Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[N:3]1.C(=O)([O-])[O-].[NH4+:15].[NH4+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7]([NH2:15])(=[O:9])=[O:8])=[N:3]1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: Cn1ccc(S(N)(=O)=O)n1

Procedure:
A mixture containing chloroform (100 ml), 13.6 g of 1-methylpyrazole-3-sulfonyl chloride and 13.6 g ammonium carbonate was heated to reflux for six hours, cooled, filtered and the solid was washed with water. The water-insoluble solid which was recrystallized from 50% ethanol-water melted at 149°-151° and showed absorption peaks in the infrared at 3100 and 3200 cm-1, consistent for the NH2 in the desired product.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]1=[O:34].[OH-].[Na+]>CO>[O:34]=[C:12]1[N:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2]
Reactant: COC(=O)CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
The product is prepared as described in example 18 from 7.5 g of 8-(2-oxo-3.4.5-triphenyl-4-imidazolin-1-yl)-caprylic acid methyl ester and 0.64 g of NaOH in 30 cc. of methanol. Further purification by chromatography on silicic acid gel using chloroform as eluant.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25]CC)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[O:34].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[O:34])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Reactant: O=C1CCCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C(Nc1cc2ccc(N3CCCCC3=O)cc2nc1C(=O)O)OCc1ccccc1
Temperature: 100 °C
Yield: 30 %

Procedure:
A mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (300 mg, 0.7 mmol), 2-piperidinone (90 mg, 0.91 mmol), Pd(OAc)2 (0.010 mg, 0.064 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.020 g, 0.049 mmol), and Cs2CO3 (0.28 g, 0.86 mmol) in dioxane (1 mL) was purged with nitrogen and then heated at 100° C. in a sealed vial for 1 h. The solution was allowed to cool and NH4Cl solution and EtOAc were added. The resulting layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were concentrated to dryness under reduced pressure. To the resulting residue, 1 mL of dioxane, 2 mL of THF, and 2 mL of 2 M NaOH were added. The reaction mixture was heated at 80° C. for 0.5 h. The mixture was neutralized with HCl and extracted with DCM. The combined organic extracts were evaporated under reduced pressure. The residue was dissolved in 20 mL of DMF and purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the title compound (88 mg, 30%). LCMS calc. for C23H22N3O5 [M+H]+: m/z=420.2. found: 420.2.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH:14]=[CH:13][O:12][C@@H:11]([CH3:15])[C@@H:10]1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C@H:9]1[CH:14]=[CH:13][O:12][C@@H:11]([CH3:15])[C@@H:10]1[O:16][CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC=C[C@H](OCc2ccccc2)[C@H]1O
Reactant: CCCCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCO[C@H]1[C@H](C)OC=C[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
To a solution of (2S,3S,4S)-4-(benzyloxy)-2-methyl-3,4-dihydro-2H-pyran-3-ol (0.100 g, 0.454 mmol) in DMF (2.67 ml) at 0° C. was added NaH (45.0 mg, 1.13 mmol, 60% dispersion in mineral oil) and the reaction was stirred for 20 min at 0° C. Tetrabutylammonium iodide (34.0 mg, 0.091 mmol) and 1-iodobutane (0.20 mL, 1.76 mmol) were added and the reaction was stirred at room temperature for 18 h. The reaction was cooled to 0° C., additional NaH in (23.0 mg, 0.575 mmol) and 1-iodobutane (0.10 mL, 0.879 mmol) were added, and the reaction was warmed to 70° C. and stirred for 4 h. The reaction was cooled to room temperature, quenched with H2O, and extracted with EtOAc. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated to yield a pale-yellow oil. Purification of the crude oil by flash chromatography (SiO2, hexanes/EtOAc gradient) yielded the title compound as a colorless oil (93.0 mg, 74%): IR (neat) 2933, 2871, 1646, 1453, 1239, 1107, 1056, 734, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.41-7.24 (m, 5H), 6.34 (dd, J=6.1, 1.3 Hz, 1H), 4.83 (dd, J=6.1, 2.5 Hz, 1H), 4.67 (d, J=11.7 Hz, 1H), 4.59 (d, J=11.7 Hz, 1H), 4.11 (ddd, J=6.5, 2.2, 1.6 Hz, 1H), 3.89 (ddd, J=13.5, 9.3, 6.7 Hz, 1H), 3.83 (dt, J=9.2, 6.5 Hz, 1H), 3.63 (dt, J=9.2, 6.6 Hz, 1H), 3.30 (dd, J=9.0, 6.6 Hz, 1H), 1.64-1.51 (m, 2H), 1.44-1.33 (m, 2H), 1.38 (d, J=6.4 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 144.82, 138.69, 128.49, 127.81, 127.69, 100.49, 80.35, 76.53, 74.29, 72.32, 70.83, 32.52, 19.47, 17.53, 14.06; HRMS-ESI (m/z) [M]+ calcd for C17H24O3, 276.1725; found, 276.1710.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Br[C:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:9]=1>C(O)(=O)C>[CH:4]([O:6][C:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:9]=1)([CH3:5])[CH3:3]
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(Br)n2)n[nH]1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3cc(O)ccc3c(OC(C)C)n2)n[nH]1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
NaH (155 mg) was added to a solution of Propan-2-ol (2 ml) and the resulting mixture was stirred for 1 hour. 1-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (100 mg) was added to the mixture, and the mixture was heated at 170° C. for 30 minutes under microwave irradiation. The reaction mixture was acidified to PH=3 with acetic acid and evaporated to oil. The residue was treated with water (50 ml) and the resulting solid was collected to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (50 mg). LC-MS: m/e 299 (MH+).
Reaction SMILES: [CH2:1]([C@H:4]1[C@:21]2(O)[C@H:16]([CH2:17][CH2:18][C:19](=[O:23])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]>CC(C)=O.O>[CH2:1]([C@H:4]1[C:21]2[C@H:16]([CH2:17][CH2:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]
Reactant: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@H]2CCC(=O)C[C@]12O
Solvent: O
Solvent: CC(C)=O
Product: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@H]2CCC(=O)C=C12
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
6β-Propargyl-5α-hydroxyestrane-3,17-dione (11). The 6β-propargyl triol 9 (0.6 mmol) was dissolved in acetone (30 ml) and cooled to 4° C. followed by dropwise addition of Jone's reagent until the solution turned light brown. The reaction mixture was stirred at 4° C. for approximately 5 minutes, was diluted with water, extracted with ethyl acetate, washed (5% NaHCO3, brine, water) and dried, The ethyl acetate was evaporated in vacuo and the product obtained was purified by column chromatography to yield the dione 11 in 90% yield: m.p. 186°-188° C.; 1H-NMR (CDCl3) δ 0.91 (s, 3H, 18-CH3), 2.65 (d, 1H, 6-H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].C(=O)([O-])[O-].[K+].[K+].Cl[CH:20]([CH3:23])[CH:21]=[CH2:22]>CN(C=O)C>[CH3:22][CH:21]([N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH:20]=[CH2:23]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CC(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: C=CC(C)N1C(=O)c2ccccc2C1=O
Temperature: 135 °C

Procedure:
To a suspension of potassium phthalimide (7.08 g, 38.2 mmol) in DMF (60 mL) was added potassium carbonate (1.06 g, 7.6 mmol) and 3-chloro-1-butene (5.0 mL, 49.7 mmol). The mixture was heated under reflux in a bath at 135° C. for 4 h. The cooled reaction mixture was concentrated in vacuo and water (65 mL) was added over 5 minutes with rapid stirring at 40° C. The resulting suspension was cooled in an ice bath and then the solid was collected by filtration, washed with water (2×7 mL), then ethanol/water (45:55, 14 mL) and dried in vacuo at 50° C. for 16 h to give the title compound as a buff solid (5.0 g, 65%). 1H NMR ((CD3)2SO, 300 MHz): 7.87-7.83 (4H, m), 6.12 (1H, ddd, J=17.3, 10.5, 5.7 Hz), 5.17 (1H, dt, J=17.3, 1.4 Hz), 5.13 (1H, dt, J=10.4, 1.4 Hz), 4.88-4.78 (1H, m), 1.51 (3H, d, J=7.1 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC.O.Cl>[CH3:15][C:13]([CH3:14])([CH3:16])[C:12]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:8]=1)=[O:17]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)n[nH]c2c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 1.43 g (6-methoxy-1H-indazol-3-yl)-2,2-dimethylpropan-1-one from the Step C above in 45 mL anhydrous DMF was added 1.13 g ethyl bromoacetate and 2.41 g cesium carbonate. The mixture was stirred under nitrogen at room temperature for 2.5 days. It was diluted with ether and cold water with 15 mL 1 N HCl. The aqueous layer was separated and extracted with ether three times. The combined ether extract was washed with water (5×) and saturated brine, dried over anhydrous Na2SO4 and evaporated to give a crude product. It was purified by SGC with 20-40% EtOAc in hexanes to give title compound as solid. 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, J=8.9 Hz, 1H), 6.985 (dd, J=2.1 & 8.9 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 5.15 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 1.50 (s, 9H), 1.28 (t, J=7.1 Hz, 3H). LC-MS: 3.93 min. (m/Z=319.3).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][C:36]2([O:44][CH2:43][CH2:42][O:41]2)[CH2:35]3)[C:28]([OH:31])=[N:29][N:30]=1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH2:37]1[C:38]2[C:34](=[CH:33][C:32]([N:27]3[C:28]([OH:31])=[N:29][N:30]=[C:26]3[C:10]3[CH:11]=[C:12]([CH:23]([CH3:25])[CH3:24])[C:13]([OH:15])=[CH:14][C:9]=3[OH:8])=[CH:40][CH:39]=2)[CH2:35][C:36]21[O:41][CH2:42][CH2:43][O:44]2
Reactant: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CC2(C3)OCCO2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CC2(C3)OCCO2)c(O)cc1O
Yield: 97.2 %

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-(1′,3′-dihydro-spiro[[1,3]dioxolane-2,2′-inden]-5′-yl)-4H-[1,2,4]triazol-3-ol (550 mg, 0.93 mmol) was subsequently hydrodebensylated using Pd/C (10%, dry, 100 mg) and H2 in THF/MeOH (1/1, mL) at 1 atm at r.t. for 2 h. The reaction mixture was filtered through a pad of celite and the mother liquid was concentrated. It was again filtered through a pad of silica gel and the filtrate was concentrated to give the title compound as a white solid (370 mg, 97%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][CH:9]([CH3:52])[C@H:10]([NH:45][C:46]1[N:51]=[CH:50][CH:49]=[CH:48][N:47]=1)[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[NH:39][C:38]([C@@H:40]5[CH2:44][CH2:43][CH2:42][NH:41]5)=[N:37][CH:36]=4)=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:12].CCN(C(C)C)C(C)C.[CH3:62][O:63][C:64]([NH:66][C@@H:67]([CH:71]([CH3:73])[CH3:72])[C:68](O)=[O:69])=[O:65].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO.CC#N.O>[CH3:62][O:63][C:64](=[O:65])[NH:66][C@H:67]([C:68]([N:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:38]1[NH:39][C:35]([C:32]2[CH:31]=[CH:30][C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:20]4[NH:19][C:18]([C@@H:14]5[CH2:15][CH2:16][CH2:17][N:13]5[C:11](=[O:12])[C@H:10]([CH:9]([CH3:52])[CH3:8])[NH:45][C:46]5[N:51]=[CH:50][CH:49]=[CH:48][N:47]=5)=[N:22][CH:21]=4)=[CH:24][CH:25]=3)=[CH:34][CH:33]=2)=[CH:36][N:37]=1)=[O:69])[CH:71]([CH3:73])[CH3:72]
Reactant: CC(C)[C@H](Nc1ncccn1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)[C@@H](Nc5ncccn5)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
To a solution of the TFA salt of (S)-3-methyl-2-(pyrimidin-2-ylamino)-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-1-one (cj-10) (0.208 g, 0.197 mmol) in DMF (4 mL) was added iPr2NEt (0.20 mL, 1.15 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.049 g, 0.28 mmol) and HATU (0.105 g, 0.276 mmol). The solution was stirred for 1.5 h at room temperature, diluted with MeOH (2 mL) and purified directly by prep HPLC (Luna 5 u C18/MeCN—H2O—NH4OAc). This material was repurified by flash chromatography (SiO2/2-10% MeOH—CH2Cl2) to give a solid which was lyophilized from CH3CN—H2O to give the title compound (48.6 mg, 32%) as a colourless solid.
Reaction SMILES: [Br:1][CH2:2][C@H:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[OH:4].CC1C=CC=C(C)N=1.[Si:21](OS(C(F)(F)F)(=O)=O)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][CH2:2][C@H:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[O:4][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: N#Cc1ccc([C@H](O)CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H](CBr)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
To a mixture of (S)-4-(2-bromo-1-hydroxyethyl)benzonitrile (6.9 g, 30.5 mmol) and 2,6-dimethylpyridine (7.82 mL, 67.1 mmol) in DCM (20 mL) was added t-butyl-dimethylsilyltrifluoromethanesulfonate (14.02 mL, 61.0 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried MgSO4, filtered and concentrated. The crude material was purified on a 80 gram silica column and eluting with an EtOAc/Hex gradient to afford 12 g of (S)-4-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)benzonitrile. MS (M+1)=340/342. HPLC Peak RT=2.16 minutes. 1H NMR (400 MHz, CDCl3) δ ppm 7.65 (2H, d), 7.45 (2H, d), 4.88 (1H, dd), 3.42 (1H, q), 3.39 (1H, dd), 0.85 (9H, s), 0.12 (3H, s), −0.09 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C:5]2([N:31]=1)[C:14]1([CH2:17][O:16][CH2:15]1)[C:13]([CH3:19])([CH3:18])[O:12][C:11]1[C:6]2=[CH:7][C:8]([NH:20][C:21]([C:23]2[CH:28]=[N:27][C:26]([O:29][CH3:30])=[CH:25][N:24]=2)=[O:22])=[CH:9][CH:10]=1.C(=O)=O>>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:31]=1)[C:14]1([CH2:15][O:16][CH2:17]1)[C:13]([CH3:18])([CH3:19])[O:12][C:11]1[C:6]2=[CH:7][C:8]([NH:20][C:21]([C:23]2[CH:28]=[N:27][C:26]([O:29][CH3:30])=[CH:25][N:24]=2)=[O:22])=[CH:9][CH:10]=1
Reactant: COc1cnc(C(=O)Nc2ccc3c(c2)C2(COC(N)=N2)C2(COC2)C(C)(C)O3)cn1
Agent: O=C=O
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(COC(N)=N2)C2(COC2)C(C)(C)O3)cn1
Yield: 35 %

Procedure:
N-[2-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-6′-yl]-5-methoxypyrazine-2-carboxamide (100 mg, 0.235 mmol) was chromatographed using supercritical CO2 (supercritical CO2/EtOH=60:40) on Chiralcel OD-H column (10×250 mm) eluting at a flow rate 10 mL/minute (40° C. column temperature). After concentration of collected fractions of the first peak (retention time=5.25 minutes) under reduced pressure, trituration of the residue with EtOAc/hexane provided N-[(4S)-2-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-6′-yl]-5-methoxypyrazine-2-carboxamide (35 mg). After concentration of collected fractions of the second peak (retention time=8.08 minutes) under reduced pressure, trituration of the residue with EtOAc/hexane provided N-[(4R)-2-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-6′-yl]-5-methoxypyrazine-2-carboxamide (35 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)([O-:20])=[O:19]>C(#N)C>[CH2:10]([N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]1=[N:21][N+:18]([O-:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])Nc1ccccn1
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])N=c1ccccn1Cc1ccccc1

Procedure:
20 ml (0.114 mole) of N,N-diisopropylethylamine and 12 ml (0.1 mole) of benzyl bromide are added to a suspension containing 14 g (0.1 mole) of 2-(nitroamino)pyridine [prepared according to J. Am. Chem. Soc. 77, 3154 (1955)] in 100 ml of acetonitrile, then the mixture is refluxed for 2.5 hours. The reaction mixture is cooled down then evaporated under reduced pressure, the residue is triturated with water, the suspension obtained is filtered and washed with a great volume of water. The filter cake is thoroughly sucked, then suspended in 50 ml of petroleum ether, filtered and washed again with petroleum ether to give 14.2 g (62%) of the named product, m.p.: 125°-126° C. (recrystallized from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16](OC)=[O:17].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][CH2:16][OH:17]
Reactant: COC(=O)CCc1cnoc1-c1cc(Cl)ccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of methyl 3-[5-(2,5-dichlorophenyl)-4-isoxazolyl]propionate (500 mg) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M toluene solution, 4.2 ml) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(2,5-dichlorophenyl)-4-isoxazolyl]propan-1-ol (420 mg, yield 93%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 1.28 (1H, t, J=5 Hz), 1.7–1.9 (2H, m), 2.5–2.6 (2H, m), 3.65 (2H, td, J=6, 5 Hz), 7.35–7.5 (3H, m), 8.27 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([OH:7])=O.CO[C:16]1C=CC=C(OC)[C:17]=1C(Cl)=O.S(Cl)(Cl)=O>>[CH3:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5](=[O:7])[CH2:16][CH3:17]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: O=S(Cl)Cl
Product: CCC(=O)c1c(OC)cccc1OC

Procedure:
2,6-Dimethoxy-benzoic acid is converted to 2,6-dimethoxybenzoyl chloride III by treatment with thionyl chloride at 70° C. for 2 hours and after removal of excess thionyl chloride the residual III is dissolved in toluene and treated at -78° C. with a solution of triethylaluminum in toluene. This procedure provides 1-(2,6-dimethoxyphenyl)propan-1-one IV in two steps from the readily available precursor II.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:17][C:18]1[CH:19]=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([OH:24])[CH:23]=1.[O:28]1[CH2:33][CH2:32][CH:31](O)[CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([CH:23]=1)[O:24][CH:31]1[CH2:32][CH2:33][O:28][CH2:29][CH2:30]1
Reactant: OC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1CCOCC1
Temperature: 25 °C

Procedure:
Di-tert-butyl azodicarboxylate (17.6 g, 76.4 mmol) was added into a solution of 5-fluoro-2-nitrophenol (10 g, 63.7 mmol), tetrahydro-2H-pyran-4-ol (7.3 mL, 76.4 mmol) and triphenyl phosphine (20 g, 76.4 mmol) in anhydrous DCM (120 mL) at 0° C. The solution was allowed to warm to ambient temperature overnight, concentrated in vacuo and the crude product triturated with n-pentane/diethyl ether (×2) to remove the triphenyl phosphine oxide (16.5 g) by-product. The sample was purified by flash column chromatography (5:1 petroleum ether (40-60° C.)/EtOAc) to yield yellow oil which was used in the next step directly.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34]>[Cu]I.O1CCOCC1>[Br:8][C:6]1[CH:7]=[C:2]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=1
Reactant: O=C(c1cccnc1)c1cc(Br)cc(Br)c1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(c1cccnc1)c1cc(Br)cc(N2CCCC2=O)c1
Temperature: 80 °C
Yield: 7.2 %

Procedure:
To a nitrogen-flushed tube were added 0.20 grams (0.72 mmol) (3,5-dibromo-phenyl)-pyridin-3-yl-methanone, 0.137 g (0.72 mmol) copper (I) iodide, 0.235 (0.72 mmol) cesium carbonate, 0.063 g (0.72 mmol) N,N′-dimethyl-ethane-1,2-diamine, 0.061 g (0.72 mmol) pyrrolidin-2-one and 5 mL dioxane. The tube was sealed and heated at 80° C. overnight. The reaction mixture was allowed to cool, and was filtered. The volatiles were removed under reduced pressure and the resulting material was chromatographed on silica gel with 2% methanol/chloroform to give 0.018 g of 1-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-pyrrolidin-2-one. This material was converted to 1-[3-(1H-indol-4-yl)-5-(pyridine-3-carbonyl)-phenyl]-pyrrolidin-2-one as described in Example 75. 1H NMR (400 MHz, CD3OD): δ 9.01 (s, 1H), 8.79 (s, 1H), 8.26-8.31 (m, 2H), 8.06 (s, 1H), 7.86 (s, 1H), 7.62 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.67 (d, J=3.1 Hz, 1H), 4.03 (t, J=7.0 Hz, 2H), 2.63 (t, J=8.1 Hz, 2H), 2.16-2.26 (m, 2H).