Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:18])[C:5]([Br:19])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1>ClCCl>[Br:19][C:5]1[C:6]([CH3:18])=[C:7]([C:2]([NH:1][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=2)(=[O:29])=[O:28])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Cc1c(Br)ccc(N)c1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Br)ccc(NS(=O)(=O)c2cccc(F)c2)c1C(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of Example 126B (760 mg, 2.1 mmol), 3-fluorobenzenesulfonyl chloride (600 mg, 3.1 mmol) in dichloromethane (10 mL) was treated with pyridine (0.690 mL, 8.5 mmol), stirred for 18 hours, diluted with dichloromethane (90 mL), washed with 0.5M HCl (2×100 mL) and brine, dried (Na2SO4), filtered, concentrated and purified on a Biotage silica gel cartridge (40 g) with 50-75% dichloromethane in hexanes to provide the desired product. MS (ESI(+)) m/e 478, 480 (M+H)+, 495, 497 (M+NH4)+, 500, 502 (M+Na)+; (ESI(−)) m/e 476, 478 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.64-7.35 (m, 10H), 6.83 (d, 1H), 5.25 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:4][C:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=2)[N:6]=1)[CH3:2]
Reactant: CC(=O)NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNC1=NN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
By a method analogous to that described in Example 1 3-acetamido-1-(3-trifluoromethylphenyl)-2-pyrazoline was reduced with lithium aluminium hydride, using tetrahydrofuran in place of diethyl ether. The hydrochloride of the resulting 3-ethylamino-1-(3-trifluoromethylphenyl)-2-pyrazoline was recrystallized from isopropanol and diethylether, m.p. 171.5°.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:4].[CH3:26][NH2:27]>CCO>[CH3:26][NH:27][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 80 °C

Procedure:
A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (18 mg, 0.054 mmol) and methylamine (1 mL, 2M in THF) in EtOH (2 mL) was heated in a sealed tube at 80° C. for 16 h. After cooling to r.t., mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (0-2% MeOH/CH2Cl2) to give 10 mg of the title compound. MS: (−) m/z 333.30 (M−1).
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:15]=3)[C:10]([C:22]3[N:23]=[N:24][N:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[O:34])=[CH:29][CH:28]=4)[CH:26]=3)=[N:9]2)=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O.O>[N:35]1([C:33]([C:30]2[CH:31]=[CH:32][C:27]([N:25]3[CH:26]=[C:22]([C:10]4[C:11]5[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:12]=5)[NH:8][N:9]=4)[N:23]=[N:24]3)=[CH:28][CH:29]=2)=[O:34])[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(OCCCO)ccc32)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(OCCCO)cc34)nn2)cc1)N1CCOCC1
Yield: 29.3 %

Procedure:
A solution of 3-[(1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)oxy]propan-1-ol (43 mg; 0.08 mmol; 1.0 eq.) and anisole (124 mL, 1.13 mmol, 15 eq.) in TFA (2 mL) and water (2.7 mL) was stirred at RT for 48 h. Reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give the title compound as a brown gum (10.5 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.35 (s, 1H), 8.15 (d, J=8.6 Hz, 2H), 7.77-7.72 (m, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.52 (d, J=9.0 Hz, 1H), 7.10 (dd, J=9.0, 2.4 Hz, 1H), 4.61 (t, J=5.2 Hz, 1H), 4.21-4.06 (m, 2H), 3.78-3.24 (m, 10H), 2.02-1.82 (m, 2H). HPLC (max plot) 97.2%; Rt %2.63 min. UPLC/MS: (MS+) 449.1, (MS−) 447.1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1>CO.[Pd]>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2cccc(NC)c2)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)cc1
Yield: 89.4 %

Procedure:
A solution of 1.7 g (6.0 mmol) of ethyl (E)-3-(3′-methylaminobiphenyl-4-yl)acrylate in 25 ml of methanol is stirred for 12 hours at room temperature in the presence of 300 mg (18% by mass) of 10% palladium-on-charcoal under a hydrogen atmosphere. The palladium is filtered off and the solvent is evaporated off. 1.52 g of ethyl 3-(3′-methylaminobiphenyl-4-yl)propanoate are obtained. Yield=90%
Reaction SMILES: CCN(CC)CC.[C:8]([NH:11][CH:12](Br)[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:10])[CH3:9].[CH3:24][SH:25]>C1COCC1>[C:8]([NH:11][CH:12]([S:25][CH3:24])[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:10])[CH3:9]
Reactant: CS
Reactant: CC(=O)NC(Br)C(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSC(NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A cooled (-78° C.) solution of Et3N (4.85 g, 48.0 mmol) in THF (20 mL) was added to a cooled (-78° C.) solution of 2-acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (4.00 g, 16.0 mmol) and BBr3 (1M in CH2Cl2, 20.0 mL, 20.0 mmol)) in THF (275 mL). A cooled (-78° C.) solution of excess MeSH (5-6 equiv) in THF (55 mL) was then added. The reaction mixture was stirred at this temperature (30 min) and then at room temperature (1 h). The insoluble materials were filtered and the filtrate was evaporated to dryness in vacuo. The oily residue obtained was purified by flash column chromatography on SiO2 gel (2% MeOH/CHCl3) to give 1.10 g (27%) of the desired product as a yellow orange oil. The product was purified by a second flash column chromatography on SiO2 gel (2% MeOH/CHCl3) to give 0.72 g of the pure product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9](=O)[CH2:8][C:7]=2[CH:24]=1.Cl>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][CH2:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2c(c1)CC(=O)N(CCCc1ccccc1)S2(=O)=O
Agent: Cl
Product: COc1ccc2c(c1)CCN(CCCc1ccccc1)S2(=O)=O

Procedure:
To a 1M BH3 solution (300 mL, 30 mmol) @0° is added a solution of 6-methoxy-2-(3-phenylpropyl)-3-oxo-3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide (3.3 g, 9.6 mmol) anhydrous THF (75 mL). After addition is complete the reaction mixture is brought to reflux for 2 hours. When the mixture has cooled to ambient temperature 6N HCl is carefully added until gas evolution ceases. The volatiles are removed in vacuo and the residue extracted with EtOAc (200 mL). The organic phase is washed with saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The resulting material is chromatographed (silica gel, 1:2 EtOAc/hexanes) to afford 6-methoxy-2-(3-phenylpropyl)-3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[F:12][CH2:13][C:14](N1CCOCC1)=[O:15]>C1COCC1>[F:12][CH2:13][C:14](=[O:15])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(CF)N1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(=O)CF
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A 0° C. solution of trimethylsilylacetylene (42.0 g, 429 mmol) in THF (400 mL) was treated with n-BuLi (2.5 M in n-hexane; 171 mL, 428 mmol) over 20 min maintaining the internal temperature below 10° C. using dry ice-acetone bath (−20° C.). After stirring for 30 min at 0° C., the mixture was treated with a solution of 2-fluoro-1-morpholin-4-yl-ethanone (8, 48.4 g, 329 mmol) in THF (50 mL+10 mL for wash), and stirring was continued for further 1 h at 0° C. The reaction was quenched by adding to a 0° C. mixture of acetic acid (250 mL) and water (150 mL) over 1 h maintaining the internal temperature below 5° C. After addition of more water (150 mL), the organic layer was separated, washed with water (200 mL), and dried over anhydrous MgSO4, and concentrated in vacuo. The residue was evaporated again with toluene (200 mL) to remove the residual acetic acid, and vacuum distillated (8 mbar, b.p. 54° C.) to give the title compound (33.7 g, 64.8%). 1H NMR (500 MHz, CDCl3) δ 4.90 (d, J=47.1 Hz, 2H), 0.26 (s, 9H). 13C NMR (125 MHz, CDCl3) d 181.0 (d, J=21.5 Hz), 104.0, 98.1, 84.8 (d, J=187 Hz).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[CH:21]=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:9]=[C:8]([C:22]([O:24]C)=[O:23])[C:7]=2[C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2].BrC1C=C(C(OC)=O)C2C(C=O)=NNC=2C=1.O[Li].O>>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[CH:21]=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]=2[C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1c(C)nn2C(C)C
Agent: COC(=O)c1cc(Br)cc2[nH]nc(C=O)c12
Agent: [Li]O
Solvent: O
Product: Cc1nn(C(C)C)c2cc(-c3cnc4[nH]ccc4c3)cc(C(=O)O)c12

Procedure:
The title compound was prepared from methyl 1-isopropyl-3-methyl-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-4-carboxylate, 1 (50 mg, 0.14 mmol) and LiOH.H2O (20 mg, 0.43 mmol) in the same manner as described for example 80 (step b). The product was collected as an off-white solid (60 mg) and used in the next step without any further purification. LCMS (ES+) m/z: 335.15.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]3=[O:25])[CH3:18])=[CH:13][CH:12]=2)=[C:6]([CH3:27])[CH:5]=[C:4]([CH3:28])[N:3]=1>CO.[Pd]>[OH:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[CH:12]=[CH:13][C:14]([CH:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]3=[O:25])[CH3:18])=[CH:15][CH:16]=2)=[C:6]([CH3:27])[CH:5]=[C:4]([CH3:28])[N:3]=1
Reactant: Cc1cc(C)c(CNC(=O)c2ccc(C(C)n3ccccc3=O)cc2)c(O)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)N3CCCCC3=O)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.8 %

Procedure:
To a solution of N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzamide (30 mg, 0.08 mmol) in methanol was added palladium on carbon (30 mg). The mixture was stirred at room temperature for 12 hours under hydrogen atmosphere. Then the mixture was filtered and the filtrate was concentrated to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(2-oxopiperidin-1-yl)ethyl)benzamide (21 mg, 67%). LRMS (M+H) m/z: calcd 381.19. found 381. HPLC purity (214 nm): 95%. 1H NMR (300 MHz, CD3OD): δ 7.78 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 6.10 (s, 1H), 6.00 (q, J=6.9 Hz, 1H), 4.49 (s, 2H), 3.23-3.19 (m, 1H), 2.83-2.79 (m, 1H), 2.46-2.42 (m, 2H), 2.36 (s, 3H), 2.24 (s, 3H), 1.81-1.63 (m, 4H), 1.54 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:32]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N>CN(C=O)C>[NH2:32][C:20](=[O:22])[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCC(N)=O)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 83.5 %

Procedure:
A solution of N-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-N-(tert-butoxycarbonyl) -β-alanine (4.06 g) obtained in Example 45b), WSC (1.92 g) and HOBt.NH3 (1.52 g) in DMF (40 mL) was stirred overnight at room temperature, and DMF was distilled off under reduced pressure. The residue was diluted with dichloromethane, washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (from ethyl acetate/hexane=1/1 to ethyl acetate) to obtain the title compound (3.38 g, 83%) as a white amorphous powder.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:49])([F:48])[F:47])=[CH:19][N:18]=2)=[C:12]([O:50][CH3:51])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1COCC1.CO.O.[OH-].[Li+].O>>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:47])([F:49])[F:48])=[CH:19][N:18]=2)=[C:12]([O:50][CH3:51])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](C(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Ethyl trans-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (Example 88, 40.0 mg, 0.055 mmol) was taken up in THF (0.073 mL, 0.90 mmol) and MeOH (0.073 mL, 1.8 mmol). This was treated with a solution of Lithium hydroxide, monohydrate (11.4 mg, 0.27 mmol) in H2O (0.073 mL, 4.1 mmol) and allowed to stir at rt for 30 hrs during which, the reaction mixture transformed from a thick slurry to a homogenous solution. The reaction was concentrated in vacuo to a solid. The product was purified by CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dried loaded, elution gradient: 0→5% MeOH in DCM] to afford 38.7 mg (100% yield) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (s, 1H), 8.38 (s, 1 H), 7.52 (br. s., 1 H), 7.19 (br. s., 1 H), 7.05 (s, 1 H), 6.90 (d, J=8.59 Hz, 1 H), 4.50 (s, 2 H), 3.95-4.06 (m, 4 H), 3.77 (s, 3 H), 3.21-3.29 (m, 2 H), 3.08 (s, 3 H), 2.67 (br. s., 1 H), 2.60 (br. s., 1 H), 2.15 (d, J=7.83 Hz, 2 H), 1.55-1.69 (m, 6 H), 1.21 (t, 6 H). MS (ES+): m/z 706.22 [MH+]. HPLC: tR=1.55 min (UPLC TOF, polar—3 min). Example 90 may be further prepared as a salt. Non-limiting examples include the sodium, potassium, ammonium, and 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salts. This can be achieved by dissolving the compound in methanol or ethanol with a suitable co-solvent such as DCM or THF and treating the resulting solution with the necessary amount of an aqueous stock solution of known concentration of sodium hydroxide, potassium hydroxide, or 2-amino-2-(hydroxymethyl)propane-1,3-diol. The resulting mixture can be thoroughly stirred or sonicated to ensure dissolution and mixing. The solvents can then be removed under reduced pressure to afford the appropriate salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:17])[CH:11]([C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:10][CH:9]1[C:41]([O:43]C)=[O:42].[OH-].[K+]>O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:20]=2)=[O:17])[CH:11]([C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:10][CH:9]1[C:41]([OH:43])=[O:42]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N(C)c3ccccc3)CC(C(=O)OC)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C(=O)C1CC(C(=O)O)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1)c1ccccc1
Yield: 47.7 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.1 g of methyl (2RS,4RS,5SR)-5-(2-fluorophenyl)-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}-2-(methylphenylcarbamoyl)pyrrolidine-4-carboxylate and 0.21 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 40 cm3 of methanol. After treatment, there is obtained 0.5 g of (2RS,4SR,5SR)-5-(2-fluorophenyl)-1-{2-[3-(3-(carboxymethyl)phenyl)ureido]acetyl}-2-(methylphenylcarbamoyl)pyrrolidine-4-carboxylic acid, melting at 164° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[CH:11]=[CH:12][CH:13]=1.[Cl-].[Na+].Cl.Cl[CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH3:34]>CC(N(C)C)=O.O.C(OCC)(=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:27][CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][N:30]2[CH3:34])[CH:11]=[CH:12][CH:13]=1
Reactant: CN1CCCC1CCCl
Reactant: Oc1ccccc1CCc1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCCC1CCOc1ccccc1CCc1cccc(Cl)c1
Yield: 52.1 %

Procedure:
1.06 g of potassium t-butoxide were added to a solution of 1.00 g of 2-[2-(3-chlorophenyl)ethyl]phenol (prepared as described in Preparation 44) in 20 ml of dimethylacetamide, whilst cooling by ice and sodium chloride and stirring. 0.949 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochoride was then added to the solution, and the mixture was stirred at 50° C. for 3 hours. At the end of this time, the reaction mixture was cooled, and 100 ml of ethyl acetate and 50 ml of water were added to the mixture, which was then shaken. The ethyl acetate layer was separated, washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate layer was then concentrated by distillation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.770 g (yield 52%) of the title compound as a colorless oil.
Reaction SMILES: O[CH2:2][C@H:3]1[O:5][C@H:4]1[C@H:6]([O:15][CH2:16][O:17][CH3:18])[CH2:7][C:8](=[CH2:14])[C:9]([O:11][CH2:12]C)=[O:10].[C:19]([O-])([O-])=O.[K+].[K+].C(C(CC)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-])C>CS(C)=O.CO.C(OCC)C>[C:2]([C@H:3]1[O:5][C@H:4]1[C@H:6]([O:15][CH2:16][O:17][CH3:18])[CH2:7][C:8](=[CH2:14])[C:9]([O:11][CH3:12])=[O:10])#[CH:19]
Reactant: C=C(C[C@@H](OCOC)[C@@H]1O[C@@H]1CO)C(=O)OCC
Reactant: O=C([O-])[O-]
Agent: CCC(CC)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Solvent: CS(C)=O
Product: C#C[C@H]1O[C@H]1[C@@H](CC(=C)C(=O)OC)OCOC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of epoxy alcohol 12 (1.4 g, 4 mmol) in DMSO (5 mL) in a round-bottomed flask was added IBX (1.68 g, 6 mmol) in one portion and the reaction mixture was stirred for 1 h at ambient temperature (25° C.). The reaction mixture was quenched with diethylether (5 mL), H2O (0.5 mL) and filtered through a pad of celite. The residue was repeatedly washed with diethyl ether (50 mL). The filtrate was washed with H2O, brine, dried (Na2SO4) and concentrated to give the crude aldehyde, which was pure enough and used in the next step without further purification. To a solution of crude aldehyde and K2CO3 (900 mg, 8 mmol) in 20 mL dry MeOH and diethyl-1-diazo-2-oxopropylphosphonate (1.26 g, 6 mmol) were added under continuous stirring till completion of the reaction was indicated by TLC (2 h) (25° C.). The reaction mixture was diluted with diethylether (100 mL), washed with aq. solution of NaHCO3 and dried over Na2SO4. Evaporation of solvent yielded analytically pure terminal alkyne 13
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:12])=[O:13])=[C:7]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1N1CCOCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(N2CCOCC2)c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of 11 (24.7 mL; 0.06 mmol) in tetrahydrofuran (5 mL) in a 2.5-5.0 mL microwave reactor tube was added aqueous lithium hydroxide (1 mL; 2M). The reaction vessel was subjected to the following microwave conditions: Temperature=140° C.; Time=15 minutes; Power=250 W; Cooling on; Absorption=Very High. The crude reaction mixture was allowed to cool to room temperature, acidified by the addition of aqueous hydrochloric acid (15 mL; 2N), and extracted with ethyl acetate (3×10 mL). The organic phases were combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a beige solid. The latter was triturated from diisopropyl ether to yield the title compound as a beige solid (24.1 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16](C1C=CC(OC)=C2C=1C=CN2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]
Reactant: Brc1cccc2cn[nH]c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1cccc2cn[nH]c12

Procedure:
3-(1H-Indazol-7-yl)-3-phenyl-acrylic acid ethyl ester CCXLVII was prepared from 7-bromo-1H-indazole using the procedure described for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).