Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([O:26][CH3:27])[CH:16]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+].O.C(O)(=O)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:23])=[O:24])=[C:17]([O:26][CH3:27])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(OS(C)(=O)=O)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1cc(CCC(=O)O)ccc1CCCc1ccc(OS(C)(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.7 %

Procedure:
600 mg (1.25 mmol) of methyl 3-{3-butoxy-4-[3-(4-methanesulfonyloxy-3-methoxyphenyl)propyl]phenyl}propanoate are dissolved in 10 ml of tetrahydrofuran and 1.8 ml (1.8 mmol) of aqueous 1N lithium hydroxide solution are then added. The reaction medium is stirred for 15 hours at room temperature. After addition of water and acidification with acetic acid, the reaction medium is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 8/2 heptane/ethyl acetate mixture. 480 mg (82%) of 3-{3-butoxy-4-[3-(4-methanesulfonyloxy-3-methoxyphenyl)propyl]phenyl}propanoic acid are obtained after crystallization from a 2/8 isopropyl ether/pentane mixture.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:22])[CH2:15][S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:22])[CH2:15][S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSCC(F)(F)F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CSCC(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(2,2,2-trifluoro-ethylsulfanyl)-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:32](=[O:33])[N:12]2[C:13]([C:29]([OH:31])=[O:30])=[C:14]([CH2:17]OC(=O)C(C3C=CC=CC=3)O)[CH2:15][S:16][C@H:11]12)=[O:8].[SH:34][C:35]1[N:39]([CH3:40])[N:38]=[N:37][N:36]=1.C(=O)([O-])O.[Na+]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:32](=[O:33])[N:12]2[C:13]([C:29]([OH:31])=[O:30])=[C:14]([CH2:17][S:34][C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(O)c3ccccc3)CS[C@H]12
Reactant: Cn1nnnc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
In water (4 ml) was dissolved 7β-(2-thienylacetamido)-3-mandelyloxymethyl-3-cephem-4-carboxylic acid (0.49 g) together with 5-mercapto-1-methyl-1H-tetrazole (0.12 g) and sodium hydrogen carbonate (0.17 g). The solution was stirred at 60° C. for 30 minutes. After the reaction had been completed, the reaction mixture was treated by a procedure similar to that described in Example 85. The procedure provided 7β-(2-thienylacetamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.40 g).
Reaction SMILES: [F:1][C:2]1([F:10])[O:7][S:4](=[O:6])(=[O:5])[C:3]1([F:9])[F:8].[F-:11].[K+].[C:13](=[C:16]([C:18](OS(F)(=O)=O)([F:20])[F:19])[F:17])([F:15])[F:14].COCCOCCOCCOCCOC>>[C:13](=[C:16]([C:18]([O:7][C:2]([C:3]([S:4]([F:11])(=[O:6])=[O:5])([F:9])[F:8])([F:10])[F:1])([F:20])[F:19])[F:17])([F:15])[F:14]
Reactant: O=S1(=O)OC(F)(F)C1(F)F
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Reactant: [F-]
Agent: COCCOCCOCCOCCOC
Agent: [K+]
Product: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)=C(F)F

Procedure:
However, in reality, it can be prepared by reacting tetrafluoroethane-β-sultone, KF and CF2═CFCF2OSO2F without isolating FOCCF2SO2F as the intermediate. Specifically, for example, in the presence of a solvent such as tetraglyme, KF and tetrafluoroethane-β-sultone are reacted under cooling, and CF2═CFCF2OSO2F is dropwise added thereto and reacted, whereby CF2═CFCF2OCF2CF2SO2F can be obtained.
Reaction SMILES: Cl.[CH2:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH2:5][CH2:4][NH:3]1.Cl[CH2:16][CH2:17][C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]2=[N:20][C:19]=1[CH3:29].[C:30]([O-:33])([O-:32])=O.[Na+].[Na+]>CC(=O)CC>[C:7]([OH:24])(=[O:8])/[CH:6]=[CH:10]/[C:30]([OH:33])=[O:32].[CH2:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH2:5][CH2:4][N:3]1[CH2:16][CH2:17][C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]2=[N:20][C:19]=1[CH3:29]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Reactant: c1ccc2c3c(oc2c1)CNCC3
Agent: Cl
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cc1nc2ccccn2c(=O)c1CCN1CCc2c(oc3ccccc23)C1
Product: O=C(O)/C=C/C(=O)O
Yield: 120.2 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridine hydrochloride (1:1) (0.007 mol), 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(0.012 mol), Na2CO3 (0.015 mol) and KI (catalytic quantity) in 2-butanone (100 ml) was stirred and refluxed overnight. The reaction mixture was filtered hot and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) from 98/2 to 97/3). The purest fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and (E)-2-butenedioic acid (1 g) was added. The mixture was boiled and then stirred at RT. The precipitate was filtered off and dried, yielding 2.00 g (61%) of 3-[2-(3,4-dihydro-benzofuro[2,3-c]pyridin-2(1H)-yl)ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (E)-2-butenedioate (2:1) (compound 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[CH:5]2.C1C(=O)N([Cl:35])C(=O)C1>CC#N>[Cl:35][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([NH:11][C:12]([C:14]2[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=2)=[O:13])[CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Solvent: CC#N
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(Cl)c2cc(F)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (300 mg, 0.824 mmol) in MeCN (20 mL) is treated with NCS (185 mg, 1.42 mmol) and the mixture is stirred at 60° C. in a sealed flask for 2 h. The mixture is then concentrated, diluted with 10% aqueous Na2S2O8 (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-20% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylicacid(3 chloro-5-fluoro-indol-1-yl)-amide (160 mg, 49%). MS: 399 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.79 (s, 1H), 8.04 (d, 1H), 7.92 (d, 1H), 7.18 (m, 1H), 7.04 (s, 1H), 7.00 (m, 3), 6.76 (m, 1), 2.52 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].[NH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[C:26]([Cl:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2>>[Cl:38][C:26]1[CH:25]=[C:24]([NH:23][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[CH:22][C:13]=3[O:12][CH2:11][CH2:10][NH:9][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:18]=[CH:17][N:16]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CS(=O)(=O)CC(=O)NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 51 %

Procedure:
The procedure described in Example 1 was repeated using methanesulfonylacetic acid and 5-(2-aminoethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.6, preparation of starting materials) to give the title compound in 51% yield; NMR spectrum (DMSO-d6) 2.99 (s, 3H), 3.74 (m, 2H), 4.04 (s, 2H), 4.34 (t, 2H), 5.29 (s, 2H), 7.13 (d, 1H), 7.22 (d, 1H), 7.35 (m, 2H), 7.55 (m, 2H), 7.71 (t, 1H), 7.87 (dt, 1H), 8.03 (d, 1H), 8.46 (s, 1H), 8.58 (d, 1H), 8.76 (t, 1H), 9.79 (s, 1H); Mass Spectrum MH+ 542.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH2:17][NH:18][O:19][CH3:20]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:18]([CH2:17][C:16]2[CH:21]=[CH:22][CH:23]=[C:14]([F:13])[CH:15]=2)[O:19][CH3:20])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1cccc(F)c1
Product: CON(Cc1cccc(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 94 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C and gave the title amide as a white solid (94% yield): mp 110–111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.70 (3H, s, OCH3), 4.82 (2H, s, NCH2), 6.40 (1H, s, CH), 6.96–7.32 (4H, m, aromatics). Anal. calcd. for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.00; H, 5.30; N, 4.49.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.C(N(CC)CC)C.S(Cl)(Cl)=O.[CH3:30][NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[CH3:30][N:31]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[O:3]
Reactant: CNC1CCCCC1
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Reaction time: 1 h

Procedure:
2.5 Grams of 6-(3-carboxypropoxy)carbostyril is suspended in 200 ml of chloroform, followed by addition of 1.5 ml of triethylamine, and then 1.2 g of thionyl chloride is added dropwise to the solution under agitation while maintaining the internal temperature at 0° to 20° C. After this addition, the mixture is agitated at the same temperature for 1 hour and then added dropwise with 2 ml of N-methylcyclohexylamine, followed by additional 3-hour agitation at room temperature. The reaction solution is washed well with a 5% aqueous K2CO3 solution, then further washed with water and diluted hydrochloric acid and then dried with anhydrous Na2SO4. After removing the solvent by distillation, the residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 10:1 chloroform/methanol (V/V)) and then recrystallized from chloroform-ethanol to obtain 0.4 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril with melting point of 184.5°-186° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1.C(N(CCCC)CCCC)CCC.O>CN1C(=O)CCC1>[CH3:21][C:17]1[CH:16]=[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
tert-Butyl piperazine-1-carboxylate (500 mg) was dissolved in NMP (10 ml), and 4-chloro-2-methylpyridine (685 mg) and tri-n-butylamine (498 mg) were added thereto, followed by stirring at 150° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 4-(2-methylpyridin-4-yl)piperazine-1-carboxylate (667 mg).
Reaction SMILES: CO[CH:3]([O:19]C)[C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10]N)=[C:6]([O:14][CH3:15])[C:5]=1[N+:16]([O-:18])=[O:17].C([N:23](CC)CC)C.[CH2:28]([S:31](Cl)(=[O:33])=[O:32])[CH2:29][CH3:30].O>C1COCC1>[CH:3]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][CH:28]([S:31]([NH2:23])(=[O:33])=[O:32])[CH2:29][CH3:30])=[C:6]([O:14][CH3:15])[C:5]=1[N+:16]([O-:18])=[O:17])=[O:19]
Reactant: COc1c(OCCN)ccc(C(OC)OC)c1[N+](=O)[O-]
Reactant: CCN(CC)CC
Reactant: CCCS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCC(CCOc1ccc(C=O)c([N+](=O)[O-])c1OC)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of 2-(4-dimethoxymethyl-2-methoxy-3-nitrophenoxy)ethylamine (0.5 g, 1.8 mmol) obtained in Step 3 in THF (10 mL) was added with triethylamine (0.38 mL, 2.7 mmol) and n-propanesulfonyl chloride (0.24 mL, 2.2 mmol), followed by stirring at room temperature for 3 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was added with methanol (6.0 mL) and 1 mol/L hydrochloric acid, followed by stirring for 15 minutes. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain [2-(4-formyl-2-methoxy-3-nitrophenoxy)ethyl]propane-1-sulfonamide (0.39 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O1CCCC1>[CH3:11][C:10]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:12]
Reactant: COc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(NC(C)=O)c1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
3-Methoxyaniline 12 (5 gm, 0.041 moles) was dissolved in 30 ml tetrahydrofuran (THF) at room temperature under argon. Acetic anhydride (5.8 ml, 0.061 moles) was added. After stirring for 2 hours, the mixture was evaporated under reduced pressure, dissolved in several mls of toluene and purified by flash chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane. 3-Methoxyacetanilide 13 (6.63 gm, 99% yield) was isolated after removing the solvent. 1H NMR (CDCl3) δ 7.6, 1H, br; 7.2, 2H, m; 6.95, 1H, d; 6.66, 1H, d; 3.78, 3H, s; 2.16, 3H, s.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.Cl.C[O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13]>>[CH:1]1([CH2:4][C:5]([NH:13][C@H:12]([C:11]([OH:15])=[O:10])[CH3:14])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: C[C@H](NC(=O)CC1CC1)C(=O)O

Procedure:
Following General Procedure A above using cyclopropylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf=0.15 in 25% ethyl acetate/hexanes) and purification was by flash column chromatography using 25% ethyl acetate/hexanes as the eluant.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]2[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N+:6]=3[O-:30])[C:13]=2[CH:14]=1)#[N:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C=C(c2ccc(O)cn2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)C=C(c2ccc(O)c[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 7.1 %

Procedure:
400 mg of 4-(5-hydroxy-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and 350 mg of m-chloroperbenzoic acid were stirred overnight in 100 ml of dichloromethane. The mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 10% (v/v) methanol/ethyl acetate for the elution. There were obtained 30 mg of 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-hydroxypyridine N-oxide of melting point 260°-262° C. (from ethanol).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH3:22])[CH:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)O)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O.C(OC)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:1]([O:4][CH2:5][CH:6]([CH3:22])[CH:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[Cl:25])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCC(C)C(O)c1ccc(Cc2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)=O
Solvent: O
Product: CC(=O)OCC(C)C(Cl)c1ccc(Cc2cccnc2)cc1
Yield: 86 %

Procedure:
In 4.6 ml of methylene chloride was dissolved 910 mg of 3-[p-(3-acetoxy-1-hydroxy-2-methylpropyl)benzyl]pyridine, and to the resulting solution was added 0.48 ml of thionyl chloride with ice-cooling, after which the resulting mixture was subjected to reaction at the same temperature for one hour. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure, and to the residue thus obtained were added 10 ml of methyl acetate and 10 ml of water, after which the resulting mixture was neutralized with sodium hydrogencarbonate. The organic layer was separated, washed with 5 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (5:1 by volume)] to obtain 740 mg (yield 86.0%) of colorless, oily 3-[p-(3-acetoxy-1-chloro-2-methylpropyl)benzyl]pyridine.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:6]=1[N+:19]([O-:21])=[O:20])(=O)C>Cl.CCO>[N+:19]([C:6]1[C:7]([C:15]([F:16])([F:17])[F:18])=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:5]=1[NH2:4])([O-:21])=[O:20]
Reactant: CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Yield: 71.2 %

Procedure:
A mixture of 1-acetamido-2-nitro-3,5-bis(trifluoromethyl)benzene (200 mg, 0.63 mmol) in concentrated HCl (3 mL) and EtOH (3 mL) was refluxed overnight, then it was extracted by ethyl acetate (2×3 mL). The extract was dried over Mg2SO4 and evaporated to give 2-nitro-3,5-bis(trifluoromethyl)aniline 123 mg (71%). 1H NMR (DMSO-d6): δ 6.392 (s, 2H), 7.131 (s, 1H), 7.375 (s, 1H).
Reaction SMILES: C[C:2]([CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)(C)C)([CH3:4])C>O>[CH3:4][CH2:2][CH2:5][CH2:6][CH2:9][CH2:4][CH2:2][CH2:5][CH2:6][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:13][CH:14]=1
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCCO)cc1
Solvent: O
Product: CCCCCCCCCc1ccc(OCCO)cc1

Procedure:
TRITON X-102 (an octylphenoxy polyethoxy ethanol, HLB 14.6, available commercially from Union Carbide) in 9:1 water-emulsifier ratio did not invert the emulsion; TRITON N-101 an nonylphenoxy polyethoxy ethanol, HLB 13.4, Union Carbide) gave similar results; TRITON X-405 (HLB 17.9) and TRITON X-305 (HLB 17.3) gave separation into two layers. Optical microscopy showed there was no flocculation with TRITON X-102 OR TRITON N-101, slight flocculation with TRITON X-405, and much more flocculation with the TRITON X-305.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]([NH:42][C:43]1[NH:44][CH2:45][CH2:46][CH2:47][N:48]=1)[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:41]=[CH:40][C:17]([CH2:18][C@@H:19]([C:33]([O:35]C(C)(C)C)=[O:34])[NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[N:23][N:22]=2)=[CH:16][CH:15]=1.C1(C)C=CC=CC=1>ClCCl>[O:8]=[C:9]([NH:42][C:43]1[NH:44][CH2:45][CH2:46][CH2:47][N:48]=1)[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:41]=[CH:40][C:17]([CH2:18][C@@H:19]([C:33]([OH:35])=[O:34])[NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[N:23][N:22]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nnnn1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(CCCOc1ccc(C[C@H](Nc2nnnn2Cc2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
2 ml of trifluoroacetic acid is added to 135 mg of ester 5-2 in 5 ml of dichloromethane, followed by agitating for 3 hours at ambient temperature, adding 10 ml of toluene, evaporating under reduced pressure, taking up in dichloromethane and crystallizing by adding an Et2O/pentane mixture. 92 mg of 5-3 is obtained.
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].COC(C1ON=C([O:31][CH2:32][C:33]2[C:34]([C:39]3C=CC=CN=3)=[N:35]OC=2C)C=1)=O.NC1CCOC1>>[CH:13]([NH2:14])([CH3:18])[CH3:12].[O:31]1[CH2:32][CH2:33][CH:34]([NH:35][C:3]([C:5]2[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:6]=2)=[O:4])[CH2:39]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)sn1
Agent: NC1CCOC1
Product: CC(C)N
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC2CCOC2)sn1
Yield: 16 %

Procedure:
As described for example 14e, 3-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid methyl ester (165 mg, 0.53 mmol), instead of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester, was converted, using 3-aminotetrahydrofuran (56 mg, 0.64 mmol), instead of isopropyl amine, to the title compound (32 mg, 16%) which was obtained as a colourless gum after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 0:1). MS: m/e=366.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][O:18][CH:19]([CH3:28])[CH2:20][O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(O)CCC>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][CH2:20][CH:19]([O:18][CH3:17])[CH3:28])[CH2:23][CH2:24]2)[N:3]=1
Reactant: COC(C)COC1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCC(OCC(C)OC)CC3)nc(N)c2cc1OC
Product: Cl
Yield: 45.1 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (3.6 g.), 4-(2-methoxy-n-propoxy)piperidine (3.0 g.) and triethylamine (1.5 g.) in n-butanol were heated under reflux for 30 hours. The solvent was evaporated in vacuo, the residue stirred with diethyl ether, the solid collected and recrystallized twice from isopropanol to give 4-amino-6,7-dimethoxy-2-[4-(2-methoxy-n-propoxy)piperidino]quinazoline hydrochloride (2.8 g.), m.p. 239°-241° C.