Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]([NH:5][C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[H-].[Na+].I[CH3:30]>O1CCCC1>[C@@H:1]([N:5]([CH3:30])[C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a solution of (S)-methyl 3-(sec-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (280.0 mg, 0.79 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (127 mg, 3.17 mmol) and stirred for 1 h at room temperature. Subsequently, iodomethane (570 mg, 3.97 mmol) was added and stirred overnight at room temperature. The reaction was concentrated in vacuo and then quenched by the addition of water (20 mL), adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-3-(sec-butyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (124.3 mg, 44%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1[N:16]=[CH:17][S:18][C:19]=1[C:20]([CH2:22][CH2:23][CH2:24]Cl)=[O:21]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:24][CH2:23][CH2:22][C:20]([C:19]2[S:18][CH:17]=[N:16][C:15]=2[CH3:14])=[O:21])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: Cc1ncsc1C(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ncsc1C(=O)CCCSc1nnnn1C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g), potassium carbonate (2.1 g) and 3-chloropropyl 4-methyl-5-thiazolyl ketone (3.1 g) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off and the filtrated is concentrated under reduced pressure. The residue is purified by silica gel column chromatography [Kieselgel 60, eluant: benzene-ether (10:1)] and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(4-methyl-5-thiazolylcarbonyl)propyl]thio-1,2,3,4-tetrazole (2.6 g) as colorless needles, m.p. 64°-65° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:42])[N:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])[CH2:25][CH2:26][CH2:27][C:28](=[O:34])[N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:20]=[C:19]([Cl:43])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[Cl:43][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[F:41])[CH2:25][CH2:26][CH2:27][C:28](=[O:34])[N:29]1[CH2:30][CH2:31][CH2:32][CH2:33]1)=[O:42]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)N2CCCC2)c2ccccc2F)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1F)N1CCCC1
Reaction time: 1 h

Procedure:
A solution of (2-{3-chloro-5-[(2-fluoro-phenyl)-(4-oxo-4-pyrrolidin-1-yl-butyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.025 g) in mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stored at room temperature for 1 h and then the solvent removed under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.024 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C>[N:4]1([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH3:11])=[O:9])[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC(=O)c1ccccc1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1ccccc1-n1cccc1

Procedure:
A mixture of 500 g of methyl anthranilate and 438 g of 2,5-dimethoxytetrahydrofuran in 670 ml of glacial acetic acid is heated at reflux temperature for 11/2 hours. The acetic acid is then evaporated under reduced pressure and the residue is distilled to yield methyl 2-(1H-pyrrol-1-yl)-benzoate, b.p. 109°/0.1 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([S:39]([C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)(=[O:41])=[O:40])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Product: Cc1c(N2CCN(S(=O)(=O)c3cccnc3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and pyridine-3-sulfonyl chloride to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(4-(pyridin-3-ylsulfonyl)piperazin-1-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 1.98 (d, J=6.0 Hz, 3H), 3.04 (t, J=4.8 Hz, 4H), 3.18 (br s, 4H), 3.33-3.37 (m, 4H), 3.69 (t, J=4.4 Hz, 4H), 6.48 (s, 1H), 7.13-7.19 (m, 1H), 7.25-7.28 (m, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.70-7.77 (m, 1H), 7.77 (d, J=2.0 Hz, 1H,), 8.19-8.22 (m, 1H), 8.34 (s, 1H), 8.90-8.91 (m, 1H), 8.95 (d, J=2.4 Hz, 1H). Mass Spectrum (ESI) m/e=582.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:33]=[C:32]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:30][N:29]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:32]1[CH:31]=[CH:30][N:29]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:33]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2ccnc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 6-(2-imidazol-1-yl-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J14) according to the general procedure K. Obtained as an orange solid (103 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1)=[O:5].[C:25]([O:29][C:30]([N:32]1[C@@:36]([CH3:40])([C:37](O)=[O:38])[CH2:35][O:34][C:33]1([CH3:42])[CH3:41])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:41][C:33]1([CH3:42])[N:32]([C:30]([O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:31])[C@@:36]([CH3:40])([C:37](=[O:38])[NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]([C:21]([F:22])([F:23])[F:24])[CH:7]=2)=[O:5])[CH2:35][O:34]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)O
Reactant: CCCCCCCCOc1ccc(C(=O)CN)cc1C(F)(F)F
Agent: Cl
Product: CCCCCCCCOc1ccc(C(=O)CNC(=O)[C@@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
Synthesis of phenyl-thiazoles is described in Scheme 4. Reaction of benzyl or allyl alcohol with substituted 4-fluorobenzoic acid 1 afforded the substituted ether-benzoate 2. The substituted ether-benzoate 2 was then coupled with hydrazine to afford benzohydrazide 3. Reaction of benzohydrazide 3 with orthogonally protected amino acid 4 under HATU conditions followed by cyclization and deprotection (or vis versa) provided phenol 6 in good yield. Mitsunobu reaction of phenol 6 with desired alcohol followed by deprotection afforded the desired final compound 8. Reaction of the alcohol 8 with diethyl chlorophosphate followed by deprotection with TMSBr gave the corresponding phosphate.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:6](=[C:19](OCC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:29])(=O)C.[CH3:30][N:31]([CH2:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37])[CH3:32]>>[CH3:32][N:31]([CH2:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH:37]/[C:19](=[C:6]1\[C:5](=[O:29])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:11]=2)/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3)ccc21)c1ccccc1
Reactant: CN(C)Cc1cccc(N)c1
Product: CN(C)Cc1cccc(N/C(=C2\C(=O)Nc3cc(-c4ccccc4)ccc32)c2ccccc2)c1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and 3-(dimethylaminomethyl)-aniline
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[S:5](=[O:12])(=[O:11])[NH:4][C:3]=1[C:13]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:14].[H-].[Na+].[CH3:23]I.[Na]>CN(C)C=O>[OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH3:23])[C:3]=1[C:13]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:14]
Reactant: O=C(Nc1nccs1)C1=C(O)c2sccc2S(=O)(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2sccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.329 g (1 mmol) of 4-hydroxy-N-(2-thiazolyl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide are dissolved in 2 ml. of absolute dimethylformamide and added at 0° C. to a stirred suspension of 0.026 g (1.1 mmol) of sodium hydride in 1 ml. of absolute dimethylformamide. The mixture is stirred at room temperature for a further 1 hour. 0.1 ml. (0.226 g; 1.6 mmol) of methyl iodide are then added to the sodium salt solution and allowed to react for a further 1 hour. After distillation of the solvent, the residue is taken up in 200 ml of methylene chloride and 10 ml. of 0.5-N hydrochloric acid. The organic phase is separated and shaken out with a total of 50 ml. of a 0.5% sodium bicarbonate solution. The aqueous layer, which now contains the desired product, is back-extracted several times with methylene chloride and acidified with hydrochloric acid. The acidic aqueous phase is extracted with methylene chloride and the combined organic extracts dried over sodium sulphate and evaporated. The crystalline residue is digested with a small amount of cold ethanol for purification. There is obtained 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of melting point 217° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@:12]2([CH3:31])[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14](CC3C=CC=CC=3)[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.ClC(OC(Cl)C)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@:12]2([CH3:31])[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@]1(C)CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@]1(C)CNC[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.65 g (3.64 mmol) rac-[(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester, 0.75 g (5.83 mmol) DIPEA and 0.78 g (5.46 mmol) 1-chloroethyl chloroformate in 40 mL toluene was stirred at room temperature and evaporated to dryness. The residue was taken up in 40 mL methanol and stirred for 2 h at room temperature and evaporated to dryness to yield the crude title compound which was used without further purification in the consecutive step.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C-:12]#[N:13].[Na+].S(=O)(O)[O-].[Na+]>O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([OH:9])[C:12]#[N:13])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc(C(O)C#N)cc1
Temperature: 25 °C

Procedure:
To a stirred suspension of 4-isopropylbenzaldehyde (21.4 g) and sodium cyanide (6.9 g) in water (25 ml) at 0° was added saturated sodium bisulfite (40 ml) dropwise over a period of 30 minutes. During the addition about 50 g of ice was also added in small portions. After the addition the mixture was warmed up to room temperature gradually. Resulting waxy 4-isopropylmandelonitrile was separated by decantation and the aqueous layer was extracted with benzene. The benzene extract was evaporated and, the residue was combined with the waxy material. The 4-isopropylmandelonitrile was dissolved in concentrated hydrochloric acid (25 ml) and the mixture was stirred at room temperature overnight. It was then stirred in a 100° oil bath for 3 hours. After cooling was added water to dissolve the solid material and the product was extracted with ethyl ether throughly. The combined extracts were washed with brine, dried (sodium sulfate) and evaporated to give 4-isopropylmandelic acid as an oil (17 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:23]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([F:32])[CH:31]=1)#[N:25]>>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:7]1([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:6]2[CH:23]=[C:2]([C:28]3[CH:27]=[C:26]([CH:31]=[C:30]([F:32])[CH:29]=3)[C:24]#[N:25])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: O=C1COC(c2ccco2)(c2ccco2)c2cc(Br)ccc2N1
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C(c2ccco2)(c2ccco2)OCC(=O)N3)c1

Procedure:
Prepared from 7-bromo-5,5-di(2-furyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-cyano-5-fluorobenzeneboronic acid generally according to the coupling procedure of example 1. 1H NMR (DMSO-d6): δ 10.34 (s, 1H), 7.73-7.87 (m, 5H), 7.59 (dt, J=10.25, 1.95 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 6.98 (d, J=1.95 Hz, 1H), 1H, 6.52 (dd, J=3.42, 1.95 Hz, 2H), 6.29 (dd, J=3.42, 0.98 Hz, 2H), 4.16 (s, 2H); MS (ESI) m/z 415 ([M+H]+); MS (ESI) m/z 413 ([M−H]−); Anal. calcd for C24H15FN2O4: C, 69.56; H, 3.65; N, 6.76. Found: C, 67.60; H, 3.77; N, 5.81.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[CH:5][C:6]=1[C:7](=[O:23])[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:3]1[C:4]([CH3:24])=[CH:5][C:6]([C:7](=[O:23])[C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[C:2]1[CH3:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)[nH]1
Reactant: ClCc1ccccc1
Product: Cc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)n1Cc1ccccc1

Procedure:
Likewise, using 2,5-dimethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole as compound "E" in this general reaction with benzyl chloride as "R--X" yields N-benzyl-2,5-dimethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (a compound according to Formula X wherein: m is 0; n is 1; R is benzyl; Y is H; and X and Z are each methyl).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].CC(C)([O-])C.[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([F:24])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CBr
Reactant: OCCOCCOCCOCCOCCOCCOCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)COCCOCCOCCOCCOCCOCCOCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
To a stirred solution of the product of step (d) (1.5 g) in toluene (30 ml) was added potassium t-butoxide (0.69 g) and the reaction stirred at room temperature for 3 hours. Ethyl bromoacetate (1.38 g) was added and the reaction was stirred at 130° C. for 48 hours. The solvent was removed in vacuo and the residue dissolved in dichloromethane (500 ml) and washed with water (2×400 ml). The organic layer was washed with brine (300 ml), dried and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel (Biotage), eluting with 65-75% ethyl acetate in cyclohexane to give the title compound as a brown oil (0.40 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH2:12][CH3:13])[C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21]>C(Cl)Cl>[C:20]([O:23][CH2:24][C:25]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH2:12][CH3:13])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:26])(=[O:22])[CH3:21]
Reactant: CCNc1cccc(N)c1C(N)=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNc1cccc(NC(=O)COC(C)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(ethylamino)benzamide (3 g) in methylene chloride (100 ml) is added pyridine (3 ml), and thereto is added dropwise acetoxyacetyl chloride (2.0 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and ether and then are recrystallized from ethanol to give the title compound (2.5 g) having the following physical properties.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[C:6]([O:16][CH2:17][O:18][CH3:19])[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[NH2:22][CH2:23][C@@H:24]([OH:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[CH3:34].C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(O)C.[Cu]I>[CH3:14][C:11]1([CH3:15])[CH2:12][O:13][CH:8]([C:7]2[C:6]([O:16][CH2:17][O:18][CH3:19])=[C:5]([O:20][CH3:21])[CH:4]=[CH:3][C:2]=2[NH:22][CH2:23][C@@H:24]([OH:35])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=2[CH3:34])[O:9][CH2:10]1
Reactant: COCOc1c(OC)ccc(Br)c1C1OCC(C)(C)CO1
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COCOc1c(OC)ccc(NC[C@@H](O)COc2ccc(C)cc2C)c1C1OCC(C)(C)CO1
Temperature: 90 °C
Yield: 641.3 %

Procedure:
A mixture of 2-(6-bromo-3-methoxy-2-methoxymethoxy-phenyl)-5,5-dimethyl-[1,3]dioxane (36 mg, 0.1 mmol), (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (30 mg, 0.15 mmol), CuI (51.4 mg, 0.27 mmol), ethylene glycol (168 mg, 2.7 mmol), and K3PO4 (573 mg, 2.7 mmol) in 2-propanol (8 mL) was heated at 90° C. in a sealed vial for 14 h and evaporated. Chromatography of the residue with hexanes and EtOAc afforded the title compound (305 mg, 71%). 1H NMR (CDCl3) δ 0.79 (s, 3H, CH3), 1.29 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.95 (br s, 1H, OH), 3.30 (m, 1H), 3.49 (s, 3H, OCH3), 3.51 (m, 1H), 3.65 (m, 2H), 3.75 (s, 3H, OCH3), 3.77 (m, 2H), 4.00 (m, 2H), 4.25 (m, 1H), 5.09 (s, 2H), 6.05 (s, 1H), 6.48 (d, J=8 Hz, 1H), 6.69 (d, J=8 Hz, H), 6.82 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 6.95 (s, 1H). ESI-MS m/z 476.8 (MH+).
Reaction SMILES: [C:1]([O:9]CCCC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O.[C:15](O)(=O)C>>[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:15]
Reactant: CCCCOC(=O)c1cccnc1
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)c1cccnc1
Yield: 61 %

Procedure:
A tubular reactor with an i. d. of 23.5 mm was filled with 270 ml (≈227 g) of catalyst from example 1. A mixture of butyl nicotinate (30 g/h), water (54 g/h) and acetic acid (210 g/h) was fed over an evaporator using a metering pump to the tubular reactor heated by a salt bath. A small flow of nitrogen (1 l/h) guaranteed the transport of the vapours. The temperature of the bath was 410° C. The reaction vapours were condensed in an aqueous circulation system. After a total running time of 35 h, the reaction solution was collected. A portion of this solution corresponding to a total of 710 g of butyl nicotinate was worked up to isolate the product. 81% of butyl nicotinate was converted to give 293 g of 3-acetyl-pyridine, corresponding to a selectivity of 75% and a yield of 61%. The selectivity of pyridine formation was 4%.
Reaction SMILES: CS([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[N:24]1([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CC(N(C)C)=O>[CH3:23][NH:22][C:20]([C:16]1[CH:15]=[C:14]([O:13][C:11]2[CH:10]=[CH:9][C:7]3[N:8]=[C:4]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][CH2:30][N:24]5[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]5)[CH:33]=4)[O:5][C:6]=3[CH:12]=2)[CH:19]=[CH:18][N:17]=1)=[O:21]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Reactant: Nc1cccc(CCN2CCCCC2)c1
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4cccc(CCN5CCCCC5)c4)oc3c2)ccn1
Temperature: 120 °C

Procedure:
The 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide from step 3 of Example 2 and 3-(2-piperidin-1-yl-ethyl)-phenylamine were dissolved in DMAC and heated in a CEM microwave reactor at 120° C. for 10 to 20 minutes. The crude reaction mixture was purified by preparatory reverse phase HPLC. MH+=472.2.
Reaction SMILES: [C:1](O)(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.S(=O)(=O)(O)O>>[O:10]=[C:1]1[CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:18]2[CH:17]=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:13]=2[O:12]1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=C(O)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc2c(c1)C(c1ccccc1)C(=O)O2
Temperature: 0 °C
Yield: 88.5 %

Procedure:
75 g of mandelic acid and 75 g of 4-hydroxyphenylacetic acid are mixed in a round-bottomed flask. 800 ml of 80% strength sulfuric acid are added and the medium is then brought rapidly to 90° C. while being stirred. It is hydrolyzed with 2 kg of ice, the aqueous phase is extracted with 3 times 500 ml of ethyl acetate and the organic phase is washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. 117 g of a yellow oil are thereby obtained, which is purified by chromatography on 1200 g of silica (70-230 mesh), using a mixture of dichloromethane and methanol (98.5:1.5 v/v) as eluant. After evaporation of the solvent, the pure product is obtained.