Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]([NH2:22])[C:14]=2[CH:13]=[CH:12][CH:11]=1.[NH:23]1[C:27]2[N:28]=[CH:29][CH:30]=[C:31]([C:32](O)=[O:33])[C:26]=2[CH:25]=[CH:24]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]([NH:22][C:32]([C:31]3[C:26]4[CH:25]=[CH:24][NH:23][C:27]=4[N:28]=[CH:29][CH:30]=3)=[O:33])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccnc2[nH]ccc12
Reactant: NC1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NC1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
In a 100 ml round-bottomed flask, a mixture of 51 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-pyrrolo[1,2-a]indol-9-ylamine obtained according to the preceding stage, 28 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (which can be obtained according to WO 2003/000688), 37 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) and 26 mg of 1-hydroxybenzotriazole (HOBt) in 5 ml of dimethylformamide is stirred for 4 hours under argon at ambient temperature. The reaction medium is evaporated to dryness under vacuum. The residue is triturated from 20 ml of water and then filtered. The solid is washed with a saturated solution of sodium bicarbonate and taken up in a mixture of dichloromethane and methanol, and the solution is evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and methanol (98/2 v/v). 47 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid [5-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-pyrrolo[1,2-a]indol-9-yl]amide are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: ClCCCCOCc1ccccc1
Product: O=C1CCN(CCCCOCc2ccccc2)CC1

Procedure:
1-(4-Benzyloxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-4-benzyloxybutane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:36][C@@H:23]5[O:24]C(C6C=CC(OC)=CC=6)[O:26][CH2:27][C@@H:22]5[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CC(O)=O>C1COCC1.O>[C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:36][C@H:23]([OH:24])[C@H:22]([CH2:27][OH:26])[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@H]6CCc7ccccc76)ncnc54)C[C@@H]3O2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Yield: 97.7 %

Procedure:
A solution of N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3.00 g, 5.90 mmol) in THF (11.6 mL), water (11.6 mL) and AcOH (34.9 mL, 614 mmol) was stirred at room temperature under an atmosphere of argon for 60 hours. The mixture was concentrated and the residue was purified via flash chromatography (0 to 10% MeOH/DCM) to afford the title compound (2.10 g, 98%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C(Cl)CCl.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (353 mg, 1.0 mmol), Hunig's base (0.35 ml, 2.0 mmol), EDC (231 mg, 1.2 mmol) and aza-HOBt (136 mg, 1.0 mmol) in dichloromethane (DCM) (10 ml) was added morpholine (0.131 ml, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. After this time, the mixture was washed with water (5 mL) and NaHCO3 solution (5 mL×3), and concentrated to provide the crude product which was purified by Combiflash automated silica gel chromatography (0-100% EtOAc in hex) to afford 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-[5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxobutanoate (244 mg, 0.58 mmol, 58% yield) as a white solid. MS: 422 ([M+H]+).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N+]=[N-].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[C:17]([N:9]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:10][C:11]([OH:13])=[O:12])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: O=C(O)CNCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
N-Benzylglycine hydrochloride (7.38 g, 36.6 mmol), tert-butyl azidoformate (10.7 mL, 73.2 mmol) and sodium bicarbonate (12.3 g) were reacted in 150 mL dioxane/H2O-1:1 (v/v) at 45° (24 hr) and then at room temperature (24 h). The reaction suspension was evaporated to dryness and the resulting white residue was dissolved in 200 mL glacial acetic acid/H2O--1:1(v/v) with cooling to 4°. Water (800 ml) was slowly added with rapid stirring and cooling. The resulting turbid solution was seeded with Boc-N-benzyl-glycine obtained from Method A and allowed to stand in an ice bath for 30 min. The resulting material was gathered by filtration, washed with water followed by petroleum ether (bp 30°-75°) and dried to give 8.34 g (86%) of crude product as a white solid. Recrystallization from dichloromethane petroleum ether (bp 30°-75°) gave 7.34 g (76%) of white, crystalline product identical to Boc-N-benzylglycine (Method A) by NMR and melting point (106°).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6]C=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17](Br)[CH:18]=[CH2:19].[CH3:21][N:22]([CH:24]=[O:25])C>>[CH2:17]([O:25][C:24]1[CH:2]=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:21][N:22]=1)[CH:18]=[CH2:19]
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: CN(C)C=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=CCOc1cc([N+](=O)[O-])ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of 2-hydroxy-3-nitropyridine (30.5 mmol) in DMF (20 ml), cesium carbonate (45.7 mmol) and allyl bromide (3.15 mL, 35.6 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours, then it was partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated to give the desired product (5.85 g, 94%). EI-MS m/z 205 (M+).
Reaction SMILES: C(OC(N[C:9]1[C:10]([CH3:21])=[C:11]([C:17](I)=[CH:18][CH:19]=1)[CH2:12][O:13][C:14](=[O:16])[CH3:15])=O)(C)(C)C.[CH2:22]=[C:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25].[C:29]([O-:32])(=[O:31])C.[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([O:13][CH2:12][C:11]1[C:17]([CH2:22][C:23]2[C:24](=[O:25])[O:26][CH2:27][CH:28]=2)=[CH:18][CH:19]=[C:9]([C:29]([O:32][C:10]([CH3:21])([CH3:11])[CH3:9])=[O:31])[C:10]=1[CH3:21])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCc1c(I)ccc(NC(=O)OC(C)(C)C)c1C
Reactant: C=C1CCOC1=O
Agent: [Pd+2]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(CC2=CCOC2=O)ccc(C(=O)OC(C)(C)C)c1C
Temperature: 80 °C
Yield: 54 %

Procedure:
Acetic acid 3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzyl ester (575 mg, 1.4 mmol) was dissolved in N,N-dimethylformamide (2.5 mL). α-Methylene-γ-butyrolactone (190 μL, 2.2 mmol) was added to the mixture followed by potassium acetate (420 mg, 4.3 mmol), and then palladium(II) acetate (16 mg, 0.07 mmol). Reaction mixture was heated at 80° C. for 26 hours. Mixture was cooled to room temperature and partitioned between ethyl acetate and aqueous sodium bicarbonate. Layers were separated. Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as off-white solid in 54% yield. MS m/e (M−H)−=374.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[N:7]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[C@H:6]([CH2:25][CH3:26])[C:5]1=[O:27])[CH:2]=[CH2:3].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[N:7]([C:15](=[O:24])[C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[C@H:6]([CH2:25][CH3:26])[C:5]1=[O:27])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(OC)cc2)c2cc(F)ccc21
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: C=CCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(O)cc2)c2cc(F)ccc21
Yield: 97 %

Procedure:
(3R)-1-Allyl-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 9) was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-1-allyl-3-ethyl-6-fluoro-4-(4-hydroxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (97%). [α]D25=−285° (c=0.0102 G/ML, CHCl3); MS (ESI) m/z 355 ([M+H]+); MS (ESI) m/z 353 ([M−H]−); HRMS: calcd for C20H19FN2O3, 354.1380; found (ESI_FT), 355.1449.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7](=[NH:9])[N:6]([CH2:10][CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:5]=2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])[CH3:17]>>[CH:1]1([C:4]2[S:8]/[C:7](=[N:9]\[C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[O:18][CH2:16][CH3:17])/[N:6]([CH2:10][CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CCOc1ccccc1C(=O)O
Reactant: N=c1sc(C2CC2)nn1CC1CCCO1
Product: CCOc1ccccc1C(=O)/N=c1\sc(C2CC2)nn1CC1CCCO1

Procedure:
The product from Example 2A and 2-ethoxybenzoic acid (Aldrich) were processed using the method described in Example 2B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.02 (m, 2H) 1.13-1.19 (m, 2H) 1.32 (t, J=7.02 Hz, 3 H) 1.65-1.73 (m, 1H) 1.79-1.90 (m, 2H) 1.92-2.00 (m, 1H) 2.30-2.37 (m, 1H) 3.64 (dd, J=13.73, 7.63 Hz, 1H) 3.77 (dd, J=14.34, 7.32 Hz, 1H) 4.07 (q, J=7.02 Hz, 2H) 4.21 (dd, J=13.12, 4.58 Hz, 1H) 4.32-4.39 (m, 1H) 4.44 (dd, J=13.43, 7.63 Hz, 1H) 6.98 (td, J=7.63, 0.92 Hz, 1H) 7.08 (d, J=7.93 Hz, 1H) 7.40-7.45 (m, 1H) 7.77 (dd, J=7.63, 1.83 Hz, 1H); MS (ESI+) m/z 374 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C@@H:7]([C:13]([N:15]2[C@@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])[CH2:8][CH2:9][CH2:10][CH:11]=O)=[CH:4][C:3]=1[CH3:26].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][C:29]=1[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([O:6][C:5]2[CH:24]=[CH:25][C:2]([F:1])=[C:3]([CH3:26])[CH:4]=2)[C:13]([N:15]2[C@@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])=[CH:30][C:29]=1[CH3:36]
Reactant: Cc1cc(CN)ccc1F
Reactant: Cc1cc(O[C@H](CCCC=O)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(CNCCCC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-5-(4-fluoro-3-methylphenoxy)-6-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-6-oxohexanal (70 mg, 0.19 mmol) in 3 mL DCE was added 4-Fluoro-3-methyl-benzylamine (32 mg, 0.23 mmol) followed by NaBH(OAc)3 (56 mg, 0.26 mmol) and AcOH (13.8 mg, 0.23 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture was extracted with more ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:7][C:8]([F:20])([F:19])[C:9]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:10][CH:11](O)[CH3:12].C([Li])CCC.C(Cl)(=O)C(C)=C>>[C:1]([O:6][CH:11]([CH3:12])[CH2:10][C:9]([C:8]([F:7])([F:19])[F:20])([OH:14])[C:15]([F:16])([F:18])[F:17])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(O)CC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)[O-]
Agent: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Product: C=C(C)C(=O)OC(C)CC(O)(C(F)(F)F)C(F)(F)F

Procedure:
The title compound was prepared in the same fashion as the above described methacrylate using 142 g (0.63 mol) of 1,1,1-trifluoro-2-trifluoromethyl-2,4-pentanediol, 793 mL (1.27 mol) of n-butyllithium (1.6M in hexane) and 73 g (0.69 mol) of methacryloyl chloride to yield, after distillation at 67° C. at 1.0 mm Hg, 142 g (76%) of the 2° methacrylate as a clear, colorless oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:5]([CH2:12][CH:13]=[CH2:14])=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.S(C1C=CC(C)=CC=1)(O[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O.Cl>CN1CCCC1=O.O>[F:21][C:20]([F:23])([F:22])[CH2:19][O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[C:5]=1[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCc1c(C)cc(C)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CCc1c(C)cc(C)cc1OCC(F)(F)F
Reaction time: 16 h

Procedure:
17 g of sodium hydroxide were metered into a mixture of 50 g of 3,5-dimethyl-2-(2-propen-1-yl)-phenol (C) and 86 g of 2,2,2-trifluoroethyl tosylate in 450 ml of N-methylpyrrolidone at 120° C. Stirring was continued for 16 hours at 120° C., and the mixture was subsequently poured into 21 of water. The pH was brought to 2 using 6N hydrochloric acid, and the mixture was extracted using dichloromethane. The combined organic phases were dried over sodium sulphate, the solvent was removed in vacuo, and the residue was distilled. This gave 32 g (43% of theory) of 3,5-dimethyl-2-(2-propen-1-yl)phenyl 2,2,2-trifluoroethyl ether of a boiling point of 100° C. at 1 mbar.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:14]=[C:13]([CH3:22])[C:12]=1[CH:23]=[O:24].[OH-].[K+].[CH3:27]O>>[Cl:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:14]=[C:13]([CH3:22])[C:12]=1[CH:23]([O:24][CH3:27])[C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: COC(c1c(C)nn(-c2ccccc2)c1Cl)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (1, 0.100 g, 0.846 mmol) and 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (100, 0.205 g, 0.931 mmol) was added 2 mL of methanol to give a solution. Potassium hydroxide (0.0475 g, 0.846 mmol) was added and the reaction was allowed to stir at room temperature for 48 hours. The reaction was extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with a gradient of 0-5% methanol in dichloromethane to give the compound (P-0079, 32 mg 11%). MS (ESI) [M+H+]+=353.2.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2)=[O:2].C(=O)([O-])[O-:22].[K+].[K+].CS(C)=O.OO>O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:22])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2)=[O:2]
Reactant: N#Cc1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 169.4 %

Procedure:
Mix 4-(5-Formyl-indol-1-ylmethyl)-benzonitrile (0.73 g, 2.8 mmol), potassium carbonate (0.19 g, 1.4 mmol), and dimethylsulfoxide (14 mL) in a flask. Cool 10 minutes in an ice bath and add hydrogen peroxide (0.95 mL, 30% wt in water) dropwise. Remove ice bath and stir at rt for 4 hrs. Pour into water (30 mL). After trituration, filter the solid formed and dry on a vacuum pump to obtain the product as a white solid (0.66 g, 88%). 1H NMR (DMSO-d6) 9.95 (s, 1H), 8.17 (s, 1H), 7.89 (bs, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.69 (d, J=3.1 Hz, 1H), 7.63-7.60 (m, 2H), 7.32 (bs, 1H), 7.23 (d, J=8.1 Hz, 2H), 6.73 (d, J=3.1 Hz, 1H), 5.54 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2O[C:25]([CH2:28][CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])=[N:26][N:27]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH2:35].CC(O)=O>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:35]([CH3:34])[C:25]([CH2:28][CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])=[N:26][N:27]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2-c2nnc(CCS(C)(=O)=O)o2)cc1
Reactant: CN
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cn1c(CCS(C)(=O)=O)nnc1-c1cc(Cl)c(F)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A 25 mL scintillation vial was charged with 4-tert-butyl-N-{4-chloro-5-fluoro-2-[5-(2-methanesulfonyl-ethyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-benzenesulfonamide (48 mg, 0.093 mmol), methylamine (13 μL, 0.372 mmol), AcOH (21 μL, 0.372 mmol), and dioxane (1.0 mL). The vial was sealed, heated to 120° C., and stirred overnight. The following day, the volatiles were evacuated in vacuo and the residue was purified via automated silica gel chromatography to afford 4-tert-butyl-N-{4-chloro-5-fluoro-2-[5-(2-methanesulfonyl-ethyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-phenyl}-benzenesulfonamide as a white powder: MS (ES) M+H expected 529.1, found 529.0.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][N:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.CC[N:16]([CH2:19][CH3:20])[CH2:17]C.Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23]>>[CH2:25]([O:24][C:22](=[O:23])[N:16]([CH3:17])[CH2:19][CH2:20][C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:11]([C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][N:5]=2)=[O:13])=[CH:3][CH:2]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: O=C(O)c1n[nH]c2c1C(=O)CCC2
Reactant: CCN(CC)CC
Reactant: CC(C)COC(=O)Cl
Product: CC(C)COC(=O)N(C)CCc1ccc(NC(=O)c2n[nH]c3c2C(=O)CCC3)cc1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A suspension of 4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (200 mg, 1.1 mmol) in isobutyl chloroformate (10 mL) was treated with Et3N (0.46 mL, 3.3 mmol) portionwise at room temperature. After 30 min. further Et3N (0.46 mL, 3.3 mmol) was added and the mixture stirred for 30 min. The mixture was evaporated and residue suspended in 1,2-DCE (15 mL). The foregoing amine (0.37 g, 1.7 mmol) added and the solution was heated at reflux for 6 h. The solvent was evaporated, the residue suspended in EtOH (1.5 mL) and then treated with 4N NaOH (5 mL). The mixture was heated at reflux for 1 h. Water (50 mL) was added to the cooled mixture, the aqueous phase extracted with 10% MeOH/DCM (×3) and the combined organic layers dried (MgSO4) and evaporated. The residue was purified by silica plug chromatography, using MeOH:DCM (6:94) as eluent, to give title compound (250 mg, 54%) a cream solid. 1H NMR (400 MHz, CDCl3) δ0.94 (6H, d, J=6.4), 1.88-1.98 (2H, m), 2.19-2.27 (2H, m), 2.7 (2H, t, J=6.1 Hz), 2.77-2.92 (5H, m), 2.98 (2H, t, J=5.8 Hz), 3.40-3.51 (2H, m), 3.85 (2H, d, J=6.44 Hz), 7.18-7.26 (2H, m), 7.74 (2H, d, J=7.9 Hz), 11.30 (1H, br, s), 12.26 (1H, s). MS, (CI)+413 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>C(O)C>[CH3:1][N:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[C:5](=[O:7])[N:14]2[CH2:21][CH2:20][CH2:19][CH:15]2[C:8]1=[O:9]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 17.7 g. of N-methyl isatoic anhydride, 11.5 g. of L-proline and 250 ml. of ethanol is heated on a steam bath for 3 hours and then concentrated to remove the ethanol. The residue is mixed with benzene and a small portion of water and the layers are separated. The benzene layer is washed twice with water and concentrated to remove the solvent. The residue is triturated with ether. The crystals which form are collected by filtration and recrystallized from ethyl acetate yielding the pure dextrorotatory isomer, melting point 120°-122°C., [α]D25 + 486°(1%, methanol).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH2:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH2:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(CC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 71.7 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(3-ethyl-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (0.25 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 2 hrs. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(3-ethyl-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.17 g, yield 71%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.Cl[CH:33]([F:35])[F:34]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10]([O:17][CH:33]([F:35])[F:34])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Reactant: FC(F)Cl
Product: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(-n4cccn4)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [8-chloro-4-methyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.