Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([OH:19])=[C:5]([C:7]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[O:8])[CH:6]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>OS(O)(=O)=O>[C:20]([O:19][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])=[O:8])(=[O:22])[CH3:21]
Reactant: O=C(Oc1ccccc1C(=O)O)c1ccccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of salsalicylic acid (salsalate) (5.0 g, 19.37 mmol) in acetic anhydride (15.0 mL, 147.0 mmol) was added 3 drops of conc. H2SO4 and the mixture was stirred at RT for 16-20 h. The mixture was diluted with ice cold water (50 mL) and precipitated solid was filtered, washed with water (2×10 mL), hexanes (20 mL) and dried to afford 2-{[2-(acetyloxy)benzoyl]oxy}benzoic acid, 11 (5.5 g, mmol) as white solid. Rf: 0.3 (50% EtOAc/hexanes).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[CH:25]([CH2:30][CH3:31])[C:26](=O)[CH2:27][CH3:28])C>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[C:25]([CH2:30][CH3:31])=[C:26]([CH2:27][CH3:28])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C(CC)C(=O)CC
Solvent: ClC(Cl)Cl
Product: CCc1c(CC)n2c(nc1=O)OC(COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 2-ethyl-3-oxo-pentanoic acid ethyl ester in accordance with the procedures of O.-S. Adetchessi, et. al., Tetrahedron, 61, (2005), 4453-4460. [α]D25 −11.20 (c 0.5, CHCl3).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[O:34])[C:21](=[O:33])[N:22]2[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O1C2C=CC(O)=CC=2OC1.[F:45][C:46]1[CH:47]=[C:48]([OH:53])[CH:49]=[CH:50][C:51]=1[F:52]>>[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([C:49]1[CH:50]=[C:51]([F:52])[C:46]([F:45])=[CH:47][C:48]=1[OH:53])([OH:34])[C:21](=[O:33])[N:22]2[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc(F)c(F)cc2O)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl (4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate and 1,3-benzodioxol-5-ol with 3,4-difluorophenol, the title compound was obtained as a white solid (42%); MS (ES+) m/z 424 (M−17), 426 (M−17), 464 (M+23), 466 (M+23).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[C:16]([CH2:18][CH3:19])[N:17]=[C:4]2[N:3]=1.N>ClCCl.[Cl-].[Na+].O.[Zn]>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:15]=[C:16]([CH2:18][CH3:19])[N:17]=[C:4]2[N:3]=1
Reactant: CCc1nc2nc(Cl)c(-c3ccccc3)c(Cl)n2n1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCc1nc2nc(Cl)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.00 g 5,7-dichloro-2-ethyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine is dissolved in 180 ml dichloromethane. 180 ml saturated brine, 120 ml ammonia solution 25% w/w and 6.00 g zinc powder are added and the mixture is stirred at room temperature for 3 h. The reaction mixture is filtrated over kieselgur and is washed with dichloromethane and water. The organic phase is separated and the water phase is extracted with dichloromethane. The combined organic layers are dried over Na2SO4 and the solvent is evaporated. The residue contained 2-ethyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine. This mixture is used without further purification for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Cc1ccccc1CN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2cc(Cl)ccc21
Yield: 68.9 %

Procedure:
A mixture of 2.05 g of 2-chloro-6,11-dihydro-5H-dibenz[b,e]azepine, 2.15 g of 4-nitrobenzoyl chloride, 1.50 g of N,N-diisopropylethylamine, 54 mg of 4-(dimethylamino)pyridine in 15 ml of dichloromethane is refluxed for 18 hours. The mixture is cooled and washed with H2O, 1N HCl, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and the residue recrystallized from dichloromethane-hexane to give 2.33 g of crystals, m.p. 198°-201° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([OH:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([O:21][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:11]([O-:13])=[O:12])[CH:20]=1
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: O=[N+]([O-])c1ccccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(OCCOc2ccccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1-(2-Chloro-ethoxy)-2-nitro-benzene (116 g) and 5-methyl-2-nitro-phenol (88 g) were dissolved in 500 ml DMF and was stirred for 4 h at 90-110° C. after careful addition of 160 g potassium carbonate. The reaction mixture was poured in a mixture of crushed ice and water (8 l) which was vigorously stirred. The residue was filtered off, washed several times with water and dried. The crude product was suspended in methanol and the pale yellow residue was again filtered off, washed with methanol and dried. Yield: 150-165 g.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.O1CCCC1.ClS([N:33]=[C:34]=[O:35])(=O)=O>O>[C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[N:13]3[C:34]([NH2:33])=[O:35])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1C(=O)Cc2ccc(-c3ccccc3)cc21
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To 4.5 g. (21.5 mmole) of 6-phenyl-2-oxindole in a mixture of 100 ml. of toluene and 25 ml. of tetrahyrofuran was added, with stirring, at 5° C., 2.2 ml. (25.8 mmole) of chlorosulfonyl isocyanate. Stirring was continued for 1 hour at 0°-5° C. and then 100 ml. of water was added. The solid was recovered by filtration and added to a mixture of 40 ml. of glacial acetic acid and 80 ml. of water. The resulting mixture was heated at 100° C. for 1 hour, cooled and filtered. The residue was dried to give 3.1 g. of the title compound, mp. 188°-189° C.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[N:13]([C@@H:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C:26]([CH3:28])=[CH2:27])[C:12]1=[O:42])[CH3:10])(C(C)(C)C)(C)C.B(F)(F)F.CCOCC>C(#N)C.C(OCC)(=O)C>[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[N:13]([C:25]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])=[C:26]([CH3:28])[CH3:27])[C:12]1=[O:42])[CH3:10]
Reactant: C=C(C)[C@H](C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)Sc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)O)[C@H]1CC(=O)Sc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
64 mg (0.104 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-1-[(R)-2-methyl-1-(p-nitrobenzyloxycarbonyl)prop-2-enyl]-4-[(phenylthio)-carbonylmethyl]-2-azetidinone were dissolved in 1.5 ml of acetonitrile. To the solution were added, with stirring at -15° C., 15 mg (0.106 mmole) of boron trifluoride etherate. After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with a dilute aqueous solution of sodium bicarbonate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to thin layer chromatography using silica gel, developed with a 2:3 by volume mixture of benzene and ethyl acetate, to afford 48 mg (yield 92%) of the title product.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH2:18].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH:18][CH2:17][CH:16]([O:19][CH3:20])[O:15][CH3:14])=[O:7])[CH:3]=1
Reactant: COC(CN)OC
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)NCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
Mono-methyl isophthalate (1 g, 5.55 mmol), amino acetaldehyde dimethyl acetal (569 μL, 5.28 mmol) and EDCI (1.52 g, 7.92 mmol) were dissolved in 55 mL DCM, followed by the addition of DIPEA (1.84 mL, 10.56 mmol). The reaction was allowed to stir at room temperature for 2 hours. It was then taken up in 50 mL of DCM, washed with saturated NaHCO3 solution (100 mL), and brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford the crude product (1.48 g) as a clear oil which was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:27][CH2:26]2)[CH2:22][CH2:23]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1N1CCN(CC2CCNCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CC2CCN(C(=O)c3ccccc3)CC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of 1-(2-methoxyphenyl)-4-piperidin-4-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 1 and triethylamine (2 equivalents, 1 mL) in CH2Cl2 (30 mL) and the solution stirred under N2 at 0° C. for 16 hours. The mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3×25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (0.91 g, 66% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid.
Reaction SMILES: [F:1][C:2]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([CH:27]=C)[CH:3]=1.O=[O+][O-].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:6](=[O:7])[N:8]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]1)[CH2:27]2
Reactant: C=Cc1cc(F)c([N+](=O)[O-])cc1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3cc(F)c([N+](=O)[O-])cc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
tert-Butyl 4-(4-fluoro-5-nitro-2-vinylbenzamido)piperidine-1-carboxylate (Step 2, 1.1 g, 2.77 mmol) in 50 mL of DCM is chilled to −78° C. Ozone was passed through the solution until the starting material was consumed, and then nitrogen was passed through the solution for 5 min. The reaction mixture was warmed to room temperature. Triphenylphosphine-resin (2.77 g) in 10 mL of DCM was added, and was stirred for another 1.5 h. The resin was filtered off, and the solution was concentrated in vacuo. The resulting crude was dissolved in DCM (15 mL), and to this solution were added TFA (15 mL) and triethylsilane (1.0 mL, 5.9 mmol) sequentially. The reaction was stirred at room temperature 2 h. After concentration, the reaction crude was poured into 10 mL of water, neutralized to pH 8 with sat. aq. NaHCO3, followed by addition of (Boc)2O (603 mg, 2.77 mmol) in 10 mL of DCM. The reaction was stirred at room temperature for 1.5 h, then extracted with DCM. The organic extracts were dried (Na2SO4), concentrated in vacuo, and purified by silica gel chromatography (EtOAc/Hexanes:1/4) to give tert-Butyl 4-(5-fluoro-6-nitro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate; ESMS m/z 380.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[C:15]1([CH2:21][N:22]2[CH:27]3[CH2:28][CH2:29][CH:23]2[CH2:24][NH:25][CH2:26]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O.O>[OH:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:25]1[CH2:26][CH:27]2[N:22]([CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:23]([CH2:29][CH2:28]2)[CH2:24]1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: c1ccc(CN2C3CCC2CNC3)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C(O)CN2CC3CCC(C2)N3Cc2ccccc2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (1.0 g, 3.7 mmol) and 8-(phenylmethyl)-3,8-diazabicyclo[3.2.1]octane (748 mg, 3.68 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to rt., the mixture was diluted with water (50 mL), extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residue was purified by TLC (MeOH/DCM=1:15) to obtain 5-{1-hydroxy-2-[8-(phenylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one. The two isomers were separated by SFC chiral chromatography to obtain two single isomers, isomer A and isomer B with the same MS m/z 393 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([C:24](=[O:29])C(F)(F)F)=[CH:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:32]>CN(C)C=O.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([C:24]([OH:32])=[O:29])=[CH:15]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(C(=O)O)c2ccc(Cl)cc21
Reaction time: 0.75 h
Yield: 92.4 %

Procedure:
To a solution of 1.7 g (4.0 mmol) (S)-2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester and 1.0 g (22 mmol) sodium hydride (50% in oil) in 40 ml dry N,N-dimethylformamide were added dropwise 0.36 ml (20 mmol) water under water-bath cooling. After stirring for 45 min the reaction mixture was diluted with 80 ml tert-butyl methyl ether. The organic layer was extracted with aqueous 1 M sodium hydroxide solution (2×100 ml). The combined aqueous layers were acidified to pH 2 with ice-cold aqueous hydrochloric acid solution and extracted with ethyl acetate (3×100 ml). The combined ethyl acetate layers were dried over sodium sulfate and concentrated to dryness to give the title compound (1.4 g, 96%) as a light yellow solid.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][C:38]([O:40]CC2C=CC=CC=2)=[O:39])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1cccc(CCC(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COP(=O)(CCC(N)C(=O)O)Oc1cccc(CCC(=O)O)c1
Yield: 87.2 %

Procedure:
Next, 0.68 g (1.03 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-{[3-(2-benzyloxycarbonylethyl)phenyl](methyl)phosphono}butanoate was dissolved in 50 mL of a solvent mixture of methanol and water at 4:1 and mixed with 240 mg of 5% palladium-carbon, and hydrogen gas was introduced at room temperature for 5 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated and the residue was freeze-dried from water to obtain 2-amino-4-{[3-(2-carboxyethyl)phenyl](methyl)phosphono}butanoic acid (0.31 g, yield 86%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[CH3:22]>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:21](=[O:23])[CH3:22])[CH2:26][CH2:27]1
Reactant: CC(=O)NC1CCNCC1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Temperature: 150 °C
Yield: 19.9 %

Procedure:
A mixture of 3.5 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 6 g of 4-acetylaminopiperidine and 30 ml of hexamethylphosphoric triamide was heated at 150° C. for 4 hours. After completion of reaction, hexamethylphosphoric triamide was distilled off under reduced pressure, and the residue was recrystallized from dimethylformamide-water. Crystals which formed were again recrystallized from dimethylformamide to give 0.82 g of 9-fluoro-8-(4-acetylamino-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 274°-277° C., white rhombic crystals.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@:3]1([NH:14][S:15]([C:18]1[S:19][C:20]([N:23]2[CH:27]=[C:26]([C:28]#[C:29][Si](C)(C)C)[CH:25]=[N:24]2)=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:11]([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].S([O-])(O)(=O)=O.[K+]>CO>[C:28]([C:26]1[CH:25]=[N:24][N:23]([C:20]2[S:19][C:18]([S:15]([NH:14][C@:3]3([C:11]([OH:13])=[O:12])[C@@H:4]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[C@H:2]3[CH3:1])(=[O:16])=[O:17])=[CH:22][CH:21]=2)[CH:27]=1)#[CH:29]
Reactant: C[C@@H]1[C@H](c2ccccc2)[C@]1(NS(=O)(=O)c1ccc(-n2cc(C#C[Si](C)(C)C)cn2)s1)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Product: C#Cc1cnn(-c2ccc(S(=O)(=O)N[C@@]3(C(=O)O)[C@H](C)[C@@H]3c3ccccc3)s2)c1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of (1S,2R,3R)-2-methyl-3-phenyl-1-[5-(4-trimethylsilanylethynyl-pyrazol-1-yl)-thiophene-2-sulfonylamino]-cyclopropanecarboxylic acid (66 mg, 0.13 mmol) in methanol (1.0 mL) was added potassium carbonate (36 mg, 0.26 mmol) at room temperature. After stirring for 1 hour without any modification, to the mixture was added 5% aqueous potassium hydrogen sulfate solution (3.0 mL). The aqueous layer was extracted three times with ethyl acetate (2.0 mL). The organic layer was washed with water (3.0 mL) and saturated aqueous sodium chloride solution (3.0 mL), and dried over sodium sulfate. After filtration and evaporation of the residue, chloroform (1.0 mL) was added to the obtained residue to allow precipitation of crystals. After slurry-washing and filtration, the residue was dried under reduced pressure to give the title compound (54 mg, yield 98%) as a pale-yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C@@H:7]([C:19](=[O:31])[NH:20][C@H:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[C@H:52]1[CH2:56][N:55]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:54]([C:64]([O:66][CH3:67])=[O:65])[CH2:53]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C(Cl)Cl>[C:15]([O:14][C:12]([N:8]1[C@H:7]([C:19](=[O:31])[NH:20][C@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][C@@H:52]3[CH2:56][N:55]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:54]([C:64]([O:66][CH3:67])=[O:65])[CH2:53]3)=[CH:3][CH:4]=2)[CH2:9]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc3c(c2)CN(C(=O)OC(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of (S)-tert-butyl 7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound D of Example 1, 50 mg, 0.12 mmol) in CH2Cl2 (1.0 mL) was added PPh3 (37 mg, 0.14 mmol), (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (Aldrich, 35 mg, 0.14 mmol) and ADDP (37 mg, 0.14 mmol). The resulting reaction mixture was allowed to stir overnight at room temperature. Additional (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (35 mg, 0.14 mmol), PPh3 (37 mg, 0.14 mmol) and ADDP (37 mg, 0.14 mmol) were then added. The reaction mixture was allowed to stir at room temperature for 60 h, then concentrated in vacuo and purified using flash column chromatography (gradient from 0% to 60% EtOAc/hexanes) to give the title compound (66 mg, 86%) as a colorless oil. MS (ESI+) m/z 650.4 (M+H)+.