Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1)[NH2:5].F[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][CH:2]([CH3:23])[CH2:3][CH:4]([NH:5][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: Cc1cc(C(N)CC(C)C)ccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)c(C)c2)nc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
A mixture of 3-methyl-1-(2-methyl-4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (250 mg, 0.778 mmol), methyl 6-fluoronicotinate (264 mg, 1.17 mmol), and potassium carbonate (323 mg, 2.33 mmol) in N,N-dimethylformamide (4 mL) was stirred for 12 hrs at 120° C. The reaction was concentrated and purification by column chromatography gave methyl 6-(3-methyl-1-(2-methyl-4′-(trifluoromethyl) biphenyl-4-yl)butylamino)nicotinate (300 mg). 1H NMR (400 MHz, CD3OD, δ): 8.65 (s, 1H), 7.87 (d, 1H), 7.58 (d, 2H), 7.33 (d, 2H), 7.13 (d, 2H), 7.09 (s, 1H), 6.20 (d, 1H), 4.65 (m, 1H), 3.78 (s, 3H), 2.17 (s, 3H), 1.72 (m, 2H), 1.67 (m, 1H), 0.94 (d, 3H), 0.91 (d, 3H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:30])[C:13](=[O:29])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Br:31]Br>CN(C)C=O.ClCCl>[Br:31][C:16]1[CH:15]=[C:14]2[C:19]([C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])=[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])[N:12]([CH3:30])[C:13]2=[O:29])=[CH:18][CH:17]=1
Reactant: BrBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(Br)ccc23)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An ice cold mixture of methyl 2-(tert-butoxy)-2-(4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (383 mg, 0.940 mmol) in N,N-dimethylformamide (DMF) (5.0 mL) was treated slowly with a solution of bromine (0.053 mL, 1.034 mmol) in dichloromethane (dichloromethane) (280 μl) to give an orange solution. The ice bath was removed and the mixture, which was excluded from light by wrapping the reaction vessel with aluminum foil, was stirred at ambient temperature overnight. The mixture was cooled to 0° C., quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-50% ethyl acetate/hexanes gradient) to give the impure desired product as a white solid. The solid was re-purified by reverse phase chromatography to afford the desired product as a white solid (128 mg, 28%). LC/MS (m/z) ES+=486 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[S:27][CH2:26][CH2:25][CH2:24][S:23]1)[CH:3]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4]1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]1([CH:6]2[CH2:5][CH2:4][CH:3]([CH:2]([O:1][C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:41])[C:22]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[S:27][CH2:26][CH2:25][CH2:24][S:23]3)[CH2:8][N:7]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(O)C2(c3ccccn3)SCCCS2)CCC1c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C(OC(=O)c2ccccc2)C2(c3ccccn3)SCCCS2)CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 5-{hydroxy[2-(pyridin-2-yl)-1,3-dithian-2-yl]methyl}-2-phenylpiperidine-1-carboxylate (0.71 g, 1.459 mmol), benzoyl chloride (0.41 g, 2.92 mmol), triethyl amine (0.51 mL, 3.65 mmol) and DMAP (8.91 mg, 0.073 mmol) in DCM (15 ml) was stirred at room temperature overnight. The mixture was diluted with DCM. The organic layer was washed with saturated KHSO4 and brine, and dried over MgSO4. The drying agent was filtered off and the filtrate was concentrated in vacuo to give the title compound. LC-MS m/e 591.13 [M+1]+.
Reaction SMILES: [OH:1][C@H:2]([C@@H:8]([OH:35])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>>[OH:1][C@@H:2]([C@H:8]([OH:35])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][N:26]=3)=[CH:22][CH:23]=2)[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)c1cn(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c2ccccc12
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Product: CCOC(=O)[C@@H](O)[C@H](O)c1cn(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c2ccccc12

Procedure:
Compound 6 was prepared according the same procedure described in Example 1 for preparing compound 4 using Ad-mix-β (Aldrich) as a starting material. Compound 6 was obtained as a yellow solid (70%): 1H-NMR (400 MHz, CD3OD): δ 8.37 (s, 1H), 8.04 (1H, dd, 2.6 & 8.6 Hz), 7.64 (1H, d, 7.8 Hz), 7.43-7.51 (m, 4H), 7.25-7.28 (m, 2H), 7.04-7.14 (m, 3H), 5.03 (dd, 1H, 0.6 & 4.6 Hz), 4.41 (d, 1H, 4.6 Hz), 4.0 (q, 2H, 7.0 Hz), 1.01 (t, 3H, 7.0 Hz); LC/MS: m/z=507.1 [M+Na+](Calc: 486.4).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6](C(OCC)=O)[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Na+].[Cl-].O>CS(C)=O>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccnc2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ccnc2ccccc12
Temperature: 160 °C
Yield: 47.7 %

Procedure:
4-(Bis-ethoxycarbonyl methyl)-quinoline (5.05 g, 17.6 mmol), NaCl (2.06 g, 35.2 mmol), and H2O (0.63 mL, 35 mmol) were combined with DMSO (22 mL) in a round-bottom flask fitted with a reflux condenser. The heterogeneous mixture was stirred and heated to 160° C. for 90 minutes. TLC analysis (silca, 20% EtOAc-hexanes) indicated complete consumption of the starting material. The reaction was allowed to cool to room temperature and then was diluted with H2O. The dilution was extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated. Purification by gradient elution chromatography (SiO2, 20% EtOAc-hexanes to 30% EtOAc-hexanes) gave 4-(ethoxycarbonyl methyl)-quinoline (1.81 g, 8.40 mmol) in 48% yield. MS (APCI) m/z 216.1 (M+H). 1H NMR (300 MHz) CDCl3 δ 8.87 (d, J=4.4 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.73 (m, 1H), 7.60 (m, 1H), 7.34 (d, J=4.5 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.07 (s, 2H), 1.23 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[Cl:50][C:51]1[C:52]([C:95](=[O:98])[NH:96][CH3:97])=[C:53]([NH:66][C:67]2[C:72]([C:73]([F:76])([F:75])[F:74])=[CH:71][N:70]=[C:69]([NH:77][C:78]3[CH:92]=[CH:91][C:81]([CH2:82][P:83](=[O:90])([O:87]CC)[O:84][CH2:85][CH3:86])=[CH:80][C:79]=3[O:93][CH3:94])[N:68]=2)[CH:54]=[CH:55][C:56]=1[C:57]1[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=1>>[Cl:50][C:51]1[C:52]([C:95](=[O:98])[NH:96][CH3:97])=[C:53]([NH:66][C:67]2[C:72]([C:73]([F:75])([F:76])[F:74])=[CH:71][N:70]=[C:69]([NH:77][C:78]3[CH:92]=[CH:91][C:81]([CH2:82][P:83](=[O:87])([OH:90])[O:84][CH2:85][CH3:86])=[CH:80][C:79]=3[O:93][CH3:94])[N:68]=2)[CH:54]=[CH:55][C:56]=1[C:57]1[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(Cl)c3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(Cl)c3C(=O)NC)n2)c(OC)c1
Yield: 112.1 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({3-chloro-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 28B, 18 mg, 24.8 μmol) to afford 19.4 mg of the title compound. 1H NMR (400 MHz, CD3OD) δ=8.29 (s, 1H), 8.21 (s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.74 (t, J=8.6 Hz, 1H), 7.05 (s, 1H), 6.76 (d, J=8.3 Hz, 1H), 4.33 (t, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 2H), 3.58 (t, J=6.1 Hz, 2H), 2.96 (s, 1H), 2.92 (s, 4H), 2.10 (quin, J=6.51 Hz, 2H), 1.13 (t, J=6.95 Hz, 3H). MS (ESI): m/z=698.19 [M+H]+. UPLC: tR=1.06 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:25]([CH3:27])[CH3:26])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)c1ccccc1O
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(C)c1ccccc1Oc1nc(C(=O)NC(C)c2cc(F)c(NS(C)(=O)=O)c(F)c2)co1
Yield: 92.9 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted with 2-isopropyl phenol (18 mg, 0.12 mmol) to give the title compound (49 mg, 97%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]1[N:12]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:11][CH:10]([C:21]([OH:23])=[O:22])[CH2:9]1.[C:24](O)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>O.CN(C)C=O.ClCCl>[O:7]=[C:8]1[N:12]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:11][CH:10]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9]1
Reactant: CC(C)(C)O
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)O)CC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With cooling with ice, oxalyl chloride (15.7 ml, 0.18 mol) was dropwise added to a dichloromethane (200 ml) solution of 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (35 g, 0.15 mol) synthesized according to the method described in J. Med. Chem., 30, 1711-1715 (1987), then a catalytic amount of N,N-dimethylformamide was added, followed by stirring as such for 1 hour, then warming up to room temperature and further stirring for 1 hour. The reaction liquid was dried to solidness under reduced pressure (toluene azeotropy three times). This was dissolved in dichloromethane (100 ml), and the solution was dropwise added to a dichloromethane (150 ml) solution containing tert-butanol (43 ml, 0.45 mol) with cooling with ice. Triethylamine (31.4 ml, 0.225 mol) was further dropwise added at the same temperature, followed by stirring at room temperature for 16 hours. Water was added to the reaction liquid, and the dichloromethane layer was collected, and this was washed with water and saturated brine. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1→1:1→1:2→1:3, v/v) to obtain the entitled compound (including mixture of optical isomers) (34.227 g in total, 79%). This was used in the next, reaction as such.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>C1(C)C=CC=CC=1.CCCCCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:40]1([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]3)=[CH:4][CH:3]=2)[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CCOC(=O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C1=Cc2ccc(N3CCCC3)cc2OC1C(F)(F)F
Temperature: 75 °C
Yield: 79 %

Procedure:
Ethyl 7-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.40 g, 1.0 mmol), was dissolved in 3 mL toluene, followed by the addition of Pd(OAc)2 (23 mg), P(t-Bu)3, 10 wt % in hexane (0.21 g), Cs2CO3 (0.56 g, 1.7 mmol) and pyrrolidine (0.10 g, 1.4 mmol), in a sealed tube flushed with argon, and stirred vigorously while heating to 75° C. for 21 hours. The reaction was cooled, filtered, and stripped, leaving a dark red-orange oil, which was purified by flash chromatography, which gave ethyl 7-pyrrolidin-1-yl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.27 g, 0.79 mmol) as a yellow solid. The product structure was consistent with 1H, 19F and 13C NMR analyses.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:17])[CH3:12].[CH2:24]([O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])C>C(O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:17])[CH3:12].[CH3:24][O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30]
Reactant: CCOC(=O)/C=C(/C)N
Agent: CCOC(=O)CC(=O)C(=O)OCC
Agent: CSc1ccc(C=O)cc1
Solvent: CCO
Product: COC(=O)/C=C(/C)N

Procedure:
A solution of 7.6 g of 4-methylmercaptobenzaldehyde, 9.5 g of oxalacetic acid diethyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol is heated to the boil overnight and evaporated in vacuo. Oil (orange). a. In the same way, 2-methyl-4-(4'-methylmercaptophenyl)-1,4-dihydropyridine-3-carboxylic acid methyl ester-5,6-dicarboxylic acid diethyl ester is obtained from 7.6 g of 4-methylmercaptobenzaldehyde, 9.5 g of oxalacetic acid diethyl ester and 5.8 g of β-aminocrotonic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]=[O:25])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[OH:25])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccccc1Br
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
After dissolving 2.04 g of 2-bromoanisole in 22 ml of tetrahydrofuran, 3.6 ml of n-butyllithium (2.66 M, n-hexane solution) was added dropwise while stirring at below −60° C., and after 30 minutes, a solution of 1.58 g of 1-benzylpiperidine-4-acetaldehyde in tetrahydrofuran (5 ml) was added and stirring was continued for 30 minutes. Saturated aqueous ammonium chloride solution was added, the temperature was raised to room temperature, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.63 g, 69% yield).
Reaction SMILES: C([N:8]1[CH:11]([C@@H:12]2[CH2:16][C@@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][N:13]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:10][C:9]1=[O:32])C1C=CC=CC=1.[Na]>>[NH:8]1[CH:11]([C@@H:12]2[CH2:16][C@@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][N:13]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:10][C:9]1=[O:32]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C1CC(=O)N1Cc1ccccc1
Agent: [Na]
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C1CC(=O)N1
Yield: 88.4 %

Procedure:
The same procedure as in Reference Example 3-3 was carried out by using (2S,4R)-2-(N-benzyl-2-azetidinon-4-yl)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidine diastereomer A (500 mg, 1.05 mmol) and sodium metal (75 mg, 3.26 mmol) to obtain (2S,4R)-2-(2-azetidinon-4-yl)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidine diastereomer A (360 mg, yield: 88.4%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:18])([CH2:14][C:15]([OH:17])=[O:16])[CH2:6][CH2:5]2.S(=O)(=O)(O)O.[C:25](=O)([O-])O.[Na+]>CO>[OH:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:18])([CH2:14][C:15]([O:17][CH3:25])=[O:16])[CH2:6][CH2:5]2
Reactant: O=C([O-])O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 72 h

Procedure:
To a suspension of 10.0 g (37.83 mM) of 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid in methanol (50 ml) was added 0.5 ml (6 mM) of concentrated sulfuric acid at room temperature and the mixture was stirred for 3 days. To this reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate at 0° C. until the pH had been brought to 5-7 and the solvent was then distilled off under reduced pressure. The residue was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide the title compound as tan-colored oil.
Reaction SMILES: [N+]([O-])([O-])=O.[N:5]([O-])=O.[CH:8]1[C:13](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=[C:12](O)[CH:11]=[C:10]2OC([CH:30]=[CH:31][C:9]=12)=O>>[NH:5]1[C:10]2[C:9](=[CH:8][CH:13]=[CH:12][CH:11]=2)[CH:31]=[CH:30]1
Reactant: O=N[O-]
Reactant: O=c1ccc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(O)cc2o1
Agent: O=[N+]([O-])[O-]
Product: c1ccc2[nH]ccc2c1

Procedure:
As assayed with the API-NFT test (bioMerieux S.A., Marcy-l′Etiole, France), strain 2.2N can grow at about 41° C., reduce nitrate to nitrite, hydrolyze esculin and gelatin, and form indole. Strain 2.2N cannot produce yellow pigments, urease, arginine dihydrolase and cytochrome oxidase.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][C:25]([CH3:27])=[N:26][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:38])[S:34]([NH2:37])(=[O:36])=[O:35].CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([NH:37][S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][C:25]([CH3:27])=[N:26][C:13]4=[CH:12][N:11]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)S(N)(=O)=O
Reactant: CC1=NC2=Cn3c(cc4c(C5CCCCC5)cccc43)-c3cc(C(=O)O)ccc3N2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC1=NC2=Cn3c(cc4c(C5CCCCC5)cccc43)-c3cc(C(=O)NS(=O)(=O)N(C)C)ccc3N2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
To a solution of 10-cyclohexyl-2-methyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylic acid (58 g, 0.14 mmol) and N,N-dimethylsulfamide (82 g, 0.66 mol) in DMF (2 mL) added DMAP (80 mg, 0.66 mmol) and then EDCI-HCl (100 mg, 0.52 mmol). The reaction mixture was stirred at 60° C. for 2 h, cooled to rt, diluted with DMSO and MeOH and purified by prep HPLC (MeOH/H2O with 10 mM TFA buffer) to yield 10-cyclohexyl-N-((dimethylamino)sulfonyl)-2-methyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxamide (32 mg, 0.062 mmol, 44%) as a pink solid. 1H NMR (300 MHz, CD3OD) δ 1.14-1.32 (m, 1H), 1.36-1.57 (m, 3H), 1.73-1.85 (m, 2H), 1.94-2.20 (m, 4H), 2.34 (s, 3H), 2.84-2.98 (m, 1H), 3.04 (s, 6H), 5.20 (d, J=16.1 Hz, 1H), 5.97 (d, J=16.1 Hz, 1H), 7.66 (dd, J=8.6, 1.7 Hz, 1H), 7.71 (s, 1H), 7.77-7.90 (m, 4H), 8.01 (d, J=8.8 Hz, 1H), 8.27 (s, 1H). LCMS: m/e 518 (M+H)+, ret time 1.80 min.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24].[I-].[Na+]>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: OCCCCCCCl
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 34.0 g (0.2 mole) or p-phenylphenol (Eastman) and 10.8 g (0.2 mole) of sodium methoxide (MCB) in 500 ml of dry dimethylformamide is heated and stirred on a steam bath for 0.5 hour, after which 27.3 g (0.2 mole) of 6-chlorohexan-1ol (MCB) and about 2 g of sodium iodide are added. The mixture is heated to reflux with stirring, and then allowed to cool to room temperature. The reaction mixture is partitioned between ether/acetone and water, and the organic phase is extracted with base, washed with water and brine, dried (Na2SO4), and the solvent evaporated. The resultant white solid product is recrystallized twice from methanol/acetone, to give the desired product, m.p. 103-105° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][CH3:17])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[F:18].[Cl:19][C:20]1[C:21]([Cl:35])=[CH:22][C:23]2[O:28][CH2:27][C:26](=[O:29])[N:25]([CH2:30][C:31]([OH:33])=O)[C:24]=2[CH:34]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]([CH3:17])[C:31](=[O:33])[CH2:30][N:25]2[C:24]3[CH:34]=[C:20]([Cl:19])[C:21]([Cl:35])=[CH:22][C:23]=3[O:28][CH2:27][C:26]2=[O:29])[CH2:9][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:4][C:3]=1[F:18]
Reactant: CNC(CN1CCOCC1)c1ccc(Br)c(F)c1
Reactant: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
To a room temperature solution containing 1.59 g of 1-(4-bromo-3-fluorophenyl)-N-methyl-2-(4-morpholinyl)ethanamine (5.02 mmols) in 17 mL of dry DMF was added 2 g of (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (7.25 mmols), 2.66 g of BOP reagent (6.02 mmols), and 1.4 mL of triethylamine (10.04 mmols). The reaction mixture was stirred at ambient temperature. After 24 h 10 mL of saturated aqueous NaHCO3 was added. The resulting precipitate was collected, washed with water, and dried in vacuo to afford an off-white solid. MS (ES) m/e 574, 576 [M+H]+.