Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])=[C:5]([CH3:18])[O:4][N:3]=1.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CNC>CO>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([OH:17])[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[O:25])=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: O=C1CCCCC1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(=O)C(=O)N2
Agent: CNC
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2c(c1)C(O)(C1CCCCC1=O)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-(3,5-dimethylisoxazol-4-yl)indoline-2,3-dione (242 mg, 1.0 mmol) is dissolved in MeOH (20 ml), cyclohexanone (196 mg, 2.0 mmol) and dimethylamine (0.4 mmol) are added and the reaction mixture is stirred for 4 h at room temperature. After that, the mixture is concentrated in vacuo and the residue was purified with chromatography on column to give two isomers (The first 50 mg, 14.7%, the second 30 mg, 8.8% and mixture 100 mg, 29.3%). The fast isomer (50 mg, 14.7%): 1H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 7.29 (d, J=1.6 Hz, 1H), 7.17 (dd, J=1.6, 8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 5.83 (s, 1H), 3.32-3.41 (m, 1H), 2.30-2.40 (m, 5H), 2.19 (s, 3H), 1.98-2.06 (m, 2H), 1.80-1.83 (m, 2H), 1.44-1.64 (m, 2H), MS (ESI) m/e [M+1]+ 341.0; the slow isomer (30 mg, 8.8%): 1H NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 7.16-7.20 (m, 2H), 6.88 (d, J=8.0 Hz, 1H), 5.92 (s, 1H), 3.08-3.12 (m, 1H), 2.59-2.62 (m, 1H), 2.36 (s, 3H), 2.29-2.35 (m, 1H), 2.19 (s, 3H), 1.77-2.00 (m, 4H), 1.62-1.68 (m, 1H), 1.42-1.50 (m, 1H), MS (ESI) m/e [M+1]+ 341.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: BrCc1ccccc1
Product: CCCCN(CCCC)C(=O)c1cn(Cc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 77.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271F, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.40 mmol) and benzylbromide (83 mg, 0.48 mmol) were converted to the title compound (180 mg, 76%). 1H NMR (CDCl3) 8.68 (d, J=1.6 Hz, 1H), 8.15 (dd, J=8.0, 2.0 Hz, 1H), 7.43 (s, 1H), 7.39-7.34 (m, 4H), 7.28-7.26 (m, 2H), 7.21-7.17 (m, 3H), 6.90-6.88 (m, 2H), 5.15 (s, 2H), 4.64 (s, 2H), 3.96 (s, 3H), 3.90 (br s, 2H), 3.43 (br s, 2H), 1.70-1.59 (m, 4H), 1.37-1.23 (m, 4H), 0.93-0.82 (m, 6H); MS(ESI+) m/z 582.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=CC=1.[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]2[S:16][CH:10]=[CH:15][CH:14]=2)[N+:3]=1[O-:9]
Reactant: Sc1ccccc1
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: [O-][n+]1c(Cl)cccc1-c1cccs1

Procedure:
The 1.64 g (0.010 moles) of 2,6-dichloropyridine N-oxide and 1.11 g (99%) (0.010 moles) of thiophenol was reacted with 0.400 g (0.010 moles) of ground sodium hydroxide of 16.4 ml of DMSO at 80° C. for 5 hours to give 2-chloro-6-thiophenylpyridine N-oxide. It was reacted with 1.20 g (0.030 moles) of ground sodium hydroxide at 80° C. for 2.5 hours to give 1-hydroxy-6-thiophenylpyridine-2-(1H)-one. After cooling, it was added 148 ml of water and was adjusted with 6N HCl to pH 3. The precipitate was filtered, washed with water and washed with hexanes to give 1.64 g (75%). It was recrystallized from ethanol: mp 180°-181° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([F:26])[F:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.[Cu]I>[F:25][CH:24]([F:26])[C:21]1[CH:22]=[CH:23][C:18]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[CH:19][CH:20]=1
Reactant: FC(F)c1ccc(Br)cc1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C)oc2c1
Temperature: 160 °C
Yield: 41 %

Procedure:
A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (252c) (1.10 g, 5 mmol), 1-bromo-4-(difluoromethyl)benzene (1.24 g, 6 mmol), Cs2CO3 (2.44 g, 7.5 mmol) and CuI (5 mg, 0.03 mmol) in DMF (5 mL) was heated in a microwave at 160° C. for 60 minutes. Water was then added and the product was extracted with CHCl3 (3×), dried over MgSO4 and concentrated to give an oil residue. The oil was purified via silica gel chromatography using hexanes/EtOAc (100/0 to 70/30) to give the title compound (710 mg, 41%) as a yellow solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.06 Hz, 3 H) 2.44 (s, 3 H) 4.37 (q, J=7.06 Hz, 2 H) 6.22 (d, J=0.94 Hz, 1 H) 6.63 (t, J=56.61 Hz, 1 H) 7.03 (d, J=8.29 Hz, 2 H) 7.46 (d, J=8.29 Hz, 2 H) 7.55 (d, J=1.13 Hz, 1 H) 7.89-8.05 (m, 1 H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[N:26]=[C:25]([S:36][CH2:37][C:38]3[N:39]=[C:40]([C:43]4[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=4)[S:41][CH:42]=3)[C:24]=2[C:50]#[N:51])=[CH:19][CH:18]=1)=[O:12])[CH3:10])=O)(C)(C)C.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>ClCCl>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[NH2:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[N:26]=[C:25]([S:36][CH2:37][C:38]3[N:39]=[C:40]([C:43]4[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=4)[S:41][CH:42]=3)[C:24]=2[C:50]#[N:51])=[CH:19][CH:18]=1)=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg (0.335 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-alaninate (Example 25A) were initially charged in 3.5 ml of dichloromethane. 0.258 ml (3.354 mmol) of trifluoroacetic acid was added, and the reaction solution was then stirred at RT overnight. After one day, another 0.125 ml (1.624 mmol) of trifluoroacetic acid was added to the reaction. The reaction solution was concentrated by evaporation and the residue was triturated with diethyl ether. The solid formed was filtered off. This gave 255 mg (98% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])[CH:32]=[CH:33][C:34]=3[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 26 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamide according to the procedures described in Scheme 9: ESMS m/e: 564.4 (M+H)+.
Reaction SMILES: [CH3:1]C1C=C(C2N=C3N(CC4CCOCC4)C(=O)NC3=NC=2)C=CC=1C1N=CNN=1.C[C:31]1[CH:32]=[C:33]([C:48]2[N:53]=[C:52]3[N:54]([CH2:58][CH2:59][CH:60]4[CH2:65][CH2:64][O:63][CH2:62][CH2:61]4)[C:55](=[O:57])[NH:56][C:51]3=[N:50][CH:49]=2)[CH:34]=[CH:35][C:36]=1[C:37]1[N:41]=[CH:40][N:39](C2CCCCO2)[N:38]=1.Cl>O1CCOCC1>[CH3:1][C:32]1[CH:31]=[C:36]([C:37]2[N:41]=[CH:40][NH:39][N:38]=2)[CH:35]=[CH:34][C:33]=1[C:48]1[N:53]=[C:52]2[N:54]([CH2:58][CH2:59][CH:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)[C:55](=[O:57])[NH:56][C:51]2=[N:50][CH:49]=1
Reactant: Cc1cc(-c2cnc3[nH]c(=O)n(CCC4CCOCC4)c3n2)ccc1-c1ncn(C2CCCCO2)n1
Reactant: Cc1cc(-c2cnc3[nH]c(=O)n(CC4CCOCC4)c3n2)ccc1-c1nc[nH]n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2nc[nH]n2)ccc1-c1cnc2[nH]c(=O)n(CCC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(3-Methyl-4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one. 6-(3-Methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one (0.283 g, 0.578 mmol) was added to 6.0 M hydrogen chloride in dioxane (4.0 mL) and stirred at 25° C. for 2 h. The solution was condensed under reduced pressure and purified using reverse-phase semi-preparatory HPLC (20-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined, neutralized with ammonium hydroxide, concentrated, diluted with water (20 mL). The desired product was collected by filtration to afford the title compound as an off white solid, 99.5% pure, (0.061 g, 26%). 1H NMR (400 MHz, CD3OD-d4) δ 8.40 (br. s., 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.94 (d, J=8.20, 1H), 7.55 (d, J=8.20, 1H), 4.04 (t, J=7.22, 2H), 3.90 (dd, J=11.32, 3.51, 2H), 3.34-3.42 (m, 3H), 2.49 (s, 3H), 1.70-1.87 (m, 4H), 1.58 (dddd, J=10.93, 7.32, 4.10, 3.81, 1H), 1.50-1.66 (m, 1H), 1.22-1.40 (m, 2H); MS (ESI) m/z 408.5[M+1]+; mp 258-260° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH2:11][C:12]([N:39]3[CH2:40][CH2:41][N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)[CH2:37][CH2:38]3)=[O:14])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)CC1CCC2(CC1)OCCO2
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CC1CCC2(CC1)OCCO2)N1CCN(c2ccccn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
An ice-cold solution of 1,4-dioxaspiro[4,5]-decane-8-acetic acid (20.0 g) (Example G) and triethylamine (20.9 ml) in 100 ml of dichloromethane is treated dropwise with a solution of isobutyl chloroformate (19.4 ml) in 100 ml of dichloromethane under nitrogen. The resulting solution is stirred at 0° C. for 10 minutes and a solution of 1-(2-pyridyl)-piperazine (32.59 g) in 100 ml of dichloromethane is added dropwise. The mixture is stirred at 0° C. for 15 minutes and then at room temperature for one hour. After washing with 1 L of a saturated solution of sodium bicarbonate, the organic phase is dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by MPLC (silica; ethyl acetate) to give 25.50 g of the title compound as a colorless solid; mp 113°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:20]([O:19][C:17]([N:13]1[CH2:12][CH2:11][N:10]([C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Cl:1])[CH:9]=2)[CH2:15][CH2:14]1)=[O:18])[CH3:21]
Reactant: O=Cc1ccc(N2CCNCC2)cc1Cl
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(c2ccc(C=O)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
2-Chloro-4-(1-piperazinyl)benzaldehyde (4) (560 mg; 2.5 mmol) is dissolved in THF (20 ml), ClCO2Et (500 mg; 4.5 mmol) and 2N Na2CO3 (20 ml) added and the reaction mixture stirred at room temperature for 20 min. The mixture is extracted with TBME three times, the combined organic phases are dried over Na2SO4 and evaporated to dryness yielding the title compound as white crystals (700 mg; 94%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[NH2-:13].[Na+].C(OCC)(=O)C.[BrH:21]>C1(C)C(C)=CC=CC=1>[BrH:21].[NH2:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: COc1ccc2ccncc2c1
Reactant: [NH2-]
Agent: Br
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Nc1nccc2ccc(O)cc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
5.6 g (35.2 mmol) of 7-methoxyisoquinoline was dissolved in 200 ml of xylene. 26.6 ml (176 mmol) of N,N,N′,N′-tetramethylenediamine and 7.28 g (186 mmol) of sodium amide were added to the obtained solution, and they were stirred at 140° C. for 1 hour. After the treatment with ethyl acetate as the extracting solvent in an ordinary manner, 50 ml of hydrobromic acid was added to the obtained crude product and they were stirred at 140° C. overnight. The solvent was evaporated to obtain the title compound.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:40]([O:42]C(C)(C)C)=[O:41])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][N:30]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:38]([O:37][C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][CH:17]([CH2:16][C:12]4[N:11]=[C:10]([C:40]([OH:42])=[O:41])[C:9]([OH:8])=[C:14]([CH3:15])[N:13]=4)[CH2:18][CH2:19]3)=[CH:28][CH:27]=2)=[N:30][CH:31]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(OCc5ccccc5)c(C(=O)OC(C)(C)C)n4)CC3)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(O)c(C(=O)O)n4)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
tert-Butyl 5-(benzyloxy)-2-[(1-{4-[5-(ethoxycarbonyl)pyridin-2-yl]phenyl}piperidin-4-yl)methyl]-6-methylpyrimidine-4-carboxylate (0.25 g, 0.40 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (10 mL) was added, followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to afford 2-[(1-{4-[5-(ethoxycarbonyl)pyridin-2-yl]phenyl}piperidin-4-yl)methyl]-5-hydroxy-6-methylpyrimidine-4-carboxylic acid.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:25]1(O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH:25]1([O:16][C:15](=[O:17])[C@@H:2]([NH:1][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3][CH2:4][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: OC1CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a solution of Boc-L-Glu(OBzl)-OH (15 g, 44.5 mmol) in dichloromethane (220 ml) in an ice-bath, was added cyclopentanol (4.8 ml, 53.3 mmol, 1.2 eq), EDC (9.4 g, 48.9 mmol, 1.1 eq) and DMAP (543 mg, 4.4 mmol, 0.1 eq). The reaction mixture was allowed to warm to room temperature and stirred for 12 hours for complete reaction. The reaction mixture was diluted with DCM (200 ml) and washed with 1M HCl, 1M Na2CO3 and brine. The organic layer was then dried over magnesium sulphate and evaporated under reduced pressure. The product was purified by column chromatography using ethyl acetate/heptane (1:4) to give 12.4 g, 69% yield of title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccncc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C

Procedure:
A mixture of 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (1g) (2.0 g, 3.90 mol), pyridine-4-boronic acid (540 mg, 4.39 mol), 1,2-dimethoxyethane (8 mL) and aqueous Na2CO3 (2 M, 1.93 mL, 3.90 mol) was mechanically stirred while purging N2 at room temperature for 10 min. To this system was added Pd(Ph3)4 (75 mg, 0.06 mmol) and heated to reflux (95° C.) for 2 h. Added another portion of Pd(Ph3)4 (75 mg, 0.06 mmol) and heated to reflux (95° C.) for further 2 h. The red-brown mixture was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 solution (3×50 mL) and brine (2×50 mL). The organic fraction was dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-(5-pyridin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[Cu](C#N)[C:15]#[N:16].CN1CCCC1=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:15]#[N:16])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1cccc(C#N)c1
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of (3-bromo-phenyl)-acetic acid ethyl ester (9.15 g, 37.6 mmol), copper cyanide (5.06 g, 56.5 mmol), and 1-methyl-2-pyrrolidinone (80 mL) was placed into an oil bath heated at 120° C. behind a protective shield. The reaction was heated to 200° C. for 1 h and additional copper cyanide (spatula tip) was added. After heating for an additional 0.5 h, the reaction was cooled to room temperature. The reaction was diluted with EtOAc and the organic solution was washed with water/ammonium hydroxide solution (2:1 v/v) until the aqueous solution was no longer blue. The organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc) provided (3-cyano-phenyl)-acetic acid ethyl ester (6.31 g) as a clear oil which solidified on standing. 1H NMR (400 MHz, CDCl3) 6 7.57-7.50 (m, 3H), 7.42 (m, 1H), 4.15 (q, 2H), 3.63 (s, 2H), 1.24 (t, 3H).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[B:16]([OH:17])[O:15][CH2:14][C:13]=2[CH:18]=1)(O)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:46]([NH:48][CH2:49][CH3:50])[CH3:47]>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[C:23]([C:21]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[B:16]([OH:17])[O:15][CH2:14][C:13]=3[CH:18]=2)=[C:6]([CH:22]=1)[O:5][CH2:4][C:1]([N:48]([CH2:49][CH3:50])[CH2:46][CH3:47])=[O:2])#[N:24]
Reactant: CCNCC
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(OCC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)COc1cc(C#N)ccc1Oc1ccc2c(c1)COB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A mixture of 5-[2-(Carboxymethoxy)-4-cyanophenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D17) (1.00 g, 3.08 mmol), EDCI (1.77 g, 9.24 mmol), HOBT (1.25 g, 9.24 mmol), diethylamine (0.96 mL, 9.24 mmol), and 4-dimethylaminopyridine (75 mg, 0.62 mmol) in DMF (20 mL) was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (9:1 chloroform/methanol). The combined fractions were put under reduced pressure to remove solvent and then washed with water and toluene. The solvent was again removed under reduced pressure. Another silica gel chromatography column was used (5:5 acetone:hexane). The desired fractions were combined and the solvent was removed under reduced pressure. The residue was recrystallized using hexanes and diisopropylether. Pure 2-(5-cyano-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)phenoxy)-N,N-diethylacetamide (0.662 g, 57%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4]([S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3]1.[CH2:38]([NH:40][CH3:41])[CH3:39]>C1COCC1>[CH2:38]([N:40]([CH3:41])[CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH3:39]
Reactant: CCNC
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Solvent: C1CCOC1
Product: CCN(C)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2C
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.398 g, 0.742 mmol) and ethylmethylamine (2.0 mL, 23 mmol) in THF (10 mL) was stirred at 80° C. in a sealed tube for 16.5 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80° C. in vacuo for 20 minutes to give ethyl-methyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine as a light brown gum (0.227 g, 72.3%). This was dissolved in chloroform, and etheric hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83° C. in vacuo to give the hydrochloride as a buff-colored foam (0.254 g); Mass Spectrum (+EI, [M+H]+) m/z 424. 1HNMR (500 MHz, DMSO-d6): δ10.26-10.27 (s, br, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.50-8.53 (m, 1H), 8.27 (d, 1H, J=8.17 Hz), 8.04 (d, 1H, J=7.56 Hz), 7.71-7.75 (m, 2H), 7.56-7.66 (m, 2H), 7.38 (d, 1H, J=2.19 H) 7.22 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.43 (t, 2H, J=4.88 Hz), 4.05 (s, 3H), 3.40-3.60 (m, 3H), 3.10-3.20 (br, 1H), 2.80 (s, 3H), 1.22-1.26 ppm (m, 3H).