Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.[H-].[Na+].CS(C)=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Yield: 14 %

Procedure:
2-Amino-4-chloropyridine (2.0 g), 5-hydroxyindole (4.1 g), sodium hydride (60% in oil, 1.25 g) and dimethylsulfoxide (20 ml) were stirred at 160° C. for 9.5 hours. Water was added, extraction was performed with ethyl acetate, and purification was performed by silica gel column chromatography (hexane:ethyl acetate=1:1, ethylacetate). The solvent was distilled off under reduced pressure, a small amount of ethyl acetate was added to the residue and the solid was filtered out to obtain 490 mg of a light brown solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][SH:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:14]([SH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:14]([S:23][S:13][CH2:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: SCCCc1ccc2c(c1)OCO2
Reactant: CCCCCCCCCS
Product: CCCCCCCCCSSCCCc1ccc2c(c1)OCO2
Yield: 56.1 %

Procedure:
6.2 g of the title compound was prepared from 10 g of 3-(1,3-benzodioxol-5-yl)propanethiol and 5 g of nonyl mercaptan as a colorless oil according to the same procedure as that described in Example 1.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][NH:5][C:6]([C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7].[OH-].[Li+].Cl>O1CCOCC1>[CH3:17][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:6]([NH:5][CH2:4][C:3]([OH:18])=[O:2])=[O:7]
Reactant: COC(=O)CNC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1c(C(=O)NCC(=O)O)cc2ccccc21
Yield: 93.2 %

Procedure:
(1-Methylindole-2-carbonyl)glycine methyl ester (1.687 g, 6.85 mmol) was dissolved in 1,4-dioxane (10 mL) and was treated with 1N lithium hydroxide (7.0 mL, aq) with stirring. The reaction mixture turned clear immediately and was acidified with 1N HCl and concentrated to remove 1,4-dioxane to result in a purple precipitate. The precipitate was filtered, washed with water, and dried in vacuo to give the title product as a purple powder (1.482 g, 93%). TLC: (methylene chloride:methanol:acetic acid, 20:1:1, silica gel): Rf =0.28; 1H-NMR (CD3OD): δ 7.61 (dt, J=8.2, 1H). 7.44 (dd, J=8.5, 0.8, 1H), 7.32-7.26 (m, 1H), 7.13-7.09 (m, 1H), 7.04 (s, 1H), 4.08 (s, 2H), 3.99 (s, 3H)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:12][CH:11]=[N:10][C:9]=2[N:8](COCC[Si](C)(C)C)[CH:7]=1.FC(F)(F)C(O)=O.C(N)CN.[OH-].[Na+]>ClCCl.CO>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:8][CH:7]=1
Reactant: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(-c2ncco2)cn3COCC[Si](C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(-c4ncco4)c23)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To N-(3-(5-(oxazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide (140 mg, 0.295 mmol) was added portionwise, a solution of trifluoroacetic acid (3.4 g, 30 mmol) in dichloromethane (10 mL). The reaction was stirred for 1 hour at 50° C., then concentrated in vacuo. To this crude reaction mixture was added ethane-1,2-diamine (35 mg, 0.59 mmol), followed by portionwise addition of a solution of sodium hydroxide (82 mg, 2.1 mmol) in methanol (10 mL). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated in vacuo and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the crude product by reverse phase HPLC using an acetonitrile gradient in water with 0.5% TFA modifier afforded N-(3-(5-(oxazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a green solid. LRMS (ESI) calc'd for C19H16N5O2 [M+H]+: 346, found 346. 1H NMR (400 MHz, CD3OD) δ 9.05 (s, 1H), 8.25 (s, 1H), 7.93 (s, 1H), 7.80 (d, 1H, J=8.0 Hz), 7.59 (s, 1H), 7.38-7.42 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 5.80 (s, 1H), 5.55 (s, 1H), 1.99 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[NH:11][C:12](=[O:15])[CH2:13]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[N:20]([C:13]1[C:12](=[O:15])[NH:11][C:10]2[C:9]([C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)Nc1ccccc1C(=O)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=Nc1c(-c2ccccc2)c2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a hot solution of 98.5 g. of 2'-benzoyl-2-bromo-acetanilide in 2 l methanol was added in one portion 39.0 g. of sodium azide. The mixture was heated to a slow reflux on a steam bath for 20 minutes. As the mixture cooled partially to room temperature, 18 ml. of benzyltrimethylammonium hydroxide (35% methanolic solution) was added. After standing overnight at room temperature, the orange-yellow needles that formed were collected, washed with methanol and dried at 60° C.; yield 76.6 g. (94%) of 3-azido-4-phenylcarbostyril, having a melting point of 120° - 140° dec. to high melting solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=C[C:21]([CH2:24][N:25]4[CH2:30]COC[CH2:26]4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@H]2[C@H]3C[C@H](C=C3)[C@H]2C(N)=O)C(Cl)=CN=1.CN(C)C1C=C(C=CC=1)C=O>>[Cl:8][C:9]1[C:10]([NH:31][C@H:32]2[C@H:37]3[CH2:38][C@H:34]([CH:35]=[CH:36]3)[C@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[C:24]([N:25]([CH3:30])[CH3:26])[CH:23]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Agent: CN(C)c1cccc(C=O)c1
Agent: NC(=O)[C@H]1[C@@H](Nc2c(Cl)cnc(N)c2N)[C@@H]2C=C[C@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cccc(-c2nc3c(N[C@@H]4[C@H](C(N)=O)[C@H]5C=C[C@@H]4C5)c(Cl)cnc3[nH]2)c1
Yield: 58 %

Procedure:
In the same fashion as for Compound III, (1R,2R,3S,4S)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-Dimethylamino-benzaldehyde were reacted to produce the title compound (58%). 1H NMR (d-chloroform): 16.03 (br s, 1H), 8.36 (d, J=9 Hz, 1H), 7.82 (s, 1H), 7.74 (s, 1H), 7.61 (d, J=9 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.09 (t, J=8 Hz, 1H), 6.50 (m, 1H), 6.42 (m, 1H), 6.04 (m, 1H), 5.69 (m, 1H), 5.37 (t, J=7 Hz, 1H), 3.17 (s, 1H), 3.13 (s, 6H), 3.04 (s, 1H), 2.71 (d, J=9 Hz, 1H), 2.33 (d, J=9 Hz, 1H), 1.68 (d, J=9 Hz, 1H). MS: 423.15 (M+H). HPLC retention time: 2.05 minutes (G Method).
Reaction SMILES: [C:1]1(=[C:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Cl)[CH:15]=[CH2:16].O>C1COCC1>[C:1]1([C:6]2([CH2:16][CH:15]=[CH2:14])[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:2][CH2:3][CH2:4][CH:5]=1
Reactant: O=C1CCCC1=C1CCCC1
Reactant: C=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC1(C2=CCCC2)CCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a stirring solution of 2-cyclopentylidenecyclopentan-1-one (62.5 g, 0.417 moles) in dry THF (450 mL) at room temperature under nitrogen, was added NaH (60% oil dispersion, 20.0 g, 0.5 moles) in one portion. The mixture was stirred at room temperature for 30 min and then a solution of allyl chloride (38.3 g, 0.5 moles) in THF (100 mL) was added dropwise over 30 min. When the addition was complete, the reaction was warmed gently to approximately 40° C. It was determined by TLC and GC that the reaction was complete after 18 hours. Water was added to the reaction mixture and the layers were separated, with the organic layer being washed successively with 10% HCl (aqueous), saturated NaHCO3 (aqueous), and brine. The resulting organic layer was dried with MgSO4, filtered, and concentrated. The brown oil was distilled under vacuum to give 2-cyclopent-1-enyl-2-prop-2-enylcyclopentan-1-one (54.5 g, 69.0% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([OH:11])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:11][CH:5]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12])(=[O:25])=[O:24]
Reactant: CCOC(=O)C(O)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(OS(C)(=O)=O)c1cccs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Hydroxy-thiophen-2-yl-acetic acid ethyl ester (4.58 g, 24.6 mmol) is dissolved in dry DCM (125 mL) and cooled at 0° C. DIPEA (5.15 mL, 29.5 mmol) and methanesulphonyl chloride (2.11 mL, 27.1 mmol) are added and the resulting solution is stirred at RT for 1 hour. DIPEA (0.859 ml, 4.92 mmol) and methanesulphonyl chloride (0.19 mL, 2.46 mmol) are added again. After being stirred at room temperature for 1 additional hour, a third portion of DIPEA (0.43 mL, 2.46 mmol) and methanesulphonyl chloride (77 ul, 0.98 mmol) is added. After 1 hour the reaction is completed. The mixture is diluted with DCM, washed with sat. NaHCO3, water and brine, dried (Na2SO4), filtered and evaporated. The resulting yellow oil is used in the next step without any further purification.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]1.Cl>C1COCC1>[O:2]=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]1
Reactant: COC(=O)c1cccc2ccn(CC(OC)OC)c12
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cccc2ccn(CC=O)c12
Temperature: 60 °C
Yield: 89.3 %

Procedure:
To a stirred solution of methyl 1-(2,2-dimethoxyethyl)-1H-indole-7-carboxylate (1.8 g, 6.7 mmol) from Step A above in THF (30 ml) was added 1N HCl (30 ml). The mixture was heated to 60° C. for 2 h. The solvent was evaporated and the residue purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 1-(2-oxoethyl)-1H-indole-7-carboxylate (1.3 g, 87%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.77 (s, 1H), 7.84 (dd, J=4.5, 1.0 Hz, 2H), 7.15 (t, J=8.0 Hz, 1H), 7.04 (d, J=1.5 Hz, 1H), 6.67 (d, J=1.5 Hz, 1H), 3.90 (s, 3H), 2.05 (s, 2H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([CH2:20][OH:21])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>ClCCl>[C:1]([NH:8][C@H:9]([CH2:20][OH:21])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](CO)C(=O)NCc1ccccc1
Solvent: ClCCl
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Reaction time: 3 h

Procedure:
Acetic anhydride (4 grams) was added to the solution of (R)-2-amino-N-benzyl-3-hydroxypropanamide compound of formula-10 (6 grams) in dichloromethane (60 ml) at 10-15° C. The reaction mixture was stirred for 3 hours and reaction mixture quenched with water. Both the organic and aqueous layers were separated. The organic layer was washed with aqueous sodium bicarbonate solution followed by water. The organic layer was distilled off completely under reduced pressure to get the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][N:27]=[N:26]2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][N:27]=[N:26]2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12][CH2:13][O:14][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 2.5.2 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (2.6 g, 6.50 mmol) and methanesulfonyl chloride (0.8 mL, 10.4 mmol) to give the title compound: Rf=0.20 (silica gel, ethyl acetate).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[CH2:15][N:16]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=34)=[O:23])[C:18]([C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[O:40][CH:41]([F:43])[F:42])=[N:17]2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([O:40][CH:41]([F:42])[F:43])=[C:33]([C:18]2[C:19]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=34)=[O:23])=[CH:20][N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][CH:8]([NH:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:13][CH2:12]3)=[O:44])[N:17]=2)[CH:38]=1
Reactant: COC(=O)CBr
Reactant: NC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-bromoacetate (30.74 mg, 0.20 mmol) was added to a mixture of N-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.18 mmol) in DMF (5 mL) and potassium carbonate (38.1 mg, 0.28 mmol). The resulting mixture was stirred at room temperature overnight. Additional amount of methyl 2-bromoacetate (30.74 mg, 0.20 mmol) was added and the resulting solution was stirred at 60° C. for 2 h. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (25.0% MeCN up to 32.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 25.0% in 2 min); Detector, UV 254/220 nm. This resulted in 68.9 mg (57%) of the formic acid salt of methyl 2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]-acetate as an off-white solid. LCMS (Method 24) [M+H]+=617.2, RT=1.53 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23-5.20 (m, 2H), 4.11-4.07 (m, 1H), 3.83-3.80 (m, 1H), 3.63 (s, 3H), 3.39-3.31 (m, 2H), 3.15-3.12 (m, 1H), 2.87-2.83 (m, 1H), 2.71-2.67 (m, 1H), 1.83-1.77 (m, 2H), 1.29-1.14 (m, 2H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:38][C:39]([C@@H:41]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C@@H:42]([CH3:45])[CH2:43][CH3:44])=[O:40])[CH2:9][C@H:10]([OH:37])[C@@H:11]([NH:19]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NCC)C>CN(C=O)C>[NH2:19][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@@H:10]([OH:37])[CH2:9][C@@H:8]([NH:38][C:39]([C@@H:41]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C@@H:42]([CH3:45])[CH2:43][CH3:44])=[O:40])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 5B (0.107 g, 0.158 mmol) in DMF (6 mL) was treated with diethylamine (1.5 mL), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:18][CH2:19][CH2:20][CH2:21][O:15][C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[N:13][CH:12]=1
Reactant: ClCCCI
Reactant: Oc1cncc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1cncc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a solution of 5-(phenylmethoxy)pyridine-3-ol (1.52 g, 7.56 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.238 g of an 80% dispersion in mineral oil, 7.94 mmol) in DMF (15 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-chloro-3-iodopropane (1.85 g, 9.07 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 4 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.C(=O)([O-])O.[Na+].Cl.[NH2:45][OH:46]>C(O)C.O>[OH:46]/[N:45]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][C@H:11]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 120 °C
Yield: 102.7 %

Procedure:
To a microwave vial was added (R)-tert-butyl 4-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-1-carboxylate (35 mg, 68.0 μmol), sodium hydrogencarbonate (17.1 mg, 204 μmol) and hydroxylamine hydrochloride (14.2 mg, 204 μmol) in ethanol (1 mL) and water (0.02 mL). The vial was capped and heated at 120° C. for 15 min. The reaction mixture was poured onto aq. sat. sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (37 mg), which contained ca. 15% of the (Z)-stereoisomer. White foam; MS (ESI+): m/z=: 530.3 [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:31](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(CC(O)C)N=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH:22]([OH:24])[CH3:31])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Agent: CC(O)Cn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CO
Product: CC(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 106 mg, 0.32 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 170 μL, 0.33 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (80 μL, 0.64 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-(3-amino-pyrazol-1-yl)-propan-2-ol (45 mg, 0.32 mmol) in methylene chloride (1 mL) and the reaction was allowed to warm up to 25° C. and stirred for 45 minutes. After this time the reaction was diluted with a small amount of methanol in methylene chloride and washed with aqueous 1 N hydrochloric acid solution (1×15 mL) and then a saturated aqueous brine solution (1×15 mL). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo with silica gel (2 g) and purified by Biotage Flash Chromatography (40S column, Silica gel, 50% ethyl acetate/hexanes to 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (88 mg, 61%, diastereomeric mixture 1:1) as a white foam: ES-HRMS m/e calcd for C21H28N3O4SCl (M+H)+ 454.1562, observed 454.1559.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)(=O)=O)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:32][C@H:33]4[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]4)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)(=O)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 90 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-methylsulfonyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (3.5 g, 7.5 mmol) and tert-butyl (3S)-3-aminopiperidine-1-carboxylate (1.8 g, 9.0 mmol) in DMF (32 mL) was added diisopropylethylamine (2.6 mL, 15.1 mmol). The reaction mixture was heated at 90° C. for 75 minutes. The mixture was cooled to room temp and diluted into aqueous saturated NH4Cl solution and extracted with EtOAc. The organic phase was washed with brine (3 times), dried (MgSO4), filtered and concentrated under vacuo. The resulting residue was purified via silica gel chromatography (0%-10% MeOH/CH2Cl2) to afford the desired product 1b as a white solid.