Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@H:5]([NH:17]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].C(NCC)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([NH2:17])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH3:2]
Reactant: CCOC(=O)[C@@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](N)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.1 %

Procedure:
The compound (1.9846 g) obtained in Example 96-1 was dissolved in DMF (19 ml) and added with diethylamine (14 ml) and the whole was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.2212 g) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22].Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CO.O>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:5]([C:7](=[O:9])[NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1-c1ccccn1
Reactant: CN(C)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: CN(C)CCNC(=O)c1nc(N)sc1-c1ccccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a solution of ethyl 2-amino-5-(2-pyridyl)-4-thiazolecarboxylate (2.49 g) in ethyleneglycol (10 ml) were added N,N-dimethylethylenediamine (1.76 g) and 36% hydrochloric acid (0.5 ml) and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured into water (50 ml), adjusted to pH 8 with aqueous potassium carbonate and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from acetonitrile to give 2-amino-4-[N-[2-(N,N-dimethylamino)ethyl]carbamoyl]-5-(2-pyridyl)thiazole (2.0 g).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11](/[CH:12]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OC2CCCCC2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
A mixture of 4-cyclohexyloxy-benzaldehyde (2.84 g, 13.9 mmol) described in Manufacturing Example 79-1-1, nitromethane (3.74 mL, 69.5 mmol), ammonium acetate (2.14 g, 27.8 mmol) and acetic acid (30 mL) was stirred for 14 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH2:7][NH:8][C:9]([NH2:11])=[O:10])([O-:3])=[O:2].C([O:22][CH:23](O)[C:24](OCC1C=CC=CC=1)=[O:25])C1C=CC=CC=1>C(O)(=O)C>[OH:25][CH:24]1[N:8]([CH2:7][C:6]2[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:9](=[O:10])[NH:11][C:23]1=[O:22]
Reactant: O=C(OCc1ccccc1)C(O)OCc1ccccc1
Reactant: NC(=O)NCc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: O=C1NC(=O)N(Cc2cccc([N+](=O)[O-])c2)C1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
N-(3-Nitrobenzyl)urea (78 g) was dissolved in 500 mL of 80% acetic acid, 120 g of benzyl 2-benzyloxy-2-hydroxyacetate was added thereto at 80° C. and the mixture was stirred at 80° C. for two hours. The mixture was concentrated in vacuo and the solvent was evaporated therefrom by means of an azeotropic distillation with toluene. The residue was purified by a silica gel column and recrystallized from a mixed solvent of ethyl acetate and hexane to give 49 g of 5-hydroxy-1-(3-nitrobenzyl)-2,4-dioxoimidazolidine.
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([C:25]([OH:27])=[O:26])[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+:29]>C(O)C.O>[CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([C:25]([O-:27])=[O:26])[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Na+:29]
Reactant: CCCCCCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCc1cc2ccc(C(=O)[O-])cc2[nH]1
Yield: 93.2 %

Procedure:
A solution of 2-(n-pentadecyl)indole-6-carboxylic acid (15.0 g) in hot ethanol (100 ml) was treated with a solution of sodium hydroxide (2.0 g) in water (50 ml), and a white precipitate was obtained. The precipitate was recrystallised from aqueous ethanol (1:1) (300 ml) to give sodium 2-(n-pentadecyl)-indole-6-carboxylate (14.8 g), in the form of white crystals, m.p. greater than 340° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([CH3:22])=[CH:20][N:19]=[N:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[ClH:23].[H][H]>CO.[Pd]>[ClH:23].[CH3:22][C:21]1[N:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:18]=[N:19][CH:20]=1
Reactant: Cc1cnnn1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cnnn1C1CCNCC1

Procedure:
The compound of step (iii) was re-dissolved in methanol to the volume of 400 ml. Then to the solution were added 5% Pd/C and concentrated HCl (50 ml). The mixture was hydrogenated for 24 hr at hydrogen pressure of 100 atm and temperature 90° C. The mixture was cooled, filtered and evaporated. The resulting oily residue was dissolved at reflux in isopropanol (100 ml) and to the solution was added concentrated HCl (50 ml). The mixture was allowed to crystallise at 5° C. for 3 days and then filtered to give the title compound (135 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@@H:32]1[CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@@H:32]1[CH2:36][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: COc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OC[C@H]2CCCN2C(=O)OC(C)(C)C)c1
Yield: 85.4 %

Procedure:
Following a procedure similar to that described in Example 40(a), 1.00 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 0.740 g of potassium t-butoxide and 2.33 g of (R)-1-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)pyrrolidine were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.54 g (yield 85%) of the title compound as a colorless oil.
Reaction SMILES: Cl.[C:2](=[NH:12])(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>CO.[OH-].[Na+]>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:2](=[NH:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: COC(CN)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(CNC(=N)c1ccccc1)OC
Reaction time: 72 h
Yield: 104.5 %

Procedure:
(EX-1A) A solution of ethyl benzimidate hydrochloride (92.25 g, 496.9 mmol) in 300.0 mL dry methanol (1.68 M) was cooled to ca 0° C. and added a solution of aminoacetaldehyde dimethyl acetal (73.10 mL, 670.9 mmol) in dry methanol (75.0 mL, 9.0 M) drop wise at such a rate the temperature was kept below 5° C. The resulting solution was allowed to stir for 3 days with the temperature being maintained below 5° C. The reaction mixture was then concentrated under reduced pressure to give a yellow oil. The residue was dissolved in 1 N NaOH (750 mL) and extracted with dichloromethane (4×250 mL). The organic solutions were combined, dried (MgSO4), and concentrated to give 108.13 g crude N-(2,2-dimethoxyethyl)benzamidine as a yellow oil. The crude N-(2,2-dimethoxyethyl)benzamidine (108.13 g, 519.2 mmol) in dry methanol (125.0 mL, 4.2 M) was added dimethyl methoxymethylenemalonate (94.13 g, 540.5 mmol) in one portion at room temperature. The resulting mixture was heated to approximately 100° C., where the solvent was slowly distilled off over a two hour period. The resulting dark brown solution was allowed to cool to room temperature and was diluted ethyl acetate (1 L). The organic solution was washed with saturated NH4Cl (2×500 mL) and brine (1×500 ml). The organic solution was dried (MgSO4), filtered and concentrated. Purification of the crude product by MPLC (25% ethyl acetate/hexane) gave pure methyl 1-(2,2-dimethoxyethyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate (EX-1A) in 73% yield as a tan oil: 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 7.59-7.49 (m, 5H), 4.86 (t, J=5.5 Hz, 1H), 4.16 (d, J=5.4 Hz, 2H), 3.95 (s, 3H), 3.32 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 165.9, 164.6, 159.3, 158.2, 134.6, 130.9, 128.93, 128.78, 114.9, 101.9, 56.0, 55.1, 52.7, 49.1; HRMS (ES) calcd for C16H19N2O5 319.1294, found 319.1288.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:5]=1[O:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][N:8]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CN(C)C=O>[Cl:3][C:4]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:5]=1[O:6][C:7]1[N:12]=[C:11]([O:13][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:10]=[CH:9][N:8]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nccc(O)n3)c(Cl)cc2F)c1=O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccnc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
30 mg of sodium hydride was added to a mixture of 0.3 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-pyrimidine, 127 mg of methyl bromoacetate and N,N-dimethylformamide at 0° C., then, the mixture was stirred at room temperature. The solution was poured into a mixture of ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.2 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxypyrimidine [present compound 1-7].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]#[N:13].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>O>[CH3:11][N:10]1[C:6]([C:2]2[O:1][C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=2)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]1
Reactant: Cn1ncc(C#N)c1-c1ccco1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1ncc(C#N)c1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Yield: 80 %

Procedure:
Add 1.0 g of 5-(2-furyl)-1-methylpyrazole-4-carbonitrile to 4.1 ml of concentrated sulfuric acid at from -10° C to -12° C and, at the same temperature, slowly add a nitrating mixture (0.91 ml of concentrated sulfuric acid and 0.45 ml of fuming nitric acid) dropwise to the resulting reaction mixture for 1 hour at this temperature, and then pour the prepared solution onto 20 g of ice and water. Crystallize the thus-prepared precipitate in an ice-bath to obtain an 80% yield of 1-methyl-5-(5-nitro-2-furyl)pyrazole-4-carbonitrile [m.p. 149.5° to 151.5° C].
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:4].[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[C:21]([NH:20][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:4]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Anhydrous citric acid (5 mmoles, 960 mg) and dicyclohexyl carbodiimide (10 mmoles, 2.06 g) were stirred in 30 ml anhydrous tetrahydrofuran for one hour. Dicyclohexylurea crystals formed during the ensuing dehydration reaction were removed by filtration, and the filtrate was dried in vacuo, yielding the dicitrate cyclic diester-containing solid residue.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][O:12][S:11]2=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH2:18]>C(Cl)Cl.C(#N)C>[C:1]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][O:12][S:11]2(=[O:18])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN2CCOS2=O)cc1
Reactant: O
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)c1ccc(CN2CCOS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 2-(4-tert-butylbenzylamino)-ethanol (1190 mg, 5.74 mmol) and triethylamine (3200 μl, 22.96 mmol) in DCM (15 ml) at −15° C. was added a solution of thionylchloride (544 PI, 7.46 mmol) in DCM (4 ml) over 10 min. The reaction mixture was stirred at −10° C. for 30 min, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography to give the desired compound (790 mg, 54%) as a white solid. To a mixture of 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2-oxide (790 mg, 3.12 mmol) in DCM (20 ml), acetonitrile (8 ml) and water (8 ml), at 0° C. was added NaIO4 (867 mg, 4.05 mmol) followed by RuO2 (2 mg). The reaction mixture was stirred at 0° C. for 2 h. Water was added and the phases were separated and the aqueous phase was extract with ethyl acetate. The organic layers were combined washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was then purified by flash column chromatography to give the desired product (640 mg, 76%) as an off white solid. MS (ISP) 287.0 (M+NH4)+.
Reaction SMILES: CC1(C)O[CH2:8][CH2:7][C@H:6]2N1[C:4](=[O:12])[C@@H:5]2[N+]#[C-].N(C(C)(C)C#N)=N[C:16](C)([CH3:19])[C:17]#N>C1C=CC=CC=1>[CH3:17][CH2:16][CH2:19][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:12]
Reactant: [C-]#[N+][C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCCCCCCC=O
Yield: 896.5 %

Procedure:
A mixture of (6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (150 mg), tribulyltinhydride (0.263 ml), and azobisisobutyronitrile (14 mg) in benzene (4.5 ml) was refluxed for 15 minutes. The resulting solution was chromatographed on silica gel (4.5 g) eluting with a mixture of benzene and acetone (15:1-6:1) to give the crude product (140 mg) as an oil, which was purified by silica gel (5 g) chromatography (eluate: a mixture of methylene chloride and ethyl acetate 30:1-5:1) to give (6R)-2,2-dimethyl-1-aza-3-oxabicycle[4.2.0]octan-8-one (98 mg) as an oil.
Reaction SMILES: [CH3:1][CH:2]([C:9]#[CH:10])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:11]([C:15]1([CH2:19]O)[CH2:18][O:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]12[CH2:16][O:17][C:6]([CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[C:9]#[CH:10])([O:8][CH2:19]1)[O:7][CH2:18]2)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#CC(C)CCCC(=O)O
Reactant: CC(C)(C)C1(CO)COC1
Product: C#CC(C)CCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-(4-methylhex-5-ynyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 5-methylhept-6-ynoic acid and 3-t-butyl-3-hydroxymethyl oxetane as described in Example I.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[CH2:10][C@@H:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C@@:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])([C:16]#[N:17])[C@H:7]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[F:33])C.[Li+].[OH-]>C1COCC1.O>[Cl:32][C:28]1[C:27]([F:33])=[C:26]([C@@H:7]2[C@:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[F:25])([C:16]#[N:17])[C@H:9]([CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:10][N:6]2[CH2:5][C:4]([OH:34])=[O:3])[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CN1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(CC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 102.4 %

Procedure:
To a mixture of rac [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid ethyl ester (14.7 mg, 0.0288 mmol, Example C1) in THF (1.8 mL) was added a solution of LiOH (Aldrich, 8.5 mg, 0.02 mmol) in water (1.2 mL) and the reaction mixture was stirred at rt for 22 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 4-5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (14.2 mg, 102%). HRMS (ES+) m/z Calcd for C24H24Cl2F2N2O2+H [(M+H)+]: 481.1256; Found: 481.1255.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][C:44]1=[O:48].OS([O-])(=O)=O.[Na+]>CCO>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C:21]2[CH:22]=[C:23]3[C:18]([C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][CH2:42][N:43]4[CH2:47][CH2:46][CH2:45][C:44]4=[O:48])=[O:34])[C:15](=[O:38])[N:14]3[CH2:13][CH2:12][NH:3][C:2]([C:10]3[C:5]([C:4]([NH:39][CH2:40][CH2:41][CH2:42][N:43]4[CH2:47][CH2:46][CH2:45][C:44]4=[O:48])=[O:11])=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:1])=[N:19][CH:20]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCCCN1CCCC1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCN1CCCC1=O)c1ccccc1C(=O)NCCn1c(=O)c(C(=O)NCCCN2CCCC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 1-(3-aminopropyl)-2-pyrrolidinone (0.0085 mL, 0.061 mmol) for 30 min. 150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional equivalent (0.0085 mL) of the amine, cooled to ambient temperature, and treated with 1N NaHSO4. The resulting suspension was filtered, washed with EtOH and the filtrate was concentrated in vacuo. The filtrate residue was purified by reversed phase HPLC. Pure fractions were combined and concentrated to afford the title compound as a pale yellow glass: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.74 (ddd, J=12.42, 6.11, 5.90 Hz, 2 H), 1.84-1.95 (m, 2 H), 1.99-2.12 (m, 4 H), 2.41 (td, J=8.14, 2.25 Hz, 4 H), 3.21-3.32 (m, 2 H), 3.35-3.50 (m, 10 H), 3.61-3.73 (m, 2 H), 4.07 (s, 2 H), 4.48 (t, J=6.74 Hz, 2 H), 6.91-7.01 (m, 2 H), 7.17-7.23 (m, 2 H), 7.47-7.62 (m, 4 H), 7.71 (dd, J=5.26, 3.44 Hz, 1 H), 7.77 (t, J=5.90 Hz, 1 H), 8.18 (s, 1 H), 8.49 (s, 1 H), 10.31 (t, J=5.76 Hz, 1 H); ES+ MS: 754 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[F:38][C:34]1[CH:33]=[C:32]([C:22]2([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH:29]3[C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]([CH3:1])[CH3:13])[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)C1NCC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.4 %

Procedure:
N,N'-carbonyldiimidazole (0.59 g) is added to a solution of (2-dimethylaminophenyl)acetic acid (0.65 g) in dry dichloromethane (20 cc) cooled to +4° C. The mixture is stirred for 90 minutes at 25° C. and a solution of 7,7-bis-(3-fluorophenyl)-4-perhydroisoindolone hydrochloride (1.3 g) and triethylamine (1.02 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 16 hours at 25° C. and washed with water (2×250 cc) and with saturated sodium chloride solution (250 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 2.3 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55/45) and collecting 15 cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is solidified using isopropyl ether to give (3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone (0.6 g), from which the hydrochloride is prepared by dissolving in ethyl acetate (1 cc) and adding a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone hydrochloride (0.48 g) is obtained in the form of a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:31])[CH2:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:30])[CH:12]=1.Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl.O>CN(C=O)C>[CH3:7][O:8][C:9](=[O:31])[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[CH:14]=[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:30])[CH:12]=1
Reactant: CN(C)CCCl
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(O)cc(CC(=O)OC)c2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc(OCCN(C)C)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
Potassium carbonate (0.46 g) was added to a solution of the product from step (i) (1.10 mmol) and 2-dimethylamino ethyl chloride hydrochloride (0.16 g) in DMF at RT. After 1 h no reaction was evident so the mixture was heated to 60° C. for 18 h. Water was added and the mixture extracted with ethyl acetate, washed (brine) and the organics dried (MgSO4) and concentrated to a green oil which was purified by flash column chromatography (eluent 1% triethylamine and 2% methanol in ethyl acetate) to give the subtitle compound as a coulourless oil (100 mg).