Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CC(O)C.[CH2:32]([CH:34]1[O:36][CH2:35]1)[Cl:33]>O>[Cl:33][CH2:32][CH:34]([OH:36])[CH2:35][NH:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: ClCC1CO1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NCC(O)CCl)no2)cc1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To a flask containing (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (84 mg, 0.23 mmol) was added 2 mL of IPA. The cloudy, white mixture was cooled to 0° C. and epichlorohydrin (20.7 μL, 0.26 mmol) was added and the reaction mixture stirred at room temperature overnight. The IPA was removed by concentration in vacuo and water (500 μl) and aliquots of epichlorohydrin (20.7 μL, 0.26 mmol) were added every hour (4 total) at room temperature until conversion was complete. The reaction mixture was concentrated, dissolved in DCM and purified by chromatography (MeOH/DCM) to provide 19.3 mg (18%) of 5-(3-((1R)-1-(3-chloro-2-hydroxypropylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile INT-15 as a white solid. LCMS-ESI (m/z) calculated for C24H25ClN4O3: 452.9. found 453.1 [M+H]+, tR=2.62 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].C([Li])CCC.[S:25](=[O:27])=[O:26].[NH2:28]OS(O)(=O)=O.[ClH:34]>>[ClH:34].[CH2:1]([N:3]([CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[S:4]([C:7]1[S:8][C:9]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:10][CH:11]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: O=S=O
Reactant: CCN(CCN1CCOCC1)S(=O)(=O)c1cccs1
Reactant: NOS(=O)(=O)O
Agent: Cl
Agent: [Li]CCCC
Product: CCN(CCN1CCOCC1)S(=O)(=O)c1ccc(S(N)(=O)=O)s1

Procedure:
The product from Step A (2.2 g, 7.24 mmol) was treated sequentially with n-butyllithium, sulfurdioxide, hydroxylamine-O-sulfonic acid and ethanolic HCl in much the same way as described in Example 4 to furnish the desired product as a hygroscopic white solid: mp 80°-85° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O-:14])(=[O:13])[CH2:11][CH3:12].[Na+].C(OC(=O)CC)(=O)CC>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([CH3:12])[C:10]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCC(=O)[O-]
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Solvent: O
Product: CC(=Cc1ccc(O)cc1)C(=O)O
Reaction time: 40 h
Yield: 75.4 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (60 g), sodium propionate (104 g) and propionic anhydride (190 ml) was stirred at 135°-140° C. for 40 hours. After the mixture was allowed to cool, water (600 ml) was added thereto, and stirred under ice cooling for 2-3 hours. The precipitate was collected by filtration, and washed well with water. Sodium hydroxide (60 g) was completely dissolved in water (800 ml) with stirring under ice cooling, and thereto was added the above-mentioned precipitate, and the mixture was stirred at the same temperature for 30 minutes. The insoluble materials were filtered off, and the filtrate was acidified with 5N hydrochloric acid under ice cooling. The resulting precipitate was collected by filtration, washed well with water to give 4-hydroxy-α-methylcinnamic acid (66 g). mp. 204°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:31][CH2:32][Cl:33])(C1C=CC(C)=CC=1)(=O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH2:31][CH2:32][Cl:33])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: CCOC(=O)c1c[nH]c2cc(Cl)ccc2c1=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cn(CCCl)c2cc(Cl)ccc2c1=O
Temperature: 100 °C

Procedure:
To a mixture containing 23.4 g of ethyl 7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate and 6.9 g of 65% sodium hydride was added 90g of 2-tosyloxyethyl chloride. The resulting mixture was heated at 100° C for 4 hours. After concentration to dryness, the residue was extracted with chloroform. The extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was removed by the distillation to leave a solid which was recrystallized from ethanol to give ethyl 7-chloro-1-(2-chloroethyl)-1,4-dihydro-4-oxo-quinoline3-carboxylate, m.p. 207.5°-209.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]=O)=[C:11]([CH3:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][C:37]=1[NH2:38])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=1)=[O:25].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[NH:38][C:37]3[CH:36]=[CH:35][C:23]([C:24](=[O:25])[NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=4)=[CH:22][C:21]=3[N:20]=2)=[C:11]([CH3:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)cc(C)c1C=O
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2ccc3[nH]c(-c4c(C)cc(CCC(=O)OC(C)(C)C)cc4C)nc3c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(4-formyl-3,5-dimethylphenyl)-propionic acid tert-butyl ester (200 mg) and 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide (Example 5-1, step 6) (194 mg) in DMSO (10 mL) was added Yb(OTf)3 (93 mg). The solution was stirred at room temperature for 18 h then the mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography (amino-column) using hexanes/ethyl acetate (1:4) and gave 3-{4-[5-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid tert-butyl ester as a red solid. MS (ESI)m/z 498 (M+H). 1H NMR (Acetone-d6, 400 MHz) δ 11.73 (s, 1H), 9.39 (s, 1H), 8.30 (s, 1H), 7.94 (t, 1H), 7.69 (m, 3H), 7.12 (s, 1H), 7.07 (s, 2H), 2.90 (t, 2H), 2.58 (t, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.16 (s, 6H), 1.45 (s, 9H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=C=O.[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([CH2:44][NH2:45])=[CH:43][C:38]=2[O:37][CH2:36]1>>[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([CH2:44][NH:45][C:24]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH2:12][N:8]3[C:6]([NH:27][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:7])=[O:26])=[CH:43][C:38]=2[O:37][CH2:36]1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: CCCCCN=C=O
Reactant: NCc1ccc2c(c1)OCO2
Product: CCCCCNC(=O)N1CC(=NOCc2ccc(OC)cc2)C[C@H]1C(=O)NCc1ccc2c(c1)OCO2

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and 1,3-benzodioxol-5-ylmethylamine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=511.4.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[NH2:19][NH2:20]>C(O)C>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]3[CH2:13][CH2:14][C:15](=[O:17])[NH:19][N:20]=3)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc2c(c1)NC(=O)CS2
Solvent: CCO
Product: O=C1CCC(c2ccc3c(c2)NC(=O)CS3)=NN1

Procedure:
4-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-6-yl)-4-oxobutyric acid (2.0 g) was suspended in 60 ml of ethanol and 1 ml of hydrazine added. The mixture was heated at reflux for three hours, then cooled slowly. Filtration gave 1.85 g of the title compound, mp 299°-302° C.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].CCN(CC)CC.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[CH3:15][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CN1CCCCC1)c1ccc([N+](=O)[O-])cc1
Yield: 105 %

Procedure:
A solution of 2.82 g (10.3 mmol) of 2-Bromo-N-methyl-N-(4-nitrophenyl)-acetamide and 2.08 g (20.6 mmol) of Et3N in 30 mL of CH2Cl2 at 0° C. under N2 is treated with 0.875 g (10.3 mmol) of piperidine for 5 min at 0° C. and refluxed for 1.25 h. The cooled reaction mixture is washed with H2O, treated with Darco, dried (MgSO4) and evaporated to give 3.00 g (100%) of brown oil. 1H NMR (DMSO-d6) δ 8.25 (d, 2H, J=6.9 Hz), 7.63 (d, 2H, J=6.9 Hz), 3.30 (s, 3H), 3.09 (s, 2H), 2.25 (s, 4H), 1.31 (m, 6H); MS (ESI) m/z 278.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([Cl:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of 4-chlorophenoxy acetic acid (9.32 g, 0.05 mol) in CH2Cl2 (150 mL) was added oxalyl chloride (32.5 mL, of 2M in CH2Cl2) and DMF (0.2 mL). The resulting mixture was stirred at rt overnight under Ar. The mixture was concentrated in vacuo to give 10.3 g (100%) of 56a as colorless oil. 1H NMR (60 MHz, CDCl3): δ 7.0-6.7 (m, 4H), 4.8 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23](F)[CH:22]=1)[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH2:17][F:18])([CH2:15][F:16])[CH3:14])[C@H:7]([CH3:19])[NH:6]1)[OH:4].[CH3:29][CH:30]([S-:32])[CH3:31].[Na+].[Cl-].[NH4+]>CN1CCCC1=O.CO>[NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([S:32][CH:30]([CH3:31])[CH3:29])[CH:22]=1)[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH2:17][F:18])([CH2:15][F:16])[CH3:14])[C@H:7]([CH3:19])[NH:6]1)[OH:4]
Reactant: C[C@@H]1N[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO[C@H]1OCC(C)(CF)CF
Reactant: CC(C)[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(C)Sc1cc(F)cc(C[C@H](N)[C@H](O)[C@H]2CO[C@@H](OCC(C)(CF)CF)[C@H](C)N2)c1
Temperature: 25 °C
Yield: 3.9 %

Procedure:
Heat a mixture of (1S,2S)-2-Amino-3-(3,5-difluorophenyl)-1-[(3R,5S,6R)-6-(2,2-di-(fluoromethyl)propoxy)-5-methylmorpholin-3-yl]-propan-1-ol (91 mg, 0.22 mol) and sodium 2-propanethiolate (328 mg, 3.34 mmol) in N-methylpyrrolidin-2-one (2.0 mL) at 90° C. in a sealed tube for 1 hour. Cool the reaction mixture to room temperature, dilute with methanol, add ammonium chloride (192 mg, 3.34 mmol), and mix well. Load mixture on SCX™ column and elute with 2.0 M ammonia in methanol to provide the desired compound (60 mg, 58%).
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4](=O)[O:3]1.[NH2:20][OH:21]>C(OCC)(=O)C>[OH:21][N:20]1[C:2](=[O:1])[C@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4]1=[O:3]
Reactant: CC(C)C(=O)O[C@@H]1C(=O)OC(=O)[C@H]1OC(=O)C(C)C
Reactant: NO
Solvent: CCOC(C)=O
Product: CC(C)C(=O)O[C@H]1C(=O)N(O)C(=O)[C@@H]1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of compound (30) (5.98 g, 22 mmol) in ethyl acetate (50 mL) at 0° C. was added a 50% aqueous solution of hydroxylamine (1.75 g, 26.4 mmol). The resulting mixture was stirred at room temperature for 3 h and washed successively with aqueous citric acid solution and brine, then dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was suspended in toluene and the reaction mixture heated under reflux for 5 h, with the azeotropically liberated water being collected in a Dean-Stark apparatus. Toluene was removed in vacuo to afford the title compound (28) (6.3 g, quantitative yield). 1H-NMR (400 MHz, CDCl3): δ 1.22 (d, J=6.8 Hz, 12H), 2.69 (hept, J=6.8 Hz, 2H), 5.48 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>C(OCC)C>[ClH:10].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[O:16])=[CH:13][CH:12]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Product: Cl
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13 G. of N-(2-aminoethyl)-morpholine are added dropwise to a solution of 17.5 g. of p-chlorobenzoyl chloride in 100 ml. of diethyl ether, with stirring and cooling with ice-water. After complete addition, the mixture is stirred for 2 hours at room temperature. The crystalline product is removed by filtration and washed with diethyl ether. 9.1 G. of p-chloro-N-(2-morpholinoethyl)-benzamide hydrochloride, melting point 207° C. to 208° C., are obtained after recrystallization from isopropanol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:23])[CH:21]=[CH2:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(Nc2ncnc3cc(N)ccc23)c1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2c(Nc3cccc(C)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.3 %

Procedure:
To a stirred solution of 7-amino-4-[(3-methylphenyl)amino]quinazoline (123 mg, 0.49 mmol), acrylic acid (0.04 mL, 0.58 mmol), triethylamine (0.15 mL, 1.1 mmol) in DMF (1.5 mL) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123 mg, 0.64 mmol). The resulting light yellow mixture was stirred at 25° C. for 20 hours and quenched with water. The solid was collected and purified by sonication with a mixture of CH2Cl2/EtOAc/MeOH to give the desired product as a yellow solid (75 mg, 49%), mp 269.7-270° C.
Reaction SMILES: [NH2:1][C:2](=[O:30])[C:3]([C:5]1[C:13]2[C:8](=[C:9]3[CH2:21][CH2:20][CH2:19][C:10]3=[CH:11][C:12]=2[O:14][CH2:15][C:16]([OH:18])=O)[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1[CH3:29])=[O:4].C(N(C(C)C)CC)(C)C.[C:40]1([S:46]([NH2:49])(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.CN(C)CCCN=C=NCC.Cl>C(Cl)Cl.C(OCC)(=O)C>[C:40]1([S:46]([NH:49][C:16](=[O:18])[CH2:15][O:14][C:12]2[CH:11]=[C:10]3[C:9]([CH2:21][CH2:20][CH2:19]3)=[C:8]3[C:13]=2[C:5]([C:3](=[O:4])[C:2]([NH2:1])=[O:30])=[C:6]([CH3:29])[N:7]3[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1)CCC3
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)NS(=O)(=O)c3ccccc3)cc3c(c2n1Cc1ccccc1)CCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.2 %

Procedure:
To a solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-benzyl-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid (83 mg, 0.20 mmol) in methylene chloride (3 mL) was added diisopropylethylamine (0.1 mL, 0.6 mmol), 4-N,N-dimethylaminopyridine (24 mg, 0.20 mmol), benzenesulfonamide (31 mg, 0.20 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.37 mmol). The mixture was stirred at room temperature for 18 h. Additional portions of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 mg), diisopropylethylamine (51 μL), and benzenesulfonamide (16 mg) were added and the resulting mixture stirred for 5 h. The mixture was poured into 1 N hydrochloric acid and extracted three times with methylene chloride. The combined methylene chloride extracts were washed once with water, once with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 7% methanol/93% chloroform) of the residue provided a solid that was slurried in hot ethyl acetate. Collection of the resulting solid via vacuum filtration provided 10 mg (9%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ 10.95 (s, 1H), 7.91 (d, J=7.7 Hz, 2H), 7.55 (t, J=7.4 Hz, 1H), 7.38 (t, J=7.7 Hz, 2H), 7.20-7.35 (m, 4H), 6.91 (d, J=7.0 Hz, 2H), 6.21 (s, 1H), 5.84 (bs, 1H), 5.48 (s, 2H), 4.55 (s, 2H), 2.98 (t, J=7.3 Hz, 2H), 2.71 (t, J=7.7 Hz, 2H), 2.48 (s, 3H), 2.01 (quintet, J=7.7 Hz, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:6]([Li])CCC.[CH3:11][C:12]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>C1COCC1>[CH3:11][C:12]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]1([C:3]1[N:2]([CH3:6])[N:1]=[CH:5][CH:4]=1)[OH:17]
Reactant: [Li]CCCC
Reactant: CC1(C)CCCC1=O
Reactant: c1cn[nH]c1
Solvent: C1CCOC1
Product: Cn1nccc1C1(O)CCCC1(C)C
Yield: 7.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 8a by using pyrazole (3.70 g, 45.1 mmol), n-butyl lithium (2.69 M solution in hexane; 17 mL, 45.7 mmol), 2,2-dimethylcyclopentanone (5.00 g, 44.6 mmol) and THF (100 mL), to yield the title compound (630 mg, 7.3%) as a colorless solid.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[C:8]=2[F:12])[C:3]1=[O:14].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]([OH:29])=[O:28])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CC#N.CCOC(C)=O>[N:22]1([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]([O:29][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[C:8]=2[F:12])[C:3]1=[O:14])=[O:28]
Reactant: O=C1c2ccc(Br)c(F)c2CCC1Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)O[C@H]1CCc2c(ccc(Br)c2F)C1=O
Temperature: 55 °C
Reaction time: 15 h
Yield: 38 %

Procedure:
To a solution of 2,6-dibromo-5-fluoro-3,4-dihydronaphthalen-1(2H)-one in MeCN (30 mL) was added (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.12 g, 5.2 mmol) and triethyl amine (0.62 mL, 4.48 mmol) and the solution was heated to 55° C. After stirring for 15 h, the solution was cooled to rt, and diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 35% EtOAc/hexanes) to afford (2S)-2-(6-bromo-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate (648 mg, 38%).
Reaction SMILES: [CH3:1]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI.[C:14]([O:18][C:19]([NH:21][C:22]1[C:23]([F:48])=[CH:24][C:25]([F:47])=[C:26]([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:40])=[C:35]([F:39])[C:36]=3[CH3:38])[C:31](=[O:41])[C:30]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:29]2)[CH:27]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O.C(OCC)(=O)C>[C:14]([O:18][C:19]([N:21]([C:22]1[C:23]([F:48])=[CH:24][C:25]([F:47])=[C:26]([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:40])=[C:35]([F:39])[C:36]=3[CH3:38])[C:31](=[O:41])[C:30]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:29]2)[CH:27]=1)[CH3:1])=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(C)c(F)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cn(-c2cc(N(C)C(=O)OC(C)(C)C)c(F)cc2F)c2c(C)c(F)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (4 ml), potassium carbonate (0.6 g) and methyl iodide (0.6 g) were added to ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.0 g), and the mixture was stirred overnight at 60° C. Ethyl acetate and water were added to the reaction mixture to collect an organic layer. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Ethanol was added to the residue, and solids deposited were collected to obtain the title compound (410 mg) as a colorless powder.
Reaction SMILES: Cl.C(O[C:5]1[C:6]2[C:7](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])C.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25]>>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][C:5]1[C:6]2[C:7](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1cnc2nn(C)cc2c1OCC
Agent: Cl
Product: CCOC(=O)c1cnc2nn(C)cc2c1NCCCN(C)C

Procedure:
2.9 (0.01 mole) of 4-ethoxy-2-methyl-2H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester, hydrochloride from Example 2 and 10 ml. of (3-dimethylaminopropyl)amine are refluxed for 3 hours. The excess of amine is removed in vacuo and the residue is treated with 10 ml. of cold water. 2.3 g. of 4-[(3-dimethylaminopropyl)amino]-2-methyl-2H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester; m.p. 61°-63° (methanol/water); is removed by filtration.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.C(OCC)(=O)C>[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27][CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (18 mg, 0.45 mmol) in anhydrous tetrahydrofuran (1 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (142 mg, 0.40 mmol) in anhydrous tetrahydrofuran (1 ml) and stirred under a nitrogen atmosphere for 0.5 hours. Ethyl 2-bromopropionate (37 μl, 0.33 mmol) was added and the mixture was stirred for 2 days, being allowed to warm to room temperature over this time. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (99:1) to pentane:ethyl acetate (0:100) to afford the title compound as a colourless oil (90 mg).