Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=2)=[CH:15][C:14]=3[O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:8][CH2:7]1)C.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][C:4]([OH:38])=[O:3])[CH2:7][N:8]=2)=[CH:19]3)=[N:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.1 %

Procedure:
A mixture of ethyl{2-[5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (690 mg), 1M aqueous sodium hydroxide solution (5 mL), ethanol (5 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for 15 hr. To the reaction solution was added 1M hydrochloric acid (5 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crystals were washed with hexane-ethyl acetate mixed solvent to give the title compound (610 mg, yield 95%) as brown crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[N:22]=[N:21][N:20]=2)[CH2:8][C@H:7]1[CH2:39][CH3:40])=[O:5])[CH3:2].[CH3:41][O:42][C:43](=[O:49])[C:44]([CH3:48])([CH3:47])[CH2:45]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[C:27]([C:35]([F:36])([F:38])[F:37])[CH:26]=3)[N:22]([CH2:45][C:44]([C:43]([O:42][CH3:41])=[O:49])([CH3:48])[CH3:47])[NH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:39][CH3:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nnnn2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Reactant: COC(=O)C(C)(C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC2=NNN(CC(C)(C)C(=O)OC)N2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 19 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(tetrazol-5-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (230 mg) is dissolved in tetrahydrofuran (3 ml), and thereto are added 3-hydroxy-2,2-dimethylpropionic acid methyl ester (58 μl), a solution (0.18 ml) of 40% diethyl azodicarboxylate in toluene and triphenylphosphine (121 mg). The mixture is stirred at room temperature for 19 hours, and partitioned by adding water and diethyl ether. The organic layer is washed with saturated brine, then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[2-(2-methoxycarbonyl-2-methylpropyl)-2H-tetrazol-5-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (243 mg). MS (m/z): 688 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].Br[CH2:12][CH2:13][O:14][CH2:15]CBr.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OC(=O)C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][CH2:13][O:14][CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: BrCCOCCBr
Reactant: N#Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(Br)cc1C#N
Reaction time: 8 h

Procedure:
5-Bromo-2-hydroxy-benzonitrile (5.4 g, 27.0 mmol), 2-bromoethylether (2.76 ml, 29.7 mmol) and K2CO3 (4.5 g, 32.4 mmol) are mixed in 50 ml DMF. The reaction mixture is stirred at 50 C overnight. Addition of water and extraction into ethylacetate yields the title compound which is further purified by tituration with ether/hexanes. 1H-NMR (400 MHz; DMSO-d6): 7.99 (d, 1H), 7.82 (dd, 1H), 7.23 (d, 1H), 4.27 (t, 2H), 3.69 (t, 2H), 3.33 (s, 3H). LC-MS (m/z, ES+): 273 (M+NH4+), retention time: 2.77 mins (LC-MS method 3)
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl>CO>[C:2]1([CH:1]=[CH:12][N+:9]([O-:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccccc1
Temperature: -18 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
Benzaldehyde (10.0 g, 94.2 mmol) and nitromethane (5.1 mL, 94.2 mmol) were dissolved in MeOH, the solution was cooled to -18° C., and NaOH (3.9 g, 98.9 mmol) in aqueous solution (80 mL) was added while maintaining the temperature below -10° C. The mixture was stirred at 0° C. for 2 hours, then stored at 5° C. overnight. The solution was then poured into stirring acid (200 mL conc. HCl/300 mL H2O). The precipitate was collected, washed, and recrystallized from EtOH to afford the title compound as light orange needles (5.15 g, 37%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=N[CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[OH:11].[CH:31](Cl)(Cl)Cl>[O-2].[O-2].[Mn+4]>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:31][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11]
Reactant: OC(c1ccc(Oc2nccnc2C2CCOCC2)cc1)c1nc2ncccc2[nH]1
Reactant: ClC(Cl)Cl
Agent: [Mn+4]
Agent: [O-2]
Product: O=C(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1nc2ncccc2[nH]1

Procedure:
To a round bottomed flask was added (1H-imidazo[4,5-b]pyridin-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanol (0.992 g, 2.459 mmol) and manganese dioxide (1.069 g, 12.29 mmol) to stir in chloroform (8.20 mL) for 1 hr. Reaction was filtered through celite. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in ACN/H2O, gradient 40% to 80% over 18 min to provide (1H-Imidazo[4,5-b]pyridin-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 401.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:29]([NH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]=[C:3]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(N)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC1CN(C(=O)OC(C)(C)C)CC=C1c1ccc(F)cc1
Temperature: 0 °C
Yield: 104.1 %

Procedure:
To a tetrahydrofuran solution (2.0 ml) of tert-butyl 5-amino-4-(4-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.342 mmol) synthesized in Reference Synthesis Example 202, triethylamine (52.0 μL, 0.374 mmol) and 4-dimethylaminopyridine (2.08 mg, 0.0170 mmol) were added and then acetic anhydride (26.0 μL, 0.374 mmol) was added with stirring at 0° C., followed by stirring the resultant reaction solution at 0° C. for 2 hours. After completion of the reaction, the reaction solution was purified by silica gel column chromatography to obtain the title compound (119 mg, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:26])[N:7](C3CCN(CC4C=CC(Cl)=CC=4)CC3)[C:8]2=O)=[CH:4][C:3]=1[S:27]([NH2:30])(=[O:29])=[O:28].O=C1C2C(=CC=CC=2)C(=O)N1.C(O)(=O)C.C(OCC)(=O)C>CO.[Zn]>[ClH:1].[O:26]=[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[C:3]([S:27]([NH2:30])(=[O:28])=[O:29])[CH:4]=2)[CH2:8][NH:7]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3ccc(Cl)cc3)CC1)C2=O
Agent: O=C1NC(=O)c2ccccc21
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: Cl
Product: NS(=O)(=O)c1ccc2c(c1)C(=O)NC2

Procedure:
Reduction of the above product (a) 1,3-dioxoisoindole (5.0 g., 0.0107 mole) with zinc and acetic acid according to the method of Example 1(c) and conversion of the free base (partially purified by trituration with ethyl acetate) to the hydrochloride salt in methanol afforded 6-chloro-2-[1-[(4-chloro-phenyl)-phenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-1H-isoindole-5-sulfonamide hydrochloride as the sesquihydrate, m.p. 256°-260° (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[CH:6][C:7]=1[CH3:8].CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C)c(C)c3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
To methyl 4-[(2-{1-[5-(3,4-dimethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.051 mmol, 21.6 mg), methanol (2.0 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.257 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.257 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (17.5 mg, yield 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[O:20][C:19]([CH2:21][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:17]=4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(F)c4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(F)c4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{3-fluoro-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.61 (bs, 2H); 9.28 (bs, 1H); 8.80 (s, 1H); 8.34 (d, 1H); 7.87 (m, 2H); 7.59 (d, 1H); 7.44 (m, 1H); 7.2–7.38 (m, 4H); 7.18 (m, 1H); 6.83 (s, 1H); 5.25 (s, 2H); 4.42 (s, 2H); 3.60 (m, 2H); 3.45 (m, 2H, obscured by water peak); 3.16 (s, 3H); MS m/z 565 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[O:17])[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
1.0 g (9.3 mmol) of 4-methylaniline is dissolved in toluene (10 ml) at 0° C., under a nitrogen atmosphere. A solution of phenylacetyl chloride (1.25 ml, 9.4 mmol) in 20 ml of toluene is added dropwise to the medium. The reaction mixture is stirred at room temperature for 2 h and the medium is then hydrolyzed with cold sodium hydrogen carbonate solution. The two-phase system is stirred vigorously for 30 min and the organic phase is then collected. The aqueous phase is extracted with ethyl acetate (twice). The organic phase is dried over MgSO4 and then evaporated. The residue obtained is purified by chromatography on a column of silica (3/7 EtOAc/PE) to give 1.9 g (92%) of compound 47.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].Cl.[CH2:7]1[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]3[CH2:15][CH2:16][C@@H:17]([CH2:19][CH2:20][NH2:21])[C:18]=3[C:8]1=2.C(N(CC)CC)C.O>CN(C)C=O>[CH2:7]1[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]3[CH2:15][CH2:16][C@@H:17]([CH2:19][CH2:20][NH:21][C:1](=[O:4])[CH2:2][CH3:3])[C:18]=3[C:8]1=2
Reactant: CCC(=O)Cl
Reactant: NCC[C@@H]1CCc2ccc3c(c21)CCO3
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)NCC[C@@H]1CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Propionyl chloride (2.57 g, 27.8 mmol.) was gradually added dropwise, under ice-cooling, to a solution of (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl) ethylamine hydrochloride (5.55 g, 23.1 mmol.) and triethylamine (4.7 g, 46.3 mmol.) in N,N-dimethylformamide (100 ml). The mixture was stirred for one hour at room temperature, which was then poured into water, followed by extracting the organic matter with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate:methanol=98:2) to afford the title compound (yield 5.25 g, 88%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[C:31]([C:37](=[N:39]O)[NH2:38])=[N:32][CH:33]=[C:34]([F:36])[CH:35]=1>>[F:29][C:30]1[C:31]([C:37]2[N:38]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:28][N:39]=2)=[N:32][CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ncc(F)cc1F
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ncc(F)cc3F)no2)C1

Procedure:
150 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 91 mg (0.56 mmol) of 3,5-difluoro-N′-hydroxypyridine-2-carboximidamide were reacted according to the General Method 2. Yield: 131 mg (63% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.O.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:23](=[O:26])([O-])[O-].[Na+].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([O:26][CH3:23])[O:7][CH3:12])=[C:4]([F:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc(Br)cc1F
Yield: 97 %

Procedure:
To a solution of 4-bromo-2-fluorobenzaldehyde (3.97 g, 18.8 mmol) in methanol (200 mL) was added p-toluenesulfonic acid monohydrate (357 mg, 1.88 mmol), and the mixture was heated to reflux for 4 h. Aqueous sodium carbonate (1 mol/L; 2 mL) was added, and the mixture was concentrated to a volume of ca. 50 mL and extracted with ether. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 4-bromo-1-dimethoxymethyl-2-fluorobenzene (4.56 g, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[H-].[Na+].Br[CH2:28][CH2:29][O:30][CH3:31]>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]([CH2:28][CH2:29][O:30][CH3:31])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCBr
Reactant: CCOC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(N(CCOC)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a mixture of ethyl 3-[(tert-butoxycarbonyl)amino]benzoate (3.8 g) and DMF (20 ml) were added 60% sodium hydride (1.1 g) and 2-bromoethylmethyl ether (3.9 g) under ice-cooling, followed by stirring at room temperature over one night. To the reaction mixture were added 60% sodium hydride (0.28 g) and 2-bromoethylmethyl ether (0.98 g), followed by stirring at room temperature for 6 hours. Water and ethyl acetate were added thereto, and the organic layer was then separated, washed with 1 M hydrochloric acid and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 3-[(tert-butoxycarbonyl)(2-methoxyethyl)amino]benzoate (2.7 g).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[OH:6][CH:7]([CH3:11])[C:8](=O)[CH3:9].C(NCC)C>CO>[NH2:4][C:3]1[O:6][C:7]([CH3:11])=[C:8]([CH3:9])[C:2]=1[C:1]#[N:5]
Reactant: CC(=O)C(C)O
Reactant: N#CCC#N
Solvent: CO
Solvent: CCNCC
Product: Cc1oc(N)c(C#N)c1C
Temperature: 10 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
To a solution of malononitrile (28.2 g) in methanol (30 mL) is added a suspension of acetoin (25 g) in methanol (30 mL) and thereto is added dropwise diethylamine (11 mL) under ice-cooling (internal temp.: 10° C.). The mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice water (300 mL) and the precipitated crystals are collected by filtration to give 2-amino-4,5-dimethyl-3-furonitrile (28.91 g, yield; 75%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: COc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC)c([N+](=O)[O-])cn1
Yield: 97.7 %

Procedure:
A solution of the product of Step 2 (950 mg, 5 mmol), sodium methoxide (695 mg, 12.5 mmol) in methanol (10 ml) was heated at reflux for 2 hours. After cooling the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried and evaporated in vacuo to give the title compound (900 mg, 98%). MS (ES+) m/e 185 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[F:18][Sb-:19]([F:24])([F:23])([F:22])([F:21])[F:20].[Na+]>CO>[F:18][Sb-:19]([F:24])([F:23])([F:22])([F:21])[F:20].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N+:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Clc1ccccn1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C[n+]2ccccc2Cl)cc1

Procedure:
4,698 g (0.03 mol) of 4-methoxybenzyl chloride and 10.22 g (0.09 mol) of 2-chloropyridine were reacted in 40 ml of methanol at 40° C. for 3 days. After the reaction, the solvent was evaporate in vacuo and ether-water was added to the residue to extract unreacted reactants in the etherial layer. To the aqueous layer containing the pyridinium chloride was added 7.764 g (0.03 mol) of sodium hexafluoroantimonate. The resulting crystals were suction filtered, washed and dried to give the title compound melting at 122°-124° C.
Reaction SMILES: O[CH:2]1[C:8]2=[C:9]([CH3:16])[C:10](=[O:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C@:7]32[O:17][C@:4]([CH3:18])([CH2:5][O:6]3)[CH2:3]1.[H][H].S(=O)(=O)(O)O>Cl(O)(=O)(=O)=O.CO>[OH:15][C:10]1[C:9]([CH3:16])=[C:8]2[C:7](=[C:12]([CH3:13])[C:11]=1[CH3:14])[O:17][C@:4]([CH3:18])([CH2:5][OH:6])[CH2:3][CH2:2]2
Reactant: [H][H]
Reactant: CC1=C(C)[C@]23OC[C@](C)(CC(O)C2=C(C)C1=O)O3
Agent: O=S(=O)(O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CO)O2
Reaction time: 15 h
Yield: 111.3 %

Procedure:
A mixture of 0.59 g of (3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one, 0.7 g of palladium-on-barium sulfate (5% by weight) and 3 drops of concentrated perchloric acid in 20 ml of methanol was hydrogenated with ca 120 ml of hydrogen under normal pressure. Subsequently, 2 ml of 2-N sulfuric acid were added and air was conducted into the mixture for 15 hours. The reaction mixture was again hydrogenated with ca 25 ml of hydrogen. After removal of the catalyst by filtration over Hyflo, the filtrate was treated with dilute sodium bicarbonate solution and extracted with ether. The combined organic phases were dried over magnesium sulfate. After distillation of the solvent on a rotary evaporator, there were obtained 0.62 g of brown crystals, which, for purification, was chromatographed on Kieselgel with acetic ester/toluene (1/1 parts by volume). The resulting (S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol crystallized from methylene chloride/hexane at a yield of 487 mg; melting point 126.5°- 128.5°.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[C:9]1[O:13][C:12]2[C:14]([O:20]C(=O)C)=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=2[C:10]=1[C:24](=[O:37])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1>O1CCCC1.C1(C)C=CC=CC=1>[N:1]1([C:9]2[O:13][C:12]3[C:14]([OH:20])=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:24](=[O:37])[C:25]2[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-n3cncn3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
To a solution of 1,2,4-triazole(22 mg, 0.32 mmol) in dry tetrahydrofuran (2 mL) was added sodium hydride (60%, 24 mg, 0.60 mmol) and resulting suspension was treated with a solution of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (50 mg, 0.10 mmol) in dry toluene (2 mL). The mixture was stirred at reflux for 6 hours (tlc), quenched with saturated ammonium chloride solution, extracted with dichloromethane (10 mL), dried over magnesium sulphate and the solvent distilled under vacuum. The crude residue was purified by PTLC (eluent=ethyl acetate: 1% triethylamine) to give the title compound as a yellow solid; (22 mg, 50%); 1H NMR (300 MHz, CDCl3) δ 8.64(bs, 1H), 8.06(bs, 1H), 7.10(d, 1H, J=8.60 Hz), 7.05(s, 2H, benzoyl Hs), 6.98(d, 1H, J=8.65 Hz), 3.98(s, 3H, OMe), 3.89(s, 3H, OMe), 3.77(s, 6H, 2×OMe).