc1O)c1ccc(F)cc1
Yield: 82.7 %

Procedure:
(3R,4S)-4-[2-(Allyloxy)-4-bromophenyl]-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.34 g, 2.15 mmol) was dissolved in deoxygenated tetrahydrofuran (20 mL). Morpholine (1.8 mL, 1.8 g, 20.6 mmol) was added with additional deoxygenated tetrahydrofuran (5 mL). The reaction was purged with nitrogen and tetrakis(triphenylphosphine)palladium(0) (220 mg, 0.19 mmol) was added. The reaction was purged with nitrogen again. After 1.5 h at room temperature the reaction was diluted with ethyl acetate, washed twice with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and filtered. The solution was treated with activated charcoal, filtered, concentrated and purified by chromatography (40 g silica gel, 6% to 80% ethyl acetate-hexane) to afford (3R,4S)-4-(4-bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.04 g, 83% yield); Rf 0.38 (1:4 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.28-7.18 (m, 6H), 7.09-6.92 (m, 6H), 5.91 (s, 1H), 4.93 (d, J=2.3 Hz, 1H), 4.65 (t, J=5.4 Hz, 1H), 3.06 (ddd, J=4.8, 2.3, 2.3 Hz, 1H), 1.98-1.77 (m, 4H), 0.86 (s, 9H), 0.006 (s, 3H), −0.16 (s, 3H) ppm; MS [M−H]+581.7.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:18][S:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:23]2[CH:22]=[N:21][C:20]([S:19][CH3:18])=[N:25][CH:24]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: CSc1ncc(B(O)O)cn1
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: CC#N
Product: CSc1ncc(-c2cncc(Cl)c2N2CCC(C(N)=O)CC2)cn1

Procedure:
General procedure E was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (75 mg, 0.27 mmol), 2-(methylthio)pyrimidine-5-boronic acid (58 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 5 mol %), acetonitrile (3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 96:4-82:18, biotage 25+S) to furnish the title compound as an off white solid (11 mg, 11%), along with recovered 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide as a white solid (41 mg, 55% RSM), LC-MS (ESI, 4 min) Rt 2.14 min, m/z 364 (100%, [M+H]+); m/z (ESI) C16H18N5OSCl requires 363.09206, found [M+H]+ 363.0922.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][C:18]1[N:19]=[N+:20]([O-:24])[CH:21]=[CH:22][CH:23]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH3:46])[CH2:33][C:34](N(OC)C)=[O:35])=[CH:28][CH:27]=1.[Cl-].[NH4+]>C1COCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([C@H:32]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH3:46])[CH2:33][C:34]([C:21]2[N+:20]([O-:24])=[N:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=2)=[O:35])=[CH:30][CH:31]=1
Reactant: COc1ccc[n+]([O-])n1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)[n+]([O-])n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97.9 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (4.21 g, 19.8 mmol) in THF (130 mL) was added n-butyllithium solution (1.6 M in hexane 12.4 mL, 19.8 mmol) at −30° C., then the solution was stirred at 0° C. for 45 min. After cooling to −70° C. a solution of 3-methoxy-pyridazine-1-oxide (Chem. Pharm. Bull. 1959, 7, 938; 2.50 g, 19.8 mmol) in THF (13 mL) was added dropwise, then a solution of (R)-3-(4-bromophenyl)-N-methoxy-N-methyl-3-o-tolylpropanamide (example 1, step 5; 1.80 g, 4.95 mmol) in THF (13 mL) was added, maintaining the temperature as close as possible to −70° C. The mixture was stirred for 30 min. Then sat. aq. ammonium chloride solution (30 mL) was added. The reaction mixture was allowed to reach room temperature, then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) afforded the title compound (2.07 g, 98%). White foam, MS: 427.0 [M+H]+.