Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C([Li])CCC.C([O:24][B:25](OCC)[O:26]CC)C.Cl>O1CCCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:25]([OH:26])[OH:24])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: CCOB(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(B(O)O)cc1
Temperature: -78 °C
Yield: 55.8 %

Procedure:
1-bromo-4-(octyloxy)benzene (14.64 g, 51.3 mmol) was dissolved in dry tetrahydrofuran in nitrogen atmosphere and cooled to −78° C. Butyllithium (50 ml, 80.0 mmol) was then added drop wise and the reaction mixture was let to room temperature. After an hour the mixture was once again cooled to −78° C. and triethylborate (23.6 g, 0.162 mol) was added drop wise. The reaction mixture was stirred over night at room temperature, acidified with 2M HCl, and the organic phase was recovered. It was washed once with water and three times with 1M sodium hydroxide to form a white soapy solid. The combined alkaline phases were acidified with 2M HCl and extracted with ether three times. The combined ether phases were washed with water and dried over magnesium sulphate. The product precipitated in dichloromethane from the reduced ether phase to yield 4-(octyloxy)phenylboronic acid (7.15 g, 28.6 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:27]([CH3:26])[C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=4)=[CH:22][CH:23]=3)=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1cccc(Cl)c1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2cccc(Cl)c2)cc1)c1ccc(OC(F)(F)F)cc1
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 3-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide, and N-methyl-4-(trifluoromethoxy)aniline, the title compound was isolated as a yellow solid in 69% yield (94% purity by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]1[S:18][C:10]2=[N:11][CH:12]=[C:13]([C:16]#[N:17])[C:14](Cl)=[C:9]2[CH:8]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25].Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]1[S:18][C:10]2=[N:11][CH:12]=[C:13]([C:16]#[N:17])[C:14]([NH:25][C:24]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:22]([O:21][CH3:20])[CH:23]=3)=[C:9]2[CH:8]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COC(=O)CCCc1cc2c(Cl)c(C#N)cnc2s1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COC(=O)CCCc1cc2c(Nc3cc(OC)c(OC)c(OC)c3)c(C#N)cnc2s1
Yield: 70.2 %

Procedure:
A mixture of 4-(4-chloro-5-cyano-thieno[2,3-b]pyridin-2-yl)-butyric acid methyl ester (60 mg, 0.20 mmol), 3,4,5-trimethoxyaniline (92 mg, 0.50 mmol), and pyridine hydrochloride (10 mg, 0.09 mmol) in 10 mL of 2-ethoxyethanol is heated at reflux for 24 hours. The solution is cooled and the solvent is evaporated. The residue is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane to provide 62 mg of 4-[5-cyano-4-(3,4,5-trimethoxy-phenylamino)-thieno[2,3-b]pyridin-2-yl]-butyric acid methyl ester as a tan solid, mp 101-103° C.; 1H NMR (DMSO-d6) δ 1.94 (quintet, J=7 Hz, 2H), 2.41 (t, J=7 Hz, 2H), 2.88 (t, J=7 Hz, 2H), 3.60 (s, 3H), 3.67 (s, 3H), 3.75 (s, 6H), 6.60 (s, 2H), 7.28 (s, 1H), 8.40 (s, 1H), 9.62 (s, 1H); MS 442.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:14]3[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[C:16]([F:23])[C:15]=3[Cl:24])OC)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.B(F)(F)F.[CH3:29]COCC.C[Zn]C.C1(C)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:14]3[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[C:16]([F:23])[C:15]=3[Cl:24])[CH3:29])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOc1ccc(F)c(Cl)c1C(OC)c1c[nH]c2ncc(Br)cc12
Reactant: CCOCC
Agent: C[Zn]C
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1ccc(F)c(Cl)c1C(C)c1c[nH]c2ncc(Br)cc12
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 5-Bromo-3-[(2-chloro-6-ethoxy-3-fluorophenyl)-methoxymethyl]-1H-pyrrolo[2,3-b]pyridine (3.0 g, 7.2 mmol) in THF (30 mL) was added BF3.OEt2 (7.1 mL, 56.3 mmol). The reaction mixture was stirred for 1 h, and 2M solution of dimethylzinc in toluene (28 mL, 56 mmol) was added dropwise. The reaction mixture was stirred for 12 h at 50° C. and was quenched with saturate aq. ammonium chloride. The organic layer was separated and aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated to give a yellowish residue. The residue was adsorbed on silica and purified (100% DCM→5% methanol/DCM) by small pad of silica. The resulting solid was recrystallized with diisopropyl ether to give the title compound. 1H NMR (CDCl3, 400 MHz): δ=1.25 (t, 3H, J=7.0 Hz), 1.79 (d, 3H, J=7.0 Hz), 3.74 (bs, 1H), 3.96 (q, 1H, J=7.0 Hz), 5.05 (q, 1H, J=7.0 Hz), 6.66-6.69 (m, 1H), 6.97 (t, 1H, J=9.0 Hz), 7.69 (s, 1H), 8.25 (s, 1H), 9.24 (s, 1H).
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4]CSC.[P:8]([O-])([O:18][CH2:19][C:20]1C=CC=[CH:22][CH:21]=1)([O:10][CH2:11][C:12]1C=CC=[CH:14][CH:13]=1)=[O:9].IN1C(=O)CCC1=O>C1COCC1.C(OCC)(=O)C>[CH3:1][S:2][CH2:3][O:4][P:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:9]
Reactant: CSCOCSC
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOP(=O)(OCCCC)OCSC
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of bis(methylthiomethyl)ether (30 mg, 2.34 mmol) and molecular sieves (300 mg) in THF (100 ml) at room temperature was added dibenzyl phosphate (2.74 g, 9.85 mmol) followed by N-iodosuccinimide (608 mg, 2.71 mmol) and the solution was stirred for 4 h. The reaction mixture was then diluted with ethyl acetate and filtered through a pad of celite. The filtrate was treated with a 1:1 (v:v) solution of saturated aqueous sodium bicarbonate and 5% aqueous sodium thiosulfate. The colorless organic extract was then washed with brine, dried over sodium sulfate and concentrated in vacuo to provide 600 mg (69%) of the title compound:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([S:25][C:26]2[N:30]=[CH:29][NH:28][N:27]=2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45]C(C)([O-])C.[K+].CI.Cl>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([S:25][C:26]2[N:30]=[CH:29][N:28]([CH3:45])[N:27]=2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](Sc2nc[nH]n2)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cn1cnc(S[C@H]2[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]2OCc2ccc(Cl)c(Cl)c2)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
Dissolve di-tert-butyl (1R,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.60 g, 0.893 mmol) in anhydrous tetrahydrofuran (3.6 mL) in a flame-dried flask and cool to −78° C. Add potassium t-butoxide (0.80 g, 0.893 mmol) and stir for 15 minutes. Add methyl iodide (0.127 g, 0.893 mmol, pretreated by filtration through basic alumina) and allow to stir at −78° C. for 15 minutes. Allow the mixture to warm to room temperature and then stir for 30 minutes at room temperature. Pour crude reaction mixture into water and adjust pH to 6 with 1N aqueous HCl and extract into ethyl acetate. Dry the organic layer over magnesium sulfate, filter and concentrate under reduced pressure. Purify by reverse phase flash chromatography (100 g C18 column eluting with 45-95% Acetonitrile/Water (with 0.1% trifluoroacetic acid in both), compound elutes at 89% Acetonitrile). Combine the desired fractions and neutralize with aqueous bicarbonate. Extract with ethyl acetate, dry the organic layer over magnesium sulfate, filter and concentrate under reduced pressure to yield the title compound as a white foam (0.16 g, 0.23 mmol, 26%): MS (m/z): 473/475/477 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([NH:16][C:17]([O:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH3:21])=[O:18])=[CH:14][O:13][N:12]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>O1CCCC1>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([NH:16][C:17](=[O:18])[O:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH3:21])=[CH:14][O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(-c2nocc2NC(=O)OC(C)c2ccccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(OC(=O)Nc1conc1-c1ccc(O)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 96.4 %

Procedure:
To a solution (20 ml) of 4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-isoxazolyl]phenyl acetate (2.11 g, 5.26 mmol) in tetrahydrofuran was added 1M aqueous sodium hydroxide solution (7.0 ml), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and water was added. The mixture was neutralized with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.82 g, 96%).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[C:8]([O:11][CH2:12][C@H:13]([O:15][CH3:16])C)(=[O:10])[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>O.[Cl-].[Zn+2].[Cl-]>[C:8]([O:11][C@@H:12]([CH3:1])[CH2:13][O:15][CH3:16])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@H](C)COC(C)=O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Cl-]
Solvent: O
Product: COC[C@H](C)OC(C)=O
Temperature: 118 °C

Procedure:
To a 25-ml flask was added 4.0 g (0.044 mole) of the (S)-PM-2/(R)-PM-1 mixture with 0.02 g anhydrous zinc chloride. A reflux condenser with drying tube was attached and 4.7 g (0.046 mole) acetic anhydride was added by lifting the drying tube momentarily. The mixture was refluxed at about 118° C. for 2 hours and then allowed to cool. GC-analysis of a 1% solution in water showed a single peak for PMA-2 with retention time matching the first peak observed for commercial PMA-2 enantiomers. These results indicated that the first PMA-2 peak is the (S) enantiomer. A single peak was also observed for the PMA-1 enantiomer. This peak also matched the first peak for PMA-1, present in ˜3% in the commercial mixture, indicating that it was (R)-2-methoxy-1-propanol acetate. These results indicate that the (R) and (S) PMA-1 enantiomers exhibit opposite elution order from that observed for the corresponding PMA-2 enantiomers. The mixture was neutralized by adding 2.44 g (0.024 mole) anhydrous sodium carbonate and stirring for approximately 1 hour with CO2 evolution. A short path distillation head was attached and the reaction product was distilled using a heat gun as heat source. About 5.0 g material boiling in the 95-137° C. range was collected. GC analysis showed sample purity to be about 95% (S-PMA-2 92.6% and R-PMA-1 2.7%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([Br:17])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccsc1C(=O)NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
A mixture of N-benzyl-3-methylthiophene-2-carboxamide (6.63 g, 28.66 mmol) and N-bromosuccinimide (5.10 g, 28.66 mmol) in anhydrous acetonitrile (70 mL) was stirred at ambient temperature for 18 h, and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (4×100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate/hexanes to afford the title compound as a colorless solid (6.48 g, 73%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.29 (m, 5H), 6.87 (s, 1H), 5.95 (br s, 1H), 4.59 (d, J=5.7 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 310.2 (M+1), 312.2 (M+1).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:43][CH2:42][C:30]3([N:34]=[C:33]([CH:35]4[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]4)[NH:32][C:31]3=[O:41])[CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:43][CH2:42][C:30]3([N:34]=[C:33]([CH:35]4[CH2:40][CH2:39][CH2:38][N:37]([C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])[CH2:36]4)[NH:32][C:31]3=[O:41])[CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1NC(C2CCCNC2)=NC12CCN(S(=O)(=O)c1cccc(Cl)c1)CC2
Reactant: O=C(Cl)N1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCCCC1)N1CCCC(C2=NC3(CCN(S(=O)(=O)c4cccc(Cl)c4)CC3)C(=O)N2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
TEA (1.143 mmol, 3 eq) and piperidine-1-carbonyl chloride (0.457 mmol, 1.2 eq) were sequentially added to a mixed solution of 8-(3-chloro-benzenesulfonyl)-2-piperidin-3-yl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one trifluoroacetate (200 mg, 0.38 mmol) in dichloromethane (3 ml). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The resulting residue was purified by HPLC to give 8-(3-chloro-benzenesulfonyl)-2-[1-(piperidine-1-carbonyl)-piperidin-3-yl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (30 mg, yield 15%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:4][C:3]=1[O:21][CH3:22].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][OH:33]>CN(C=O)C>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:19])[CH3:20])[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH:31]([CH3:30])[CH2:32][OH:33])=[C:3]([O:21][CH3:22])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1N
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1NC(C)CO
Temperature: 70 °C
Yield: 23.6 %

Procedure:
3-(4-amino-3-methoxyphenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA20d) (30 mg, 0.10 mmol) was dissolved in DMF (0.400 ml). K2CO3 (55 mg, 0.4 mmol) was added and reaction was stirred at 70° C. 3-bromo-1-propanol (0.050 ml, 0.6 mmol) was added and reaction was stirred overnight. Solid K2CO3 was removed by filtration. Solvent was partially removed in vacuo. Sodium citrate (50 ml) was added and reaction was extracted with saturated NaCl and CH2Cl2. Organic phases concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA99 (8.4 mg, 24% yield). ESI-MS (M+H)+ m/z calcd 357.2, found 357.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=O.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:20]([CH3:22])[C:19]([C:18]([O:24][CH2:25][CH3:26])=[O:23])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C)nc2ccc(Cl)cc2c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)-(4-fluorophenyl)methanone (10.0 g) in 100 mL of toluene was added 8.3g (1.6 equivalents) of ethyl acetoacetate and 0.30 g of p-toluenesulfonic acid. The resulting mixture was heated to reflux with azeotropic removal of water. After one and one-half hours, the mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by flash chromatography over silica gel to give 10.18 g of 6-chloro-4-(4-fluorophenyl)-2-methyl-3-quinolinecarboxylic acid, ethyl ester as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[CH2:11]([N+:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O-:1])=[CH:3][CH:4]=1)=[O:7].[CH2:24]([N+:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: O=Cc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: O=Cc1ccc([O-])cc1
Temperature: 60 °C

Procedure:
A glass flask with reflux condenser, heatable oil bath, mechanical stirrer and internal thermometer was charged at room temperature with 7.64 g of 4-hydroxybenzaldehyde and 93.86 g of water and these components were stirred together thoroughly. Subsequently 40.54 g of tetrabutylammonium hydroxide (40% strength in MeOH) were added and the reaction mixture was heated to 60° C. It was stirred at 60° C. for one hour (the contents of the flask became clear). Then the reaction mixture was cooled and the solvents (methanol and water) were distilled off under reduced pressure, 20 mbar, at 30-45° C. The product was then washed with butyl acetate and dried at 80° C. and 10 mbar in a vacuum drying cabinet. This gave a white-beige solid.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[CH3:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.Cl[Si](C)(C)C.O>CN(C=O)C>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])=[CH:20][CH:19]=4)=[C:3](/[CH:1]=[CH:31]/[C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Cc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of compound 5f (0.68 g, 1.7 mmol) and 2-methylquinoline (0.26 mL, 2.0 mmol) in DMF (5 mL) was added chlorotrimethylsilane (0.64 mL, 5.0 mmol) dropwise. The resulting mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled, and water (20 mL) was added. The precipitated solid was collected by filtration, washed with MeOH (2×5 mL), and dried under high vacuum. Compound 5g was obtained as an orange solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H31 N5O3: 534.2 (M+H). found: 534.4.
Reaction SMILES: [OH:1][C@@H:2]([CH3:22])[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)=[O:4].N1C=CC=CC=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31].C(OC(=O)C)C.C1CCCCC1>ClCCl>[O:13]=[C:12]1[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=2[C@@H:6]1[NH:5][C:3]([C@@H:2]([O:1][C:30](=[O:31])[O:32][C:33]1[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=1)[CH3:22])=[O:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Yield: 0.1 %

Procedure:
0.17 g (0.57 mmol) (S)-2-hydroxy-N—((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-propionamide in 5 ml dichloromethane were stirred with 93 μl (1.15 mmol) pyridine and 0.14 g (0.69 mmol) 4-nitrophenyl chloroformate at room temperature overnight. Chromatography on silicagel with ethylacetate/cyclohexane (0-100/100-0) gave 0.27 mg (75%) carbonic acid 4-nitro-phenyl ester (S)-1-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester as white solid; MS: m/e: 462.3 (M+H+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:5][CH:6]=1>O>[CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Solvent: O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Yield: 125.2 %

Procedure:
A suspension of 31.73 g of L-N-[(4-methoxyphenyl)sulfonyl]-glutamic acid (0.1 mol) in 400 ml of water was stirred and heated till all solid entered solution. Then there were added 20.43 g of tetramisole (0.1 mol) and stirring while heating was continued for a while. The thus obtained homogeneous solution was further stirred for 4 hours while the temperature was allowed to reach room temperature. The precipitate was filtered off, washed with water and dried under vacuo at 50° C., yielding 25.58 g levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (yield 98.1%) αD20 =-64.2° (c5. 1N HCl); mp. 127.9°-129.4° C.
Reaction SMILES: [OH-].[Co+2:2].[OH-].[NH2:4][C@H:5]([C:11]([OH:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].CCCCCC>O>[NH2:4][C@H:5]([C:11]([O-:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[Co+2:2].[NH2:4][C@H:5]([C:11]([O-:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [Co+2]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: NCCCC[C@H](N)C(=O)[O-]
Reaction time: 3 h

Procedure:
The recovered cobalt hydroxide was then placed into a beaker provided with a reflux condenser and Dean Stark water trap. 29.2 grams (0.2 Mole) of lysine was added and thereafter 100 ml hexane was subsequently added and stirred and boiled at atmospheric pressure for 3 hours. In the course of reaction about 3.6-3.8 ml of water was removed from the reaction media and acquired in the Dean Stark apparatus. The reaction mixture was then cooled and filtered yielding 35 grams of cobalt lysinate in the form of a fine pink powder.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:23]([O:22][C:20]([CH2:19][O:18][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][CH:15]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above 4-ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was dissolved into a 40% TFA/methylene chloride solution, and stirred at room temperature for 4 hours. Evaporation of solvent gave 4-ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid in quantitative yield.