Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=2)[NH:3]1.CCN(C(C)C)C(C)C.[C:37]1([CH2:43][C:44](Br)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[NH4+].[Cl-]>C(Cl)Cl.CCOCC>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si:21]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:26][CH3:27])([C:12]([F:15])([F:14])[F:13])[C:16]([F:17])([F:18])[F:19])[CH:8]=2)[N:3]1[C:44](=[O:45])[CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Br)Cc1ccccc1
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2C(=O)Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A solution of 101 mg (0.24 mmol) of 2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole (example 51.2) in CH2Cl2 was treated with 0.05 mL (0.3 mmol) of DIPEA and then with 0.03 mL (0.24 mmol) of phenylacetylbromide at 0° C. The mixture was stirred at RT for 3 hrs and then distributed between Et2O a saturated aqueous solution of NH4Cl. The combined organic phases were dried over Na2SO4 and evaporated to yield 120 mg of 1-[2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-yl]-2-phenyl-ethanone. This crude was dissolved in 2 mL of THF and treated with 0.9 mL of a 1M BH3 soution in THF. After stirring for 10 hrs at RT the mixture was distributed between Et2O and a saturated aqueous solution of NH4Cl. The combined organic phases were dried over Na2SO4 and evaporated to yield 135 mg of 2-methyl-1-phenethyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole, of which 30 mg were dissolved in 1 mL of THF and treated with 0.07 mL of 1M TBAF in THF. Stirring for 30 min, evaporation, and column chromatography on silica gel with n-heptane/EtOAc (4:1) yielded 12 mg (51%) of 1,1,1,3,3,3-hexafluoro-2-(2-methyl-1-phenethyl-2,3-dihydro-1H-indol-5-yl)-propan-2-ol, colorless waxy solid, MS: 404 (MH+).
Reaction SMILES: C(OC(=O)C)(=O)C.[NH:8]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13].[C:28]1([C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S(=O)(=O)(O)O>C(O)(=O)C.O>[NH:8]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH:13][C:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
1.1 ml of acetic anhydride (12 mmol) are added to a mixture of 2.8 g of Z-Gln-OH (10 mmol), 5.2 g of triphenylmethanol (20 mmol) in 30 ml of acetic acid, and the mixture is stirred at 50° for 15 minutes. Then 0.05 ml of conc. sulfuric acid (about 1 mmol) is added, resulting in a clear yellow solution after a few minutes. After 2 hours, the solution is added dropwise to 500 ml of water, while stirring and cooling in ice, and the precipitate is filtered off and thoroughly washed with water. The moist material is dissolved in ethyl acetate, the aqueous phase is separated off, and the organic phase is washed once with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to 20 g. Z-Gln(Trt)-OH is crystallized by addition of hexane in portions, m.p. 161°-162°.
Reaction SMILES: CN(S(F)(F)[F:5])C.O[CH:9]([C:17]1[CH:26]=[N:25][C:24]2[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22](=[O:36])[N:21]3[N:37]=[CH:38][N:39]=[C:20]3[C:19]=2[CH:18]=1)[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C.C(=O)(O)[O-].[Na+]>[F:5][CH:9]([C:17]1[CH:26]=[N:25][C:24]2[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22](=[O:36])[N:21]3[N:37]=[CH:38][N:39]=[C:20]3[C:19]=2[CH:18]=1)[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CN(C)S(F)(F)F
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(O)CN4CCOCC4)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(F)CN4CCOCC4)cnc32)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
(Dimethylamino)sulfur trifluoride (0.010 mL, 0.18 mmol) was added to a stirred solution of 9-(1-hydroxy-2-morpholinoethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 83, 49 mg, 0.090 mmol) in ACN (1 mL). After 4 h, additional (dimethylamino)sulfur trifluoride (0.035 mL, 0.36 mmol) was added and the mixture was stirred at 60° C. for 20 h, and cooled to room temperature. The reaction mixture was diluted with aqueous sodium bicarbonate (3 mL) and extracted with DCM (2×3 mL). The combined organic layers were concentrated under a stream of nitrogen and the residue was taken up in methanol, and filtered. Purification (HPLC, 10-75% ACN in water) afforded the title compound but retained impurities. The product was diluted with aqueous sodium bicarbonate (3 mL) and extracted with DCM (2×3 mL). The combined organic layers were concentrated under a stream of nitrogen. Purification (FCC, SiO2, 0 to 40%, IPA/EtOAc) afforded the title compound (9 mg, 21%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 2.58-2.72 (m, 4H), 2.82 (ddd, J=27.98, 13.93, 3.39 Hz, 1H), 3.01 (ddd, J=18.85, 14.15, 7.53 Hz, 1H), 3.72-3.76 (m, 4H), 3.76 (s, 3H), 5.75 (s, 2H), 5.84 (d, J=47.93 Hz, 1H), 6.76-6.88 (m, 2H), 7.60 (d, J=8.66 Hz, 2H), 8.36 (s, 1H), 8.64 (d, J=1.88 Hz, 1H), 8.80 (s, 1H). [M+H]=439.1.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:13]([OH:15])=[O:14])[NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].[CH2:18](O)CCCC=C>>[CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:13]([OH:15])=[O:14])[NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:18])=[O:6]
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=CCCCCO
Product: C=CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
3-Methyl-N-[(hex-5-enyloxy)carbonyl]-L-valine was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine by using 5-hexenol instead of 4-pentenol. LRMS (ESI) m/z 258 [(M+H)+; calcd for C13H24NO4: 258].
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:21])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[CH:12][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:23]1[CH:28]=[CH:27][O:26][C:25](=[O:29])[CH:24]=1>C1COCC1>[C:3]([O:7][C:8](=[O:21])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][C:23]2[CH:28]=[CH:27][O:26][C:25](=[O:29])[CH:24]=2)=[CH:12][CH:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: O=c1cc(Cl)cco1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccoc(=O)c2)c2ccccc12
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (0.070 g of 60% oil dispersion) in 5 mL of anhydrous THF at 0° C. was added (4-hydroxy-naphthalen-1-yl)-carbamic acid tert-butyl ester (0.414 g) (Example 5). The mixture was stirred 20 min, then 4-chloro-2H-pyran-2-one (Helvitica Chemica. Acta, 1990, 73, 883) (0.208 g) was added and the reaction stirred 5 h at 0° C. Removal of the volatiles in vacuo provided a residue which was purified by flash chromatography on silica gel eluting with 33% EtOAc in hexanes. Concentration of the product rich fractions provided [4-(2-oxo-2H-pyran-4-yloxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH3:26][NH2:27]>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:27][CH3:26])[S:8]1(=[O:25])=[O:24]
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Reactant: CN
Solvent: CO
Product: CNCCOCCN1c2ccccc2N(c2c(F)cccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with 8N methylamine in methanol to give 2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N-methylethanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.24 g, 25%). HRMS: calcd for C17H19F2N3O3S+H+, 384.11879; found (ESI, [M+H]+Obs'd), 384.1184.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CI>C1COCC1>[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([CH3:2])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a -78° C. solution of LDA (10.79 mmol) in THF (30 mL) was added 1-benzyl-4-piperidone (2.0 mL, 10.8 mmol). The reaction mixture was warmed to 0° C. for 20 min and then cooled back to -78° C. Methyl iodide (0.67 mL, 10.8 mmol) was added to the enolate solution which was stirred at 0° C. for 2 h then warmed to RT overnight. The reaction mixture was quenched with sat. NH4Cl and concentrated. The residue was suspended in H2O and extracted with CH2Cl2. The combined organic layers were dried with MgSO4, filtered and concentrated. The product was purified by flash chromatography on silica gel eluting with 1:1 hexane-EtOAc to give the 1-benzyl-3-methyl-4-piperidone 4 as a yellow oil (0.65 g, 30%).
Reaction SMILES: C(NCC)C.[NH:6](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:7]([C:15]([N:17]1[CH2:61][CH2:60][CH2:59][C@H:18]1[C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:41]([NH:43][C@H:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:42])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39])=[O:31])[CH2:23][S:24][S:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20])=[O:16])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:14])[NH2:13]>CN(C)C=O>[NH2:6][C@H:7]([C:15]([N:17]1[CH2:61][CH2:60][CH2:59][C@H:18]1[C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:41]([NH:43][C@H:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:42])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:40])=[O:31])[CH2:23][S:24][S:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:20])=[O:16])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:13])[NH2:14].[CH3:44][C:52]([OH:54])=[O:53].[CH3:44][C:52]([OH:54])=[O:53].[CH3:44][C:52]([OH:54])=[O:53]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSSC(C)(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSSC(C)(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N
Reaction time: 0.17 h

Procedure:
3.32 ml of diethylamine are added to a solution of 3.3 g of Fmoc-Arg-Pro-Cys(StBu)-Arg-Phe-OtBu (crude substance) in 20 ml of dimethylformamide. After 10 minutes at room temperature, the mixture is concentrated in vacuo. The residue is triturated with ether and filtered off with suction.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1.O>C1COCC1>[C:3]([C:2]([NH:1][C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)=[O:24])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC(C)(C(N)=O)C(C)C)cc1
Reaction time: 1 h

Procedure:
A stirred mmixture containing 13.0 g (0.10 mol) of 2-amino-2,3-dimethylbutyramide and 15.3 mL (0.11 mole) of triethylamine in 150 mL of dry THF is treated dropwise at 5° to 10° C. with a solution of 15.5 g (0.10 mol) of p-toluoyl chloride in 25 mL dry THF. After being allowed to warm to ambient temperatures over a 16 hour period, the reaction mixture is treated with 50 mL water and stirred for one hour. The resulting three phases are filtered; the filtrate is separated and the aqueous phase is extracted with 150 mL ethyl acetate. All organic phases are combined, washed with 100 mL of a saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo. A white solid residue is obtained which weighs 17.3 g, mp 145°-152° C. The nmr spectrum is consistent with the desired structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20].[CH:21]([OH:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([O:24][CH:21]([CH3:23])[CH3:22])=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20]
Reactant: CC(C)O
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)Cl)c(Cl)cc2F)C1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(c2cc(C(=O)OC(C)C)c(Cl)cc2F)C1=O

Procedure:
6 g of N-(2-fluoro-5-chlorocarbonyl-4-chlorophenyl)-2,3-dimethylmaleic acid imide are added dropwise, while stirring at room temperature, to a mixture of 4 ml of isopropanol, 4 ml of triethylamine and 100 ml of toluene. After a reaction time of 6 hours, the triethylamine hydrochloride is separated off by filtration and the filtrate is concentrated by evaporation. By recrystallising the residue from ethanol/water, 4.2 g of N-(2-fluoro-4-chloro-5-isopropoxycarbonylphenyl)-2,3-dimethylmaleic acid imide having a melting point of 161°-162° are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[F:16][C:17]([F:37])([F:36])[C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[N:24]=[CH:23]2)=[O:19]>C1COCC1.CCOCC>[F:37][C:17]([F:16])([F:36])[C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[N:24]=[CH:23]2)([C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1)[OH:19]
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: COc1ncc(Br)cc1C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ncc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C
Reaction time: 0.5 h

Procedure:
To a chilled (−78° C.) solution of 5-bromo-3-methyl-2-methoxypyridine (1.56 mmol) in 2 mL THF was added dropwise n-butyllithium (1.71 mmol from a 2.5 M solution in hexanes). The mixture was stirred for 30 minutes and then 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (1.39 mmol) in 3 mL THF was added. After 30 minutes, the mixture was diluted with ether and quenched with aqueous ammonium chloride. The organic layer was washed with brine and dried over magnesium sulfate. Removal of the volatiles in vacuo provided a residue which was purified by Combiflash chromatography using ethyl acetate-hexane. The product-rich fractions were concentrated in vacuo to provide the title compound.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][CH:12]([C:44](OC)=[O:45])[C@H:13]([NH:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[OH:45][CH2:44][C@@H:12]([CH3:11])[C@H:13]([NH:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: COC(=O)C(C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H](CO)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 20 h
Yield: 349 %

Procedure:
Diisobutylaluminum hydride (20.57 ml of 1.0 M in hexanes, 20.57 mmol) was added drop-wise over 10 min to a cooled (−78° C.) THF (120 mL) solution of (2S)-1-benzyl 4-methyl 3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.37 g, 6.86 mmol) prepared above, and stirred at −78° C. for 20 hr. The reaction mixture was removed from the cooling bath and rapidly poured into ˜1M H3PO4/H2O (250 mL) with stirring, and the mixture was extracted with ether (100 mL, 2×). The combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. A silica gel mesh of the crude material was prepared and submitted to chromatography (25% EtOAc/hexanes; gravity elution) to afford 11.1 g of (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate, contaminated with benzyl alcohol, as a colorless viscous oil and (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate containing the (2S,3R) stereoisomer as an impurity. The later sample was resubmitted to the same column chromatography purification conditions to afford 750 mg of purified material as a white foam. [Note: the (2S,3S) isomer elutes before the (2S,3R) isomer under the above condition]. (2S,3S) isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.81 (m, 2H), 7.39-7.08 (m, 16H), 4.67 (d, J=12.3, 1H), 4.43 (d, J=12.4, 11H), 4.21 (app t, J=5.2, OH), 3.22 (d, J=10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H), ˜2.5 (m, 1H, overlapped with the solvent signal), 1.58 (m, 1H), 0.88 (d, J=6.8, 3H). LC (Cond. 1): RT=2.00 min; LC/MS: Anal. Calcd. for [M+H]+ C31H30NO3: 464.45; found 464.22. (2S,3R) isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.81 (d, J=7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, J=12.1, 1H), 4.50 (app t, J=4.9, 1H), 4.32 (d, J=12.1, 11H), 3.59-3.53 (m, 2H), 3.23 (m, 1H), 2.44 (dd, J=9.0, 8.3, 1H), 1.70 (m, 1H), 0.57 (d, J=6.8, 3H). LC (Cond. 1): RT=1.92 min; LCMS: Anal. Calcd. for [M+H]+ C31H30NO3: 464.45; found 464.52.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[O:12])=[CH:6][CH:5]=1.[CH2:13]=[O:14].C1[CH2:19][O:18]CC1>>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:19][OH:18])([CH2:13][OH:14])[CH2:11][OH:12])=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: C=O
Reactant: O=CCc1ccc(Br)cc1
Agent: N#N
Product: OCC(CO)(CO)c1ccc(Br)cc1
Temperature: 63 °C
Reaction time: 72 h

Procedure:
To a 50-mL three-neck 14/20 round-bottomed flask equipped with a stir bar, a reflex condenser, a thermometer, and N2 inlet was added samples of 11 (6.00 g, 30.1 mmol), paraformaldehyde (5.90 g, 196 mmol), Ca(OH)2 (1.79 g, 24.2 mmol), and THF (22 mL). The cloudy white mixture was heated to 63° C. and stirred at this temperature for 3 d. The reaction mixture was then cooled and filtered through Celite. The filtrate was concentrated to a viscous, pale yellow oil. The residue was pumped on under high vacuum at 100° C. (to remove volatiles) for 1 h. Column chromatography (silica, EtOAc) afforded a pale yellow viscous oil which was mostly pure by TLC. This oil was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].O.[NH2:23][NH2:24]>CCO>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:23][NH2:24])=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(C#N)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
To a suspension of methyl 4-[(4-cyanobenzoyl)amino]benzoate (680 mg, 2.43 mmol) in EtOH (8 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (1×2 mL) and water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 432 mg of the title compound (64%) as a pale yellow solid in 94.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][CH2:10][CH2:9][C:7](=O)[C:5]=2[CH:6]=1.O1C2C(=CC=CC=2)CCC1O>>[O:11]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:9][CH2:10]1
Reactant: O=C1CCOc2ccccc21
Agent: OC1CCc2ccccc2O1
Product: C1=Cc2ccccc2OC1

Procedure:
Then, the so-obtained chromanone compound was converted to a chromanol compound in the same manner as described in Example 2, and the dehydration reaction was carried out. Then, the separation and purification were carried out to obtain a 5.84 g of a chromene compound represented by the following formula: ##STR76##
Reaction SMILES: [F:1][C:2]1[C:3](N)=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:11][CH2:12][C:13](O)=O.[NH4+:16].[OH-]>Cl>[Cl:11][CH2:12][C:13]1[NH:9][C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[CH:6][C:5]=2[N:16]=1
Reactant: [NH4+]
Reactant: O=C(O)CCl
Reactant: Nc1ccc(F)c(F)c1N
Agent: Cl
Agent: [OH-]
Product: Fc1cc2nc(CCl)[nH]c2cc1F
Temperature: 100 °C

Procedure:
A mixture of 1 g of 3,4-difluoro-1,2-phenylenediamine (6.94 mmol) and 0.983 g of chloro-acetic acid (10.41 mmol, 1.5 eq) in 13 mL of 4N aqueous HCl was heated to 100° C. for 3 h. The mixture was poured onto ice (10 g), neutralized by the addition of NH4OH and extracted with three 30 mL portions of ethyl acetate. The organic extracts were combined and dried over Na2SO4, filtered and concentrated by rotary evaporation to give 1.28 g of 2-chloromethyl-5,6-difluoro-1H-benzoimidazole as a brown solid. 1H NMR (300 MHz, CDCl3/CD3OD): δ 7.30-7.25 (m, 2H), 4.68 (s, 2H); MS (ESI): Calcd m/z for C8H5ClF2N2.H+=203.1. Found m/z=203.2/205.2 [(M+1)+/(M+3)+].
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.C(N(CC)CC)C.CN(C)C=O.[CH2:25]([O:27][CH2:28][CH2:29][NH2:30])[CH3:26]>O>[NH2:12][C:4]1[N:3]=[C:2]([NH:30][CH2:29][CH2:28][O:27][CH2:25][CH3:26])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Reactant: CCOCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCNc1nc(N)nc2c1CCCC2
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 32.4 %

Procedure:
To a mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100 mg, 0.545 mmol), triethylamine (221 mg, 2.18 mmol) and dimethylformamide (2 ml) was added ethoxyethylamine (98 mg, 1.10 mmol) at room temperature. After the mixture was stirred for 2.5 hours at 90° C., the reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the solvent in the filtrate was removed in vacuo. The residue was purified by preparative TLC (10% MeOH/CHCl3) to give the object compound (41.7 mg, 32.4%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[CH3:22])=[C:11]([CH3:23])[O:10][N:9]=1.O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[NH2:27].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]3[O:19][N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[N:25]=3)=[CH:15][C:14]=2[CH3:22])=[C:11]([CH3:23])[O:10][N:9]=1
Reactant: COc1ccccc1C(N)=NO
Reactant: Cc1cc(C(=O)O)ccc1-c1c(C)noc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3c(C)noc3C)c(C)c2)n1

Procedure:
Oxalyl chloride (132 μL; 1.56 mmol; 3 eq.), Intermediate 30 (120 mg; 0.52 mmol; 1 eq.), Intermediate 1 (86 mg; 0.52 mmol, 1 eq.) and DIEA (268 μL; 1.56 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 80/20) afforded the title compound as an orange foam.