Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:21][CH2:22][O:23][CH3:24])[N:10]=1.C(O)C.[BH4-].[Na+].O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][C:14]=2[O:21][CH2:22][O:23][CH3:24])[N:10]=1
Reactant: COCOc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzaldehyde (15.50 g) in tetrahydrofuran (100 mL)-ethanol (50 mL) was gradually added sodium borohydride (1.71 g) at 0° C. After stirring at room temperature for 2 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)phenyl)methanol as colorless crystals (14.11 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 92-93° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:21]2[CH:20]=[C:19]([CH3:22])[N:18]=[CH:17][C:16]=2[NH:15][C:14]1=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[I-].[CH3:32][N:33]1[C:41]2[C:36](=[C:37]([CH3:42])[CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:43][N+](C)(C)C)=[CH:34]1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:21]2[CH:20]=[C:19]([CH3:22])[N:18]=[CH:17][C:16]=2[N:15]([CH2:43][C:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][C:37]=3[CH3:42])[N:33]([CH3:32])[CH:34]=2)[C:14]1=[O:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(C)cc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cnc(C)cc21
Temperature: 60 °C
Yield: 66.3 %

Procedure:
To a solution of (R)-3-(6-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]pyridin-1-yl)-3-phenyl-propionic acid ethyl ester (80 mg, 0.25 mmol) in DMF (3 mL) were added K2CO3 (41 mg, 0.30 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (102 mg, 0.30 mmol). The reaction mixture was heated to 60° C. for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 80 mg (67%) of the title compound. LCMS, M++1, m/z: 484.10.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(OCC)(=O)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>[Cl-].[Na+].O>[O:21]1[CH2:22][CH2:23][N:18]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:19][CH2:20]1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(N2CCOCC2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
Methyl 2-chloroisonicotinate (320 mg, 1.89 mmol) was dissolved in morpholine (5 mL) and stirred at 90° C. for 4 hours. The reaction mixture was added with saturated brine and ethyl acetate, and the organic layer was separated, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain methyl 2-morpholinoisonicotinate (50 mg, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([O:32][CH2:33][CH3:34])[C:30]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=C(OCC)C=1[N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)C=O)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([O:32][CH2:33][CH3:34])[C:30]=1[N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OCC)c1F
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cncn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OCC)c1-n1cncn1

Procedure:
In analogy to the procedure described in example 50k), N-piperidin-4-yl-3-(1H-tetrazol-5-yl)-benzamide (example 178) was reacted with 3,5-diethoxy-4-[1,2,4]triazol-1-yl-benzaldehyde (example 129a), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 518.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16]O>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 45 %

Procedure:
To a suspension of 5-hydroxy-4-methoxy-2-nitrobenzoic acid (8.0 g, 37.5 mmol) in methanol was added concentrated sulfuric acid (3 drops) and it was heated at 80° C. overnight. After solvent was removed under reduced pressure, to it was added water and EtOAc. The organic layer was washed with saturated NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure to afford methyl 5-hydroxy-4-methoxy-2-nitrobenzoate as a solid (3.86 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.63 (s, 1H), 7.08 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:71]=[CH:70][C:13]([CH2:14][NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([C:36]4[CH:41]=[CH:40][C:39]([O:42][C:43]([N:45]5[CH2:50][CH2:49][N:48]([C:51](=[O:69])[NH:52][CH2:53][C:54]6[CH:59]=[CH:58][C:57]([CH2:60][NH:61]C(OC(C)(C)C)=O)=[CH:56][CH:55]=6)[CH2:47][CH2:46]5)=[O:44])=[CH:38][CH:37]=4)([CH3:35])[CH3:34])=[CH:29][CH:28]=3)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1)=O)(C)(C)C.[ClH:72]>O1CCOCC1>[ClH:72].[ClH:72].[NH2:8][CH2:9][C:10]1[CH:71]=[CH:70][C:13]([CH2:14][NH:15][C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([C:36]4[CH:41]=[CH:40][C:39]([O:42][C:43]([N:45]5[CH2:46][CH2:47][N:48]([C:51](=[O:69])[NH:52][CH2:53][C:54]6[CH:55]=[CH:56][C:57]([CH2:60][NH2:61])=[CH:58][CH:59]=6)[CH2:49][CH2:50]5)=[O:44])=[CH:38][CH:37]=4)([CH3:35])[CH3:34])=[CH:31][CH:32]=3)=[O:25])[CH2:22][CH2:23]2)=[O:17])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)N2CCN(C(=O)Oc3ccc(C(C)(C)c4ccc(OC(=O)N5CCN(C(=O)NCc6ccc(CNC(=O)OC(C)(C)C)cc6)CC5)cc4)cc3)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(c1ccc(OC(=O)N2CCN(C(=O)NCc3ccc(CN)cc3)CC2)cc1)c1ccc(OC(=O)N2CCN(C(=O)NCc3ccc(CN)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
0.14 g of 2,2-bis-{4-[4-(4-tert-butoxycarbonylaminomethylbenzylcarbamoyl)-1-piperazinylcarbonyloxy]-phenyl}propane is dissolved in 2 ml of abs. dioxane, and 2 ml of an approx. 20% solution of hydrogen chloride in dioxane is added to this solution. The mixture is stirred overnight and the precipitate is filtered off with suction, washed twice with diethyl ether and dried in vacuo. 0.08 g of the title compound, having a m.p. of from 250° C. (decomposition), is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[C:32]([CH3:34])([CH3:33])[O:31]C(C)(C)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:37]>CCO>[ClH:37].[CH3:34][C:32]([OH:31])([CH3:33])[C@H:28]([C:25]1[N:24]=[C:23]([NH:22][C:10]2[C:9]([O:8][C:7]3[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][N:11]=2)[S:27][N:26]=1)[OH:29]
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC(C)(C)OC2(C)C)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)C(C)(C)O)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
(S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)-1,2,4-thiadiazol-5-amine (145 mg, 0.2774 mmol) was dissolved in EtOH (5 mL), and 6M HCl (0.3 mL) was added. The reaction was stirred at ambient temperature for 2 hours and then at 70° C. for 2 hours. The reaction was cooled to ambient temperature and partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried, filtered, concentrated and purified over silica gel (10% methanol in EtOAc) to afford (S)-2-methyl-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol hydrochloride (111.7 mg, 0.215 mmol, 77.6% yield) as a pale yellow solid after HCl salt formation. Mass Spectrum (apci) m/z=465.2 (M+H−HCl).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([S:28][CH2:29][C:30]3[CH:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+]>CCOC(C)=O>[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([S:28][CH2:29][C:30]3[CH:31]=[N:32][C:33]([NH:8][CH2:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:34][CH:35]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nc3)c2CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(NCC4CCCCC4)nc3)c2CC1
Temperature: 170 °C
Yield: 40 %

Procedure:
Add cyclohexylmethylamine (3 mL) to a flask containing 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (340 mg, 0.8 mmol) and ammonium chloride (50 mg, 0.92 mmol). Heat the contents in a sealed flask at 170° C. for 7 h. Cool the flask to room temperature, dilute with EtOAc (50 mL) and wash with water (20 mL). Collect the organic layer and concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 4:1 gradient) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(6-cyclohexylmethylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (160 mg, 40%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:30]3[CH:31]=[N:26][CH:27]=[N:28][CH:29]=3)[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(N2CCOCC2)n1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1nc(-c2cncnc2)cc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-1H-benzimidazole (200 mg, 0.547 mmol), pyrimidine-5-boronic acid (203 mg, 1.64 mmol), PdCl2(dppf) (45 mg, 0.0551 mmol), and aq. K2CO3 (2M, 4 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 2.5 hrs. Additional pyrimidine-5-boronic acid (203 mg, 1.64 mmol) and PdCl2(dppf) (23 mg, 0.0282 mmol) were added, and the mixture was refluxed for additional 16.5 hrs under nitrogen. The mixture was cooled to room temperature, diluted with H2O, extracted with CH2Cl2 (4×), and the combined organic extracts were dried (Na2SO4), and the solvents were removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 97:3), followed by recrystallization from CH2Cl2/MeOH/i-Pr2O gave 2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4,5′-bipyrimidine (177 mg, 79%): mp 209-211° C.; 1H NMR (CDCl3) δ9.37 (s, 2H), 9.37 (s, 1H), 8.37 (m, 1H), 7.93 (m, 1H), 7.59 (t, JHF=53.7 Hz, 1H), 7.49-7.41 (m, 2H), 6.86 (s, 1H), 3.91 (m, 4H), 3.85 (m, 4H); Anal. Calcd. for C20H17F2N7O: C, 58.7; H, 4.2; N, 23.95. Found: C, 58.4; H, 3.9; N, 23.9%.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]1[CH:13]([C:14]([OH:16])=[O:15])[C:12](=[O:17])[CH2:11][CH2:10][N:9]1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Br:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>C(O)(C)(C)C>[CH3:7][CH:8]1[C:13]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[Br:26])([C:14]([OH:16])=[O:15])[C:12](=[O:17])[CH2:11][CH2:10][N:9]1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1C(C(=O)O)C(=O)CCN1C(=O)c1ccccc1
Reactant: BrCc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1N(C(=O)c2ccccc2)CCC(=O)C1(Cc1ccccc1Br)C(=O)O
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of potassium t-butoxide (16.8 g, 0.15 mol) in t-butanol (300 ml) was added methyl 1-benzoyl-4-oxo-3-piperidinecarboxylic acid (36.1 g, 0.146 mol) according to the method of G. Stork, J. Am. Chem. Soc. 68, 1053 (1946). The mixture was stirred 1 hour and 2-bromobenzyl bromide was added dropwise in a solution of t-butanol. The reaction was heated to reflux for 2 days, cooled and filtered. The salts were washed with ether and the organic filtrate was washed with 5% hydrochloric acid (100 ml), saturated sodium bicarbonate (100 ml), water (100 ml) and saturated sodium chloride (100 ml). The organic layer was dried (MgSO4), filtered, and concentrated to yield a crude oil. The material was recrystallized from isopropyl ether to yield a pale yellow solid (23.4 g, 37%) An additional recrystallization produced the title compound a white solid, mp 105°-107° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][C:14]3=[O:25])[CH2:7][CH2:6]2)[O:4]CC1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([N:16]=[CH:15][C:14](=[O:25])[N:13]2[CH2:12][CH2:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)=[CH:18][CH:19]=1
Reactant: COc1ccc2ncc(=O)n(CCC3CCC4(CC3)OCCO4)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CCC3CCC(=O)CC3)c2c1
Reaction time: 0.25 h

Procedure:
To 0.16 g of 1-(2-(1,4-dioxaspiro(4.5)decan-8-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one, 1.5 mL of an 80% aqueous trifluoroacetic acid solution was added at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Thereto was added ethyl acetate under cooling with ice, and the reaction mixture was adjusted to pH 8.0 with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.18 g of a brown oily substance, 7-methoxy-1-(2-(4-oxocyclohexyl)ethyl)quinoxalin-2(1H)-one.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[O:1]=[C:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C2(CCCC2)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a solution of tert-butyl 4-hydroxy-2-azaspiro[4.4]nonane-2-carboxylate (10.82 g, 44.8 mmol) in DCM (225 mL) was added 4 Å molecular sieve (22.00 g), then added PDC (42.17 g, 112.1 mmol) slowly. After addition, the reaction mixture was stirred at rt overnight and filtered. The filter cake was washed with EtOAc (50 mL×3) and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/15) to give the product as colorless oil (5.92 g, 55.2%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:23]([Si:27]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[O:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][CH:47]=1)[CH2:32][C@:33]1([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=O)([CH3:26])([CH3:25])[CH3:24].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([C:34]3[C@:33]([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])([CH2:32][C:31]4[CH:45]=[CH:46][CH:47]=[C:29]([O:28][Si:27]([C:23]([CH3:26])([CH3:24])[CH3:25])([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[CH:30]=4)[CH2:38][CH2:37][CH2:36][CH:35]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCCC2=O)c1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [Li]CCCC
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of (4,5-diphenyl)oxazole (17 g) in THF (100 ml) was added n-BuLi (57 ml, 1.6N-solution in hexane) at −78° C. After stirring for 30 minutes, a solution of (R)-1-[3-(tertbutyldiphenyl-silyloxy)benzyl]-1-trimethylsilyoxy-2-cyclohexanone (27 g) in THF (50 ml) was added to the above mixture at the same temperature. After stirring for 1 hour, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with 1N-HCl solution and brine. The organic solvent was evaporated in vacuo to give a residue. The residue was dissolved in toluene (100 ml) and then added with (methoxycarbonylsulfamoyl)triethyl-ammonium hydroxide, inner salt(20.4 g) at room temperature. After refluxing under stirring for 5 hours, the reaction mixture was evaporated in vacuo. The residue was purified by chromatography on silica gel to give (R)-2-(4,5-diphenyloxazol-2-yl)-1-trimethylsilyloxy-1-[3-(tertbutyldiphenylsiloxy)benzyl]-2-cyclohexene (36 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1.N1CCCCC1>CO>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:28]1
Reactant: COc1ccc2c(c1CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperidine-1-carboxylate (0.0518 g, 0.143 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0220 g, 0.151 mmol) and piperidine (0.100 mL, 1.01 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperidine-1-carboxylate (0.0525 g, 75%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[O:13]1[C:17]2[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:16]=2[CH:15]=[CH:14]1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][C:14]1[O:13][C:17]2[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:16]=2[CH:15]=1
Reactant: O=C(O)c1ccc2ccoc2c1
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)c1ccc2cc(CCCCBr)oc2c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
n-Butyllithium solution (2.29 M in hexane, 44 ml., 0.1 mole) is added to a solution of diisopropylamine (10.1 g., 0.1 mole) in tetrahydrofuran (150 ml.) and hexamethylphosphoramide (15 ml.). The resulting solution is treated with benzofuran-6-carboxylic acid (8.1 g., 0.05 mole) and then with 1,4-dibromobutane (10.8 g., 0.05 mole) at 0° C. The mixture is stirred at 0° C. for 6 hours. It is then quenched with water, acidified with hydrochloric acid and extracted with ethyl acetate. Evaporation of the solvent gives 2-(4-bromobutyl)benzofuran-6-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1.CO.[NH4+].[Cl-]>[Fe].O>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1c(F)ccc(N)c1Nc1ccccc1
Temperature: 90 °C
Yield: 87.9 %

Procedure:
To a mixture of (3-fluoro-2-methyl-6-nitrophenyl)phenylamine (1.5 g, 6.1 mmol) in a 3:1 mixture of MeOH:water (40 mL) were added NH4Cl (1.88 g, 36.5 mmol) and iron powder (1.36 g, 24.4 mmol) and the reaction mixture heated at 90° C. for 1 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (×3) and the combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as a pink solid (1.16 g, 88%). 1H NMR (CDCl3, 400 MHz): δ 7.22-7.15 (2H, m), 6.88-6.77 (2H, m), 6.64-6.55 (3H, m), 5.03 (1H, br s), 3.68 (2H, br s), 2.11 (3H, d, J=2.24 Hz).
Reaction SMILES: [Mg].[CH2:2]([O:4][CH2:5][CH2:6][CH2:7]Br)[CH3:3].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[CH:19]=[CH:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15](=[O:24])[C:14]=2[CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[CH:19]=[CH:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]([CH2:7][CH2:6][CH2:5][O:4][CH2:2][CH3:3])([OH:24])[C:14]=2[CH:25]=1
Reactant: Nc1ccc2ccc3ccccc3c(=O)c2c1
Reactant: CCOCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOCCCC1(O)c2ccccc2C=Cc2ccc(N)cc21
Reaction time: 0.25 h

Procedure:
Magnesium turnings (6.2 g., 0.255 mole) covered with dry tetrahydrofuran (30 ml.) in carefully-dried apparatus are treated with a solution of 3-ethoxypropylbromide (42.5 g., 0.255 mole) added dropwise to maintain reflux. After preparation of the Grignard reagent according to standard procedures, the mixture is cooled, and 16 g. (0.072 mole) of 3-amino-5H-dibenzo[a,d]cyclohepten-5-one added in portions over 5 minutes. The reaction is stirred 15 minutes, then poured into 200 ml. of saturated aqueous ammonium chloride. The layers are separated, and the aqueous layer extracted once with ether. The ether layer, combined with the original organic phase, is washed once with water, dried over sodium sulfate, and evaporated in vacuo to give the title compound in essentially quantitative yield.