Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([C:36]([CH3:38])=[CH2:37])[C:33]([F:39])=[CH:32][C:31]=3[O:40]C)[C@H:14]2[CH3:42])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl-].[Li+].[OH-].[Na+]>CN(C=O)C>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([C:36]([CH3:38])=[CH2:37])[C:33]([F:39])=[CH:32][C:31]=3[OH:40])[C@H:14]2[CH3:42])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c(OC)cc1F
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c(O)cc1F
Temperature: 160 °C

Procedure:
To a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropenyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 300, 50 mg, 0.078 mmol) in DMF (450 μL) was added lithium chloride (13.4 mg, 0.315 mmol). The vial was sealed and the reaction was heated at 160° C. for 14 h. 10% NaOH (10 mL) was added and the resultant solution was extracted with ether (3×10 mL). The aqueous layer was acidified to pH˜3 with 3N HCl and was re-extracted with ether (3×25 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-hydroxy-5′-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one as a clear glass. LCMS=622.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.90 (s, 1 H), 7.76-7.70 (m, 4 H), 7.48-7.45 (m, 1 H), 7.11-7.07 (m, 1 H), 6.75 (d, J=11.7 Hz, 1 H), 5.71 (d, J=7.8 Hz, 1 H), 5.59-5.56 (m, 1 H), 5.25-5.21 (m, 2 H), 4.81 (d, J=15.4 Hz, 1 H), 4.04 (d, J=15.6 Hz, 1 H), 3.97-3.92 (m, 1 H), 2.13 (s, 3 H), 0.58 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:11]=[C:12]([C:14](Cl)=[O:15])[S:13][C:3]1=2.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:11]=[C:12]([C:14]([N:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)=[O:15])[S:13][C:3]1=2
Reactant: Cn1c2ccccc2c2cc(C(=O)Cl)sc21
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cc3c4ccccc4n(C)c3s2)CC1
Reaction time: 336 h
Yield: 64.7 %

Procedure:
Preparation as for (30) from (26) (0.96 g) and N-methylpiperazine (0.46 g), stirring for 14 days, rinse up on silica gel column using dichloromethane/methanol (9/1) as eluent. Precipitation as the oxalate salt gave (31) (0.78 g), m.p. 219.1°-219.5° C.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3].[CH3:17][N:18]1[C:23]([N:24]2CCCN(C3C=CC=CC=3[N+]([O-])=O)[CH2:26][CH2:25]2)=[CH:22][C:21](=[O:40])[N:20]([CH3:41])[C:19]1=[O:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH3:17][N:18]1[C:23]([NH:24][CH2:25][CH2:26][N:4]([CH2:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:2]([CH3:1])[CH3:3])=[CH:22][C:21](=[O:40])[N:20]([CH3:41])[C:19]1=[O:42]
Reactant: CC(C)NCCCc1ccc([N+](=O)[O-])cc1
Reactant: Cn1c(N2CCCN(c3ccccc3[N+](=O)[O-])CC2)cc(=O)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)N(CCCc1ccc([N+](=O)[O-])cc1)CCNc1cc(=O)n(C)c(=O)n1C
Yield: 178.1 %

Procedure:
N-(1-methylethyl)-3-(4-nitrophenyl)propylamine (0.6 g), 0.5 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6) and 50 mg of p-toluenesulfonic acid monohydrate was dissolved in 30 ml acetonitrile, and then the solvent was removed in vacuo. The resultant oil was allowed to react at 80° C. for 3 hours and subjected to silica gel column chromatograph (chloroform/methanol=40:1 (v/v)) for purification. Thus, 1.0 g of 1,3-dimethyl-6-{2-[N-(1-methylethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione was obtained.
Reaction SMILES: O[CH:2]([C:7]1[CH:8]=[C:9]([CH:19]2[CH2:21][CH:20]2[C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]=[C:29]3[CH:32]([CH3:34])[CH3:33])=[CH:24][CH:23]=2)[CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([C:17]#[N:18])[CH:13]=[CH:12]2)[CH2:3][CH:4]([CH3:6])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCCOCC)C>[CH:32]([C:29]1[C:30]2[C:25](=[CH:24][CH:23]=[C:22]([CH:20]3[CH2:21][CH:19]3[C:9]3[CH:10]=[C:11]4[C:16](=[C:7](/[CH:2]=[CH:3]/[CH:4]([CH3:6])[CH3:5])[CH:8]=3)[CH:15]=[C:14]([C:17]#[N:18])[CH:13]=[CH:12]4)[CH:31]=2)[CH2:26][CH2:27][N:28]=1)([CH3:34])[CH3:33]
Reactant: CC(C)CC(O)c1cc(C2CC2c2ccc3c(c2)C(C(C)C)=NCC3)cc2ccc(C#N)cc12
Agent: CCOCCOCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)/C=C/c1cc(C2CC2c2ccc3c(c2)C(C(C)C)=NCC3)cc2ccc(C#N)cc12
Temperature: 185 °C
Reaction time: 3 h

Procedure:
A solution of Example 8G (120 mg, 0.27 mmol) in 1,2 diethoxyethane was treated with para-toluenesulfonic acid (253 mg, 1.3 mmol) and 3 Å molecular sieves (500 mg), heated to 185° C., and stirred for 3 hours. The mixture was cooled to room temperature, quenched with saturated NaHCO3, and extracted with ethyl acetate. The combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][C:17]=3[Br:28])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[Br:28])=[CH:29][CH:30]=2)=[O:10])=[CH:31][CH:32]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reaction time: 3 h
Yield: 84.7 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (30 mg, 0.058 mmol) was diluted with dioxane (500 μL) followed by the addition of NaOH (0.093 ml, 0.46 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetic acid (24 mg, 85% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.70 (d, 2H), 7.60 (s, 1H), 7.22-7.32 (m, 3H), 7.19 (d, 2H), 7.05 (d, 1H), 6.90 (d, 2H), 3.62 (m, 4H), 2.90 (t, 2H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Reactant: NCc1ccccc1
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][Mg]Br)[CH:14]=[CH:15][CH:16]=1.COC1C=C(CCBr)C=CC=1.[Mg]>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:8])[CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cccc(CC[Mg]Br)c1
Agent: COc1cccc(CCBr)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(CCC(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzaldehyde (920 μl, 9 mmol) in dry THF (20 mL) was added slowly a solution of 2-(3-methoxyphenyl) ethylmagnesium bromide prepared from 2-(3-methoxyphenyl) ethyl bromide (2.1 g. 9.77 mmol) and magnesium (300 mg, 12 mmol). The mixture was stirred at room temperature for ½ hour then quenched with saturated NH4Cl. The mixture was then extracted into EtOAc, washed with H2O, dried (Na2SO4), filtered and concentrated in vacuo, then purified by silica gel chromatography (30% EtOAc/Hexane) to provide the desired product as a colorless viscous oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C)C=O>[OH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCCCCCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCO
Temperature: 100 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 45 g of 12-bromododecanol in 500 ml of dimethylformamide was added 75 g of potassium phthalimide and the mixture was stirred at 100° C. for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was dispersed with water. The crude crystal thus separated out was recovered by filtration and recrystallized from methanol to afford 54 g of the title compound as a crystal.
Reaction SMILES: [OH-].[Li+].[CH:3]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([CH3:16])[CH:7]=2)[CH2:5][CH2:4]1>O.C1COCC1.CO>[CH:3]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:16])[CH:7]=2)[CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C2CC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of lithium hydroxide (90 mg, 1.97 mmol) in H2O (1 mL) was added in one portion to a stirred solution of methyl 4-cyclopropyl-2-methylbenzoate (125 mg, 0.66 mmol) in THF (2 mL) and MeOH (2 mL). The mixture was stirred at room temperature for 30 min then at 50° C. for 2 hours. A further aliquot of lithium hydroxide (90 mg) in H2O (1 mL) and MeOH (1 mL) was added, and the mixture was stirred at 50° C. overnight. The organics were removed under vacuum and H2O (20 mL) was added. The mixture was adjusted to pH 4-5 by the use of 1N HCl (a precipitate emerges) and then extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and the filtrate concentrated under vacuum to give the product (110 mg, 95%) as a solid. 1H NMR (CDCl3; 400 MHz) δ 7.98 (1H, d), 6.96-6.92 (2H, m), 2.63 (3H, s), 1.94-1.87 (1H, m), 1.07-1.01 (2H, m), 0.80-0.76 (2H, m).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][C:15]=3[F:24])[N:6](S(C3C=CC(C)=CC=3)(=O)=O)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=3[F:24])[NH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(C2CC2)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3[nH]cc(C4CC4)c23)c(F)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
192 mg (0.40 mmol) of N-[4-({3-cyclopropyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]-pyridin-4-yl}oxy)-3-fluorophenyl]acetamide are dissolved in 7 ml of ethanol. 3.5 ml of 20% strength aqueous sodium hydroxide solution are added, and the reaction mixture is stirred at 90° C. overnight. The reaction mixture is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, and the solvent is removed under reduced pressure. The crude product is reacted without further purification.
Reaction SMILES: [CH:1]([S:4][CH2:5][CH2:6][N:7]([C:9]([O:11][C@@H:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=[O:10])[CH3:8])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[CH:1]([S:4][CH2:5][CH2:6][N:7]([C:9]([O:11][C@@H:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([OH:15])=[O:14])=[O:10])[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(C)SCCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)SCCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of benzyl 2(S)-[N-(2-isopropylthioethyl)-N-methylaminocarbonyloxy]-3-phenylpropionate (623 mg) in ethanol (10 ml) was added 1 N potassium hydroxide (3 ml) at ambient temperature, and the mixture was stirred at the same temperature for 1 hour. The solution was concentrated in vacuo, and the residue was partitioned between water (20 ml) and diethyl ether (20 ml). The aqueous layer was separated and acidified to pH 2 with 10% hydrochloric acid, and the product was extracted with chloroform (20 ml×2). The extract was washed with water (30 ml) and dried over magnesium sulfate. Evaporation of the solvent gave 2(S)-[N-(2-isopropylthioethyl)-N-methylaminocarbonyloxy]-3-phenylpropionic acid (485 mg).
Reaction SMILES: CCCCCC.[H-].[Na+].[F:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[C:12]([CH3:20])[CH:11]=1.[C:21](#[N:23])[CH3:22]>C(OCC)(=O)C.Cl.C1COCC1>[F:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=[O:16])[CH2:22][C:21]#[N:23])=[C:12]([CH3:20])[CH:11]=1
Reactant: COC(=O)c1ccc(F)cc1C
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(F)ccc1C(=O)CC#N
Temperature: 70 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a suspension of hexane-washed sodium hydride (60% oil dispersion, 995 mg, 24.9 mmol) was added dropwise a THF solution (20 mL) of methyl 4-fluoro-2-methylbenzoate (3.8 g, 22.6 mmol) and anhydrous acetonitrile (2.4 mL, 45.2 mmol). The mixture was stirred at 70° C. for 16 h, and then cooled to rt. The resulting mixture was diluted with ethyl acetate (20 mL) and 1 N HCl (10 mL) and the layers were partitioned. The organic phase was washed with water (3×20 mL) and brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure to afford 4.0 g of yellow oil, which was taken to the next step without further purification. ES-MS m/z 178.2 (MH+); HPLC RT (min) 2.22.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Cl[C:10]([C:12]([CH3:19])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])=[O:11]>>[I:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:10]([C:12]([CH3:19])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])=[O:11])=[N:3][CH:4]=1
Reactant: CC(=O)OCC(C)(C)C(=O)Cl
Reactant: Nc1ccc(I)cn1
Product: CC(=O)OCC(C)(C)C(=O)Nc1ccc(I)cn1

Procedure:
The title compound, a white solid, MS: m/e=363.2 (M+H+), can be prepared in accordance with the general method of example 39, step 1 from 2-amino-5-iodopyridine and acetic acid 2-chlorocarbonyl-2-methyl-propyl ester (example 40, step 2).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH:14]([O:21][C:22](=[O:40])[C@@H:23](NC(OC(C)(C)C)=O)[CH2:24]C2C=CC(O)=CC=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl.C(O)C>[C:8]1([CH:14]([O:21][C:22](=[O:40])[CH2:23][CH3:24])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
Triethylamine (4.0 g, 39 mmol) was added dropwise to a suspension of (S)-2-[[(1,1-dimethylethoxy)carbonyl]-amino] -3-(4-hydroxyphenyl)propanoic acid diphenylmethyl ester (17.0 g, 38 mmol) and N-phenyl-N-trifluorosulfonyl -1,1,1-trifluoromethyl sulfonamide (13.6 g, 38 mmol) in dichloromethane (170 mL) at 0° C. After 1 hour the reaction mixture was warmed to room temperature and washed with 1N sodium hydroxide (2×25 mL), saturated aqueous sodium bicarbonate (2×25 mL) and water (2×25 mL). The organic layer was dried (K2CO3), filtered and concentrated. Recrystallization of the solid from hexane gave (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[4-trifluoromethyl)sulfonyl]oxy]phenyl]propanoic acid diphenylmethyl ester (13.7 g, 24 mmol) in 62% yield, mp. 110°-112° C., [α]D -14.23° (0.12% in ethanol).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7](=O)[CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)N)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.CC(O)=O>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:31]2[C:28]3[C:27](=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:35][CH:36]=1
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 39 g methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate (Ketone 2) in a mixture of toluene (300 mL) and HOAc (150 mL) was added NaOAc (15 g) and 1-(4-methoxyphenyl)-1-(4-chlorobenzyl)-hydrazine hydrochloride (50 g). The reaction was stirred at r.t. for 3 days under argon in the dark. The mixture was poured onto H2O (1 L) and extracted with 3× EtOAc (500 mL). The EtOAc was washed with 3× H2O (500 mL) then once with NaHCO3 solution. The organic phase was dried (MgSO4), evaporated to dryness, and the residue crystallised from Et2O/hexane 2:1 to afford the title compound; m.p. 102°-103° C.
Reaction SMILES: [OH-].[K+].O1CCCC1.[O:8]=[C:9]([CH3:20])[CH2:10][C:11]([CH:17]1[CH2:19][CH2:18]1)([CH:14]1[CH2:16][CH2:15]1)[CH:12]=O.[Cl-].[Na+]>C(OCC)C>[CH:14]1([C:11]2([CH:17]3[CH2:19][CH2:18]3)[CH2:10][C:9](=[O:8])[CH:20]=[CH:12]2)[CH2:16][CH2:15]1
Reactant: CC(=O)CC(C=O)(C1CC1)C1CC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1C=CC(C2CC2)(C2CC2)C1
Yield: 91.6 %

Procedure:
To a mixture of 5% aqueous solution of potassium hydroxide (4.7 ml) and tetrahydrofuran (4.7 ml) was added a solution of 4-oxo-2,2-dicyclopropylpentanal (1.88 g) in diethyl ether (9.4 ml). The mixture was heated at 38° C. to 45° C. for 3 hours and cooled. The aqueous layer was saturated with sodium chloride. The mixture was extracted with diethyl ether and the extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by distillation under reduced pressure to give 4,4-dicyclopropyl-2-cyclopenten-1-one (1.55 g).
Reaction SMILES: N[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:24]>O>[F:24][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: F[B-](F)(F)F
Reactant: CN1Cc2c(N)ncn2-c2ccccc2C1=O
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CN1Cc2c(F)ncn2-c2ccccc2C1=O
Reaction time: 0.33 h

Procedure:
A solution of 5 g (22 mmol) of 3-amino-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 100 ml of hydrofluoboric acid (50 percent in water) is diazotized at 0° to 5° with a solution of 1.95 g (28 mmol) of sodium nitrite in 4 ml of water. The yellow solution is stirred in an ice-bath for 20 minutes, diluted with 85 ml of hydrofluoboric acid, poured into a quartz vessel and irradiated overnight with a UV-lamp. Subsequently, the mixture is extracted with chloroform. The chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on a silica gel column there is obtained 3-fluoro-4,5 -dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 171°-172°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)=[CH:8]2)=[O:4].CO.C1COCC1>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)cc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]c(-c3ccc(N)cc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
An oven dried 2L round bottom flask with magnetic stirbar under argon was charged with 2-(4-Nitro-phenyl)-1H-indole-5-carboxylic acid methyl ester (9.33 g, 31.52 mmol), methanol (600 mL), and THF (300 mL). The palladium catalyst (3.358, 10% wt, 3.152 mmol) was carefully added in portions then acetic acid (2 ml) was added. The mixture was evacuated then a balloon filled with H2 (g) was placed over the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was filtered through a pad of celite. The celite pad was washed with ethyl acetate. The filtrate was concentrated to about 250 ml then filtered through a plug of silica gel and eluted with 70% Ethyl acetate:30% Hexanes then with ethyl acetate. The filtrate was concentrated and slurried in about 70 ml boiling methanol. The crude product was then purified on silica gel using 7:3 ethylacetate:hexanes as eluant to give 4.5 g of the pure product. Yield (4.5 g, 53.7%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[CH2:19]([O:26]C1C=CC(O)=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].BrCCCCCCC(OCC)=O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[CH3:2]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CCCCCCOc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCCOc1ccc(OCc2ccccc2)cc1
Yield: 90 %

Procedure:
An alternative method for the synthesis of the title compound was carried out analogous to the preparation of 61.1 using 60.2 (0.45 g, 2.255 mmol), 18-crown-6 (1.056 g, 4 mmol), potassium carbonate (1.38 g, 10 mmol), and Br(CH2)6COOEt, (0.8 g, 3.37 mmol) in dry acetone (40 mL). Purification by flash column chromatography on silica gel (20% diethyl ether-hexane) gave 61.2/20.4 (1.08 g, 90% yield) as a white solid (m p 57-61° C.).