Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[C:15](Br)Br)=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:32][O:33][P:34](Cl)([CH2:36][C@@H:37]([O:43][Si:44]([C:57]([CH3:60])([CH3:59])[CH3:58])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:35]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[C:15][P:34]([O:33][CH3:32])([CH2:36][C@@H:37]([O:43][Si:44]([C:57]([CH3:58])([CH3:60])[CH3:59])([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:35])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1nc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=C(Br)Br
Reactant: COC(=O)C[C@@H](CP(=O)(Cl)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](CP(=O)(C#Cc1c(-c2ccc(F)cc2)nc(-c2ccccc2)nc1C(C)C)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
In a separate flask, a solution of 4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenyl-5-(2,2-dibromovinyl)-pyrimidine obtained in step (v) above (1.000 gm, 2.10 mmol) in tetrahydrofuran (THF) (10 ml) was added dropwise to a -78° C. THF solution (15 ml) of n-butyl lithium (nBuLi) (2.5M in hexane, 1.68 ml, 4.20 mmol). The solution was allowed to stir 1 hour at -78° C., then cannulated into a THF solution (20 ml) of (S)-4-(methoxychlorophosphinyl)-3-[[(t-butyl)diphenylsilyl]-oxy]butanoic acid, methyl ester obtained in step (f) above which had also been cooled to -78° C. The resultant solution was stirred for 30 minutes, then quenched with saturated NH4Cl (15 ml) and warmed to 0° C. Then, saturated NaHCO3 was added to the solution which was subsequently warmed to room temperature. The mixture was diluted with ether and the organic layer was washed with brine, then dried over Na2SO 4, filtered and concentrated to give an orange oil. The oil was purified by flash chromatography on Merck silica gel in 30-50% EtOAc in hexane. The desired fractions were combined and evaporated to afford the title compound as yellow foam (0.732 gm, 49%). TLC: Rf =0.50 (50% EtOAc in hexane).
Reaction SMILES: [C:1]([C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([O-:7])=[O:6])#[N:2].[Na+].S(OC)(O[CH3:17])(=O)=O>>[C:1]([C:3]([F:10])([F:11])[C:4]([F:8])([F:9])[C:5]([O:7][CH3:17])=[O:6])#[N:2]
Reactant: N#CC(F)(F)C(F)(F)C(=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Product: COC(=O)C(F)(F)C(F)(F)C#N
Reaction time: 8 h
Yield: 58 %

Procedure:
After being maintained at about 25° for 2 more days, the reaction mixture, which contained sodium 3-cyanotetrafluoropropionate, was treated with 69.3 g (0.55 mole) of dimethyl sulfate, stirred, and allowed to stand overnight. Fractionation of the volatile products gave 53.3 g (58%) of methyl 3-cyanotetrafluoropropionate, bp 90°-97°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]=[O:15]>C1COCC1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][NH:13][C:14]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)=[O:15])[CH3:21]
Reactant: CCOC(=O)CN=C=O
Reactant: Cc1cc(N)c2ccccc2n1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Nc1cc(C)nc2ccccc12
Temperature: -14 °C
Reaction time: 4 h

Procedure:
A suspension of 4-amino-2-methylchinoline (4.0 g, 25.3 mmol) in dry THF (80 mL) is cooled to −14° C. and ethyl isocyanatoacetate (3.3 mL, 27.4 mmol) is added dropwise under vigourous stirring. The reaction is warmed to room temperature and stirred for 4 h. Further ethyl isocyanatoacetate (0.6 mL, 5 mmol) is added and the reaction mixture stirred for 15 h. The solvent is evaporated and the residue crystallized from CHCl3-heptane (1/5) to provide the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([CH:14]1[S:18][CH2:17][NH:16][C@H:15]1[C:19]([OH:21])=O)=[O:13].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([CH:14]1[S:18][CH2:17][NH:16][C@H:15]1[C:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:13]
Reactant: O=C(C[C@H]1CCc2ccccc2C1)C1SCN[C@H]1C(=O)O
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C(C[C@H]1CCc2ccccc2C1)C1SCN[C@H]1C(=O)N1CCCC1
Yield: 65 %

Procedure:
Colorless crystals of 1-{3-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-D-thioprolyl}pyrrolidine were prepared in the same manner as in Example 1, except that 3-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-D-thioproline prepared in Reference Example 32 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]([F:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC#N>[CH2:29]([N:10]1[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:22])=[C:9]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2F)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(4-chloro-2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1.33 g, 3.96 mmol) in dry MeCN (20 mL) was added K2CO3 (1.10 g, 7.92 mmol) and benzyl bromide (521 μL, 4.36 mmol). The reaction mixture was stirred overnight at 80° C. Addition of silica (ca. 2 g) was followed by filtration; the filtrate was concentrated in vacuo. The product was co-evaporated twice with toluene (30 mL), to result in 1.75 g (99%, 95% purity) of the desired product as a clear oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1>[F:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccc(F)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 163.2 %

Procedure:
To a solution of 6-fluoro-2-pyridinecarboxylic acid (15.0 g, 106.3 mmol) in tetrahydrofuran (200 ml) was added 1,1′-carbonylbis-1H-imidazole (19.0 g, 116.9 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled and monoethyl malonate magnesium salt (16.8 g, 58.5 mmol) was added. The mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid (200 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(6-fluoro-2-pyridyl)-3-oxopropionate (20.16 g, 90%) as a brown oil.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.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>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[C:10]3[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=2)[CH:28]=[N:27]1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(N3CCOCC3)ncnc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N4CCOCC4)c23)cn1
Temperature: 100 °C

Procedure:
To a solution of 5-iodo-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (P1) (500 mg, 1.1 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (272 mg, 1.31 mmol) in a mixture of ethanol and water (4:1, 10 mL) were added dichlorobis(triphenylphosphine)palladium(II) (41 mg, 58 μmol) and potassium carbonate (447 mg, 3.23 mmol). The reaction mixture was degassed and purged with nitrogen; this procedure was carried out a total of three times. It was then heated at 100° C. for 18 hours. After concentration in vacuo, the residue was purified via chromatography on silica gel (Eluent: 1:1 ethyl acetate/petroleum ether) to provide the product as a yellow solid. Yield: 200 mg, 0.48 mmol, 44%. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 5.57 (s, 2H), 3.90 (s, 3H), 3.50-3.58 (m, 6H), 3.20-3.27 (m, 4H), 0.83 (dd, J=8.0, 7.9 Hz, 2H), −0.09 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[N:8]([C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][C:25]=2[CH3:33])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:10][CH:11]=1)C.[OH-].[Na+]>CO>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([N:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=3[O:22][CH3:23])=[CH:10][CH:11]=[C:7]2[CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[C:25]([CH3:33])[CH:26]=1)(=[O:32])[NH2:31]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C(=O)OC)cc2OC)n1-c1ccc(C(N)=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(C(N)=O)cc2C)c(OC)c1
Reaction time: 18 h
Yield: 64.9 %

Procedure:
3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-methoxycarbonylmethoxy-phenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester 16B (57 mg, 0.12 mmol) was dissolved in 1 mL methanol. 1 N NaOH (0.25 mL, 0.25 mmol.) was added. After 18 hrs, the reaction was concentrated in vacuo and diluted with water. The pH was adjusted to 1 with 1 M HCl and extracted with EtOAc (3×4 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with hexanes and dried under high vacuum to yield 3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-methoxycarbonyl-methoxyphenyl)-1H-pyrrol-2-yl]-propionic acid (16C) (34 mg, 65%, light yellow powder).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](O)=[C:8]([C:11]#[N:12])[CH:7]=[N:6][N:5]2[CH:13]=1.O=P(Cl)(Cl)[Cl:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([Cl:16])=[C:8]([C:11]#[N:12])[CH:7]=[N:6][N:5]2[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnn2cc(Br)cc2c1O
Product: N#Cc1cnn2cc(Br)cc2c1Cl
Temperature: 75 °C
Yield: 47.7 %

Procedure:
To a 25 mL round bottom flask was added 6-bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carbonitrile (16.5 g, 69.47 mmol) and POCl3 (85 mL, 0.88 mol) and the reaction mixture was stirred and heated at 75° C. for 3 hours. The POCl3 was removed under vacuum and the resulting residue was dissolved in CH2Cl2. The solution was cooled to 0° C. and saturated aq. NaHCO3 solution was added and the biphasic mixture was stirred vigorously while allowing to warm to rt. The organic layer was separated and concentrated and the obtained residue was purified by flash silica gel column chromatography to yield 8.5 g (29%) of the title compound as a yellow solid. HPLC (condition P): retention time=16.74 min. 1H NMR (400 MHz, CDCl3) δ ppm: 8.09 (1H, s), 7.94 (1H, d, 2.0 Hz), 7.06 (1H, d, 2.0 Hz).
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])[CH:2]=[CH2:3].CCN(CC)CC.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>C1COCC1>[CH2:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:13])([F:14])[F:15])[CH:8]=[CH:7][C:5]=1[NH:6][C:23](=[O:26])[CH:24]=[CH2:25])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: C=CCc1cc(OC(F)(F)F)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCc1cc(OC(F)(F)F)ccc1NC(=O)C=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-allyl-4-(trifluoromethoxy)aniline (17.5 g, 80.6 mmol) in THF (1000 ml), cooled in a dry ice bath to a temperature below −10° C. was added Et3N (8.96 g, 17.3 mmol) and acryloyl chloride (7.98 g, 88.7 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. The resulting mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and brine. The organic portion was dried over Na2SO4, filtered and concentrated in under reduced pressure to give a white solid which was washed with ethyl acetate to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16].[Cl-].[Li+].C1(C)C=CC=CC=1>CCOC(C)=O.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>[CH3:13][C:3]1[C:2]([CH2:16][CH:15]=[CH2:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][O:7][C:8]2=[O:12]
Reactant: Cc1c(Br)ccc2c1CCOC2=O
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1C)CCOC2=O

Procedure:
To a flask charged with 6-Bromo-5-methyl-3,4-dihydro-1H-isochromen-1-one (100 mg, 0.42 mmol), Allyl Tri-n-butyltin (165 mg, 0.50 mmol), Palladium Tetrakis (48 mg, 0.041 mmol), and Lithium Chloride (35 mg, 0.83 mmol) was added Toluene (5 ml). The mixture was sealed with a condenser and purged three times with N2. The mixture was then heated to reflux for 6 hours. TLC and LC showed complete reaction. The reaction was diluted with EtOAc (50 mL), washed with brine, dried over sodium sulfate, adsorbed onto silica, and purified by MPLC (Hex/EtOAc gradient) to furnish the product. LC-MS (IE, m/z): 203 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([C:14]2[CH:15]=[C:16]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:17]=[C:18]([C:20]([O:22]C)=[O:21])[CH:19]=2)[C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])C.O.O[Li].O>C1COCC1>[C:20]([C:18]1[CH:19]=[C:14]([N:9]2[C:10]([CH:11]([CH3:13])[CH3:12])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]2)[CH:15]=[C:16]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[CH:17]=1)([OH:22])=[O:21]
Reactant: CCOC(=O)c1nnn(-c2cc(C(=O)OC)cc(-c3ccc(C)cc3)c2)c1C(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnc(C(=O)O)c3C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 5-isopropyl-1-(5-methoxycarbonyl-4′-methyl-biphenyl-3-yl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester from step 1 was dissolved in THF (7 mL) and water (4 mL) and LiOH.H2O (184 mg, 4.38 mmol) were added as a single portion. The reaction mixture was stirred at room temperature for three hours. Solvent was removed under reduced pressure and the remaining aqueous solution was acidified with concentrated HCl to pH˜1. The solution was extracted with EtOAc and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-(5-carboxy-4′-methyl-biphenyl-3-yl)-5-isopropyl-1H-[1,2,3]triazole-4-carboxylic acid light yellow solid (260 mg), which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][C@@H:11]([CH3:24])[NH:12][C:13](=[O:23])[CH2:14][NH:15]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>CCOC(C)=O>[ClH:26].[CH2:1]([O:8][C:9](=[O:25])[CH2:10][C@@H:11]([CH3:24])[NH:12][C:13](=[O:23])[CH2:14][NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CN
Reaction time: 0.5 h

Procedure:
N-t-Butoxycarbonylglycyl-3(R)-methyl-β-alanine benzyl ester 2-4 (3.32 g) in EtOAc (100 mL) cooled to -60° C. was treated with HCl gas until saturated. The mixture was stirred for 30 minutes then the solvent was removed and the residue triturated with ether to give 2-5 as a solid. ##STR59##
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:43][N:44]1[CH2:47][CH:46]([NH2:48])[CH2:45]1>>[CH3:41][C@@H:39]1[CH2:40][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([NH:48][CH:46]4[CH2:47][N:44]([CH3:43])[CH2:45]4)=[O:29])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:36][C@H:37]([CH3:42])[O:38]1
Reactant: CN1CC(N)C1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)NC4CN(C)C4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1-methylazetidin-3-amine
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:15][C:14]=1[C:25]1[C:26]([S:31]([N:34]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[C:42]=2[CH3:47])COCCOC)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.CC1C(C)=C(NS(C2C(C3C=CC(C4N=CC=CN=4)=CC=3C=O)=CC=CC=2)(=O)=O)ON=1>CN(C)C=O.O>[CH3:46][C:43]1[C:42]([CH3:47])=[C:41]([NH:34][S:31]([C:26]2[C:25]([C:14]3[CH:15]=[CH:16][C:17]([C:19]4[N:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:18][C:13]=3[CH2:12][N:4]3[CH2:5][CH2:6][C:2]([CH3:8])([CH3:1])[C:3]3=[O:7])=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:33])=[O:32])[O:45][N:44]=1
Reactant: CC1(C)CCNC1=O
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncccn2)cc1CBr
Agent: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncccn3)cc2C=O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncccn3)cc2CN2CCC(C)(C)C2=O)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of the 3,3-dimethyl-2-pyrrolidinone so prepared (0.033 g, 0.29 mmol) in 1 mL of dimethylformamide ("DMF"), NaH (60% suspension in mineral oil, 0.015 g, 0.36 mmol) was added and the mixture was stirred at room temperature under argon for 10 minutes. 2'-(Bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)[1,1'-biphenyl]-2-sulfonamide (prepared as described in Step A of Example 14, except that the title compound of Step F of Example 11 was employed in place of N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)[1,1'-biphenyl]-2-sulfonamide; 0.085 g, 0.145 mmol) was then added and the mixture was stirred for 3 hrs. The mixture was then added to 50 mL water and the solution was extracted with 3×25 mL EtOAc. The combined organic extracts were washed with water and dried and evaporated to afford 0.086 g (95%) of the title compound of this step as a colorless gum.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]([C@@:14]([NH:30][S:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:33])=[O:32])([B:16]([O:18][C:19]2([CH3:29])[CH2:24][CH2:23][CH:22]3[CH2:25][C:20]2([OH:28])[C:21]3([CH3:27])[CH3:26])[OH:17])[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([C:8]1[CH:9]=[C:10]([C@@:14]([NH:30][S:31]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:33])=[O:32])([B:16]([O:18][C:19]2([CH3:29])[CH2:24][CH2:23][CH:22]3[CH2:25][C:20]2([OH:28])[C:21]3([CH3:26])[CH3:27])[OH:17])[CH3:15])[CH:11]=[CH:12][CH:13]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1cccc([C@@](C)(NS(=O)(=O)Cc2ccccc2)B(O)OC2(C)CCC3CC2(O)C3(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(OB(O)[C@](C)(NS(=O)(=O)Cc2ccccc2)c2cccc(C(=O)O)c2)CCC2CC1(O)C2(C)C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
A solution of 15b (90 mg, 0.16 mmol) in dichloromethane (2 mL) was cooled to −10° C. and treated with an excess of trifluoroacetic acid (10% v/v soln in dichloromethane, 2 mL). After 10 min at −10° C., the mixture was allowed to react at room temperature for 5 h. The solution was concentrated in vacuo and the residue crystallized from diethyl ether affording (+)-pinanediol (1R)-2-[3-carboxyphenyl]-1-(phenylmethanesulfonylamino)ethaneboronate (79 mg, 100% yield) as a cream coloured solid. Mp 155-158° C. [α]D+25.9 (c 0.6, CHCl3). 1H-NMR (400 MHz, CDCl3): δ 0.87 (3H, s, pinanyl CH3), 1.06 (1H, d, J 10.8, pinanyl Hendo), 1.31 (3H, s, pinanyl CH3), 1.33 (3H, s, pinanyl CH3), 1.88-2.38 (5H, m, pinanyl protons), 2.99 (1H, dd, J 13.7, 6.0, CHCH2), 3.15 (1H, dd, J 13.7, 5.6, CHCH2), 3.37 (1H, br, BCH), 4.31 (2H, s, CH2SO2), 4.40 (1H, d, J 7.7, CHOB), 4.51 (1H, br, SO2NH), 7.30-7.58 (7H, m, HArom), 7.97-8.01 (2H, m, HArom), 10.2 (1H, br, COOH). 13C-NMR (100 MHz, CDCl3): δ 24.0, 26.3, 27.0, 28.3, 35.0, 38.2, 38.5, 39.4, 42.4 (CB), 51.1, 59.2, 78.8, 87.3, 128.5, 128.6, 128.7, 127.2, 129.3, 129.4, 130.8, 131.2, 135.6, 139.0, 171.8. Anal. Calcd. for C26H32BNO6S: C, 62.78; H, 6.48; N, 2.82; S, 6.45. Found: C, 62.61; H, 6.72; N, 2.64; S, 6.21.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][CH2:11][C:10]=2[CH:20]=1>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([C:1]([Cl:4])=[O:2])[CH2:11][C:10]=2[CH:20]=1
Reactant: Clc1ccc2c(c1)CNc1ccccc1O2
Reactant: O=C(Cl)Cl
Product: O=C(Cl)N1Cc2cc(Cl)ccc2Oc2ccccc21

Procedure:
2-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carbonyl chloride (43) is prepared in the manner described in Example 2 using phosgene and 2-chloro-10,11-dihydrodibenz[b,f][1,4]-oxazepine (42), prepared in the manner described above in Example 42.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:7]1([C@@H:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]=2[CH2:36]Br)=[O:18])[CH2:14][CH3:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)C>O1CCCC1>[C:7]1([C@@H:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]=2[CH2:36][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[O:18])[CH2:14][CH3:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCCN1
Reactant: CC[C@H](NC(=O)c1c(CBr)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(CN2CCCC2=O)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of 2-pyrrolidinone (0.1 ml) in tetrahydrofurane (2 ml) sodium hydride (20 mg, 60% dispersion in mineral oil) was added. The reaction mixture was stirred at ambient temperature until the gas evolution ceased then 3-bromomethyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (30 mg) was added. After 30 min acetic acid (0.05 ml) was added and volatiles were removed in vacuo. The product was purified by flash chromatography on SiO2 (5 g, 1,2-dichloroethane then gradient 50% to 100% ethyl acetate in heptane) to give 17 mg of white solid. Yield 56%. LC-MS (m/z) 480.5 (MH+); tR=1.21.