Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:7])[CH3:6].[OH-].[Na+]>CO>[CH2:12]([O:11][C:9]([NH:8][C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([OH:19])=[O:2])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CC(C)(C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A solution of 18.27 g (68.9 mmol) of 3-benzyloxycarbonylamino-3-methylbutanoic acid methyl ester in 20 mL of methanol at room temperature was treated dropwise with 51 mL of 2N NaOH (102 mmol). The mixture was stirred at room temperature for 16 hours then transferred to a separatory funnel and washed with hexane (3×). The aqueous layer was removed, cooled to 0° C. and slowly acidified to pH 2 (paper) by dropwise addition of 6N HCl. This mixture was extracted with ether (6×); combined extracts were washed with 1N HCl and brine, then dried over magnesium sulfate, filtered and solvent removed under vacuum to afford 17.26 g (68.7 mmol, 99%) of the product. 1H NMR (200 MHz, CDCl3): 1.42 (s, 6H), 2.77 (s, 2H), 5.06 (s, 2H), 5.2 (br s, 1H), 7.3 (s, 5H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH2:32]>>[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH:32][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:24]
Reactant: COC(CN)OC
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: COC(CNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1)OC
Yield: 78 %

Procedure:
By the same procedure as described in the example 24, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2,2-dimethoxyethylamine. And then, the product was crystallized with ethanol and hexane to give a desired compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[H-].[Na+].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([O-:13])=[O:12].O>CN(C)C=O.O1CCCC1>[CH3:1][N:2]1[CH2:8][C:6](=[O:7])[N:5]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[C:3]1=[O:4]
Reactant: CN1CC(=O)NC1=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)N(Cc2ccc([N+](=O)[O-])cc2)C1=O
Reaction time: 0.5 h

Procedure:
To a mixture solution of 685 mg (6.0 mmol) of 1-methylhydantoin in 10 mL of N,N-dimethylformamide and 10 mL of tetrahydrofuran was added 240 mg (6.9 mmol) of sodium hydride (60% oily) at room temperature, and the mixture was stirred for 30 minutes at the same temperature. Then, 1.08 g (5.0 mmol) of p-nitrobenzyl bromide was added to the reaction mixture, and the mixture was stirred for over night at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 1.38 g (quantitative) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].[C-:13]#[N:14].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]([OH:8])[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1
Reactant: [C-]#N
Reactant: O=Cc1cccc(OC(F)F)c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(O)c1cccc(OC(F)F)c1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To 3-difluoromethoxybenzaldehyde (1.77 g, 10 mmol) in ethyl acetate (25 mL) was added a solution of KCN (2.0 g) and NaHSO3 (3.2 g) dissolved in H2O (25 mL). It was left stirring overnight before it was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 131A (1.85 g, 92% yield) as an oil.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[F:13][CH:14]([F:49])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]1[N:27]2[CH:28]=[C:29]([C:32]3[CH:33]=[N:34][C:35]([C:38]4[CH2:43][CH2:42][CH:41]([C:44]([O:46][CH3:47])=[O:45])[CH2:40][CH:39]=4)=[N:36][CH:37]=3)[CH:30]=[CH:31][C:26]2=[N:25][C:24]=1[CH3:48]>CS(C)=O.C(Cl)Cl>[F:49][CH:14]([F:13])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]1[N:27]2[CH:28]=[C:29]([C:32]3[CH:33]=[N:34][C:35]([C:38]45[CH2:7][CH:43]4[CH2:42][CH:41]([C:44]([O:46][CH3:47])=[O:45])[CH2:40][CH2:39]5)=[N:36][CH:37]=3)[CH:30]=[CH:31][C:26]2=[N:25][C:24]=1[CH3:48]
Reactant: COC(=O)C1CC=C(c2ncc(-c3ccc4nc(C)c(Cc5ccccc5OC(F)F)n4c3)cn2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)C1CCC2(c3ncc(-c4ccc5nc(C)c(Cc6ccccc6OC(F)F)n5c4)cn3)CC2C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
A solution of trimethylsulfoxonium iodide (176 mg, 0.79 mmol) and potassium tert-butoxide (85 mg, 0.75 mmol) in DMSO (2 mL) was stirred at 50° C. for 45 minutes. A solution of methyl 4-[5-(3-{[2-(difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-2-yl]cyclohex-3-ene-1-carboxylate (prepared in an analogous manner to that described for Example 39, 100 mg, 0.2 mmol) in DMSO (2 mL) was added and the mixture was stirred at 50° C. for 4 h, then at room temperature for 3 days. The reaction mixture was diluted with DCM (10 mL) and washed with water (3×3 mL). The aqueous washes were combined and further extracted with DCM (2×3 mL). The organic extracts were combined, dried over sodium sulfate and evaporated. The resulting crude brown residue was diluted with DCM (3 mL) and washed with 1N aqueous NaOH solution (3×1 mL). The organic phase was dried over sodium sulfate and evaporated. The resulting pale brown residue was purified by preparative TLC, eluting with 1% MeOH in DCM, to afford the title compound (38.3 mg, 37%) as an off-white solid. Method B HPLC-MS: MH+ m/z 519, RT 1.80 minutes.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:18])=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][CH2:3][C:4]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2[NH:10][N:9]=[C:8]([CH3:18])[C:7]=2[N:6]=1
Reactant: COCC(=O)Nc1c(C)n[nH]c1-c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1nc2c(C)n[nH]c2c2ccccc12
Temperature: 120 °C

Procedure:
To a suspension of 320 mg of 2-methoxy-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-acetamide in 6 mL of phosphorous oxychloride was added 2.70 g of phosphorous pentoxide and the resulting suspension was heated at 120° C. for 5 h. The reaction mixture was cooled to rt and quenched with the addition of ice and water and then neutralized with solid sodium carbonate. The aqueous mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by recrystallisation from ethyl acetate. The title compound was obtained as a reddish, tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C1C=CC=CC=1.[CH2:18]([S:34](Cl)(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(N(CC)CC)C>[CH2:18]([S:34]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1CO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCS(=O)(=O)OCc1ccccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To a stirred solution of 7.65 g (0.05 mol) of 2-nitrobenzyl alcohol in 75 ml of benzene containing 5.05 g (0.05 mol) of triethylamine was added 16.25 g (0.05 mol of hexadecanesulfonyl chloride. The mixture was stirred an additional four hours. The mixture was evaporated to dryness in vacuo and the solid taken up into a mixture of ether and water. The ether layer was separated and dried over MgSO4. Evaporation of the ether gave a solid which was crystallized from absolute ethanol (yield 14.3 g, m.p. 63°-65° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:27][CH:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])=[CH:31][N:30]=3)[CH2:25]2)=O)=CC=1)([O-])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH:9][C:22]([N:24]2[CH2:25][CH:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])=[CH:31][N:30]=3)[CH2:27]2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)nn1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)N2CC(Oc3ccc(-c4ccccc4F)cn3)C2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
To a solution of 6-Methoxy-pyridazin-3-ylamine (39 mg, 0.31 mmol, [Cas. No. 7252-84-8]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg, 0.5 mmol, 60% disp. in mineral oil). After stirring at 0° C. for 15 min. a solution of 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid 4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was added dropwise. After stirring for 16 hrs at ambient temperature the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by flash chromatography (ethyl acetate) to give the title compound (35 mg, 37%)
Reaction SMILES: [OH2:1].O.O.[ClH:4].Cl.Cl.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([CH2:21][CH2:22][CH:23]([CH2:40][CH2:41][CH2:42][CH2:43][CH:44]1[C:53]3[C:48](=[CH:49][C:50]([O:56][CH3:57])=[C:51]([O:54][CH3:55])[CH:52]=3)[CH2:47][CH2:46][NH:45]1)[CH2:24][CH2:25][CH:26]1[C:35]3[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=3)[CH2:29][CH2:28][NH:27]1)[NH:14][CH2:13][CH2:12]2>CCOCC.C(Cl)(Cl)Cl>[OH2:8].[OH2:1].[OH2:8].[ClH:4].[ClH:4].[ClH:4].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][CH2:22][CH:23]([CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[C:53]3[C:48](=[CH:49][C:50]([O:56][CH3:57])=[C:51]([O:54][CH3:55])[CH:52]=3)[CH2:47][CH2:46][N:45]=1)[CH2:24][CH2:25][C:26]1[C:35]3[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=3)[CH2:29][CH2:28][N:27]=1)=[N:14][CH2:13][CH2:12]2
Reactant: COc1cc2c(cc1OC)C(CCCCC(CCC1NCCc3cc(OC)c(OC)cc31)CCC1NCCc3cc(OC)c(OC)cc31)NCC2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(cc1OC)C(CCCCC(CCC1=NCCc3cc(OC)c(OC)cc31)CCC1=NCCc3cc(OC)c(OC)cc31)=NCC2

Procedure:
To purify the intermediate (1.1a), the crude residue obtained after stripping off the chloroform is converted to the hydrochloride, in ether, and the resulting salt taken up in chloroform. Precipitation with ether, followed by two further reprecipitations from chloroform solution by either yields (1.1a) 1,1'-{3-[2-(3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl)ethyl]heptamethylene}bis[3,4-dihydro-6,7-dimethoxyisoquinoline] trihydrochloride trihydrate, as a yellow solid, m.p. 130-150° (dec.).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2O[C:10](=[O:27])[C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([C:21]4[CH:26]=[N:25][CH:24]=[CH:23][N:22]=4)=[O:20])[C:12]=3[N:13]=2)=[C:5]([CH3:7])[N:6]=1.[CH3:28][NH2:29]>CO>[CH3:1][C:2]1[S:3][C:4]([C:8]2[N:29]([CH3:28])[C:10](=[O:27])[C:11]3[C:12](=[C:14]([NH:18][C:19]([C:21]4[CH:26]=[N:25][CH:24]=[CH:23][N:22]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CN
Reactant: Cc1nc(C)c(-c2nc3c(NC(=O)c4cnccn4)cccc3c(=O)o2)s1
Solvent: CO
Product: Cc1nc(C)c(-c2nc3c(NC(=O)c4cnccn4)cccc3c(=O)n2C)s1
Temperature: 80 °C
Yield: 31 %

Procedure:
N-(2-(2,4-dimethylthiazol-5-yl)-4-oxo-4H-benzo[d][1,3]oxazin-8-yl)pyrazine-2-carboxamide 18 (100 mg, 0.26 mmol) was dissolved in 30 wt % solution of CH3NH2 in methanol (10 mL). The reaction mixture was heated at 80° C. for 12 h. The resulting precipitate was collected by filtration and rinsed with DME to give Compound 287 (32 mg, 31% yield). MS (ESI) calc. for C19H16F3N6O2S: 392.11. found: 393 [M+H].
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13]>C(OCC)C>[CH2:10]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCNCCCC
Solvent: CCOCC
Product: CCCCN(CCCC)C(=O)CC(C)=O
Temperature: 150 °C
Yield: 67.7 %

Procedure:
A! A mixture of ethyl acetoacetate (50 g, 0.38 mole) and dibutylamine (49.65 g, 0.38 mole) was heated to 150° C. for one day. After cooling, the reaction mixture was taken up in 500 ml of ethyl ether and washed with 200 ml of 1N HCl and 200 ml of water. The ether phase was anhydrified over sodium sulfate, and evaporated to dryness thus yielding 86.7 g of a crude which was distilled under vacuum to give 54.86 g (yield: 67%) of N,N-dibutyl-3-oxo-butanamide.
Reaction SMILES: CC([C:4]1[C:12]2[O:11][C@@H:10]3[CH2:13][C@H:14]([OH:26])[C@@H:15]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C@@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)=O.C(=O)([O-])O.[Na+].ClC1C=CC=[C:35]([C:39]([O:41]O)=[O:40])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:39]([O:41][C:4]1[C:12]2[O:11][C@@H:10]3[CH2:13][C@H:14]([OH:26])[C@@H:15]([NH:16][S:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:18])=[O:19])[C@@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:40])[CH3:35]
Reactant: CC(=O)c1cccc2c1O[C@@H]1C[C@H](O)[C@@H](NS(=O)(=O)c3ccccc3)[C@H]21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1cccc2c1O[C@@H]1C[C@H](O)[C@@H](NS(=O)(=O)c3ccccc3)[C@H]21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(1S, 2S, 3aR, 8bS)-1-benzenesulfonamido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl methyl ketone (112) (1.57 g) was dissolved in methylene chloride (30 ml) followed by the addition of sodium hydrogencarbonate (2.12 g) and metachloroperbenzoic acid (potency: 70%, 4.61) and stirring for 5 hours at room temperature. A 4% aqueous solution of sodium sulfite (100 ml) was added to the reaction mixture followed by extraction with methylene chloride (100 ml+50 ml×2). The organic layer was washed with saturated brine (50 ml×2) and concentrated to a solid after drying with anhydrous magnesium sulfate. The residue was purified with column chromatography (silica gel: n-hexane/ethyl acetate 1:1-1:2) to obtain (1S, 2S, 3aR, 8bS)-1-benzenesulfonamido-2-hydroxy- 2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl acetate (1.26 g).
Reaction SMILES: O=C(C)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[CH3:19][C:20]([CH3:31])([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:19][C:20]([CH3:31])([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:22])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)C(C)(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
Ethyl 3-oxobutanoate (1.09 g, 8.3 mmol) in methylene chloride (16 mL) was mixed with anhydrous magnesium chloride (158 mg, 1.66 mmol), and the reaction solution was cooled to 0° C. and mixed with pyridine (1.34 mL, 16.6 mmol), stirred for 30 minutes, then mixed with 2,2-dimethyl-3-phenylpropanoyl chloride (1.64 g, 8.3 mmol) and stirred for another 30 minutes at the same temperature. The reaction solution was warmed to room temperature and stirred for 20 hours. The methylene chloride was distilled off under reduced pressure, and the residue was with ethanol (2 mL) and at room temperature for 2 days and with toluene (2 mL) at 60° C. for 5 hours. After completion of the reaction, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (50 mL×2). The solvent was removed from the resulting organic layer under reduced pressure, and the resulting brown oil was purified by intermediate pressure silica gel column chromatography (silica gel 12 g, ethyl acetate:hexane=1:19 to 1:9) to give 370 mg of the desired product as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[S:7][C:6]=2[CH:31]=1.[OH-].[Na+].Cl>CO.[Cl-].[Na+].O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=3)=[O:11])=[C:8]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[S:7][C:6]=2[CH:31]=1
Reactant: COC(=O)COc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)COc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 25 °C

Procedure:
To [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl][4-carbomethoxymethoxyphenyl]methanone (132 mg, 0.30 mmol) stirring in methanol (5 mL) was added sodium hydroxide (0.43 mL of a 5 N aqueous solution, 2.13 nmol). The red mixture was heated to reflux for 0.5 hour, cooled to room temperature, and made acidic with hydrochloric acid (0.70 mL of a 5N aqueous solution). The mixture was then poured into brine and extracted with ethyl acetate. The combined organic extracts were washed thoroughly with brine, dried (magnesium sulfate), and filtered. Concentration afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.CN(C)[CH:13]=[C:14]([N:20]=[CH:21]N(C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16].FC(F)(F)C(O)=O>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:20]=[CH:21][C:9]=2[CH:8]=[CH:7]1
Reactant: CCOC(=O)C(=CN(C)C)N=CN(C)C
Reactant: COCCCn1cccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(ccn2CCCOC)cn1
Yield: 64.8 %

Procedure:
A solution of 1-(3-methoxypropyl)-1H-pyrrole (3.92 g), ethyl 3-dimethylamino-2-(dimethylaminomethyleneamino)acrylate (7.20 g) (ref. Liebigs Ann. Chem. 1980, 344-357) and trifluoroacetic acid (8.33 mL) in acetic acid (32 mL) was stirred at room temperature for 18 hours, and then heated to reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure. To the resulting residue was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1→AcOEt) to give ethyl 1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(105.2)] (4.79 g) as a brown oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12.[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:19][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN
Reactant: CCn1ncc2c(Cl)c(CO)cnc21
Product: CCCCNc1c(CO)cnc2c1cnn2CC
Yield: 87 %

Procedure:
51 g. of 4-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-methanol (0.24 mol.) and 300 ml. of n-butylamine are heated at 100° in an autoclave for seven hours. After cooling, the surplus butylamine is removed by distillation in vacuo and the residue is treated with a total amount of 200 ml. of ether. The etheral solution is evaporated, yielding 51.9 g (87%) of the alcohol, m.p. 60°-72°. Recrystallization with hexane provides the pure 4-butylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-methanol, m.p. 85°-86°.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:6][CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.C[O-].[Na+]>O>[F:19][C:18]([F:21])([F:20])[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][C:2]=2[N:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1Cl)c1ccccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ccc(C(F)(F)F)nc2Oc2ccccc21
Temperature: 220 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a stirring solution of title compound 73 (0.76 g, 2.4 mmol) in tetraglyne (10 mL) was added sodium methoxide (0.220 g, 4.08 mmol) and the reaction mixture was stirred at 220° C. for 3 h. The reaction mixture was cooled to room temperature diluted with water (25 mL), stirred for 20 min then filtered to give a light brown solid which was purified by flash chromatography (0% to 60% ethyl acetate in hexanes) to afford title compound 74 (0.37 g, 55%). LRMS (ESI): (calc) 280.05. (found) 281.3 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N+:17]([C:3]1[CH:4]=[C:5]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:19])=[O:18]
Reactant: Brc1cccnc1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 90.5 %

Procedure:
4-Amino-3-nitrophenylboronic acid pinacol ester (1.60 g, 6.06 mmol), 3-bromopyridine (1.10 g, 6.96 mmol), cesium carbonate (3.33 g, 10.22 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (491 mg, 0.60 mmol) were suspended in dimethylformamide (20 mL). The solution was degassed by vacuum several times and placed in an argon atmosphere. It was then heated to 65° C. for 6 hr. After cooling, EA (100 mL) and water (40 mL) were added. When additional water (50 mL) was added to the organic layer, a precipitate was formed in the separatory funnel. The biphasic solution was filtered, and the filtrate was transferred to the separatory funnel and separated. The organic phase was washed twice with water (50 mL each), then with brine, and then dried with sodium sulfate and concentrated under reduced pressure to give 2-nitro-4-(pyridin-3-yl)benzenamine (1.18 g). 2-Nitro-4-(pyridin-3-yl)benzenamine (700 mg, 3.26 mmol) in 1:1 ethanol/EA (40 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (90 mg, 0.08 mmol) at room temperature for 2 days. Filtration and concentration under reduced pressure gave 4-(pyridin-3-yl)-benzene-1,2-diamine (621 mg).