Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11])(=[O:4])=[O:3].[CH3:15][NH2:16].O1CCCC1>ClCCl>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([NH:16][CH3:15])=[O:11])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1cc(S(N)(=O)=O)ccc1F
Reaction time: 16 h
Yield: 23 %

Procedure:
To a suspension of 5-(aminosulfonyl)-2-fluorobenzoic acid [prepared according to Chem. Pharm. Bull. 1995, 43(4), 582-7] (3.0g, 13.7mmol) in dichloromethane (100 mL) at room temperature under nitrogen was added 1-(3-dimethylaminopropyl)-3-ethylcarbodlimide hydrochloride (WSCDI) (2.89 g, 15.06 mmol) followed by a solution of methylamine in tetrahydrofuran (2 M, 8.21 mL, 16.42 mmol), dropwise and the reaction allowed to stir for 16 hours. The crude reaction mixture was then evaporated to dryness and the residue chromatographed on silica gel, eluting with dichloromethane:methanol:ammonia (84:14:2) as solvent to give the amide (732mg, 23%) as a white powder. 1H NMR (300 MHz, d4-MeOH): δ=2.97 (3 H, s), 7.40 (1 H, t), 8.05 (1 H, m), 8.29 (1 H, d). MS m/z 250 (MNH4)+
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCCCCCCCCCCC>C(O)(C)C>[CH:7]1[CH:6]=[CH:5][C:4](/[CH:3]=[CH:2]/[CH2:1][OH:10])=[CH:9][CH:8]=1
Reactant: O=CC=Cc1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: CC(C)O
Product: OC/C=C/c1ccccc1

Procedure:
In a three-necked flask provided with reflux condenser and magnetic stirrer, 0.5 g (3.8 mmol) of cinnamaldehyde (trans-3-phenyl-2-propanol) and 12 g of isopropyl alcohol (for a starting material/catalyst ratio=1:1) or 1.5 g (11.3 mmol) of cinnamaldehyde and 36 g of isopropyl alcohol (starting material/catalyst=3:1) were refluxed under argon with 0.5 g of catalyst and 1.5 g of dodecane (as GC standard). After the end of the reaction time, the reaction mixture was analyzed by gas chromatography and the yield was determined. The results are summarized in Table 2 below:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([F:28])=[C:12]([C@H:17]([NH:20][CH:21]([CH:25]([CH3:27])[CH3:26])[CH2:22][C:23]#[N:24])[CH2:18][CH3:19])[CH:13]=[CH:14][C:15]=2[Cl:16])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:30].C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([F:28])=[C:12]([C@H:17]([NH:20][C@@H:21]([CH:25]([CH3:27])[CH3:26])[CH2:22][C:23]([NH2:24])=[O:30])[CH2:18][CH3:19])[CH:13]=[CH:14][C:15]=2[Cl:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CC[C@@H](NC(CC#N)C(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@@H](N[C@H](CC(N)=O)C(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step 2 To a rapidly stirred solution of crude 3-{[(1R)-1-{3-[(6-aminopyridin-3-yl)carbonyl]-4-chloro-2-fluorophenyl}propyl]amino}-4-methylpentanenitrile (0.911 mmol) in toluene (2.91 mL) and water (0.145 mL) at 0° C. was added sulfuric acid (0.966 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was made neutral by the addition of saturated Na2CO3 solution followed by saturated NaHCO3 solution and was extracted into EtOAc (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by chiral preparative HPLC to give (3R)-3-{[(1R)-1-{3-[(6-aminopyridin-3-yl)carbonyl]-4-chloro-2-fluorophenyl}propyl]amino}-4-methylpentanamide which was converted to the HCl salt, 0.0656 g and (3S)-3-{[(1R)-1-{3-[(6-aminopyridin-3-yl)carbonyl]-4-chloro-2-fluorophenyl}propyl]-amino}-4-methylpentanamide which was also converted to the HCl salt, 0.0259 g.
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[C:18]1([CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.O>[C:18]1([CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=[CH:14][C:15]([OH:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC=CC=Cc1ccccc1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=CC=CC=Cc1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
Butyllithium (12.8 mL of 2.5 N solution) was added to 65 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (2.92 g) in 25 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of 5-phenyl-2,4-pentadienal (2.4 g) in 15 mL of anhydrous THF was added to the reaction at −65° C. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. To the reaction was added 30 mL of water, acidified with 5% hydrochloric acid (14 mL) to a pH of 4.7 and then added an additional 20 mL of water. The aqueous layer was extracted with 10 mL of ether twice and with 10 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 50 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 2.4 g of the desired 7-phenyl-2,4,6-heptatrienoic acid. 1H NMR (DMSO-d6, 300 MHz), δ(ppm) 7.52 (m, 2H), 7.33 (m, 4H), 7.06 (m, 1H), 6.86 (m, 2H), 6.58 (m, 1H), 5.95 (d, 1H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:25][CH2:26][O:27][CH3:28])=[N:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:28][O:27][CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([NH:6][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:8])=[O:9])=[CH:19][CH:18]=2)[CH:13]=[CH:14][N:15]=1
Reactant: COCCN1CCCC1c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3nccs3)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CCCC1c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(2,4-dimethoxybenzyl)-1-(1-(2-methoxyethyl)pyrrolidin-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.046 g, 0.080 mmol) was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was washed twice with methanol, then the product was liberated by flushing the column several times with a 2.0M ammonia/methanol solution. The product-containing solution was concentrated to afford 1-(1-(2-methoxyethyl)pyrrolidin-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm=8.79 (br. s., 1H), 8.53 (d, J=5.7 Hz, 1H), 8.46 (s, 1H), 8.00 (d, J=5.9 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.17 (d, J=4.2 Hz, 1H), 6.74 (d, J=4.3 Hz, 1H), 4.60 (br. s., 1H), 3.55 (br. s., 2H), 2.96 (s, 3H), 2.82 (br. s., 1H), 2.71 (br. s., 2H), 2.42 (br. s., 1H), 2.00 (d, J=11.6 Hz, 2H), 1.95 (d, J=12.8 Hz, 1H). m/z (ESI) 419.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:29]=1
Reactant: Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Reactant: O=Cc1cccnc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(NCc2cccnc2)c1

Procedure:
A solution of 1-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (prepared in Steps (a)-(d) of the procedure used for the synthesis of EXAMPLE I1, 70.2 mg, 0.205 mmol) and nicotinaldehyde (20 μL, 0.21 mmol) in DCM (1 mL) under N2 was treated with TFA (1 mL) and after 5 min was heated at reflux for 2 h. The cooled reaction mixture was then treated with Et3SiH (70 μL, 0.44 mmol) and the mixture re-heated to reflux for 19 h. After this time the solvents and excess reagents were removed by concentration in vacuo and the crude residue purified by column chromatography over silica gel eluting with 0.7-15% MeOH/DCM to provide the title compound; MS (ES+): m/z 435 [MH+]
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH2:27])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH:27][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([OH:1])[N:7]=3)=[O:10])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=C(O)c1cccc(O)n1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1cccc(O)n1
Yield: 21.8 %

Procedure:
Using the general method of Example 97 6-hydroxypicolinic acid (0.24 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.15 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-hydroxy-2-pyridinecarboxamide as a white powder, m.p. 258-260° C. Analysis: Calculated for C21H23N7O2+1/2 CH3CN: %C, 62.03; %H, 5.80; %N, 24.66; Found: %C, 61.87; %H, 5.70; %N, 24.60.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9]([C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=4)=[C:10]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[C:11]3=[O:28])=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:43])[CH3:42]
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a 10 mL round-bottomed flask, 6-(3-(piperazin-1-yl)propoxy)-3-(3,5-difluorophenyl)-2-(pyridin-3-yl)-1H-inden-1-one (40 mg, 0.09 mmol) obtained in Step 1 of Example 66 and CH2Cl2 (2 mL, 0.05M) were charged. Pyridine (0.01 mL, 1.2 eq) was added and then the mixture was cooled to 0° C. and treated with acetic anhydride (0.01 mL, 1.2 eq). After being stirred for 15 h, the mixture was diluted with CH2Cl2 and washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by being purified by silica gel column chromatography (CH2Cl2/MeOH=9:1) and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (25.9 mg, 59%).
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26](=[O:27])[NH:9][CH2:8][C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:10][CH2:11][N:12]([CH:16]([CH3:17])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH3:30]
Reactant: CC(C)N(CCC(CN)(c1ccccc1)c1ccccc1)C(C)C
Reactant: CCOC(N)=O
Product: CCOC(=O)NCC(CCN(C(C)C)C(C)C)(c1ccccc1)c1ccccc1

Procedure:
From 2,2-diphenyl-4-diisopropylamino-butyl-amine in analogy to 3a. The urethane was used in a crude state.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)CC(c2ccccc2)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(C(=O)CC(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[1-(3,3-Diphenyl-propionyl)-pyrrolidin-3-ylmethy-carbamic acid tert-butyl ester (1.04 g, 2.54 mmol) was dissolved in dry CH2Cl2 (15 ml) followed by addition of TFA (10 ml). The resulting solution was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure. The resulting residue was dissolved in water (15 ml) and pH of the solution was adjusted to 10. The water phase was extracted with CH2Cl2 (100 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product in almost quantitative yield
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N+:11]([O-:23])[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CCc2ccc[n+]([O-])c21
Temperature: 0 °C

Procedure:
To a mixture of 25.1 grams (0.103 mole) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 175 ml of dry CH2Cl2 at 0° C. under an argon atmosphere was added dropwise over 70 minutes a solution of 24.12 grams of 3-chloroperoxy-benzoic acid in 150 ml of CH2Cl2. After the addition the solution was stirred for 1/2 hour after which the ice bath was removed. After two days the reaction was poured into 1.0N aqueous NaOH and extracted with CH2Cl2. The organic portions were combined, washed once with water, dried over MgSO4, filtered and concentrated in vacuo. The resultant product was triturated with isopropyl ether and filtered to provide 25.8 grams (96%) yield of the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13]Br)=[N:5]1)(=[O:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)n1nc(CBr)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)n1nc(CN2CCN(c3ccc(F)cc3)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
1-Acetyl-3-bromomethyl-1H-indazole (160 mg, 0.63 mmol) in CH2Cl2 (5 mL) was treated with 1-(4-fluorophenyl)piperazine (228 mg, 1.26 mmol) and Hunig's base (102 mg, 0.79 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (10%→25% EtOAc in hexane) to give the title compound as a white solid. This was recrystallised from ether/hexane to give colourless crystals (184 mg, 83%); mp 119°-120° C. (from ether/hexane); 1H NMR (360 MHz, d6 -DMSO) δ8.31 (d, J=8.3 Hz, 1 H, indazole), 8.08 (d, J=8.3 Hz, 1H, indazole), 7.63 (t, J=8.3 Hz, 1H, indazole), 7.43 (t, J=8.3 Hz, 1H, indazole), 7.03 (m, 2H, Ph), 6.93 (m, 2H, Ph), 3.95 (s, 2H, Ar--CH2N), 3.08 (m, 4H, piperazine), 2.70 (s, 3H, Ac), 2.64 (m, 4H, piperazine); MS (CI+) m/e 353 M+H+); Anal. calcd for C20H21N4OF: C, 68.16; H, 6.01; N, 15.90. Found: C, 68.15;H, 5.85; N, 15.64.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][NH:7][CH2:6]2.[CH:13]([O-])=O.[Na+].C=O.O>C(O)=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][N:7]([CH3:13])[CH2:6]2
Reactant: Oc1cc2c(cc1O)CNC2
Reactant: O=C[O-]
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CN1Cc2cc(O)c(O)cc2C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
15.39 g (66 mmol) of 5,6-dihydroxyisoindoline hydrobromide and 4.48 g (66 mmol) of sodium formate were dissolved in 100 ml of a 50% formic acid aqueous solution, and then 5.17 ml (70 mmol) of 37% formalin was added thereto. The mixture was stirred at 80° C. for 4 hours. Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in 200 ml of water and subjected to active carbon treatment. The active carbon was filtered off, and the filtrate was stirred under cooling with ice, and adjusted to pH 8.0 with a saturated sodium hydrogen carbonate aqueous solution, and then it was stirred at the same temperature for about 30 minutes. The precipitates were collected, and washed with water to obtain yellowish green primary crystalline powder. This powder was combined with secondary crystalline powder obtained from the filtrate, and after an addition of 300 ml of water, stirred for 30 minutes. The insolubles was collected to obtain 7.87 g (yield: 72.3%) of the above identified compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:39](=[O:41])[CH3:40])=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)CC(Cc2ccc(N)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(C(=O)CC(Cc2ccc(NC(C)=O)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Temperature: 22 °C
Yield: 62.9 %

Procedure:
In an oven-dried round bottomed flask was added L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-aminophenyl)ethylamide (100 mg, 0.23 mmol), and tetrahydrofuran (5 mL). The solution was stirred at 22° C., and treated with pyridine (0.037 mL, 0.45 mmol, 2.0 eq) followed by acetyl chloride (0.024 mL, 0.34 mmol, 1.5 eq). The reaction mixture was allowed to stir for one hour. The solvent was removed in vacuo and the residue partitioned between EtOAc (50 mL) and sat. NaHCO3 (50 mL). The organic layer was washed with sat. aq. NaCl, dried (MgSO4) and concentrated to an oil. The oil was purified by flash chromatography to provide 70 mg of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-(N-acetyl)aminophenyl)ethylamide as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10](Br)[CH:11]=1)=[O:5])[CH3:2].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[CH:31][CH:32]=2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C1CCCCO1
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OC3CCCCO3)cc2)nc2c1c(C)nn2C1CCCCO1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To a mixture of 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (6.00 g), 4-(tetrahydro-2H-pyran-2-yloxy)-phenylboronic acid (4.34 g) and potassium carbonate (2.93 g) in DME/water (v/v=2/1, 200 mL) was added at r.t. under Ar-atmosphere palladium(0) bis(tri-tert-butylphosphine) (0.42 g) and the mixture was stirred at 85° C. for 90 min. To the mixture water was added and it was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to give 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (7.00 g, 92%). This material was dissolved in isopropanol (30 mL), and 1N sodium hydroxide solution (15 mL) was added. The solution was stirred overnight, then the mixture was contentrated in vacuo to about a third of its volume. The precipitated solid was isolated by filtration and dried in air giving the sodium salt of 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (6.2 g, 87%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1([CH:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH2:12][CH2:11][CH2:10]1)=[O:8].[BH4-].[Na+]>C1COCC1.CO>[OH:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]1([CH:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C(=O)c3ccccn3)CCC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C2(C(O)c3ccccn3)CCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of Example 265D (140 mg, 0.43 mmol) in THF (4 mL) and MeOH (4 mL) was added NaBH4 (60 mg, 2.5 mmol) and the solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution and the resulting mixture extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC to obtain the title compound (0.11 g, 76% yield) as a white solid. MS: m/z 333 (M+H); 1H NMR: (400 MHz, CDCl3): δ 8.57 (d, J=4.3 Hz, 1H), 7.67 (t, J=6.8 Hz, 1H), 7.31-7.23 (m, 2H), 4.73 (s, 1H), 4.55-4.43 (m, 1H), 3.56-3.26 (m, 2H), 3.13-2.79 (m, 2H), 2.28-2.07 (m, 3H), 2.05-1.85 (m, 2H), 1.75-1.70 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:33]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH:30][S:39]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)(=[O:41])=[O:40])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CC(C)CC(NS(=O)(=O)N1CCOCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 65 %

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-(2-amino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (397 mg, 0.90 mmol), morpholine-4-sulphonyl chloride (334 mg, 1.8 mmol, prepared by the method of von Geldem, et al., J. Med. Chem., 1996;39:968-981), N,N-diisopropylethyl-amine (246 mg, 1.9 mmol), and DMAP (25 mg) in benzene (5 mL) was heated under reflux for 3 hours, then concentrated in vacuo and the residue dissolved in ethyl acetate, and washed with saturated NaHCO3 solution, water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The amber oil thus obtained was purified via flash chromatography (silica gel, 35% EtOAc/Hexane) to give 346 mg (65%) of the title compound as a yellow foam, mp=54-57° C.