Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CCOC(C)=O>[OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[C:3]([O:5][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: Cc1cccc(C[C@@H](O)C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cccc(C[C@@H](O)C(=O)OCc2ccccc2)c1

Procedure:
A solution of (R)-2-hydroxy-3-(3-methylphenyl)-propionic acid (6.3 g, 35.0 mmol), benzyl bromide (5.4 mL, 45.5 mmol) and triethylamine (7.31 mL, 52.4 mmol) in EtOAc (100 mL) is refluxed for 6 hours. After cooling, the solution is washed with 1 N HCl (150 mL), water (200 mL), sat'd NaHCO3 (200 mL) and brine (300 mL), dried (MgSO4), evaporated and chromatographed (silica, 10% EtOAc/hexane) to yield benzyl (R)-2-hydroxy-3-(3-methylphenyl)-propionate, as a clear oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:3]([OH:15])[CH2:4][NH:5][C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.Cl[Si:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C@@H:3]([O:15][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH2:4][NH:5][C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:11])[CH3:12]
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)CCOC(=O)NC[C@H](O)[C@@H](N)CC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)NC[C@H](O[Si](C)(C)C)[C@@H](N)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 2-(trimethylsilyl)ethyl (2S,3S)-3-amino-4-cyclohexyl-2-hydroxybutylcarbamate (0.18 g, 0.54 mmol) in anhydrous CH2Cl2 (1.5 mL) at 0° C., triethylamine (0.41 mL, 2.70 mmol) was added, followed by chlorotrimethylsilane (176 mg, 1.62 mmol). The resulting white mixture was warmed to rt slowly, and stirred at rt for another 40 min. Solvent was removed under vacuum, and the residue was redissolved in anhydrous CH2Cl2 (1 mL), and evaporated to dryness under vacuum to give 2-(trimethylsilyl)ethyl (2S,3S)-3-amino-4-cyclohexyl-2-(trimethylsilyloxy)butylcarbamate (quant.) as a white solid; MS m/z 403 (M+H+).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:12]=[C:11]([CH:13]=[N:14]O)[C:10]([Cl:16])=[CH:9][N:8]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[C:10]([Cl:16])=[CH:9][N:8]=1
Reactant: ON=Cc1cc(Cl)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)ncc1Cl
Temperature: 0 °C
Yield: 77.4 %

Procedure:
To 100 ml of acetonitrile was added 24.5 g of POCl3, followed by 27.1 g of 2,5-dichloro-4-pyridinecarboxaldehyde oxime (prepared as described in Example 4). The reaction mixture was heated at reflux temperature for 1 hour, then cooled and poured onto 300 g of ice. The pH of the mixture was adjusted to about pH 6 with K2CO3 and filtered. The filtrate was extracted with 100 ml of CH2Cl2. The filter cake and the CH2Cl2 solution were combined, diluted with equal volumes of hexane, treated with charcoal, dried, and concentrated. The residue was purified by distillation on a Kugelrohr distillation apparatus (boiling point 80° C. at 0.2 mm pressure) to give 19.0 g (77%) of the desired 2,5-dichloro-4-pyridinecarbonitrile as a white solid, m.p. 58°-60° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].O1CCCC1.[OH-].[Na+]>CO>[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-[5-(methoxycarbonyl)-2-thiazolyl]-1-piperazinecarboxylate (i.e. the product of Example 4, Step A) (2.56 g, 8 mmol) in 15 mL of methanol and 15 mL of tetrahydrofuran was added 1 N aqueous NaOH solution (10 mL), and the mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure, diluted with water, washed with ether, and acidified with excess 20% aqueous citric acid solution to give a precipitate. The precipitate was filtered, washed with water and dried to give 2.12 g of the title compound as a slightly pink solid.
Reaction SMILES: B(O)O.[C:4]([O:8][C:9](=[O:20])[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH2:19])([CH3:7])([CH3:6])[CH3:5].CC[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:4]([O:8][C:9](=[O:20])[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:14]1[CH:13]=[C:12]2[C:26](=[CH:27][CH:15]=1)[N:23]([CH2:24][CH:25]1[CH2:6][CH2:4][CH2:5]1)[N:10]=[CH:11]2)([CH3:7])([CH3:5])[CH3:6]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCc1cc(F)ccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(F)ccc1Nc1ccc2c(cnn2CC2CCC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.8 %

Procedure:
To a flask containing boronic acid (0.175 g, 0.76 mmol), amine (6q) (0.22 g, 0.915 mmol), Cu(OAc)2 (0.135 g, 0.76 mmol) and 4 Å sieves (0.2 g) in DCM, Et3N (0.52 mL, 3.7 mmol) was slowly added. The mixture was stirred at room temperature for 3 days. DCM was added to the reaction mixture and filtered. The filtrate was washed with H2O (2×), brine and dried over Na2SO4. After concentration, the residue was purified by chromatography (Sep-Pak; 10 g) with hexane/Et2O (3:1). The fractions containing the product were combined to afford (7q-2) (0.12 g, 37% yield). 1HNMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.24 (br s, 1H), 7.13 (d, J=8.6 Hz, 1H), 6.94-6.84 (m, 3H), 5.02 (br s, NH), 4.35 (d, J=7.8 Hz, 2H), 4.29 (d, J=6.2 Hz, 2H), 2.98-2.85 (m, 1H), 2.10-1.98 (m, 2H), 1.95-1.79 (m, 4H), 1.44 (s, 9H); MS (APCI+) m/z 425 (M+H) was detected.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[C:14]([C:18]1[CH:19]=[C:20]([OH:25])[C:21](=[CH:23][CH:24]=1)[OH:22])([CH3:17])([CH3:16])[CH3:15]>>[C:8]([C:7]1[CH:10]=[C:11]([CH:4]=[CH:5][C:6]=1[C:12]#[N:13])[O:22][C:21]1[CH:23]=[CH:24][C:18]([C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:19][C:20]=1[O:25][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]#[N:13])[CH:5]=1)#[N:9]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Product: CC(C)(C)c1ccc(Oc2ccc(C#N)c(C#N)c2)c(Oc2ccc(C#N)c(C#N)c2)c1

Procedure:
The experimental procedure and reaction conditions were the same as described for Examples 5 and 6. Reagents used were 3.60 g (0.02 moles plus 0.14 g excess) of 4-nitrophthalonitrile and 1.66 g (0.01 moles) of 4-tert-butylcatechol (Aldrich). After workup and recrystallization 3.2 g (76.55% theoretical yield) of off-white crystals of the title compound were obtained. The product had the formula: ##STR14## The melting point was 161°-162° C. The elemental analysis for C26H18N4O2 was calc.: C, 74.64%; H, 4.30%; N, 13.39%; found: C, 74.55%; H, 4.25%; N, 13.39%.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH2:7][CH2:8][OH:9])[N:6]=1.[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][C:21](O)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][C:21]([O:9][CH2:8][CH2:7][C:5]3[N:6]=[C:2]([Br:1])[S:3][C:4]=3[CH3:10])=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:12]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: Cc1sc(Br)nc1CCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(Br)sc3C)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.2 %

Procedure:
To a solution of Example 173 (975 mg, 4.39 mmol) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (1.06 g, 4.83 mmol) in THF (20 mL) were added Ph3P (1.88 g, 7.46 mmol) and ADDP (1.96 g, 7.46 mmol). The mixture was vigorously stirred at rt for 72 hours, the solvent removed under reduced pressure, and the residue purified by silica gel flash chromatography (6:1 hexanes/EtOAc) to yield the product (1.4 g, 76%) as a colorless oil that solidifies upon standing. (C19H22BrNO3S) LC-MS, RT 3.92 min., M+H 424.5; 1H NMR (CDCl3): δ 1.26 (t, 3H), 1.65-1.81 (m, 1H), 2.28-2.45 (m, 2H), 2.37 (s, 3H), 2.69 (dd, 1H), 2.75-2.93 (m, 2H), 3.07 (t, 2H), 3.44-3.56 (m, 1H), 4.15 (t, 2H), 4.18 (q, 2H), 6.67 (dd, 1H), 6.73 (d, 1H), 7.03 (d, 1H).
Reaction SMILES: [N:1]1([CH:10]=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2N=N1.[F:12][C:13]([F:23])([F:22])[O:14]C1C=CC(N)=CC=1>O1CCCC1>[F:12][C:13]([F:23])([F:22])[O:14][C:8]1[CH:7]=[CH:6][C:5]([NH:1][CH:10]=[O:11])=[CH:4][CH:9]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=Cn1nnc2ccccc21
Solvent: C1CCOC1
Product: O=CNc1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 22.5 h
Yield: 97.3 %

Procedure:
1H-1,2,3-benzotriazole-1-carbaldehyde (299 mg, 2.032 mmol, Sigma-Aldrich) was added to a solution of 4-[(trifluoromethyl)oxy]aniline (0.227 mL, 1.694 mmol) in tetrahydrofuran (THF) (6 mL). The solution was heated to 60° C. and stirred for 22.5 hours. 1H-1,2,3-benzotriazole-1-carbaldehyde (199 mg, 1.355 mmol) was added and the reaction mixture stirred for a further 20 hours before concentrating in vacuo. The resulting solid was dissolved in DCM (30 ml), washed with 2M HCl (15 ml), the organic layer was passed through a hydrophobic frit and reduced in vacuo. The crude material was purified by silica chromatography (Biotage SP4, eluting iso-hexane (5 column volumes) followed by a gradient from 0-20% EtOAc in iso-hexane (over 15 column volumes)) to yield the title compound as a white solid (0.338 g).
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].[NH2:6][CH2:7][CH2:8][C:9]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:10]1>C(OC(=O)C)(=O)C>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:12]2[CH2:11][CH2:10][C:9]([CH2:8][CH2:7][NH:6][C:1](=[O:3])[CH3:2])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:14][C:13]2=[O:15])[CH:17]=1
Reactant: NCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reaction time: 2 h
Yield: 32.1 %

Procedure:
In a 5 dram vial, sodium acetate (3 mg, 0.04 mmol) was added to 6-(2-aminoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (5.13 mg, 0.013 mmol) in acetic anhydride (0.5 mL). The reaction was stirred for 2 h. The solvent was evaporated and the crude residue purified via prep HPLC to afford 1.88 mg of N-(2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)acetamide. LC-MS Method 1 m/z=451 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][O:23][C:24](=O)[O:25]C1C=CC([N+]([O-])=O)=CC=1>O.C1COCC1.Cl>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][O:23][C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9])=[O:25]
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Reactant: O=C(OCc1cccs1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@H]1CCCC[C@H]1C(=O)O)OCc1cccs1
Temperature: 25 °C

Procedure:
To a solution of Trans-2-amino-1-cyclohexane carboxylic acid (100 mg, 0.7 mmol) in 1 mL of water is added 2M aqueous Na2CO3 until pH=9-10 (2 mL). A solution of the carbonic acid 4-nitro-phenyl ester thiophen-2-ylmethyl ester (195 mg, 0.7 mmol) in THF (1 mL) is added at 0° C. and, after 10 minutes, 1 ml of the 2M Na2CO3 is added to the reaction. The mixture is allowed to warm to RT and vigorously stirred overnight. The reaction mixture is diluted with 0.5N HCl until pH=4-3 and the water layer is extracted three times with CH2Cl2 (10 ml). The organic phases are combined, dried (MgSO4), and concentrated under reduced pressure. The resulting product is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH2:14][C:15]#[CH:16])[CH:12]=1)[CH2:8][OH:9])[C:2]#[CH:3].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[C:17]([O:9][CH2:8][C:7]1[CH:10]=[C:11]([O:13][CH2:14][C:15]#[CH:16])[CH:12]=[C:5]([O:4][CH2:1][C:2]#[CH:3])[CH:6]=1)(=[O:19])[CH3:18]
Reactant: C#CCOc1cc(CO)cc(OCC#C)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: C#CCOc1cc(COC(C)=O)cc(OCC#C)c1
Temperature: 95 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
3,5-Dipropargyloxybenzyl alcohol (I) (6.3 g, 0.029 mol) was stirred in acetic anhydride (7 mL, 0.07 mol). Concentrated sulfuric acid (2 drops) was added and the solution was stirred (90-100° C.) for 3 hours. The solution was then poured into ice water, neutralized with a saturated sodium carbonate solution and after the reaction was worked up, the product was purified using silica in a sintered glass funnel and the solvents were removed leaving a yellow oil, which solidified upon standing, 7.2 g in 96% yield.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:9][C:10]1[Te:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[N+:14]=1[CH3:15].[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>C(O)C.N1CCCCC1>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH:9][C:10]2[Te:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[N+:14]=2[CH3:15])=[CH:24][CH:23]=1
Reactant: Cc1[te]c2ccccc2[n+]1C
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc(C=Cc2[te]c3ccccc3[n+]2C)cc1

Procedure:
2,3-Dimethylbenzotellurazolium trifluoromethanesulfonate (Example 30) (0.80 g, 0.002 mole) and 4-dimethylaminobenzaldehyde (0.30 g, 0.002 mole) were heated together in ethanol (about 30 ml), with one drop of piperidine present, to boiling and maintained at boiling for ten minutes. An intense red color developed. The dye separated as crystals on cooling. After overnight chilling they were isolated by filtration and recrystallized from ethanol, using diethyl ether to aid in reprecipitation. Yield 0.21 g (19% of theory).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[C:28](B(O)O)=[CH:29][S:30][CH:31]=1.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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[C:27]([CH3:26])=[CH:31][S:30][CH:29]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1cscc1B(O)O
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+]
Product: Cc1cscc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 200 mg, 64%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 200 mg, 64%).
Reaction SMILES: C(OP([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][CH:19]=2)[CH:11]=1)[F:9])OCC)C.[Li+].CC([N-]C(C)C)C.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.Cl>O.C1COCC1>[CH:36]1([CH:39]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:25]([F:26])[F:27])=[CH:22][CH:23]=3)[CH:11]=2)[F:9])[CH2:38][CH2:37]1
Reactant: CCOP(OCC)C(F)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reactant: O=CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: FC(=CC1CC1)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reaction time: 0.5 h

Procedure:
Into a cold solution of diethyl[(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)(fluoro)methyl]phosphonite (2.0 g, 4.08 mmol) and THF (20 mL) was added dropwise LDA (14.64 mL, 1.0M). The mixture was stirred for 30 minutes and then cyclopropanecarbaldehyde (410 mg, 5.8 mmol) was added and the mixture was allowed to come to room temperature and stirred for 24 hours. Then, HCl (5 mL, 2N) was added and the mixture was stirred for 30 minutes, poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by ICSO (hexane/EtOAc 20/1) gavel-(2-cyclopropyl-1-fluorovinyl)-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene 1:1 Z/E isomers as a yellow oil (0.72 g); MS m/e (M)+ 328.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][N:8]3[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=[C:7]3[C:6]=2[CH:26]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C@:33]([OH:37])([C:35]#[CH:36])[CH3:34])[CH:29]=1>>[OH:37][C@:33]([C:30]1[CH:29]=[C:28]([CH3:27])[O:32][N:31]=1)([CH3:34])[C:35]#[C:36][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][N:8]3[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=[C:7]3[C:6]=2[CH:26]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(CN1CCOCC1)C2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: COC(=O)c1cn2c(n1)-c1cc(C#C[C@@](C)(O)c3cc(C)on3)ccc1OC(CN1CCOCC1)C2

Procedure:
Similar to as described in General Procedure G, racemic methyl 10-bromo-6-(morpholinomethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to produce methyl 10-((R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-6-(morpholinomethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate as a diasteromeric mixture. A suspension of methyl 10-((R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-6-(morpholinomethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate (220 mg, 0.45 mmol, 1.00 equiv) in aqueous ammonia (40 mL) was stirred overnight at 60° C. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column with dichloromethane/methanol (20:1). This resulted in 43 mg (20%) of 10-((R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-6-(morpholinomethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide as a colorless solid. The two diasteromers were separated by Chiral-Prep-HPLC with the following conditions: Column, CHIRALPAK IC-3; mobile phase, Hex (0.1% TEA):EtOH=50/50; Detector, 254 nm. This resulted in 12.2 mg (30%) of Compound 1 and 15.3 mg (38%) Compound 2.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:41])[NH:14][CH2:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21](=[O:26])[C:20]=2[CH:19]=[CH:18][C:17]=1[O:27][C@@H:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)[CH2:9][CH2:10][S:11][CH3:12])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]([CH2:9][CH2:10][S:11][CH3:12])[C:13]([NH:14][CH2:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21](=[O:26])[C:20]=2[CH:19]=[CH:18][C:17]=1[O:27][C@@H:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)=[O:41]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CSCC[C@H](N)C(=O)NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 59.7 %

Procedure:
To a solution of ((S)-1-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-3-methylsulfanyl-propyl)-carbamic acid tert-butyl ester (153 mg, 0.258 mmol) in MeOH (1 mL) was added 4 M HCl in dioxane (3 mL). The mixture was concentrated after 3 h. The residue was neutralized with aqueous NaHCO3 and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a pale yellow oil. Purification by chromatography (5% MeOH/CH2Cl2 with 1% NH4OH) afforded the title compound as a white foam (76 mg, 0.154 mmol, 60%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)=[O:2].[CH3:11][N:12]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>>[CH:1]([C:3]1[S:7][C:6]([C:8]([N:23]([CH3:24])[CH2:22][CH2:21][CH2:20][N:12]([CH3:11])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: CNCCCN(C)C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(C(=O)O)s1
Product: CN(CCCN(C)C(=O)c1ccc(C=O)s1)C(=O)OC(C)(C)C
Yield: 79.1 %

Procedure:
5-Formylthiophene-2-carboxylic acid (300 mg, 1.92 mmol) and tert-butyl methyl[3-(methylamino)propyl]carbamate (466 mg, 2.31 mmol) were used to give the title compound (517 mg; yield, 83%) as a colorless oily substance according to the method described in Example 41a.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:27]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:27][C:26]1[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:24]([F:23])[CH:25]=1
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1cc(F)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 54.6 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 25 mg, 0.08 mmol), tetrabutylammonium iodide (30 mg, 0.08 mmol) and 3-fluoro-5-trifluoromethyl-benzyl bromide (75 mg, 0.29 mmol) in dimethylformamide (1 mL) was heated at 100° C. overnight. The reaction mixture was diluted with dichloromethane (50 mL) and the solution was washed with water/brine (1:1; 20 mL), water (2×20 mL), sodium thiosulfate (20 mL) and brine (20 mL). The solution was dried (magnesium sulfate), filtered, concentrated and purified by chromatography, eluting with 50% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-1-(3-fluoro-5-trifluoromethyl-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (21 mg, 53%) as an off-white solid. APCI(+)-MS (M+H) 481.