Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:50])[CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:10][C:9]([C:22](=[O:39])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:26]=2)=[CH:8][C:7]=1[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=1.[K+].[Br-]>>[CH2:32]([O:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:22]([C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:6]([O:5][CH2:4][C:3]([OH:50])=[O:2])=[C:7]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:48])([F:49])[F:47])[CH:41]=2)[CH:8]=1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)COc1c(-c2cccc(C(F)(F)F)c2)cc(C(=O)NCc2cccc(OCc3ccccc3)c2)cc1-c1cccc(C(F)(F)F)c1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(-c2cccc(C(F)(F)F)c2)cc(C(=O)NCc2cccc(OCc3ccccc3)c2)cc1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared as a white foam (0.286 g, 74%) from [5′-(3-benzyloxy-benzylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-yloxy]-acetic acid methyl ester using a procedure similar to step 2 of Example 192. 1H NMR (DMSO-d6) δ 12.60 (bs, 1H); 9.50 (bt, 1H); 8.00-7.92 (m, 6H); 7.80-7.68 (m, 4H); 7.44-7.22 (m, 7H), 6.98-6.94 (m, 2H); 5.08 (s, 2H); 4.42 (s, 2H); 3.81 (s, 2H) IR (KBr) 3350, 2950, 1720, 1630, 1610, 1540, 1510, 1460, 1320, 1230, 1210, 1180, 1160, 1120, 1080 cm−1; mass spectrum [(−)ESI], m/z 678 (M−H)−; Anal. Calcd. for C37H27F6NO5: C, 65.39; H, 4.00; N, 2.06, Found: C, 63.35; H, 4.31; N, 2.59.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]([CH3:15])([OH:13])[CH2:14][O:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]([F:26])([F:27])[F:16])=[CH:24][CH:23]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC1(CCn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Product: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(OC(F)(F)F)cc1
Yield: 77 %

Procedure:
Reaction of epoxide 140 with 4-trifluoromethoxyphenol as in Example 2AA at 82° C. for 10 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 0-2% EtOAc/CH2Cl2, gave 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methyl-1-[4-(trifluoromethoxy)phenoxy]-2-butanol (141) (77%) as a pale yellow oil; 1H NMR (CDCl3) δ 7.81 (s, 1H), 7.17 (br dd, J=9.1, 0.7 Hz, 2H), 6.90 (dt, J=9.2, 3.1 Hz, 2H), 4.29 (ddd, J=14.1, 9.5, 6.3 Hz, 1H), 4.24 (ddd, J=14.1, 9.6, 6.5 Hz, 1H), 3.85 (d, J=9.0 Hz, 1H), 3.82 (d, J=9.0 Hz, 1H), 2.23 (ddd, J=13.8, 9.3, 6.5 Hz, 1H), 2.21 (s, 1H), 1.40 (s, 3H); HRESIMS calcd for C15H16ClF3N3O5 m/z [M+H]+ 412.0697, 410.0725. found 412.0700, 410.0722.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[N:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:17]1.C[Mg]Br.[Cl-].[NH4+]>O>[C:7]([C:8]1[C:9]([NH:10][C:5](=[O:6])[C:1]([CH3:4])([CH3:3])[CH3:2])=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:15])[CH3:17]
Reactant: CC(C)(C)c1nc2ncccc2c(=O)o1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)c1cccnc1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-tert-butyl-4H-pyrido[2,3-d][1,3]oxazin-4-one (10.2 g, 50 mmol) and tetrahydrofuran (50 mL) was added methyl magnesium bromide (0.97M tetrahydrofuran solution, 100 mL, 97 mmol) dropwise at −78° C., after the dropwise addition was finished, which was stirred at −78° C. for 30 minutes. To the reaction mixture were added a saturated aqueous solution of ammonium chloride and water, which was extracted with ethyl acetate, and the organic layer was washed with an aqueous solution of ammonium chloride. The solvent was evaporated under a reduced pressure and the precipitated solid was filtered to obtain the title compound (9.1 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=O)C.C[Al](C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:18]([N:17]([CH2:20][CH3:21])[CH2:16][CH2:15][N:14]1[CH2:13][CH2:12][C:7]2[NH:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:4]1=[O:3])[CH3:19]
Reactant: CCOC(=O)c1c(C)c[nH]c1CCNCCN(CC)CC
Agent: C[Al](C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CCN1CCc2[nH]cc(C)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A stirred solution of 2-[2-(2-diethylamino-ethylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (295 mg, 1 mmol) in 5 ml of toluene was added dropwise slowly with 2 M trimethyl aluminum in toluene (1 ml, 2 mmol) under an argon atmosphere. The mixture was stirred for 1 hour at room temperature and heated to reflux for another 4 hours. The reaction mixture was cooled down to 0° C., added with 1N hydrochloric acid (3 ml) and cold water (10 ml), and stirred for 5 minutes. The mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (30 ml×4). The combined organic extracts were filtered through a pad of Celite. The filtrate was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-4-one (242 mg, 97%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[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.O>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:9][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1c(F)cc(O)cc12
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
A 25 ml RBF was charged with (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (629 mg, 1.723 mmol), tetrakis(triphenylphosphine)palladium (199 mg, 0.172 mmol), and pyrimidin-5-ylboronic acid (320 mg, 2.58 mmol). DMF (8613 μL) and sodium carbonate (2M solution) (2584 μL, 5.17 mmol) were added and the mixture was stirred at 85° C. for 2.5 hrs. The mixture was cooled to RT, water (˜5 ml) was added and stirring was continued for 10 min. The precipitate was filtered out, washed with water (3×5 mL), 1:1 i-PrOH/water to remove color and dried in vacuo to afford (S)-2-amino-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as yellow solid. Step 2: A vial was charged with (S)-2-amino-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (61.0 mg, 0.167 mmol), cesium carbonate (82 mg, 0.251 mmol), and DMF (670 μL). The resulting mixture was stirred vigorously for 10 min, then the vial was placed in large ice-bath for 10 min and 2-fluoro-2-methylpropyl trifluoromethanesulfonate (33.3 μL, 0.201 mmol) was added dropwise. The ice bath was removed after 5 minutes and the mixture was stirred at RT for 6 hours before being diluted with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12 g Redi-Sep column, eluting with 5-60% gradient of DCM/MeOH/NH4OH (90:10:1) in DCM to give (S)-4′-fluoro-2′-(2-fluoro-2-methylpropoxy)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([F:10])[CH:9]=1.Cl[CH2:13][CH2:14][CH2:15][OH:16]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([F:10])[CH:9]=1)[O:11][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: Oc1cc(F)cc(F)c1
Reactant: OCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCOc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.77 g (69.18 mmol) of sodium hydride (60% in mineral oil) were dissolved in 80 ml of DMF. At 0° C., 7.50 g (57.65 mmol) of 3,5-difluorophenol in 15 ml of DMF were added dropwise and, after the gas evolution subsided, the mixture was stirred at RT for 30 min. The solution was cooled to 0° C., 5.45 g (57.65 mmol) of 3-chloro-1-propanol in 15 ml of DMF were added, and the mixture was then stirred at 60° C. for 2 h and at 75° C. for 16 h. The precipitated salts were filtered off, and DMF was removed in a rotary evaporator. The residue was taken up in water and extracted twice with diethyl ether. The combined organic phases were washed successively with water, 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) to result in 8.15 g (75% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=3[CH:18]=[N:17]2)=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:25][C:20]2[C:19]3[CH:18]=[N:17][N:16]([CH2:15][C:14]4[CH:26]=[CH:27][C:11]([O:10][CH3:9])=[CH:12][CH:13]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(Cn2ncc3c(N)cccc32)cc1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(Cn2ncc3c(Nc4ccnc(Cl)n4)cccc32)cc1
Temperature: 90 °C
Reaction time: 65 h
Yield: 63.8 %

Procedure:
A suspension of 2,4-dichloropyrimidine (3.71 g, 24.87 mmol), 1-(4-methoxybenzyl)-1H-indazol-4-amine (6 g, 23.69 mmol) and N,N-diisopropylethylamine (4.54 mL, 26.06 mmol) in ethanol (60 mL) was stirred at 90° C. for 65 hours. The reaction mixture was concentrated to dryness, diluted with ethyl acetate (100 ml), washed with water (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 5 to 70% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-indazol-4-amine (5.53 g, 64%) as a pink solid. NMR Spectrum: (DMSOd6) 3.70 (s, 3H), 5.57 (s, 2H), 6.86 (d, 2H), 6.93 (d, 1H), 7.22 (d, 2H), 7.37 (dd, 1H), 7.48 (d, 1H), 7.59 (d, 1H), 8.22 (d, 1H), 8.23 (s, 1H), 10.13 (s, 1H); Mass spectrum: MH+ 366
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:27]([O:29]C)=O)[CH2:25][OH:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11])=[O:6])[CH2:3][OH:4].O.[NH2:39][NH2:40]>>[NH:1]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:27]([NH:39][NH2:40])=[O:29])[CH2:25][OH:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11])=[O:6])[CH2:3][OH:4]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)NN
Reaction time: 2 h

Procedure:
17 g of Boc-Ser-Asn-Leu-Ser-OMe are dissolved in 200 ml of hydrazine hydrate, stirred for 2 hours at 20°, and evaporated to dryness at 25°. The residue is washed with diethylether, dried, and the title compound is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[CH:10][C:9](=[O:21])[N:8]([CH3:22])[CH:7]=1)=[O:5])C.[OH-].[Na+]>CCO>[F:20][C:14]1[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]([CH3:22])[C:9](=[O:21])[CH:10]=1
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 70 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester was dissolved in EtOH (100 mL) and treated with NaOH (2.60 g, 72.0 mmol). This mixture was stirred at 70° C. for 20 hours. The mixture was cooled to room temperature and solvent was removed under reduced pressure. The residue was acidified with 1N HCl then the resulting precipitate was filtered and washed with water. The solid was dried under high vacuum pump to afford 4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid as a white solid (9.0 g, 96%). 1H NMR [(CD3)2SO, 400 MHz] δ 13.27(v br s, 1H), 9.60 (s, 1H), 8.49 (s, 1H), 7.74 (dd, J=10.1, 1.9 Hz, 1H), 7.59 (dd, J=8.4, 1.7, 0.8 Hz, 1H), 7.29 (dd, J=8.5 Hz, 1H), 5.48 (dd, J=0.7 Hz, 1H), 3.38 (s, 3H). (APCI+) calcd for C13H10FIN2O3 388.13 (M−1), found 386.9.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15](Cl)[CH:14]=3)=[N:10][C:9]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[C:19]([F:21])([F:22])[F:20])=[N:10][C:9]=2[CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc2oc(-c3cc(Cl)ncc3C(F)(F)F)nc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2oc(-c3ccncc3C(F)(F)F)nc2c1
Yield: 52.6 %

Procedure:
A mixture of 0.40 g of 5-tert-butyl-2-(2-chloro-5-trifluoromethylpyridin-4-yl)benzoxazole, 0.59 g of 5% palladium on carbon and 25 ml of acetic acid was stirred under about one atmosphere of hydrogen at room temperature for 15 hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.19 g of 5-tert-butyl-2-(3-trifluoromethylpyridin-4-yl)benzoxazole (hereinafter, referred to as “active compound 107”).
Reaction SMILES: [N:1]1([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1.[O:20]=[C:21]1[N:27]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C@@H:37]([C:55](O)=[O:56])[CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[C:41]([CH3:54])[CH:40]=3)=[O:35])[CH2:30][CH2:29]2)[CH2:26][CH2:25][C:24]2[CH:58]=[CH:59][CH:60]=[CH:61][C:23]=2[NH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:20]=[C:21]1[N:27]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C@H:37]([CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[C:41]([CH3:54])[CH:40]=3)[C:55]([N:17]3[CH2:16][CH2:15][CH:14]([N:1]4[CH2:2][CH2:3][CH:4]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6]4)[CH2:19][CH2:18]3)=[O:56])=[O:35])[CH2:30][CH2:29]2)[CH2:26][CH2:25][C:24]2[CH:58]=[CH:59][CH:60]=[CH:61][C:23]=2[NH:22]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: CCOC(=O)COC1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Reaction time: 4 h

Procedure:
220 mg (0.64 mmol) ethyl ([1,4′]bipiperidinyl-4-yloxy)-acetate (used as the bis-hydrochloride salt) were added at RT to a solution of 330 mg (0.58 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1g), 200 mg (0.62 mmol) TBTU and 0.30 mL (2.16 mmol) triethylamine in 3 mL DMF and the mixture was stirred for 4 h. The reaction mixture was combined with saturated NaHCO3 solution while cooling with ice and the precipitate was suction filtered. This was dissolved in a little DCM and EtOH and purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].[CH2:12]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>[Pd]>[F:11][C:6]1[C:7]([F:10])=[CH:8][CH:9]=[C:2]([C:20]2[CH:19]=[CH:18][C:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:22][CH:21]=2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Br)ccc(F)c1F
Reactant: CCCCCc1ccc(B(O)O)cc1
Agent: [Pd]
Product: CCCCCc1ccc(-c2ccc(F)c(F)c2C=O)cc1

Procedure:
2-bromo-5,6-difluorobenzaldehyde is reacted with 4-pentylphenylboronic acid in the presence of a Pd catalyst to give 3,4-difluoro-4′-pentylbiphenyl-2-carbaldehyde. This compound is reacted with trimethylsulfonium iodide, to give 3,4-difluoro-2-(oxiran-2-yl)-4′-pentyl-biphenyl. Without further purification, this compound is converted into 1,2-difluoro-7-pentylphenanthrene in the presence of BF3 etherate. The raw product is purified by the procedure typical for this type of liquid-crystal materials (cf. DE-A 195 00 768), yielding 1,2-difluoro-7-pentylphenanthrene in the form of colorless crystals. Kumar, J. Org. Chem. 1997, 62, 8535-8539 discloses the coupling of boronic acid compounds with a bromo compound having aldehyde functionality.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:33])[C@@H:14]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+].[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[BH4-].[Na+]>C1COCC1.CO>[ClH:1].[CH2:39]([NH:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:33])[C@@H:14]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])=[CH:8][CH:7]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)[C@@H](Cc2ccccc2)NC(=O)OCc2ccccc2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of N-[4-(trans-2-aminocyclopropyl)phenyl]-Nα-[(benzyloxy)carbonyl]-D-phenylalaninamide hydrochloride (100 mg) described in a document (J. Am. Chem. Soc. 2010, 132, 6827.), sodium hydrogen carbonate (27.0 mg), and methanol (4.00 mL) was added benzaldehyde (0.022 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was diluted with dehydrated THF (6.00 mL), and cooled in an ice bath. Sodium borohydride (24.4 mg) was added and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl is acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the fractions containing the object product were combined and concentrated. The residue was dissolved in methanol (5.00 mL), 10% hydrochloric acid methanol solution (1.00 mL) was added, and the mixture was concentrated under reduced pressure to give the title compound (84.6 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[C:33]([NH:36][C:37]1[S:38][C:39]([S:43](Cl)(=[O:45])=[O:44])=[C:40]([CH3:42])[N:41]=1)(=[O:35])[CH3:34]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:43]([C:39]5[S:38][C:37]([NH:36][C:33](=[O:35])[CH3:34])=[N:41][C:40]=5[CH3:42])(=[O:44])=[O:45])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NCCN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)s1

Procedure:
N-[5-({2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}sulfamoyl)-4-methyl-1,3-thiazol-2-yl]acetamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and 2-acetamido-4-methyl-5-thiazolesulfonyl chloride following General Procedure U.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:20]=1[C:21](OCC)=[O:22].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:30][C:27]1[CH:26]=[C:20]2[C:19]([CH2:18][N:1]([C:2]3[CH:3]=[CH:4][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=3)[C:21]2=[O:22])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cc(Cl)ccc1CBr
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)OC(C)(C)C)c1ccc(N2Cc3ccc(Cl)cc3C2=O)cc1
Temperature: 100 °C
Yield: 53.7 %

Procedure:
A mixture of tert-butyl 2-(4-aminophenyl)propanoate (0.24 g, 1.08 mmol), ethyl 2-(bromomethyl)-5-chlorobenzoate (0.25 g, 0.901 mmol) and N,N-diisopropylethylamine (0.14 g, 1.08 mmol) in ethanol (5 mL) was heated in a sealed tube at 100° C. overnight. After this time, the mixture was cooled with an ice bath and the solids collected by filtration to afford tert-butyl 2-(4-(6-chloro-1-oxoisoindolin-2-yl)phenyl)propanoate (0.18 g, 55%) as a white solid: mp 169-171° C.; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.56 (dd, J=8.0, 2.0 Hz, 1H), 7.45 (d, J =8.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 4.84 (s, 2H), 3.63 (m, 1H), 1.45 (d, J=7.5 Hz, 3H), 1.41 (s, 9H); ESI MS m/z 404 [M+H+CH3OH]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:48][C:49]1[CH:54]=[CH:53][C:52](O)=[CH:51][C:50]=1[CH:56]1[O:61][CH2:60][CH2:59][CH2:58][O:57]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:15][C:52]2[CH:53]=[CH:54][C:49]([Br:48])=[C:50]([CH:56]3[O:57][CH2:58][CH2:59][CH2:60][O:61]3)[CH:51]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)c(C2OCCCO2)c1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)C)Oc2ccc(Br)c(C3OCCCO3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (1600 mg, 7.21 mmol) in toluene (72 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2728 mg, 10.81 mmol) at 0° C., followed by the additions of tributylphosphine (2.69 mL, 10.81 mmol) and 4-bromo-3-[1,3]dioxan-2-yl-phenol (2240 mg, 8.65 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving the titled compound (1000 mg).