Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:12][C:11]=2[O:30][CH3:31])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl.CCN(C(C)C)C(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CO>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([C:5]3([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]3)=[C:11]([O:30][CH3:31])[CH:12]=2)[CH2:18][CH2:19]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: COC(=O)C1(c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)CCCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 1-(1-(1-(4-(N-Boc-4-piperidinyloxy)-2-methoxyphenyl)cyclopentylcarboxylic acid methyl ester (0.20 g, 0.46 mmol) from Step 7 above in MeOH (5 mL) was added aqueous NaOH (1.15 mL of a 2.0 N solution, 2.3 mmol). The mixture was refluxed for 5 days. The mixture was acidified to pH 2 by the addition of 2 N aqueous HCl and the solvent was removed under reduced pressure. The residue was suspended in DMF (5 mL) and to the mixture was added DIEA (0.17 mL, 1.0 mmol) and di-tert-butyldicarbonate (0.10 g, 0.46 mmol) were added and the mixture was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and 0.25 M aqueous citric acid (25 mL). The organic phase was washed with water (25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 1-(1-(1-(4-(N-Boc-4-piperidinyloxy)-2-methoxyphenyl)cyclopentylcarboxylic acid as an amorphous solid (HPLC retention time=10.0 min (method A)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:24]4[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=4)[C:18]#[N:19])[CH:3]=3)[O:8][CH2:9][CH2:10]2)[N:12]=1
Reactant: CN1OC2(CCOc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CCOc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 10.5 %

Procedure:
Pd(PPh3)2Cl2 (7 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 6-bromo-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (59.4 mg, 0.2 mmol) in 1,4-dioxane (2.0 mL), Cs2CO3 (2 N, 1 mL) and 3-cyanophenylboronic acid (58.8 mg, 0.4 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (6.7 mg, 10%). 1H-NMR (MeOD): 2.31 (m, 1H), 2.62 (m, 1H), 3.39 (m, 3H), 4.32 (m, 1H), 4.46 (m, 1H), 7.00 (d, 1H), 7.58-7.71 (m, 3H), 7.95 (m, 3H).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26](=[O:36])[NH:27][CH2:28][C@H:29]([CH3:35])[CH2:30][C:31]([F:34])([F:33])[F:32])[CH:24]=2)[N:19]([CH3:37])[CH:18]=1)[C:9]([O:11]C)=[O:10]>O.CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26](=[O:36])[NH:27][CH2:28][C@H:29]([CH3:35])[CH2:30][C:31]([F:33])([F:32])[F:34])[CH:24]=2)[N:19]([CH3:37])[CH:18]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Yield: 102.3 %

Procedure:
A solution of lithium hydroxide monohydrate (7.68 g) in water (50 mL) was added to a stirred solution of methyl (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate (14.38 g) in methanol (120 mL) and distilled tetrahydrofuran (120 mL) under an inert atmosphere. After 18 h the solvent was evaporated, the residue was dissolved in water (250 mL) and distilled tetrahydrofuran (23 mL), acidified to pH 1 by addition of concentrated hydrochloric acid, and diluted with water (150 mL). The precipitate was collected and washed with water to give (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoic acid (14.28 g, 100%); mp 218°-223° C.; partial NMR (300 MHz, DMSO-d6): 1.00 (d, 3H, CH3), 2.04-2.28 (m, 2H, CF3CH2), 2.32-2.44 (m, 1H, CHCH3), 3.21 (br t, 2H, CH2N), 3.76 (s, 3H, NCH3), 3.90 (s, 3H, OCH3), 4.07 (s, 2H, ArCH2Ar'), 8.43 (br t, 1H, NHCO).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[N:11]([O-])=O.[Na+].[OH-].[K+]>Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH3:9])[N:11]=[N:10][C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: CNc1ccc(Br)cc1N
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cn1nnc2cc(Br)ccc21
Temperature: 5 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
To a solution of 4-bromo-N1-methylbenzene-1,2-diamine (4.2 g, 21 mmol) in hydrochloric acid (2N, 50 ml) was added a solution of NaNO2 (1.52 g, 22 mmol) in water (5 ml) at 0° C. The resulting solution was stirred for 4 h at 0-10° C., adjusted to pH 8 with potassium hydroxide (3N), extracted with dichloromethane (2×200 ml), and the organic layers combined and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (50% dichloromethane in petroleum ether) to afford 5-bromo-1-methyl-1H-benzo[d][1,2,3]triazole as a red solid (1.5 g, 31%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O)#[N:2].CCN(C(C)C)C(C)C.[NH2:23][CH2:24][CH:25]([OH:37])[CH2:26][N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([NH:23][CH2:24][CH:25]([OH:37])[CH2:26][N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)=[O:10])#[N:2]
Reactant: N#Cc1cccc(OCC(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.6 %

Procedure:
To a stirred mixture of 2-(3-cyanophenoxy)acetic acid (100 mg, 0.565 mmol) in DCM (5 mL) was added DIEA (109 mg, 0.85 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (116 mg, 0.565 mmol) and BopCl (173 mg, 0.678 mmol). The resulting mixture was stirred at 25° C. for 16 hours until LCMS showed the completion of the reaction. The reaction mixture was quenched by addition of water (20 mL) then extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the desired final product (24 mg, Yield 12%). 1H NMR (400 MHz, METHANOL-d4) δ 7.48 (dd, J1=J2=7.6 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.25-7.21 (m, 2H), 7.13-7.03 (m, 4H), 4.60 (s, 2H), 4.04-4.00 (m, 1H), 3.71 (s, 2H), 3.44 (d, J=6.0 Hz, 2H), 2.93-2.80 (m, 4H), 2.62 (d, J=5.6 Hz, 2H). LCMS (m/z): 366.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([OH:20])=O)[CH3:2].O=S(Cl)[Cl:23]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([Cl:23])=[O:20])[CH3:2]
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Yield: 89.9 %

Procedure:
A solution of Example B1 (35 g, 126 mmol) in toluene (400 mL) was treated with SOCl2 (120 g, 1.01 mol) and one drop of DMF, and was heated to reflux for 2 h. The mixture was concentrated in vacuo to afford 4-ethoxy-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl chloride (33.5 g, 100% yield). The residue was carried into the next reaction without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[OH-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][C:7]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COc1ccc(-c2ccc3ccc(OC)cc3c2)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of 7-methoxy-2-naphthyl trifluoromethanesulfonate (3.15 g, 10.3 mmol), 4-methoxy-phenylboronic acid (2.2 g, 14 mmol) sodium carbonate (10 mL of 2N aqueous solution), tetrakis(triphenylphosphine)palladium (0.59 g, 0.05 mmol), and 100 mL ethylene glycol dimethyl ether were heated to reflux for 8 hr. The mixture was cooled to room temperature and poured into 100 mL of 1N NaOH, The mixture was extracted with ethyl acetate (3×250 mL), washed with brine (2×100 mL), dried over magnesium sulfate, filtered, evaporation of the solvent and purification by silica chromatography (5%–10% ethyl adetate-hexanes) yielded 2.17 g (79%) of the title compound as a white solid: mp 154° C.; 1H NMR (CDCl3): δ 3.87 (3H, s), 3.94 (3H, s), 7.02 (2H, d, J=8.72 Hz), 7.13 (1H, dd, J=2.54 Hz, J=9.09 Hz), 7.18 (1H, J=2.55 Hz), 7.56 (1H, dd, J=1.82 Hz, J=8.36 Hz), 7.65 (2H, d, J=8.72 Hz), 7.74 (1H, d, J=9.09 Hz), 7.81 (1H, d, J=8.36 Hz), 7.89 (1H, d, J=1.09 Hz); MS (EI) m/z 264 (M).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH:12]=[C:11]3[CH:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Product: Cc1ccc(S(=O)(=O)n2cc(C3CCN(C)CC3)c3cc(OC4CCCCC4)ccc32)cc1

Procedure:
from 5-cyclohexyloxy-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5a, 15.7 mg, 0.05 mmol) and 4-methylphenylsulfonyl chloride (50 mg, 0.26 mmol); HRMS-FAB+ for C27H34N2O3S: calculated MH+ : 467.23685; found: 467.23882.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[C:17]([O:25][C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:66]>C1COCC1.O1CCOCC1>[ClH:66].[F:22][C:21]([F:23])([F:24])[C:20]1[CH:15]=[CH:16][C:17]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:28][CH:27]=2)=[CH:18][CH:19]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of t-butyl-4-hydroxy-1-piperidine carboxylate (1.0 g, 5.0 mmol) in anhydrous THF (5 mL) was added 4-[(4-trifluoromethyl)phenoxy]phenol (1.65 g, 6.5 mmol) in THF (5 mL) and triphenyl phosphine (1.57 g, 6 mmol) in THF (5mL). The resulting mixture was cooled to 0° C. using ice-water bath and purged with nitrogen. Diisopropyl azodicarboxylate (1.21 g, 6 mmol) was dissolved in 5 mL of THF and added to above solution drop wise over a period of 30 min under nitrogen. Reaction then was stirred at 0° C. for 0.5 h heated at 70° C. for 16 h. THF was removed in vacuo and crude mixture was purified by silica gel flash chromatography (10% EtOAc/Hexane) to obtain the product. To a solution of the product in dioxane (4 mL) was added 4M HCl in dioxane (10 mL) at rt and the resulting mixture was stirred for 2 h at that temperature. The solvent was removed in vacuo and residue was triturated with ether to obtain a white solid (1.21 g, 65%): MS; m/z 338.4 (M+H), 1H NMR (400 MHz, DMSO-d6); δ 1.83-1.90 (m, 2H), 2.09-2.14 (m, 2H), 3.03-3.09 (m, 2H), 3.20-3.26 (m, 2H), 3.32 (s, 1H), 4.62-4.66 (m, 1H), 7.06-7.10 (m, 7H), 7.70 (d, 2H, J=8.8 Hz), 9.08 (s, 2H); HPLC (UV); 97%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:9]3[O:10][C:11]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=4[CH:8]3[C:6]=2[CH:7]=1.C1C(=O)N([Br:26])C(=O)C1.[Al]>CN(C=O)C>[Br:26][C:4]1[C:5]2[O:18][CH:9]3[CH:8]([C:6]=2[CH:7]=[C:2]([CH3:1])[CH:3]=1)[C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=1[O:10]3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)OC1Oc3ccc(C)cc3C21
Agent: [Al]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)OC1Oc3c(Br)cc(C)cc3C21
Reaction time: 72 h

Procedure:
The backbone 2,8-dimethyl-5a,10b-dihydrobenzofuro-[2,3-b]benzofuran (1.5 g, 6.3 mmol) and NBS (2.016 g, 11.3 mmol) are dissolved in DMF (100 mL) and stirred at RT for 1 day (flask is covered with aluminium foil). The conversion is monitored by GC/MS. After three days, a mixture of the monobrominated product, the dibrominated product, and the unmodified backbone (monobromo/dibromo/backbone) is formed, in a 75/23/2 ratio, based on weight percents. The solvent is evaporated to dryness and the solid is washed with water and extracted with dichloromethane. The dichloromethane solution is then dried over MgSO4 and evaporated to dryness. The solid obtained is washed with ethanol to give a white solid (1.5 g, containing a mixture of monobromo/dibromo, 75/25). This product (“bromobackbone”) is used in step (b) without further purification.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:14]=[CH:15][CH:16]=2)=[C:8]([C:26]#[N:27])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([C:26]#[N:27])=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH:14]=[CH:15][CH:16]=3)[CH:24]=[CH:25][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: N#Cc1cc(N)ccc1Oc1cccc(NC(=O)C(F)(F)F)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1c(Oc2cccc(NC(=O)C(F)(F)F)c2)ccc2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
Potassium thiocyanate (2.89 g, 29.8 mmol) was suspended in acetic acid (20 mL), and the mixture was stirred at room temperature for 10 min. N-[3-(4-Amino-2-cyanophenoxy)phenyl]-2,2,2-trifluoroacetamide (2.4 g, 7.47 mmol) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (1.31 g, 8.21 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (200 mL)/tetrahydrofuran (40 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (240 mL×2) and saturated brine (240 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was slurry washed with diisopropyl ether to give the title compound (1.68 g, 59%) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:34])[N:4]([C:19]2[CH:20]=[C:21]([NH:26][C:27](=[O:33])OC(C)(C)C)[CH:22]=[CH:23][C:24]=2[F:25])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(N(CC)CC)C.[C:42]([O:45][CH2:46]C(Cl)=O)(=[O:44])[CH3:43].[Cl-].[NH4+]>O1CCCC1>[C:42]([O:45][CH2:46][C:27]([NH:26][C:21]1[CH:22]=[CH:23][C:24]([F:25])=[C:19]([N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Br:1])[C:3]2=[O:34])[CH:20]=1)=[O:33])(=[O:44])[CH3:43]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(NC(=O)OC(C)(C)C)ccc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the compound of Example 722 (0.5 g, 1.05 mmol) in tetrahydrofuran (20 mL) was treated with triethyl amine (0.3 mL, 2.1 mmol) and acetoxy acetylchloride (0.12 mL, 1.15 mmol). After stirring at room temperature for 2 h, the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride. The solids were filtered off and were washed with water and diethyl ether. Title product was isolated as a white solid (0.32 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.65 (m, 3H), 7.32 (t, J=8.4 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.64 (s, 1H), 5.35 (s, 2H), 4.68 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ−111.56 (1F), −115.99 (1F), −129.48 (1F) ppm. LC/MS, tr=5.35 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 540 (M+H). Step 2 Preparation of N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorophenyl}-2-hydroxyacetamide
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)=[CH:7][CH:6]=1.[NH2:28][C:29]([NH2:31])=[S:30].C(N(CC)CC)C>C(O)(=O)C>[NH2:31][C:29]1[S:30][C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=2)=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[N:28]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Agent: BrBr
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(N)sc2-c2ccnc(N)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Bromine (0.68 mL, 13 mmol) was added to a solution of 1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone (4.5 g, 13 mmol) in acetic acid (100 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (40 mL) and to the solution was added thiourea (1.1 g, 14 mmol) and triethylamine (1.9 mL, 14 mmol) were added and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated. A saturated aqueous sodium hydrogencarbonate (200 mL) was added to the residue and the resulting solid was collected by filtration and washed with water. 2N hydrochloric acid (35 mL) was added to the solids and the mixture was stirred at 100° C. for 45 minutes. The reaction mixture was cooled to room temperature and, thereafter, 8N aqueous sodium hydroxide (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (100 mL) were added. The resulting crude crystals were collected by filtration, and were washed with water. The crude crystals were recrystallized from ethanol to obtain 2.7 g of the title compound (9.1 mmol, yield 69%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.Cl.CN(C)CCCN=C=NCC.C(N1CCOCC1)C.OC1C2N=NNC=2C=CC=1.Cl.[CH2:52]([O:54][C:55](=[O:62])[C@H:56]([CH2:58][CH:59]([CH3:61])[CH3:60])[NH2:57])[CH3:53]>C1COCC1>[CH2:52]([O:54][C:55](=[O:62])[C@@H:56]([NH:57][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([N:7]2[CH2:6][CH2:5][CH:4]([CH:3]([O:2][CH3:1])[O:19][CH3:20])[CH2:9][CH2:8]2)=[CH:18][CH:17]=1)[CH2:58][CH:59]([CH3:60])[CH3:61])[CH3:53]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: COC(OC)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(C(OC)OC)CC2)cc1
Yield: 24.2 %

Procedure:
A solution of 4-(4-(dimethoxymethyl)piperidinyl)benzoic acid (0.450 g, 1.6 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide HCl (0.340 g, 1.77 mmol), N-ethyl morpholine (0.50 mL, 3.9 mmol), hydroxybenzotriazole (0.239 g, 1.77 mmol), and L-leucine ethyl ester HCl (0.322 g, 1.8 mmol) in THF (15 mL) was stirred at ambient temperature overnight. The solvent was evaporated in vacuo and the residue was dissolved in methylene chloride. The organic phase was washed with 1N HCl, 1N NaOH, brine and dried (Na2SO4). The solvent was evaporated in vacuo and the residue purified by flash chromatography (methylene chloride-methanol, 19:1) to give 0.163 g of the title compound.
Reaction SMILES: [CH2:1]([N:28]1[C:32]([CH3:34])([CH3:33])[C:31](=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[C:38](C(F)(F)F)[CH:37]=2)[C:29]1=[O:49])[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16](C(F)(F)F)[CH:15]=2)[C:7]1=[O:27].CC1(C)NC(=O)N(C2C=CC([N+]([O-])=O)=C([C:66]([F:69])([F:68])[F:67])C=2)C1=O>>[CH2:1]([N:28]1[C:32]([CH3:33])([CH3:34])[C:31](=[O:35])[N:30]([C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][C:41]=2[C:66]([F:69])([F:68])[F:67])[C:29]1=[O:49])[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:66]([F:69])([F:68])[F:67])[C:7]1=[O:27]
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])cc2C(F)(F)F)C(=O)N1CCCCCN1C(=O)N(c2ccc([N+](=O)[O-])cc2C(F)(F)F)C(=O)C1(C)C
Yield: 12 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, intermediate 11.1 replacing 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-imidazolidine-2,4-dione. The expected compound is obtained in the form of a light yellow foam with a yield of 12%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(O)CCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Yield: 40.9 %

Procedure:
4-Chlorophenylboronic acid (501 mg) was combined with 4-iodobenzoic acid (795 mg), cesium carbonate (5.22 g), toluene (16 mL), water (8 mL) and n-butanol (4 mL). The mixture was degassed under vacuum with argon purging after which, tetrakis-triphenylphosphine palladium (40 mg) was added. The reaction was heated to 80° C. for 20 hours after which, it was cooled to room temperature and diluted with ethyl acetate (16 mL). The solids were collected on a Celite pad and washed with hot methanol. The methanol filtrate was concentrated to dryness giving 4′-chloro-4-biphenylcarboxylic acid (305 mg). Yield=41%