Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].C([SiH](CC)CC)C>ClCCl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:18]1[C:17]2[CH2:33][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:35](=[O:36])[C:16]=2[C:15]([OH:14])=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2.[C:47]([OH:49])([C:46]([F:51])([F:50])[F:45])=[O:48]
Reactant: O=C1c2c(c(-c3c(F)cccc3F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(c(-c3c(F)cccc3F)c3cccnc3c2O)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 283a (9 mg) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford 5-(2,6-difluoro-phenyl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 284, TFA salt, (3.2 mg) as a yellow solid: 1H NMR (CDCl3) δ 9.0 (d, 1H), 8.0 (d, 1H), 7.6 (m, 1H), 7.5 (dd, 1H), 7.2 (m, 2H), 7.1 (m, 4H), 4.7 (s, 2H), 4.2(s, 2H); MS: 421 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[N:5]=[C:4]([NH:13]C(=O)C)[CH:3]=1.[OH-].[K+].[CH3:19][CH2:20]O.O>>[C:20]1([CH3:19])[CH:4]=[CH:3][CH:2]=[CH:1][C:1]=1[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[N:5]=[C:4]([NH2:13])[CH:3]=1
Reactant: CCO
Reactant: CC(=O)Nc1cc(C)n(C2CCCCO2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccccc1-c1cc(N)nn1C1CCCCO1

Procedure:
Crude N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acetamide (28.86 mmol) was dissolved in EtOH/H2O (2:3, 100 mL) together with potassium hydroxide (11 g, 202 mmol) and was refluxed for 16 hrs. The reaction mixture was concentrated and then extracted with CHCl3. The combined organic layers were washed with brine and dried over Na2SO4. Solvent evaporation and purification by silica gel column chromatography (PE-EtOAc, 7:3 to 3:7) gave 5-tolyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (2.99 g regioisomer A and 4.39 g regioisomer B, 99% over 4 steps).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([N+:21]([O-])=O)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCCC1.[Pd]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH2:21])[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cc([N+](=O)[O-])c3nnc(C)n32)n1Cc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(cc(N)c3nnc(C)n32)n1Cc1ccccc1

Procedure:
A degassed suspension of 6-benzyl-1,7-dimethyl-4-nitro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.20 g, 0.62 mmol, from Step 2) in methanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenated over Palladium (10% on carbon (Degussa type, Aldrich), 0.066 g, 0.062 mmol) under 1 atm H2 overnight. The reaction mixture was filtered, and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 7% MeOH/DCM (0.7% NH4OH). The product thus obtained (190 mg) was triturated in 2.5 mL MTBE and 0.25 mL DCM. The solid title product of step 3 was isolated by filtration and dried at 40° C. under vacuum overnight. Yield: (0.13 g, 69%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:37]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]3[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][CH2:7]3)[CH:12]=2)=[O:29])=[CH:21][C:22]=1[O:27][CH3:28])(=[O:39])[CH3:38]
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
N-[3-(4-tert-Butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide (100 mg) obtained in Example 20, triethylamine (94 mg) and 4-dimethylaminopyridine (5 mg) are dissolved in methylene chloride (5 ml), and thereto is added dropwise acetyl chloride (40 mg) under ice-cooling. The mixture is stirred at 25° C. for 18 hours, and the reaction solution is washed with water. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[CH2:11][CH2:10]1.O.NN.O>C(O)C>[NH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:13]1
Reactant: COc1ccccc1N1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccccc1N1CCN(CCN)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a stirred solution of 1-(2-methoxyphenyl)-4-[(2-phthalimido)-ethyl] piperazine (23.4 mmol) in 160 mL of ethanol were added hydrazine hydrate (31 mL) and water (40 mL) The mixture was stirred at room temperature for 18 hours. The volatiles were evaporated. The residue was partitioned between ethyl acetate and saturated potassium carbonate solution. The organic layer was washed with brine and water, dried over magnesium sulfate, filtered and concentrated to give 4-[(2-amino)ethyl]-1-(2-methoxyphenyl)piperazine (5.45 g, 99%).
Reaction SMILES: CS[C:3](=[N:12][C:13]#[N:14])[NH:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:11])[CH:10]=1.[C:15]1([S:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOCC>N1C=CC=CC=1>[Br:11][C:9]1[CH:10]=[C:5]([NH:4][C:3]([NH:12][C:13]#[N:14])=[N:24][CH2:23][CH2:22][S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[N:7][CH:8]=1
Reactant: NCCSc1ccccc1
Reactant: CSC(=NC#N)Nc1cncc(Br)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#CNC(=NCCSc1ccccc1)Nc1cncc(Br)c1

Procedure:
S-Methyl N-(5-bromo-3-pyridyl)-N'-cyanoisothiourea (650 mg) and 2-phenylthioethylamine (740 mg) in pyridine (0.5 ml) were heated to 50° C. for 5 hours. To the resulting clear solution was added ether (10 ml), and the desired pure compound was collected by filtration and washed with ether.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.CN(C=O)C.O[NH:24][C:25](=[NH:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([O:6]/[N:24]=[C:25](\[NH2:27])/[CH3:26])=[O:5]
Reactant: CC(=N)NO
Reactant: O=C(O)c1c(F)cccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C/C(N)=N/OC(=O)c1c(F)cccc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
To a heterogeneous mixture of 2-fluoro-6-iodobenzoic acid (1.51 g, 5.66 mmol) at 0° C. in DCM (28 mL) was added oxalyl chloride (0.635 mL, 7.36 mmol) followed by DMF (0.15 mL). Gas evolution commenced immediately and after 5 min the ice bath was removed. When gas evolution had ceased and the mixture was homogeneous an aliquot was removed and quenched with MeOH. Formation of the methyl ester was confirmed by HPLC and the mixture was concentrated in vacuo. The viscous liquid was dissolved in fresh DCM (28 mL) and treated with solid N-hydroxyacetamidine (503 mg, 6.79 mmol) in several portions followed by TEA (1.2 mL, 8.49 mmol) at 0° C. After stirring for 14 h at ambient temperature the mixture was washed with saturated aqueous NaHCO3 solution. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 100% EtOAc/Hex) afforded the desired product as a colorless oil (1.57 g, 86%). MS (ESI) mass calculated for C9H8FIN2O2, 321.96; m/z found, 323.0. 1H NMR (500 MHz, CDCl3): 7.70-7.65 (m, 1H), 7.15-7.11 (m, 2H), 4.87 (br s, 2H), 2.06 (s, 3H).
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:20][CH2:19][C@@H:18]([O:21][Si](C(C)(C)C)(C)C)[C@H:10]1[C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:8])(C)(C)C.[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:45]([NH:47][C@@H:48]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C@H:49]([OH:53])C(O)=O)=[O:46])[CH2:41][C:42](=[O:44])[NH2:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1.CO>[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:45]([NH:47][C@@H:48]([CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C@H:49]([OH:53])[C:7]([N:9]1[CH2:20][CH2:19][C@@H:18]([OH:21])[C@H:10]1[C:11]([NH:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:8])=[O:46])[CH2:41][C:42](=[O:44])[NH2:43])=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)[C@@H]1[C@H](O)CCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
1.5 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 50 mg (0.13 mmol) of (3R)-1-t-butoxycarbonyl-N-t-butyl-3-t-butyldimethylsilyloxy-L-prolinamide (prepared as described in Preparation 12) in 0.5 ml of methanol, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with benzene. The excess hydrogen chloride was then removed by distillation as an azeotrope with the benzene. The resulting residue was dried in vacuo for 2 hours and the whole of the resulting (3E)-N-t-butyl-3-t-butyldimethylsilyloxy-L-prolinamide hydrochloride was reacted with 55 mg (0.13 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) following a procedure similar to that described in Example 1, to obtain 33 mg of the title compound as a white powder, melting at 109°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[N+:17]([O-])=O)=[CH:5][CH:4]=1.Cl[Sn]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[NH2:17])=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: COc1ccc(Sc2ccc(C)cc2N)cc1

Procedure:
The product from Example 50a was reduced with SnCl2 following the procedure from Example 1f giving the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:20])[CH3:19].Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:22][C:3]1([NH:2][C:24]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:19])[CH3:20]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)Nc1ncc(C(F)(F)F)cn1

Procedure:
A solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (Intermediate 27; 2.0 g, 6.01 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 1.21 g, 6.61 mmol) and DIPEA (3.15 ml, 18.02 mmol) in dry DMSO (15 ml) was subjected to microwave irradiation at 140° C. for 4 hours. The reaction was partitioned between ethyl acetate and brine. The aqueous layer was extracted further with ethyl acetate (2×100 ml). The combined organics were washed with brine (3×125 ml), dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-30% diethyl ether/petrol) to afford the title compound as a single trans-enantiomer.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:14])[CH2:9][CH2:8]3.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:22]=1[C:23]([NH:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:14])[CH2:9][CH2:8]3)=[O:24]
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CC1CCC2O1
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Product: O=C(Nc1sc2c(c1C(=O)c1ccco1)CC1CCC2O1)c1c(F)cccc1C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 15A and commercially available 2-fluoro-6-trifluoromethyl-benzoyl chloride according to the procedure described for Example 1C. 1H NMR (CDCl3, 300 MHz) δ 1.63-1.71 (m, 1H), 2.13-2.17 m, 4H), 3.26 (dd, J=16.3, 5.1 Hz, 1H), 4.71 (dd, J=4.9, 4.9 Hz, 1H), 5.14-5.15 (m, 1H), 6.58-6.60 (m, 1H), 7.16-7.17 (m, 1H), 7.35-7.41 (m, 1H), 7.55-7.64 (m, 3H), 11.13 (br s, 1H); MS (ESI+) m/z 466 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:21]1(=[O:27])[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:22]2[C:21](=[O:27])[CH2:26][CH2:25][CH2:24][CH:23]=2)=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][N:9]=1
Reactant: O=Cc1cc(-c2ccccc2)cnc1Cl
Reactant: O=C1C=CCCC1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: O=C1CCCC=C1C(O)c1cc(-c2ccccc2)cnc1Cl
Yield: 95 %

Procedure:
The clear solution of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.25 g).
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])[C:6](=[O:20])[N:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H][H]>CO.[Pd]>[OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=[O:11])[C:6](=[O:20])[N:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Agent: [Pd]
Solvent: CO
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Yield: 96 %

Procedure:
To a stirring solution of benzyl 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (300 mg, 789 μmol) in MeOH (10 mL) was purged with argon for 10 min. To this solution was added Pd/C (40 mg), and the mixture was stirred for 3h under balloon of hydrogen. Reaction was monitored by LCMS. The reaction mixture was filtered through a bed of celite and concentrated under reduced pressure to give the title compound (220 mg, 96.1% yield) as an off-white solid. MS (ESI pos. ion) m/z: 291 (MH+). Calc'd exact mass for C15H18N2O4 290.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[Cl:13].[NH2:14][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:16][C:17]([OH:19])=[O:18]>C(O)(=O)C>[Cl:13][C:12]1[CH:11]=[C:5]2[C:6](=[O:8])[N:14]([CH:15]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:10])[C:4]2=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)cc1
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of 4.5-dichlorophthalic anhydride (0.91, 4.19 mmol) and 3-amino-3-(4'-methoxyphenyl) propionic acid in 10 mL acetic acid was stirred under nitrogen for 6 hours. The reaction was cooled and removed some of the solvent. The slurry was filtered and the solid was dried to afford 1.20 g (61%) of 3-(4',5'-dichlorophthalimido)-3-(4'-methoxyphenyl)propionic acid as a white powder. mp 182°-185° C.; 1H NMR (DMSO-d6, 250 MHz) δ 8.19 (s, 2H), 7.34 (d, 2 H, J=8.7), 6.90 (d, 2H, J=8.7), 5.61 (t, 1H, J=7.8), 3.72 (s, 3H), 3.50-3.20 (m, 2H). 13C NMR (DMSO-d6) δ 171.6, 165.8, 158.8, 137.6, 131.0, 130.4, 128.4, 125.4, 113.9, 55.1, 50.0, 35.8. Anal. Calcd for C18H14N2O7. Theoretical: pending
Reaction SMILES: Br[C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:22]1([CH3:53])[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([Sn](CCCC)(CCCC)CCCC)[CH:37]=3)[CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:12][C:11]1[C:2]([C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[CH2:39][N:31]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:53])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:32]3)=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(Br)ccc2c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CN(S(=O)(=O)c1ccc(C)cc1)C2
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(-c3ccc4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)ccc2c1=O
Yield: 79 %

Procedure:
In the same manner as in Example 1, 0.45 g of ethyl 7-bromo-8-chloro-1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylate was reacted with 1.02 g of 2-(p-toluenesulfonyl)-5-tributylstannylisoindoline to obtain 0.54 g of ethyl 8-chloro-1-cyclopropyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[N:3]1.[Li]CCCC.CN([CH:21]=[O:22])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][N:2]1[C:6]([CH:21]=[O:22])=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[N:3]1
Reactant: CN(C)C=O
Reactant: Cn1cc(-c2ccccc2)nn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccc2)c1C=O
Temperature: -75 °C
Reaction time: 0.67 h
Yield: 67.3 %

Procedure:
To a solution of 1-methyl-4-phenyl-1H-[1,2,3]triazole (165 mg, 1.04 mmol) in THF (5.2 mL) was added n-BuLi (1.6 M in hexane, 777 μL, 1.24 mmol) dropwise at −75° C. under Argon. The resulted orange solution was stirred at −75° C. for 40 min, then DMF (104 μL, 1.35 mmol) was added dropwise at −75° C. and the reaction mixture was allowed to warm up to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (131 mg, 68%) as a white solid. MS: m/e=187.0 [M]+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[C:20]([CH3:22])[N:19]=[C:18](Cl)[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>[Pd].CN(C=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][N:19]=[C:20]([CH3:22])[CH:21]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3cc(C)nc(Cl)c3)nc(=O)c1-2
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccnc(C)c3)nc(=O)c1-2
Temperature: 60 °C
Reaction time: 6.5 h
Yield: 82.5 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(2-chloro-6-methyl- 4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one (1.3 g, 3.6 mmol), DMF (75 ml), triethylamine (1.0 ml, 7.2 mmol) and 10% palladium on carbon (0.13 g) was placed on a parr hydrogenator at 50 psi and heated via an external heating jacket to 60° C. for 2 hours, then at 70° C. for 6.5 hours. Additional catalyst was added and the mixture was placed back on the parr hydrogenator for 4 hours at 70° C. The mixture was filtered through a celite plug while hot, and the filtrate was concentrated in vacuo. Water was added to the residue and a white solid was collected by filtration to afford 0.96 g (82%) of 1-cyclopentyl-3-ethyl-6-(2-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one as a white powder, m.p. 258°-259° C. when recrystallized from DMF/acetonitrile.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[C:12]23[C@:28]([CH3:33])([CH2:29][CH2:30][C:31](=[O:32])[CH:11]12)[C@@H:27]1[C@H:15]([C@H:16]2[C@:24]([CH3:34])([CH2:25][CH2:26]1)[C@@H:19]([C@H:20]([CH3:23])[CH2:21][OH:22])[CH2:18][CH2:17]2)[CH2:14][CH2:13]3.[N-:35]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>CS(C)=O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C:11]1[C:31](=[O:32])[CH2:30][CH2:29][C@@:28]2([CH3:33])[C:12]=1[CH:13]=[CH:14][C@@H:15]1[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:34])[C@H:16]1[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:23])[CH2:21][OH:22]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Agent: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a vigorously stirred solution of (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one benzoate (1.0 g, 2.22 mmole) in dimethyl sulfoxide (35 mL), heated to 60° C., there was added sodium azide (2.7 g) and the concentrated sulfuric acid (0.2 mL). The mixture was quickly brought to a temperature of 100° C. and held at that temperature for 1 hour. The cooled mixture was then poured onto cold water (250 mL). The resulting mixture was extracted with ether (300 mL) and the ether solution was washed with brine, dried over magnesium sulfate and filtrate and the filtrate was concentrated to give a yellow solid which was purified by chromatography to give (20S)-4-amino-21-hydroxy-20-methylpregna-4,6-dien-3-one benzoate (0.8 g, 80.1%) melting at 163°-167° C. with decomposition. IR 3470, 3366, 1718, 1682 (m), 1656, 1608 (m), 1586 (m), 1567 (m), 1274, 1268, 718 cm-1 ; MS (CI) 448 (100%, M+1), 326 (35%, M+1 - PhCOOH); 1H NMR (CDCl3) δ 0.82 (3H, s, C18 -Me), 1.07 (s, C19 -Me), 1.15 (d, C22 -Me), 3.71 (2H, v br, NH2)4.07 (1H, dd, 1/2 C21 -CH2), 4.35 (1H, dd, 1/2 C21 -CH2), 5.98 (1H dd), 6.30 (1H dd), 7.35 (2H, t), 7.57 (1H, t), 8.04 (2H, dd).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:26][CH3:27])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:26][CH3:27])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[C:32](=[O:33])[CH2:31][O:30][CH3:29])[CH:11]=1)[CH3:2]
Reactant: COCC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)cnc1OC
Product: CCOC(=O)Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)COC)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-6-methoxy-pyridin-3-yl]-acetic acid ethyl ester and methoxyacetyl chloride were reacted as described in Example 5, Step 4 to provide [5-(2-{[N-ethyl-N-(2-methoxy-acetyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-6-methoxy-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 3, Step 7.