Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][OH:20])[O:16][C:15]3=[O:21])[CH:11]=2)[N:6]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:4][C:2]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][S:40]([CH3:39])(=[O:42])=[O:41])[O:16][C:15]3=[O:21])[CH:11]=2)[N:6]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])([CH3:1])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C1Cc2cc(N3C[C@H](CO)OC3=O)ccc2N1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C1Cc2cc(N3C[C@H](COS(C)(=O)=O)OC3=O)ccc2N1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
The alcohol prepared in Step 5 (11.3 g, 26.6 mmol) is dissolved in CH2Cl2 (125 ml) with triethylamine (11.0 ml, 79 mmol) and cooled to 0°. Methanesulfonylchloride (2.4 ml, 31 mmol) is added and the reaction stirred for 2 hours. Extra CH2Cl2 (100 ml) is added and the solution washed with water (100 ml) and brine (50 ml) then dried (MgSO4). Evaporation gave a gum which is chromatographed over silica gel (500 g) eluting with 25-60% ethyl acetate-hexane. The product is obtained as a white foam (10.95 g, 82%): HRMS (FAB): Calcd for m+Na=525.1672; Found: 525.1671. Anal: Calcd. for C25H30N2O7S: C, 59.74; H, 6.02; N, 5.57. Found: C, 59.44; H, 6.07; N, 5.49.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12]([CH2:16]Cl)[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6].[I-:61].[Na+]>CC(C)=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12]([CH2:16][I:61])[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6]
Reactant: [I-]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The oily substance obtained in (A) was dissolved in 120 ml of acetone, and 1.6 g (10.7 mmol) of sodium iodide was added thereto. The mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, and extracted with ethyl acetate. The extract solution was washed with a 5% sodium thiosulfate aqueous solution, with water and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:27])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2ccccc2O1
Reaction time: 2 h
Yield: 76.3 %

Procedure:
130 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of dichloromethane at room temperature and 93 mg of m-chloroperbenzoic acid were added. After 2 hours thin-layer chromatography indicated that some starting material was still present, whereupon further m-chloroperbenzoic acid was added until the reaction was complete. The mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated to give 105 mg of 2-(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide in the form of an oil. NMR (300 MHz, CDCl3): 8.36-8.30 (1H, m) 7.21-7.04 (4H, m), 6.89-6.76 (3H, m), 5.36-5.25 (1H, m), 2.46 (1H, dd, 14Hz, 6.5Hz), 1.75 (1H, broad t, 14Hz), 1.44 (3H, s), 1.40 (3H, s). MS (EI): 255 (M+ , 238 (M+ -OH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][NH:11][C:10](=[O:16])[CH:9]=2)[CH:7]=1.Br[CH:22]([CH3:26])[C:23]([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[C:10](=[O:16])[CH:9]=2)[CH:7]=1
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: CC(Br)C(=O)O
Product: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
127 mg (0.42 mmol) of 4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 90° C. Yield: 220 mg of crude product which was reacted in the next step without further purification
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[N:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)[S:3]1.[OH:29]S(O)(=O)=O.O1CCOCC1>O>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:29])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CC2SC(=N)NC2=O)cc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 58.8 %

Procedure:
A mixture of 2-imino-5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-thiazolidinone (11.4 g), 1N.H2SO4 (100 ml) and dioxane (100 ml) was stirred at 80° C. for 5 hours, and poured in water. The aqueous mixture was extracted with chloroform. The chloroform layer was washed with water, dried (MgSO4) and concentrated. The oily residue was chromatographed on a column of silica gel (200 g), and from the fractions eluted with chlorform-methanol (100:1, V/V), there was obtained 5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-2,4-thiazolidinedione (6.7 g, 58.8%). Recrystallization from ethyl acetate-hexane afforded colorless plates. m.p. 162°-163° C. Elemental analysis for C21H18N2O4S, Calcd.: C, 63.95; H, 4.60; N, 7.10. Found: C, 63.84; H, 4.63; N, 6.90. This product showed the IR and NMR spectra in accordance with those of the compound obtained in Example 6.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]=O)=[N:8][CH:9]=1.C(OP([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(OCC)=O)C.[H-].[Na+]>C1COCC1>[C:26]([O:25][C:23](=[O:24])[CH:22]=[CH:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([O:12][CH3:13])[O:2][CH3:1])=[CH:9][N:8]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: COC(OC)c1ccc(C=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc(C=CC(=O)OC(C)(C)C)nc1
Yield: 89.2 %

Procedure:
5-dimethoxymethyl-pyridine-2-carbaldehyde (355 mg, 1.97 mmol) was dissolved in THF (10 ml), and the resulting solution was added to a stirring mixture of tert-butyl diethylphosphonoacetate (547 mg, 2.169 mmol) and NaH (102 mg, 2.56 mmol, 60% oil dispersion) in THF (5 ml). After 15 minutes the reaction was quenched by addition of water and the resulting slurry was extracted with Et2O. The organic phase was dried over Na2SO4 and evaporated under vacuo. The crude product was purified by silica gel chromatography (petroleum ether/EtOAc 95:5) to give 491 mg of 3-(5-dimethoxymethyl-pyridin-2-yl)-acrylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5].[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[CH2:12]([O:11][C:9]([C:8]1[S:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:14]([OH:20])[C:15]=1[OH:16])=[O:10])[CH3:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CSCC(=O)OCC
Product: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O

Procedure:
The diethyl thioglycolate and diethyl oxalate are mixed, and then added to a first solution containing a first electron donor in the microwave reactor. The microwave reactor is heated by the 2.45 GHz microwave at a power of 100-500 W to perform a condensation reaction for 20-60 minutes to obtain 2,5-diethoxycarbonyl-3,4-dihydroxythiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:16](O)[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][CH3:30])[C:10]=2[C:9]1=[O:31].[Cl:38][C:39]1[CH:40]=[C:41]([CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71])[CH:42]=[CH:43][C:44]=1[N:45]1[C:53](=[O:54])[C:52]2[C:51]([O:55][CH2:56][C:57]([F:60])([F:59])[F:58])=[C:50]3[CH:61]=[CH:62][CH:63]=[CH:64][C:49]3=[C:48]([O:65][CH2:66][CH3:67])[C:47]=2[CH:46]1O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:5]=[CH:6][C:7]=1[N:8]1[C:9](=[O:31])[C:10]2[C:11]([O:28][CH2:29][CH3:30])=[C:12]3[CH:27]=[CH:26][CH:25]=[CH:24][C:13]3=[C:14]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])[C:15]=2[CH2:16]1.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71])[CH:42]=[CH:43][C:44]=1[N:45]1[C:53](=[O:54])[C:52]2[C:51]([O:55][CH2:56][C:57]([F:60])([F:59])[F:58])=[C:50]3[CH:61]=[CH:62][CH:63]=[CH:64][C:49]3=[C:48]([O:65][CH2:66][CH3:67])[C:47]=2[CH2:46]1
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2O)c(Cl)c1
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC(F)(F)F)C2O)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(Cl)c1
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC(F)(F)F)C2=O)c(Cl)c1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (3-chloro-4-{4-(ethyloxy)-1-hydroxy-3-oxo-9-[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate-ethyl (3-chloro-4-{4-(ethyloxy)-3-hydroxy-1-oxo-9-[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate (0.163 g, 0.30 mmol) in trifluoroacetic acid (5 ml) cooled to 0° C., was added triethylsilane (0.07 ml, 0.45 mmol). Stirring continued at 0° C. for 10 minutes and then the mixture was evaporated. The isomers were separated using MDAP (shallow gradient)
Reaction SMILES: [Br:1]Br.[CH2:3]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)[CH3:4]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:3][CH3:4])=[CH:7][C:8]=1[F:12]
Reactant: CCSc1cccc(F)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCSc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Bromine (0.3 ml) was added to a solution of 1-ethylsulfanyl-3-fluoro-benzene (1 g) in chloroform (20 ml) at 0° C. then warmed to RT. After 2 h the mixture was diluted with DCM, washed with aq. sodium thiosulphate solution, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% diethylether/iso-hexane. Yield 1.2 g
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([C:8]1[O:9][C:10](=[O:30])[C:11]2[C:16]([C:17]=1[C:18]1[S:19][C:20]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:21][CH:22]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]>C(Cl)Cl>[BrH:2].[Br:2][CH:6]([C:8]1[O:9][C:10](=[O:30])[C:11]2[C:16]([C:17]=1[C:18]1[S:19][C:20]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:21][CH:22]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Br
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1
Yield: 38.6 %

Procedure:
1M PBr3 in DCM (1.82 mL, 1.82 mmol) was added to 3-(1-hydroxyethyl)-4-(5-(morpholinomethyl)thiophen-2-yl)-1H-isochromen-1-one (intermediate B16, 258 mg, 0.695 mmol) in DCM (2.6 ml) at RT. The reaction mixture concentrated under reduced pressure and the crude was crystallized from boiling DCM/MeOH 4/1 (5 ml) to give the title compound as colourless solid (138 mg, 38.6%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:12]3[CH2:17][CH2:16][CH2:15][N:14](C([O:20][C:21]([CH3:24])(C)C)=O)[CH2:13]3)[N:9]=[C:10]([I:11])[C:3]=12.Cl.CC(C)=[O:28]>>[C:21]([OH:20])(=[O:28])[CH3:24].[I:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])[N:8]([C@H:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC(C)=O
Agent: Cl
Product: CC(=O)O
Product: Nc1ncnc2c1c(I)nn2[C@H]1CCCNC1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a mixture of (S)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (3.4 g, 0.0077 mol) in acetone (80 mL) was added an aqueous 6N solution of hydrogen chloride (20 mL) at room temperature. The mixture was stirred at 45° C. for 4 hours, then at room temperature for 18 hours. Acetone was removed under reduced pressure, and the aqueous layer was washed with toluene (2×20 mL) and dichloromethane (2×20 mL). The aqueous layer was basified with an aqueous 5N solution of sodium hydroxide (25 mL) at 0° C. The aqueous layers were concentrated to dryness, and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 2%-30% over 15 min with 0.1 M ammonium acetate, 21 mL/min) to yield (S)-3-iodo-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.75 g, 0.0019 mol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([Br:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(Br)c1
Temperature: 60 °C
Reaction time: 42 h

Procedure:
A suspension of 3-bromo-4-methylbenzoic acid (2.0 g, 9.30 mmol) in methanol (20 ml) was treated with sulfuric acid (0.04 ml) and the reaction mixture was stirred at 60° C. for 42 hours. The reaction mixture was concentrated and the residue was taken up in ethyl acetate. The organic solution was washed with sat'd NaHCO3(aq.), dried (MgSO4), filtered, and concentrated to give the title compound as an orange oil which was suitable for use without further purification (2.25 g, quant.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[O:20]=[C:21]([CH2:27][C:28](=[O:31])[CH2:29][CH3:30])[C:22](OCC)=[O:23]>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[N:1]([C:2]3[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:22](=[O:23])[C:21](=[O:20])[CH:27]2[C:28](=[O:31])[CH2:29][CH3:30])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: Cc1cc(N)cn(C)c1=O
Product: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 57.1 using 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2), 4-chlorobenzaldehyde and ethyl 2,4-dioxohexanoate under reflux for 7 hr. The crude product was purified by silica gel chromatography (hexane/CH2Cl2/MeOH 40:60:10 to 0:60:10). tR: 0.82 min (LC-MS 2); ESI-MS: 387 [M+H]+ (LC-MS 2).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O-:9])=[O:8])=[CH:4][CH:3]=1.[Na+:13].O.[Cl-:15].[Na+]>>[C:7]([OH:9])(=[O:8])[CH:6]=[O:10].[C:2]1([OH:1])[CH:12]=[CH:11][CH:5]=[CH:4][CH:3]=1.[Cl-:15].[Na+:13]
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=CC(=O)O
Product: Oc1ccccc1

Procedure:
More recently solid monohydrate sodium parahydroxymandelate containing sodium chloride (about 10% by weight) has been isolated from its aqueous preparing solution from glyoxylic acid and phenol with salting by sodium chloride (see Belgium patent 867.287, Chemical Abstracts, 1979, 90, 870 67 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:18])[CH:8]=[CH:9][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CS(O[CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[O:18][CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: COc1cc(O)ccc1CN1CCOCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN1CCOCC1
Temperature: 80 °C
Yield: 105.9 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.30 g, 6.88 mmol) in dry DMF (5 mL) under nitrogen was cooled by a water-bath. A solution of 7A (1.17 g, 5.24 mmol) in DMF (10 mL) was added drop-wise over 15 minutes. The mixture was stirred for one h and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.7 g, 6.77 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. for 3 days and then cooled to RT. Water and some aqueous NaOH were added and the mixture was extracted three times with EtOAc. The combined organic solutions were dried (MgSO4) and evaporated. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 2.1 g (104%) of 7B as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.39-2.56 (m, 4H), 3.48 (s, 2H), 3.65-3.75 (m, 4H), 3.79 (s, 3H), 3.95-4.04 (m, 2H), 4.23-4.33 (m, 2H), 4.82-4.91 (m, 1H), 6.19 (d, 1H), 6.38 (s, 1H), 7.21 (d, 1H).
Reaction SMILES: [Li+].[OH-].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20])[CH2:14][CH:13]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].O1CCOCC1.Cl>O.C1COCC1>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]([CH3:24])[C:19]([OH:21])=[O:20])[CH2:14][CH:13]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=2)=[CH:10][CH:11]=1)([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(C)C1CCN(c2ccc(C(C)C)cc2)C(c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)c1ccc(N2CCC(C(C)C(=O)O)CC2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 110 °C

Procedure:
A solution of LiOH (27 mg, 1.1 mmol) in H2O (0.5 ml) was added to a stirred solution of the ester (Step 1, 100 mg, 0.22 mmol) in THF (1 ml) at room temperature. After 60 hours an extra portion of LiOH (30 mg) and dioxane (1 ml) were added. The mixture was heated at 110° C. for 16 hours. After cooling to room temperature the mixture was acidified with 5N HCl. The mixture was partitioned between EtOAc/H2O. The layers were separated and the aqueous layer was further extracted with EtOAc (×2). The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by reverse phase HPLC to give the acid as a 3:2 mixture of diastereomers (90 mg, 94%) as colourless solid. 1H NMR (500 MHz, CDCl3) δ: 1.12-1.14 (6H, m), 1.21-1.26 (3H, m), 2.01-2.25 (3H, m), 2.26-2.40 (1H, m), 2.50-2.59 (2H, m), 2.78-2.83 (1H, m), 3.48-3.51 (1H, m), 3.91-3.95 (1H, m), 4.35-4.40 (1H, m), 7.12-7.14 (2H, m), 7.24-7.26 (2H, m), 7.42-7.53 (4H, m); M/Z (ES+) 420 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br-:13].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.O>[C:1]([C:5]1[CH:10]=[C:9]([Br:13])[CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Br-]
Reactant: COc1ccccc1C(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of 2-(t-butyl)anisole (16.38 g, 0.0997 mol) in CH2Cl2 (350 mL) was added pyridinium tribromide (35.09 g, 0.110 mol). The resulting mixture was allowed to stir at RT overnight. The mixture was diluted with CH2Cl2 and H2O and the layers were separated, the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were washed with H2O, brine and dried with MgSO4. The mixture was filtered and the solvents evaporated to give 2-(t-butyl)-4-bromoanisole as an oil (23.16 g, 95%). 1H NMR (300 MHz, CDCl3): δ 1.35 (s, 9H), 3.82 (s, 3H), 6.74 (d, J=8.7 Hz, 1H), 7.28 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCO
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOC(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-trifluoromethylphenylacetic acid (150.0 g), n-octanol (130.0 g), p-toluenesulphonic acid (9.5 g) and benzene (800 ml) is refluxed for 7 hours with a Dean-Stark separator. The solution is washed with a 10% aqueous solution of sodium carbonate (3×500 ml) and with water (3×500 ml). After drying over magnesium sulphate, the solvent is evaporated in vacuo. The residue is distilled (95°-97°/2·10-2Torr) to yield n-octyl 3-trifluoromethylphenylacetate.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.CCN(CC)CC>CCO>[CH:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 100 °C
Yield: 0 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (50 mg, 0.16 mol), 4-chloro-6-(trifluoromethyl)quinazoline (48 mg, 0.20 mol) and Et3N (100 mg, 1.0 mol)in EtOH (2 ml) was added to a microwave reaction tube, sealed, and heated in a microwave oven at 100° C. for 60 minutes. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel (3%–5% (NH4OH/MeOH)/CH2Cl2) to give 25 mg of the title product, (1R,2S,5R)-methyl 5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=508.24.