Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:13]=[C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([F:7])[CH:9]=2)[O:12][CH:5]=1
Reactant: NC(=O)c1cccc(F)c1
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: Fc1cccc(-c2nc(CCl)co2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 39.5 %

Procedure:
1,3-Dichloroacetone (3.65 g, 28.75 mmol) was added to a solution of 3-fluorobenzamide (2 g, 14.37 mmol) in dry toluene (20 mL). The resulting reaction mixture was stirred at 100° C. for 5 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10% EtOAc in petroleum ether) to afford 4-(chloromethyl)-2-(3-fluorophenyl)oxazole (1.2 g, yield 39%) as a yellow liquid. NMR (300 MHz, CDCl3) δ 7.85-7.83 (m, 1H), 7.77-7.73 (m, 2H), 7.48-7.41 (m, 1H), 7.20-7.14 (m, 1H), 4.58 (d, J=0.9 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1>CN(C=O)C.O>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([O:1][C:2]2[CH:14]=[C:13]3[C:5]([C:6]4[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][C:11]=4[NH:12]3)=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(Oc3ccc([N+](=O)[O-])cc3)ccc12
Temperature: 140 °C
Yield: 44.8 %

Procedure:
To a round bottom flask containing Compound 9 (80 mg, 0.268 mmol) in DMF (2 mL) was added potassium carbonate (74.1 mg, 0.536 mmol) and 4-fluoro-nitrobenzene (41.6 mg, 0.295 mmol). The reaction mixture was heated for 20 min at 140° C. After cooling down to rt, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The organic layers were dried, concentrated. The residue was purified on a silica gel column (EtOAc: Hexanes=3:7) to afford Compound 10 as a yellow solid (50 mg, 0.12 mmol, 44% yield). 1H NMR (400 MHz, CDCl3) δ: 8.22 (d, J=9.2 Hz, 2H), 8.10 (br, 1H), 8.00-7.90 (m, 3H), 7.12 (s, 1H), 7.06-6.90 (m, 4H), 6.70 (br, 1H), 1.56 (s, 9H); LRMS for C23H21N3O5+H+, calc'd: 420.2. found: 420.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].C[Si](Cl)(C)C.CC1(C)[O:20][C:19](=O)[CH2:18][C:17](=[O:22])[O:16]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:19](=[O:20])[CH2:18][C:17]([OH:22])=[O:16]
Reactant: Nc1ccccc1F
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: O=C(O)CC(=O)Nc1ccccc1F
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a suspension of 2-fluorobenzeneamine (1 mL, 7.80 mmol) in DCM (78 mL) was added TMSCl (0.99 mL, 7.80 mmol) at RT [Rigo, B.; Fasseur, D.; Cauliez, P. and Couturier, D. Tetrahedron Lett.; 30; 23; 1989; 3073-3076.]. The reaction mixture was stirred for 30 min then 2,2-dimethyl-1,3-dioxane-4,6-dione (1.12 g, 7.80 mmol) was added and the combined mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO3 solution, which was washed with EtOAc. The organic phase was discarded and the aqueous phase was acidified with conc. HCl to pH˜3, extracted with EtOAc; extract was dried (anhydrous Na2SO4) and concentrated. The residue was purified by flash chromatography (eluent CHCl3/MeOH/AcOH 8:1:0.1) to afford the acid 29 (0.4 g, 26% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 12.67 (s, broad, 1H), 9.95 (s, 1H), 7.95 (m, 1H), 7.25 (m, 1H), 7.12 (m, 1H), 3.43 (s, 2H). MS (m/z): 198.0 (M+H).
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.Cl[CH2:44][CH2:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.O>[F:33][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([S:46]([CH:45]=[CH2:44])(=[O:48])=[O:47])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(OC2CCNCC2)nc(N2CCOCC2)n1
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCC(Oc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
To a solution of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-piperidinyloxy)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 16) (1.52 g, 3.29 mmol) and DIPEA (2.3 ml, 4 eq.) in CH2Cl2 (30 mL) at 0° C. was added 2-chloroethanesulfonyl chloride (1 mL, excess). The reaction mixture was stirred at 20° C. for 20 hrs and diluted with water (50 mL). The CH2Cl2 layer was separated and the aqueous layer was further extracted with CH2Cl2 (3×20 mL). The combined organic fractions were washed successively with aq. HOAc, aq. K2CO3, and water, and dried (MgSO4). Evaporation of the solvent and chromatography of the residue on silica, eluting with CH2Cl2/EtOAc (9:1) gave 2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{[1-(vinylsulfonyl)-4-piperidinyl]oxy}-1,3,5-triazin-2-yl)-1H-benzimidazole (1.17 g, 65% yield): mp (CH2Cl2/MeOH) 266-269° C.; 1H NMR (DMSO-d6) δ 7.95 (d, J=7.9 Hz, 1H), 7.70 (t, JHF=52.8 Hz, 1H), 7.44 (t, J=8.2 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.88 (dd, J=16.5, 10.0 Hz, 1H), 6.19 (d, J=10.0 Hz, 1H), 6.15 (d, J=16.5 Hz, 1H), 5.26-5.20 (m, 1H), 3.98 (s, 3H), 3.84 (m, 4H), 3.74-3.32 (m, 4H), 3.39-3.32 (m, 2H), 3.14-3.08 (m, 2H), 2.14-2.09 (m, 2H), 1.90-1.18 (m, 2H); Anal. Calcd. for C23H27F2N7O5S.0.5CH2Cl2: C, 47.7; H, 4.7; N, 16.5. Found: C, 47.8; H, 4.7; N, 16.8%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH3:19][N:20]([CH3:33])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][O:31][CH3:32])[CH:24]=[O:25].[Cl-].[NH4+]>O1CCCC1>[CH3:33][N:20]([CH3:19])[C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:25])[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][O:31][CH3:32]
Reactant: Brc1ccccn1
Reactant: COCOc1ccc(C=O)cc1N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C(O)c2ccccn2)cc1N(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromopyridine (3.05 g, 19.3 mmol) in dry tetrahydrofuran (100 ml) was added dropwise n-butyl lithium in hexane (1.6M, 12.0 ml, 19.2 mmol) under nitrogen atmosphere. After stirring at -78° C. for 30 minutes, thereto was added dropwise a solution of the aldehyde compound (Compound A) (3.00 g, 14.3 mmol) in dry tetrahydrofuran (20 ml), and the mixture was stirred at -78° C. for 2 hours. A saturated aqueous solution of ammonium chloride (10 ml) was added thereto, and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (200 ml) and extracted with ethyl acetate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[N:12]=[CH:13][N:14]([CH3:17])[C:15]=2Br)[CH:6]=1)=[O:4].[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2B(O)O)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[C:15]2[N:14]([CH3:17])[CH:13]=[N:12][C:11]=2[C:7]2[CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][N:8]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)c1ccnc(-c2ncn(C)c2Br)c1
Reactant: OB(O)c1c(F)cccc1OCC1CC1
Product: Cn1cnc(-c2cc(C(=O)O)ccn2)c1-c1c(F)cccc1OCC1CC1
Yield: 3 %

Procedure:
The title compound was prepared in 3% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carboxylic acid methyl ester and 2-(cyclopropylmethoxy)-6-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A followed by hydrolysis. 1H NMR (400 MHz, DMSO-d6): δ 0.12 (2H, m), 0.33-0.40 (2H, m), 0.83-0.94 (1H, m), 3.60-3.70 (1H, m), 3.72-3.84 (1H, m), 6.84 (1H, t, J=8.4 Hz), 6.92 (1H, d, J=8.2 Hz), 7.35 (1H, t, J=5.0 Hz), 7.40 (1H, t, J=7.8 Hz), 7.86 (1H, s), 8.08 (1H, d, J=4.7 Hz), 8.27 (1H, s). [M+H] Calc'd for C20H18FN3O3, 368. Found, 368.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:26][C:27]([Si:30]([CH3:43])([CH3:42])[O:31][CH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)([CH3:29])[CH3:28]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2OC)CCCCC1>[CH3:29][C:27]([Si:30]([CH3:43])([CH3:42])[O:31][CH2:32][C:33]1[CH:34]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=2)[CH:36]=[CH:37][CH:38]=1)([CH3:26])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(B(O)O)c1
Reactant: Cc1ccc(Br)cc1CNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc2ccccc2c1-c1c(P(C2CCCCC2)C2CCCCC2)ccc2ccccc12
Solvent: C1COCCO1
Product: Cc1ccc(-c2cccc(CO[Si](C)(C)C(C)(C)C)c2)cc1CNC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 90.6 %

Procedure:
1,1-Dimethylethyl [(5-bromo-2-methylphenyl)methyl]carbamate (2.7 g, 9.0 mmol), Pd(OAc)2 (81 mg, 0.36 mmol), dicyclohexyl[2′-(methyloxy)-1,1′-binaphthalen-2-yl]phosphane (216 mg, 0.45 mmol) and K3PO4 (2.5 g, 11.7 mmol) were dissolved in dioxane (50 mL). The mixture was heated at 80° C. for 30 min, and then [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (3.1 g, 11.7 mmol) was added. The mixture reaction was stirred at reflux for two days. The solvent was removed under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic layer was washed with water (30 mL), brine (30 mL), and dried over Na2SO4. After removing the solvent, 3.6 g of the crude product 1,1-dimethylethyl {[3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-4-methyl-3-biphenylyl]methyl}carbamate was obtained. Yield: 90%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:24]([NH:26][C@@H:27]([CH2:61][OH:62])[C@@H:28]([OH:60])[C@@H:29]([OH:59])[C@H:30]([OH:58])[C:31]([NH:33][C@H:34]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:35][C:36]([O:38][CH:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])=[O:32])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:63](OC(=O)C)(=[O:65])[CH3:64]>N1C=CC=CC=1>[C:63]([O:62][CH2:61][C@H:27]([NH:26][C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C@@H:28]([OH:60])[C@@H:29]([OH:59])[C@H:30]([OH:58])[C:31]([NH:33][C@H:34]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:35][C:36]([O:38][CH:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])=[O:32])(=[O:65])[CH3:64]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-((N-benzyloxycarbonyl-L-valyl)-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (200 mg) in pyridine (1 ml) was added acetic anhydride (0.0243 ml) and the mixture was stirred at room temperature for 14 hours. After concentration under reduced pressure, the residue was passed through silica gel column chromatography, followed by elution with ethyl acetate-methanol (20:1). The effective fractions were combined and concentrated under reduced pressure to give a residue, which was recrystallized from mthanol-diethylether to provide the title compound (103 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36]>CN(C=O)C>[CH:27]1[C:28]2[C:23](=[CH:22][C:21]([NH:20][C:18](=[O:19])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:34][C:35](=[O:36])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:3][CH:4]=3)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:30][CH:29]=2)[CH:24]=[CH:25][N:26]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OCC(=O)c2ccccc2)cc1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 2-(4-hydroxyphenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E249) in DMF cooled to −35° C. was added NaH and the solution was stirred at −35° C. for 30 min. Then, 2-bromoacetophenone was added and the solution was warmed and stirred at 0° C. for 2 h. The solution was poured into NaHCO3(sat)/EtOAc and further extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3% MeOH/CH2Cl2) gave tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-(2-oxo-2-phenylethoxy)phenyl)propylcarbamate (E275).
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:17][OH:18])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[ClH:1].[C:2]1([C:8]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:20]=3)[CH2:17][O:18][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: OCC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: COC(=O)COCC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This was prepared in a similar manner as Example 2 using the compound of Example 1 (d) and methyl bromoacetate. 1H NMR (360 MHz, d6 -DMSO) δ7.98 (1H, s), 7.75 (2H, s), 7.41-7.24 (5H, m), 4.68 (1H, t, J=5 Hz), 4.11 (2H, s), 3.62 (3H, s), 3.69-3.30 (4H, m), 3.29-3.10 (2H, m), 2.78-2.60 (2H, m), 2.39-2.00 (4H, m). MS (Cl+) 520 (M+H)+.
Reaction SMILES: [CH3:1][C:2]12[O:8][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3]2.[OH-].[NH4+:10]>O>[NH2:10][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1([CH3:1])[OH:8]
Reactant: CC12CCCCC1O2
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC1(O)CCCCC1N
Temperature: 50 °C

Procedure:
To a solution of 1-methyl-7-oxabicyclo[4.1.0]heptane, 30a, (1.0 g, 7.1 mmol) in water was added ammonium hydroxide (6.0 mL, 154.1 mmol). The mixture was heated to 50° C. for 48 hours. The mixture was diluted with water, extracted with EtOAc and then twice with 20% MeOH/CHCl3. The organic phases were dried (MgSO4), filtered and concentrated in vacuo to provide the desired product, 30b, as an amorphous white solid.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[C:14]=1[CH3:21]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:19][C:16]1[C:15]([CH3:20])=[C:14]([CH3:21])[C:13]([CH3:12])=[CH:18][C:17]=1[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: Cc1ccc(C)c(C)c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1cc(C(O)C(=O)c2ccccc2)c(C)c(C)c1C
Yield: 70.7 %

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and 1,2,3,4-tetramethylbenzene (0.60 ml, 4 mM were dissolved in dichloroethane (5 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 10 minutes. Using the same procedure as in Example 1, 2',3',4',5'-tetramethylbenzoin was obtained (378.2 mg, 70.7% yield).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[N+:12]([O-:14])=[O:13]>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:9]1[CH:8]=[CH:7][C:6]([O:10][CH3:11])=[C:5]([N+:12]([O-:14])=[O:13])[C:4]=1[F:3]
Reactant: BrBr
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c(F)c1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 17 h
Yield: 99.3 %

Procedure:
Bromine (1.55 mL, 30.1 mmol) was added dropwise to a solution of 1-fluoro-3-methoxy-2-nitrobenzene (1.29 g, 7.53 mmol) in acetic acid (15.1 mL). The reaction mixture was warmed to 55° C. and stirred at 55° C. for 17 h, after which time the reaction mixture was concentrated in vacuo to give a crude solid. The crude solid was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. Layers were separated and the organic layer was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo to give the desired product (1.87 g, 99%) as a yellow solid that was used in further step without purification.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7]N)=[CH:3][CH:2]=1.Cl.[CH2:11]([C:14]1([CH3:22])[C:19](=O)[CH2:18][CH2:17][N:16]([CH3:21])[CH2:15]1)[CH:12]=[CH2:13].OS(O)(=O)=O>O1CCOCC1>[CH2:11]([C:14]1([CH3:22])[C:19]2[NH:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:9])=[CH:6][C:5]=3[C:18]=2[CH2:17][N:16]([CH3:21])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: C=CCC1(C)CN(C)CCC1=O
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=CCC1(C)CN(C)Cc2c1[nH]c1ccc(C)cc21

Procedure:
To a stirred solution of p-tolylhydrazine.HCl (1.2 g, 7.56 mmol) and 3-allyl-1,3-dimethyl-piperidin-4-one (1.5 g, 9.077 mmol) in 1,4-dioxane (12 mL) at 25° C. was added conc. H2SO4 (1 mL). The reaction mixture was heated at 100° C. for 30 min after which the dioxane layer was decanted and residue was basified with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (3×50 mL), organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.7 g of 4-allyl-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](=[O:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]([OH:11])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., to a solution of ((S)-tert-butyl(2-oxo-1-phenylpropyl)carbamate (0.7 g, 2.8 mmol) in MeOH (10 mL) was added NaBH4 (0.1 g, 2.8 mmol) and the contents were stirred at ambient temperature. After 30 min, the reaction mixture was quenched carefully with ice cold H2O (10 mL), and the organic contents were extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated to afford tert-butyl((1S)-2-hydroxy-1-phenylpropyl)carbamate. The product thus obtained was pure and taken directly for the next step without further purification. MS: [M+H-Boc]+ m/z 152.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([CH2:20]O)[CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:5][CH2:20][C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: COc1cc(CO)cc2c(OC)cccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CCl)cc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A solution of 3.92 g of methanesulphonyl chloride in 20 ml of methylene chloride was added dropwise to a solution, cooled to -10° C., of 7.7 g (35.3 mmol) of (4,8-dimethoxy-naphthalen-2-yl)-methanol and 4.4 g (38.8 mmol) of triethylamine in 50 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 hours. For the working-up, the mixture was extracted with 50 ml of ice-cold sodium hydrogen carbonate solution and the aqueous phase was separated and back-extracted with 25 ml of methylene chloride. The combined organic phases were dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the residue was filtered over a layer of silica gel using methylene chloride as the eluent. There were obtained 7.2 g of 2-chloromethyl-4,8-dimethoxy-naphthalene as a beige solid; MS: 296 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=2)[CH:17]=1.CN(C(O[N:36]1N=N[C:38]2C=CC=[CH:42][C:37]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH:37]([CH3:42])[CH3:38])=[O:23])=[CH:20][N:19]=2)[CH:17]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1nnc(-c2ccccc2Cl)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4Cl)nnn3C)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a solution of 6-(4-(4-(2-chlorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.194 mmol) and TBTU (69 mg, 0.214 mmol) in DMF (2.0 mL) was added DIPEA (170 μL, 0.972 mmol). Then isopropylamine (19 μL, 0.214 mmol) was added and the mixture was stirred at room temperature under Ar for 2 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (52 mg, 63%) as a white solid. MS: m/e=422.1 [M+H]+.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3][CH2:4]1)=[O:17]
Reactant: O=C(Cl)CCCCl
Reactant: c1ccc2c(c1)NCCCO2
Product: O=C(CCCCl)N1CCCOc2ccccc21

Procedure:
2,3,4,5-tetrahydro-1,5-benzoxazepine and 4-chlorobutyryl chloride were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH:19]=O>>[CH3:25][O:24][C:22]1[CH:21]=[C:18]([CH:19]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=2)=[O:3])[CH:17]=[C:16]([O:15][CH3:14])[CH:23]=1
Reactant: C=CCOc1ccc(C(C)=O)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Product: C=CCOc1ccc(C(=O)C=Cc2cc(OC)cc(OC)c2)cc1
Reaction time: 18 h
Yield: 91.3 %

Procedure:
1.76 g (10 mmol) of 4-allyloxyacetophenone and 1.66 g (10 mmol) of 3,5-dimethoxy-benzaldehyde were dissolved in 10 ml of dry freshly distilled ethanol under an inert atmosphere (argon), and the solution was admixed with 100 mg of sodium hydroxide and left under stirring for 18 h. The reaction mixture was filtered to give 2.96 g (99%) of 3,5-dimethoxy-4′-prop-2-enyloxychalcone which was recrystallized from methanol, m.p. 88.5-90° C.