Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH:6]=[CH:7][CH:8]=O.[CH3:27][O:28][C:29]([CH2:31]P(OC)(OC)=O)=[O:30]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:7]/[CH:8]=[CH:31]/[C:29]([O:28][CH3:27])=[O:30])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: COc1cc(C=CC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COC(=O)/C=C/C=C/c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1

Procedure:
In substantially the same manner as in Reference Example 16, 3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamaldehyde was allowed to react with trimethyl phosphonoacetate to produce methyl (E,E)-5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadienoate, which was recrystallized from ethyl acetate to give colorless prisms, m.p.166-167° C.
Reaction SMILES: [Li+].CCC[CH2-].[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:30][CH3:31])=[C:11]([CH:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:14]2[C:15]([F:21])=[N:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:12]=1.[CH2:32]([Sn:36](Cl)([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:30][CH3:31])=[C:11]([CH:13]([O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[C:14]2[C:15]([F:21])=[N:16][C:17]([F:20])=[C:18]([Sn:36]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH3:35])[CH:19]=2)[CH:12]=1
Reactant: COc1ccc(Br)cc1C(O[Si](C)(C)C(C)(C)C)c1ccc(F)nc1F
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C(O[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2OC)c(F)nc1F

Procedure:
DIPA (1.2 mL, 8.49 mmol) (freshly distilled) was dissolved in dry THF (40 mL) under nitrogen and cooled in a dry ice bath to −78°. N-butyllithium solution (2.5 m in hexanes, 3.0 mL, 7.50 mmol) was added and the solution stirred for a few minutes. A solution of 3-((5-bromo-2-methoxyphenyl)(tert-butyldimethylsilyloxy)methyl)-2,6-difluoropyridine (3.20 g, 7.20 mmol) in dry THF (20 mL) was added dropwise via an addition funnel and the solution stirred for 1 hour. Tributyltin chloride (2.0 mL, 7.37 mmol) was added to the pale yellow solution and it was stirred for 10 minutes. The reaction was quenched by addition of saturated ammonium chloride (10 mL). Water (100 mL) and diethyl ether (200 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (2-15% diethyl ether in hexane gradient) gave 3-((5-bromo-2-methoxyphenyl)(tert-butyldimethylsilyloxy)methyl)-2,6-difluoro-5-(tributylstannyl)pyridine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)Cc1ccc2occc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Methyl benzofuran-5-ylacetate (1.2 gm, 6.3 mmol) was dissolved in methanol (10 mL) and 2N sodium hydroxide (6.5 mL) was added under nitrogen and the mixture was stirred at rt for 3 hr. It was then diluted-with water and extracted with ether. The aqueous layer was acidified with 2N hydrochloric acid and again extracted twice with ethyl acetate. The organic layers were washed with brine, combined, dried over sodium sulfate and evaporated to give 1.1 gm of title compound suitable for the next step.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:17])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C([C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21)N1CCCC1
Yield: 62 %

Procedure:
A pale yellow amorphous solid of 1-[1-(2-indenyl-acetyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(2-indenylacetyl)-L-proline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 62%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C1COCC1>[NH2:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([NH:36][O:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:6]
Reactant: Nc1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1c(F)c(F)c(F)c(F)c1C(=O)NOCc1ccccc1
Yield: 106.1 %

Procedure:
Following the procedure for Example A, 2-amino-3,4,5,6-tetrafluorobenzoic acid (3.0 g, 14.4 mmol) was reacted with carbonyldiimidazole (2.8 g, 17.2 mmol), O-benzylhydroxylamine hydrochloride (3.44 g, 21.5 mmol), and triethylamine (3.0 mL, 21.5 mmol) in THF (50 mL) to provide 4.8 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:41]([C:37]4[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][CH:38]=4)(=[O:43])=[O:42])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Cl)ccc4ncc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 2, 50 mg, 0.14 mmol) and triethylamine (28 mg, 0.28 mmol) in dichloromethane (6 ml) was added 3-methylbenzene-1-sulfonyl chloride (40 mg, 0.21 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 29 mg (40%); 1H NMR (CDCl3, 300 MHz): δ 9.605 (s, 1H), 8.023-8.093 (m, 3H), 7.72-7.748 (dd, 2H, J=6.6 Hz, 1.8 Hz), 7.44-7.551 (m, 5H), 6.855-6.862 (d, 1H, J=2.1 Hz), 2.44 (s, 3H), 1.82 (s, 6H); MS: m/z 517 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15]CC1C=CC=CC=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]>CO.C(Cl)Cl.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reaction time: 24 h

Procedure:
To a solution of 4-Benzyloxy-1H-indole-2-carboxylic acid ethyl ester (29 g, 98.2 mmol) in a mixture of MeOH (750 ml) and DCM (500 ml) is added 1 gram of Pd/C (10%). It is hydrogenated under normal pressure for 24 hours. After filtration and evaporation a white powder is obtained.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22]=[C:21]([CH2:24]OC(=O)C)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1.CCOCC.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>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH2:24][C:21]1[CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:23][CH:22]=1)[C:1]([O:8][CH3:9])=[O:7]
Reactant: CC(=O)OCC1=CCN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)CC(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(CC1=CCN(C(=O)OC(C)(C)C)C1)C(=O)OC
Temperature: 25 °C
Yield: 77.6 %

Procedure:
5.28 g (40 mmol) dimethyl malonate were cautiously added to an ice-cooled suspension of 864 mg (36 mmol) sodium hydride in 80 ml THF. The resulting clear solution was added to a solution of 4.82 g (20 mmol) 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester and 462 mg (0.4 mmol) Pd(PPh3)4 in 40 ml THF and the mixture was heated to reflux for 20 h. The reaction mixture was cooled to room temperature, diluted with ether and quenched with sat. NH4Cl. The organic layer was washed with sat. NH4Cl and brine, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (ethyl acetate/petrol ether 4:1 to 2:1) and bulb-to-bulb distilled to yield 4.86 g (77%) of 2(1-tert.-butoxycarbonyl-2,5-dihydro-1H-pyrrol-3 -yl-methyl)-malonic acid dimetylester as a colorless oil, b.p. 130° C./0.2 mbar.
Reaction SMILES: C([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)(C)(C)C.[OH-].[Na+]>CO.Cl>[F:26][C:18]1[C:19]([F:25])=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[N:16]1[C:12]([C:11]2[C:6]([NH2:5])=[N:7][CH:8]=[CH:9][CH:10]=2)=[N:13][N:14]=[N:15]1
Reactant: COc1ccc(-n2nnnc2-c2cccnc2NC(C)(C)C)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2nnnc2-c2cccnc2N)c(F)c1F
Temperature: 0 °C
Yield: 99.3 %

Procedure:
As shown in step 1-iv of Scheme 1, Compound 1004 (5.0 g, 13.9 mmol) was taken up in 15 mL of methanol and 30 mL of 6M HCl. After refluxing for 10 hrs, the mixture was cooled to 0° C. and the pH adjusted to 8 with 6M sodium hydroxide. The resulting white precipitate was collected by vacuum filtration, washed well with water, and dried at 55° C. under vacuum for 16 hours to afford 3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (4.2 g): ESMS (M+1)=305.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]=1[Cl:21]>>[Cl:10][C:11]1[CH:16]=[C:15]([N+:1]([O-:4])=[O:2])[C:14]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:13][C:12]=1[Cl:21]
Reactant: CC(C)(C)c1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a stirred and cooled (-5° C) mixture of 325 parts of nitric acid and 975 parts of a concentrated sulfuric acid solution are added dropwise 220 parts of 1,2-dichloro-4-(1,1-dimethylethyl)benzene. Upon completion, stirring is continued for 30 minutes at 5° C. The reaction mixture is poured onto water: the product precipitates as an oil. The supernatant aqueous water: is decanted and the residual oil is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol. The product is filtered off and recrystallized from 2-propanol, yielding 34.5 parts of 1,2-dichloro-4-(1,1-dimethylethyl)-5-nitrobenzene; mp. 80° C.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:14])[C:3]=1[O:15]CC1C=CC=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:15][C:3]1[C:4](=[O:14])[O:5][C:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[OH:1]
Reactant: CC1(c2ccccc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC1(c2ccccc2)OC(=O)C(O)=C1O

Procedure:
The 4-hydroxy-5-methyl-5-phenyl-3-phenylmethoxy-2-(5H)-furanone (1.2 g) was subjected to hydrogenation over 100 mg of 5% Pd/BaSO4 in 100 mL of MeOH at room temperature and under 30 psi H2. The reaction was monitored periodically by TLC analysis. The suspension was filtered through two #1 filter papers, concentrated to a white solid and recrystallized from MeOH/H2O to give 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone as a white crystalline material: mp 173-175° C. dec. 1H NMR (acetone-d6) δ 7.53-7.36 (m, 5H), 1.84 (s, 3H). Anal Calcd for C11H10O4 +0.125H2O): C, 63.38; H, 4.96. Found: C, 63.30; H, 4.96.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:23]1CCC(N)CC1>>[CH3:13][C:12]1[C:7]([NH:6][CH:1]2[CH2:5][CH2:4][O:23][CH2:3][CH2:2]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: NC1CCOCC1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CCOCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using tetrahydro-2H-pyran-4-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (bs, 2H), 1.52 (bs, 2H), 1.79 (d, J=16.39 Hz, 3H), 2.06 (d, J=8.87 Hz, 3H), 3.17 (d, J=11.01 Hz, 2H), 3.74 (d, 2H), 3.85 (bs, 1H), 4.44 (d, J=6.18 Hz, 2H), 5.81 (d, J=7.52 Hz, 1H), 6.73 (s, 1H), 7.12-7.16 (m, 1H), 7.23 (d, J=7.79 Hz, 1H), 7.65 (t, J=7.66 Hz, 1H), 8.45 (d, J=4.84 Hz, 1H); MS (ESI) m/z 314.4 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])([NH:19][C:20]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:21])[C:9]1=[O:38].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])([NH:19][C:20]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:21])[C:9]1=[O:38]
Reactant: COC(=O)CCC1(NC(=O)c2cc3ccccc3cn2)C(=O)N(c2ccccc2F)c2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)N(c1ccccc1F)C(=O)C2(CCC(=O)O)NC(=O)c1cc2ccccc2cn1

Procedure:
A mixture of 62.53 g of (+)-methyl 3-[1-(2-fluorophenyl)-2,3-dihydro-3-(3-isoquinolinyl)carbonylamino-6-methoxy-2-oxo-1H-indol-3-yl]propionate, 56.78 ml of a 3N--NaOH aqueous solution and 576 ml of methanol was stirred at room temperature overnight under ice cooling. The reaction mixture was concentrated under reduced pressure, and the residue was made acidic with an aqueous 15% citric acid solution and extracted with ethyl acetate. The organic layer was collected by separation and washed with water successively with water and a saturated sodium chloride solution, and treated with 15 g of activated charcoal was added to the organic layer, and the mixture was dried over anhydrous sodium sulfate. After insolubles were removed by filtration, the filtrate was concentrated under reduced pressure to afford (+)-3-[1-(2-fluorophenyl)-2,3-dihydro-3-(3-isoquinolinyl)carbonylamino-6-methoxy-2-oxo-1H-indol-3-yl]propionic acid as an oily product. [α]D25 : +80.3° (c=0.426, chloroform). To the product obtained above were added 7.36 g of sodium carbonate and 200 ml of water. After the solution was concentrated to dryness under reduced pressure, the residue was dissolved in 500 ml of acetonitrile under heating, and the insolubles were filtered off. After cooling, the crystals precipitated from the filtrate were collected by filtration to afford 60.07 g of (+)-sodium 3-[1-(2-fluorophenyl)-2,3-dihydro-3-(3-isoquinolinyl)carbonylamino-6-methoxy-2-oxo-1H-indol-3-yl]propionate as a colorless solid (yield: 95%). Melting point: 206° to 211° C. FAB-MS (m/z): 522 (MH+), 177, 23 (base). [α]D25 : +89.7° (c=0.406, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20](/[CH:22]=[N:23]/O)[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.CS(Cl)(=O)=O>N1C=CC=CC=1.C(OCC)(=O)C.[O-]S([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([C:22]#[N:23])[CH:21]=1)[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(/C=N/O)c2)CC1
Agent: [Cu+2]
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(C#N)c2)CC1
Temperature: 60 °C

Procedure:
To a solution of tert-butyl 4-{3-bromo-5-[(E)-(hydroxyimino)methyl]phenoxy}piperidine-1-carboxylate (157 mg, 0.393 mmol) in pyridine (1.2 mL) was added methanesulfonyl chloride (0.12 mL, 1.6 mmol). The reaction mixture was heated at 60° C. for 2 hours. The reaction solution was diluted with ethyl acetate and saturated CuSO4 solution. The organic layer was washed with CuSO4 twice, 1N HCl, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column to give the desired product as white solid. LCMS (M+H)+: 381.1, 383.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Sn](C)(C)C)[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][CH2:33][OH:34].[F-].[Cs+].N#N>CN(C=O)C.[Cu]I.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:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][CH2:32][CH2:33][OH:34])[CH:17]=[N:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCCc1ccccc1I
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([Sn](C)(C)C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2ccccc2CCCO)c1
Temperature: 130 °C
Reaction time: 26 h

Procedure:
3-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)pyridine (214 mg, 0.50 mmol) and 3-(2-iodophenyl)-1-propanol (131 mg, 0.50 mmol) were dissolved in anhydrous DMF (2 mL) in a 10 mL round-bottom flask with a magnetic stirrer. CsF (152 mg, 1.0 mmol, 2.0 equiv.), CuI (9.5 mg, 50 μmol, 0.1 equiv.) and Pd(PPh3)4 (29 mg, 25 μmol, 0.05 equiv.) were added. The flask was equipped with a condenser, and the atmosphere was exchanged with N2 (3 times). The mixture was stirred in a 130° C. oil bath for 26 h and cooled to room temperature. The solvent was evaporated (oil pump, 60° C.), and the residue was purified by CC on silica gel (28×1.0 cm, EtOAc) to give the crude product as a yellow oil. This material was further purified by preparative HPLC in two portions (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 23.4-24.5 min) to give, after evaporation, the product as a colorless glass (128 mg, 64%). [α]546−51.3; [α]589−43.3 (c 9.15 g/L, EtOAc). 1H NMR (CDCl3, 400 MHz) δ 8.34 (d, 1H, J=2.8 Hz), 8.19 (d, 1H, J=1.4 Hz), 7.37-7.32 (m, 2H), 7.29-7.23 (m, 2H), 7.20 (d, 1H, J=7.3 Hz), 4.56-4.49 (m, 1H), 4.40 (dd, 1H, J=10.0, 4.6 Hz), 4.61 (dd, 1H, J=10.1, 2.7 Hz), 3.90 (t, 2H, J=7.8 Hz), 3.55 (q, 2H, J=5.5 Hz), 2.70-2.64 (m, 2H), 2.42-2.28 (m, 2H), 1.80-1.71 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]1[CH2:11]CC[CH2:8]1.[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[CH:47]=O)[N:43]=[CH:42][CH:41]=[CH:40]2>C(OCC)(=O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[CH:47]=[CH:8][O:7][CH3:11])[N:43]=[CH:42][CH:41]=[CH:40]2
Reactant: COc1cc2cccnc2cc1C=O
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: COC=Cc1cc2ncccc2cc1OC
Reaction time: 0.17 h

Procedure:
While cooling on ice, 0.82 g of potassium t-butoxide was added to 20 ml of a tetrahydrofuran suspension containing 2.50 g of (methoxymethyl)triphenylphosphonium chloride under nitrogen atmosphere. The obtained mixture was then stirred at the same temperature for 10 minutes. Thereafter, 3 ml of a tetrahydrofuran solution containing 545 mg of 6-methoxyquinoline-7-carbaldehyde was added to the reaction solution while cooling on ice, and the obtained mixture was then stirred at the same temperature for 15 minutes. Thereafter, the reaction solution was diluted with ethyl acetate, and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate), so as to obtain 1.41 g of 6-methoxy-7-(2-methoxyvinyl)quinoline containing triphenylphosphine oxide. This compound was used in the next reaction without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][F:22])C1C=CC=CC=1.[H][H].[ClH:25]>CO.[Pd]>[ClH:25].[ClH:25].[F:22][CH2:21][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: FCC1CNCCN1

Procedure:
A mixture of a solution of 23.85 g (0.08 mole) of 1,4-dibenzyl-2-fluoromethylpiperazine [prepared as described in step (c) above] in 500 ml of methanol and 33 ml of concentrated aqueous hydrochloric acid was stirred vigorously at room temperature for 1 hour in an atmosphere of hydrogen and in the presence of 1.0 g of 20% w/w palladium-on-carbon. At the end of this time, the catalyst was removed by filtration and washed with water. The filtrate and washings were concentrated by evaporation under reduced pressure, and the residue was dissolved in 200 ml of water. The resulting aqueous solution was washed vigorously with ethyl acetate and separated. The aqueous layer was concentrated by evaporation under reduced pressure, and the residue was washed with ethanol to afford 13.76 g of 2-fluoromethylpiperazine dihydrochloride as a colorless powder, melting at 205°-218° C.