Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(N(CC)CC)C>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][N:10]1[C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=[CH:9]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: BrCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(ncn2CCCBr)n(C)c1=O
Reaction time: 24 h
Yield: 76.6 %

Procedure:
A solution of theophylline (10.0 g, 0.0555 mol), 1,3-dibromopropane (11.6 ml, 23.1 g, 0.114 mol) and triethylamine (10.5 ml, 7.62 g, 0.0753 mol) in N,N-dimethylformamide (250 ml) was stirred at 60° C. overnight. The stirring was continued one day at room temperature. The solvent was evaporated under reduced pressure. The residue was suspended in CH2Cl2 and water. An emulsion was caused by a fine solid suspended in the mixture. The solid was filtered out and discarded. The aqueous layer was extracted three times with CHCl3. The combined organic layers were dried with MgSO4. Evaporation of the solvent under reduced pressure gave 7-(3-bromopropyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione (12.8 g, 77% yield).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH3:33])[C@H:20]([NH:22]C(=O)OCC3C=CC=CC=3)[CH3:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1>C(O)C.[Pd]>[NH2:22][C@H:20]([CH3:21])[CH:19]([NH:18][C:16]([C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:37][CH:36]=[CH:35][C:34]=3[F:38])[C:7]2=[N:14][C:13]=1[CH3:15])=[O:17])[CH3:33]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)[C@@H](C)N
Reaction time: 1.5 h

Procedure:
235 mg of benzyl {(2R)-3-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-carbonyl)amino]butan-2-yl}carbamate (Example 184A, 0.45 mmol, 1 equivalent) were dissolved in 260 ml of ethanol, and 63 mg of palladium on activated carbon (10%, 0.45 mmol, 1 equivalent) were added. The mixture was hydrogenated at RT under atmospheric pressure for 1.5 h and then filtered through silica gel and concentrated. The residue was dissolved in methanol and purified by preparative HPLC (Method 9). This gave 96 mg (55% of theory) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.Cl>>[OH:1][CH2:2][CH2:3][N:4]([CH2:31][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[S:26][C:19]3[C:18]([NH:17][C:13]4[CH:12]=[C:11]5[C:16](=[CH:15][CH:14]=4)[NH:8][CH:9]=[CH:10]5)=[N:23][CH:22]=[N:21][C:20]=3[CH:24]=2)=[CH:34][CH:33]=1)[CH2:5][CH2:6][OH:7]
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: OCCNCCO
Agent: Cl
Product: OCCN(CCO)Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 2-(2-hydroxy-ethylamino)-ethanol and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. M.P. 110-127° C.; LC-MS: 460 (MH+); HPLC RT: 3.50 minutes.
Reaction SMILES: C(OC([N:8]([CH2:41][C@H:42]([O:49][Si](C(C)(C)C)(C)C)[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:25][S:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:28])=[O:27])=[O:24])=[C:19]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:18]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:57]>O1CCOCC1>[ClH:57].[ClH:57].[CH:35]1([O:34][C:19]2[CH:18]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][CH2:41][C@H:42]([OH:49])[C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)=[CH:16][CH:15]=3)[CH:22]=[CH:21][C:20]=2[C:23]([NH:25][S:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:27])=[O:28])=[O:24])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCC(=O)O)c(OC3CCCCC3)c2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3cccnc3)cc2)cc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 3-[[[[4′-[2-[(tert-Butoxycarbonyl)[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylyl]carbonyl]amino]sulfonyl]-propionic acid (49.7 mg) was added 4N hydrogen chloride in 1,4-dioxane (1.5 ml). After stirring at room temperature for 12 hours, the mixture was evaporated to give 3-[[[[3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-4-biphenylyl]carbonyl]amino]sulfonyl]propanoic acid dihydrochloride (41.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[C:19]4[C:14](=[N:15][CH:16]=[CH:17][N:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][N:3]=1.ClC(OC1C=CC=CC=1)=O.ClC1N=C2C(C=CC(N3C(O)C4C(=NC=CN=4)C3=O)=N2)=CC=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[C:19]4[C:14](=[N:15][CH:16]=[CH:17][N:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:10][CH:11]=1
Reactant: O=C(Oc1ccccc1)OC1c2nccnc2C(=O)N1c1ccc2cnc(Cl)cc2n1
Agent: O=C(Cl)Oc1ccccc1
Agent: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 60 °C

Procedure:
6-(7-Chloro-1,6-naphthyridin-2-yl)-7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine can be prepared by adding phenyl chloroformate (9.4 g.) to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (6.3 g.) in anhydrous pyridine (63 cc.), with stirring and whilst keeping the temperature at about 5° C. When the addition is complete, the reaction mixture is gradually heated to 60° C. and this temperature is maintained for 1 hour. The reaction mixture is cooled and is then poured into distilled water (350 cc.) whilst keeping the temperature at about 10° C. The insoluble product is filtered off, and washed successively with water (120 cc.), acetonitrile (40 cc.) and diisopropyl ether (40 cc.). After drying, 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (7.2 g.), melting at 270° C., is obtained.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[I:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[I:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][O:17][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)=[CH:12][CH:13]=1
Reactant: OCCCc1ccc(I)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: Ic1ccc(CCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
3,4-Dihydro-2H-pyran (2.5 mL, 27.4 mmol) and pyridinium p-toluenesulfonate (450 mg, 1.79 mmol) were added to a chloroform (50 mL) solution of 3-(4-iodophenyl)propan-1-ol (4.73 g, 18.0 mmol), and stirred overnight at room temperature. The reaction liquid was diluted with chloroform, washed with saturated saline, dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (C-200, ethyl acetate:hexane=1:9 to 1:4) to obtain the entitled compound (6.22 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CCO[C:12]([C:14]1[C:23](=[O:24])[O:22][C:21]2[C:16](=[CH:17][C:18]3C[CH2:30][CH2:29][N:28]4[C:19]=3[C:20]=2C[CH2:26][CH2:27]4)[CH:15]=1)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:30][CH2:29][N:28]([C:19]1[CH:18]=[CH:17][C:16]2[CH:15]=[C:14]([C:12]3[S:8][C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:1]=3)[C:23]([O:22][C:21]=2[CH:20]=1)=[O:24])[CH2:27][CH3:26]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc2cc(-c3nc4ccccc4s3)c(=O)oc2c1
Temperature: 25 °C

Procedure:
The diphenyl analog of coumarin 6 was prepared by the thermal condensation of 2-aminothiophenol with the diphenyl analog of coumarin 314. 7.5 g of the diphenyl analog of coumarin 314 prepared according to Example 1, 2.45 g of 2-aminothiophenol, 15 g diphenyl, and 15 g phenyl ether were placed in a 50 ml round bottom flask and taken to reflux for 30 minutes. After cooling to room temperature, 50 ml of toluene was added and the product was isolated by filtration, washed with ether, dried in vacuum, and recrystallized from methylene chloride/ethyl acetate.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]([NH:8][C@H:9]([C:17]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCC1

Procedure:
2.65 g (10 mmol) BOC-L phenylalanine was coupled to 1.48 ml (17.8 mmol) pyrrolidine according to procedure B. Yield of active ester 3.22 g (8.9 mmol, 89%). Yield of crude product 3.33 g. The product was purified with a silica column using 1–2% methanol in dichloromethane as eluent. Yield 1.76 g (5.5 mmol, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:10])[CH3:9]>>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccccc1
Yield: 79 %

Procedure:
Acetanilide is prepared by the method of Example 5 using 5.0 mls (0.055 mole) of aniline, 7.5 grams of Type 3A molecular sieves, and 4.58 mls (0.064 mole) of acetyl chloride. The crude product is recrystallized from toluene to obtain 5.87 grams (81% of theoretical) of pure acetanilide, m.p. 112°-114° C. (literature m.p. 114° C.).
Reaction SMILES: C(N)C1C=CC=CC=1.C(N)C.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.[F:21][C:22]1[CH:44]=[CH:43][C:25]([CH2:26][N:27]2[CH2:31][CH2:30][N:29]([C:32]3[CH:33]=[C:34]([CH:39]=[CH:40][N:41]=3)[C:35](OC)=[O:36])[C:28]2=[O:42])=[CH:24][CH:23]=1>>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:35](=[O:36])[C:34]2[CH:39]=[CH:40][N:41]=[C:32]([N:29]3[CH2:30][CH2:31][N:27]([CH2:26][C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:44][CH:43]=4)[C:28]3=[O:42])[CH:33]=2)=[CH:15][CH:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: CCN
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 50 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 4-fluorobenzylamine ethanamine to react with methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate, N-(4-fluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 50% yield: mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.41-7.39 (m, 1H), 7.31-7.21 (m, 4H), 7.04-6.96 (m, 4H), 6.84 (br s, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.40 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.36 (t, J=8.1 Hz, 2H); MS (ES+) m/z 423.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:28]([C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]>C1COCC1.C(OCC)(=O)C>[C:28]([C:30]1[CH:31]=[C:32]([S:37]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 70.8 %

Procedure:
N-(2,4-Dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 18, 42.8 g, 170 mmol) was dissolved in anhydrous THF (600 mL) and stirred under a nitrogen atmosphere at −78° C. A 1M solution of LiHMDS in THF (238 mL, 238 mmol) was added dropwise over 30 minutes maintaining the temperature between −65° C. and −70° C. The reaction mixture was left at −78° C. for 5 minutes, then allowed to warm to −10° C. over 1.5 hours. Upon reaching −10° C., the brown reaction mixture was cooled to −78° C. again, and a solution of 3-cyano-4-fluorobenzene sulfonyl chloride (48.6 g, 221 mmol) in THF (200 mL) was added dropwise over 30 minutes maintaining the temperature between −65° C. and −70° C. The brown solution was allowed to warm gradually to ambient temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with a saturated ammonium chloride solution, and extracting with further ethyl acetate. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a brown residue. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution) to afford the title compound as a white solid (52.3 g, 71%).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([Br:28])[CH:25]=[C:24]([Br:29])[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])C.[OH-].[Na+]>C(O)C>[C:32]([CH2:31][CH2:30][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([Br:29])[CH:25]=[C:26]([Br:28])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:37])=[O:3])([OH:34])=[O:33]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(Br)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(Br)c2)c1CCC(=O)O
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of 4-{3-[6-(3,5-dibromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (1.5 g, 2.33 mmol) in ethanol (30 mL) was added aqueous 1 N sodium hydroxide (25 mL) at room temperature. The resulting suspension was heated to 50-55° C. and the mixture was stirred for 3 h. Then, the reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with diethyl ether (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1 N hydrochloric acid and the organic compound was extracted into ethyl acetate (2×50 mL). The combined ethyl acetate extracts were washed with brine solution (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give the crude product which was purified by using an ISCO 40 g column, eluting with 0-100% ethyl acetate/hexanes to isolate 4-{2-(2-carboxy-ethyl)-3-[6-(3,5-dibromo-phenoxy)-hexyl]-phenoxy}-butyric acid (1.26 g, 92%) as a white solid: ES(+)-HRMS m/e calculated for C25H30Br2O6 (M+Na)+ 607.0301, found 607.0298.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])([CH3:24])([CH3:23])[CH3:22]
Reactant: Oc1ccc(F)cc1Br
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(F)cc1Br
Yield: 83.3 %

Procedure:
A solution of 2-bromo-4-fluorophenol (2.15 g, 11.25 mmol) in DMF (60 ml) was treated with potassium carbonate (7.77 g, 96.25 mmol) and t-butyl bromoacetate (1.99 ml, 13.5 mmol) at 60° C. for 12 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5%-10% ethyl acetate/hexanes gradient to give the product as colorless oil (2.86 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH2:18][CH3:19]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(O)ccc1Br
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(Br)c(OC)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
Prepare a solution of 4-bromo-3-methoxyphenol (6.5 g, 32 mmole), and potassium carbonate (15 g) in acetone (250 mL) under argon. Add n-propyl iodide (9.0 g, 5.2 mL, 53 mmole) and heat to reflux overnight. Cool to room temperature and filter. Rotovap to condense and evaporate the solvents. Check by thin layer chromatagraphy (25% ethyl aceate/75% hexane). Wash three times with 100 mL 3% potassium hydroxide. Dry the organic layer with magnesium sulfate. Filter and rotovap. Purify by chromatography and place under high vacuum to obtain the title compound (6.9 g, 88%). Rf=0.60 (EtOAc/hexane; 25:75).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:30])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)ccc1OC(=O)N1CCOCC1
Yield: 95.1 %

Procedure:
Using 5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[C:35]1([C:41](=[O:47])[CH2:42][C:43](=O)[CH2:44][CH3:45])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:44](/[C:43](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:42]/[C:41](=[O:47])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:45]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCC(=O)CC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 1.03 g (2.1 mmol) of Intermediate 45 (as the TFA salt) and 740 mg (4.2 mmol) of Intermediate 16 to yield 500 mg of Example 20 as a white solid: TLC (EtOAc/MeOH, 7/3): Rf=0.35; 1H NMR (DMSO-d6, 400 MHz) δ11.55 (d, 1H, J=9.6), 7.93 (d, 2H, J=7.8), 7.84 (d, 2H, J=7.8), 7.57 (m, 3H), 7.52 (m, 3H), 7.18 (d, 2H, J=8.4), 6.87 (d, 2H, J=8.4), 5.58 (s, 1H), 4.21 (t, 2H, J=6.6), 4.16 (m, 1H), 3.21 (m, 1H), 2.95 (t, 2H, J=6.6), 2.80 (dd, 1H, J=13.5, 9.0), 2.42 (s, 3H), 2.08 (m, 2H), 1.04 (t, 3H, J=7.8); low resolution MS (ES+)m/e 525 (MH+).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[CH2:35][C@H:34]([OH:36])[CH2:33][C@H:32]3[CH2:37][OH:38])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.[C:49](OC(=O)C)(=[O:51])[CH3:50]>ClCCl.Cl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([CH3:17])[C:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:22][C:21]([N:31]3[CH2:35][C@H:34]([OH:36])[CH2:33][C@H:32]3[CH2:37][O:38][C:49](=[O:51])[CH3:50])=[N:20][CH:19]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1-c1cc(N2C[C@H](O)C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1C[C@@H](O)CN1c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
To a solution of 1.5 g (2.4 mmol) (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide and 0.4 ml (5 mmol) pyridine in 24 ml dichloromethane were added dropwise at room temperature 0.22 ml (2.4 mmol) acetic anhydride. After stirring at room temperature for 20 h the reaction mixture was diluted with a 0.1 M aqueous hydrochloric acid solution and extracted with 3 portions of dichloromethane. The combined organic extracts were washed with a 2 M aqueous sodium carbonate solution, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 1.1 g (71%) of the title compound as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][C:30]=4[F:32])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccc(F)cc1F
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(F)cc1F
Yield: 16.4 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2,4-difluorophenylboronic acid (available from Frontier Scientific, Inc.; 79 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′,4′-difluoro-biphenyl-2-carboxylic acid (19 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ 13.17 (br s, 1H), 8.46-8.52 (m, 2H), 8.33 (d, J=2.0 Hz, 1H), 8.26-8.31 (m, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.44-7.52 (m, 1H), 7.27-7.36 (m, 1H), 7.15-7.24 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].I[CH3:12].[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH2:9][O:10][CH3:12])=[CH:5][N:6]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of (5,6-dichloro-pyridin-3-yl)-methanol (356 mg, 2.0 mmol, Aldrich) and iodomethane (0.25 mL, 4.0 mmol, Aldrich) in DMF (3.0 mL) was added NaH (120 mg, 3.0 mmol, Aldrich, 60% dispersion in mineral oil) portionwise with stirring at room temperature. The mixture was stirred for 30 min at room temperature, saturated aqueous solution of NH4Cl (10 mL) was added, and the mixture was extracted with EtOAc (2×30 mL). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 20% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 192 (M+1).