Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])/[CH:3]=[N:4]/[S:5]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6].C1C(=O)N([Br:29])C(=O)C1.ClC1C=CC=CC=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[CH3:1][N:2]([CH3:21])/[CH:3]=[N:4]/[S:5]([C:8]1[C:9]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][Br:29])=[CH:18][CH:19]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)/N=C/N(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: O
Product: CN(C)/C=N/S(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 100 °C
Yield: 41 %

Procedure:
4′-Methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide (540.0 mg, 1786 μmol), NBS (318 mg, 1.8 mmol), and benzoyl peroxide (4.3 mg, 17.8 μmol) were dissolved in chlorobenzene (7.0 mL, 69 mmol) and the resulting solution was heated at 100° C. for 90 minutes. The mixture was cooled to room temperature and water was added. The mixture was extracted with DCM, washed with saturated NaHCO3 and saturated aqueous NaCl, extracted again with DCM, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (40 g, 0-100% EtOAc in hexanes), then taken up in EtOAc (4.5 mL) and DCM (1.5 mL). Additional DCM (3.0 mL) was added and the mixture was heated at 60° C. The mixture was cooled in the freezer overnight, then concentrated. The material was taken up in DCM (2 mL), EtOAc (6 mL) was added, and the resulting solution placed in the freezer. A precipitate formed and was filtered to yield the title compound (279 mg) as a white solid.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClCCCl.C1C=CC=CC=1.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: c1ccccc1
Solvent: ClCCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (1.00 g) in 1,2-dichloroethane (10 ml) was added rhodium(II) octanoate (10 mg) under refluxing. After refluxing for 30 minutes, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in benzene (5 ml) and evaporated. This operation was repeated once again and the residue was dried in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]-heptane-2-carboxylate. The compound obtained was dissolved in acetonitrile (10 ml) and cooled to 0°~2° C. under atmosphere of nitrogen. To this solution were added diphenyl phosphorochloridate (0.56 ml) and N,N-diisopropyl-N-ethylamine (0.49 ml) successively and the mixture was stirred at 0° C. for 40 minutes. To the resulting solution were added dropwise a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-{4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidin-4-yl}-methylpyrrolidine (1.62 g) in acetonitrile (5 ml) and N,N-diisopropyl-N-ethylamine (0.77 ml) with stirring at 0°~2° C. and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added ethyl acetate (80 ml) and the solution was washed with water and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone 1, V/V). The fractions containing the desired compound were collected and concentrated in vacuo to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S) -1-(4-nitrobenzyloxycarbonyl)-2-{4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidin-4-yl}methyl pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (0.79 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]([B:12]([OH:14])[OH:13])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:16]([C:19](O)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:11]([B:12]3[O:13][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:14]3)=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1ccnn1-c1ccccc1
Reactant: CC(C)(O)C(C)(C)O
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Temperature: 40 °C
Yield: 64.4 %

Procedure:
To a mixture of (1-phenyl-1H-pyrazol-5-yl)boronic acid (8.57 g, 45.6 mmol) in toluene (86 mL) was added pinacol (5.39 g, 45.6 mmol) at room temperature. The mixture was heated to 40° C. for 2 days. The mixture was concentrated in vacuo and triturated with hexane to yield the title compound (7.93 g, 64% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 1.23 (12H, s), 6.84 (1H, s), 7.34-7.59 (5H, m), 7.75 (1H, d, J=1.9 Hz)
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.[O:25]=[CH:26][C@@H:27]([C@H:29]([C@H:31]([CH2:33][OH:34])[OH:32])[OH:30])[OH:28].CC(S[C@@H]1[O:44][C@H:43]([CH2:45][OH:46])[C@H:42]([OH:47])[C@H:41]([OH:48])[C@H:40]1[OH:49])C>>[CH2:26]([OH:25])[C@@H:27]([C@H:29]([C@@H:31]([CH2:33][OH:34])[OH:32])[OH:30])[OH:28].[O:46]=[CH:45][C@@H:43]([C@H:42]([C@H:41]([CH2:40][OH:49])[OH:48])[OH:47])[OH:44]
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 24 h

Procedure:
To test the activity of the XR/Lad1/Alx1 operon, plasmid pATX112 was inserted into strain ZUC99 by electroporation (ZUC99/pATX112). The strain was inoculated from a single colony into 3 mL LB media supplemented with ampicillin (200 mg/L) and incubated overnight at 30° C. with shaking (250 RPM). After incubation, an aliquot of the culture was diluted 100-fold into 20 mL of fresh LB media contain L-arabinose (1% w/v) and ampicillin (200 mg/L) and incubated (30° C., 250 RPM) for 2 hrs. The culture was induced with isopropyl-β-D-thiogalactopyranoside (IPTG, 1 mM). The culture was incubated at 30° C. with shaking (250 RPM) and aliquots were removed at various time points after the IPTG induction. The samples were monitored for xylitol formation from L-arabinose by HPLC analysis using an Aminex HPX-87P column (BioRad, USA). After 24 hrs post induction, the XR/Lad1/Alx1 operon strain (ZUC99/pATX112) displayed a 2% conversion of L-arabinose to xylitol, showing that the recombinant bacterium acquires the ability to produce xylitol from L-arabinose (Table 6).
Reaction SMILES: [NH2:1][C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=CC2N([OH:26])N=NC=2C=1.[CH3:27][C:28]([O:31][C:32]([NH:34][C@H:35]([C:41](OC1C=CC([N+]([O-])=O)=CC=1)=[O:42])[CH2:36][CH2:37][C:38]([NH2:40])=[O:39])=[O:33])([CH3:30])[CH3:29].CN1CCOCC1>CN(C=O)C>[NH:34]([C:32]([O:31][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:33])[C@H:35]([C:41]([NH:1][C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][C:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:26])=[O:42])[CH2:36][CH2:37][C:38](=[O:39])[NH2:40]
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(=O)OC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 462.1 %

Procedure:
H-Asp(OBzl)-OH (33.48 g, 150 mM) was suspended in DMF (400 ml). HOBT (2.03 g, 15 mM), BOC-Gln-ONP (55.10 g, 150 mM) and DMF (100 ml) were added thereto. The reaction mixture was adjusted to pH 7 by adding NMM (2 ml) at -10° C. and the mixture was stirred at room temperature overnight. The pH of the mixture was adjusted three times to pH 7 by adding NMM (16 ml). After the reaction (pH 6), the DMF was removed in vacuo. A citric acid solution (300 ml) and chloroform (300 ml) were added thereto and the mixture was shaken. The aqueous layer was extracted with chloroform (300 ml and 100 ml). The chloroform layers were combined and washed four times with saturated sodium chloride, acidic water (pH 3) and acidic water (pH 4), in that order. The aqueous layer was dried with anhydrous sodium sulfate and concentrated in vacuo. Ether was added to the residue and the precipitate formed was collected by filtration. Methanol was added to the collected precipitate and then the material was concentrated in vacuo, and then twice recrystallized from chloroform-ether to yield the substance [35] (32.31 g, yield: 47.7%). The mother liquor was concentrated in vacuo and recrystallized twice from chloroform-ether to obtain the substance [35] (6.3 g). Then the mother liquor was charged on a column of silica gel (100 g) and eluted with chloroform-ethanol-ethyl acetate (5:1:5). Corresponding fractions checked by TLC were dried in vacuo to obtain substance [35] (2.98 g). Total yield: 44.12 g (65.1%).
Reaction SMILES: COC1C=CC=C2C=1OC1C(OC)=C(OC)C(OC)=C(OC)C=1C2=O.C[O:27][C:28]1[C:29]([O:51]C)=[C:30]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[C:37]1[C:36]([O:43]C)=[C:35]([O:45]C)[C:34]([O:47]C)=[C:33]([O:49]C)[C:32]=1[O:31]2>>[OH:27][C:28]1[C:29]([OH:51])=[C:30]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[C:37]1[C:36]([OH:43])=[C:35]([OH:45])[C:34]([OH:47])=[C:33]([OH:49])[C:32]=1[O:31]2
Reactant: COc1ccc2c(=O)c3c(OC)c(OC)c(OC)c(OC)c3oc2c1OC
Agent: COc1c(OC)c(OC)c2c(=O)c3cccc(OC)c3oc2c1OC
Product: O=c1c2ccc(O)c(O)c2oc2c(O)c(O)c(O)c(O)c12
Yield: 90.8 %

Procedure:
2-hydroxy-3,4,5-trimethoxybenzoic acid (1.14 g, 0.005 mol) and 1,2,3,4-tetramethoxybenzene (0.99 g, 0.005 mol) and 25 ml of a 9% solution of P2O5 in methanesulfonic acid were shaken in a 50 ml cylindrical glass tube with a Teflon-lined screw-cap at room temperature for 54 hours. The dark orange mixture was then poured onto crushed ice (150 ml). After melting, the product was extracted with methylene chloride (3×40 ml). After removal of the solvent, the residue was chromatographed on silica gel (30 g) with CH2Cl2. Of the three fractions obtained (the eluent was monitored by thin-layer chromatography), the middle one was uniform and left pure 2-hydroxy-3,4,5,2',3',4',5'-heptamethoxybenzophenone (0.51 g, 25%) as a yellow oil upon evaporation of the solvent. This was dissolved in 100 ml 75% alcohol whereafter 5 ml of 10N NaOH were added and the mixture was heated to boiling in a beaker for three hours; the volume was kept at 100 ml by occasional addition of water. The mixture was then transferred to a 250 ml round bottom flask and refluxed for another 17 hours. After cooling, suction filtration yielded 0.36 g of 2,3,4,5,6,7-hexamethoxyxanthone as a white product (small needles, matted, 77%). In a deprotection procedure, similar to the one described above for pentamethoxyxanthone, 0.42 g of the hexamethoxyxanthone produced 0.296 g of hexahydroxyxanthone (91%) as a pale yellow powder. It was found advantageous to circumvent the need for centrifugation by stirring the methylene chloride-water mixture (from the quenching of the BBr3 -solution) in a wide-mouthed container for several hours, leading to the evaporation of the methylene chloride; the mixture is then easily filterable.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:15]=[CH:14][N:13]3[C:16]([CH3:29])=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:18]=[C:12]3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:15]=[CH:14][N:13]3[C:16]([CH3:29])=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:42])[NH2:28])=[CH:25][CH:26]=4)[N:18]=[C:12]3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 62 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 62% of theory, C29H31N5O3 (497.60); Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5); EKA mass spectrum: (M+H)+=498.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]\[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([OH:15])[CH:7]=1.S(Cl)(Cl)=O.[OH:26][CH2:27][CH2:28][NH2:29].Cl>CCCCCCCC.N1C=CC=CC=1>[OH:26][CH2:27][CH2:28][NH:29][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([O:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:7][C:8]=1[OH:15]
Reactant: NCCO
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)c(O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCCCCCCC
Solvent: O=S(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCO)c(O)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
In 50 ml of n-octane was dissolved 2.00 g (6.9 mmol) of 4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzoic acid, and 5.0 ml (35 mmol) of thionyl chloride was added to the solution, followed by heating at 90° C. for 5 hours to conduct a reaction. After completion of the reaction, the reaction mixture was cooled, and n-octane was removed by evaporation. The residue was dissolved in n-octane, and a pyridine solution of 0.84 g (13.8 mmol) of 2-hydroxyethylamine was added thereto dropwise at room temperature. After the dropwise addition, the mixture was stirred for 10 minutes, poured into a 12% hydrochloric acid aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The resulting crude product was recrystallized from an ethyl acetate/hexane mixed solvent to obtain 0.50 g (yield: 22%) of N-(2-hydroxyethyl)-4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzamide represented by the following structural formula (hereinafter referred to as compound 46) as white crystals. The analytical results are shown below. ##STR67##
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:20]=1[NH2:21].C([O-])(O)=O.[Na+].O>CS(C)=O.C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:21][C:20]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:19]=3[CH3:18])[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Nc2ccnc(Cl)n2)no1
Reactant: COc1cc(C)c(N)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(C)c(Nc2nccc(Nc3cc(C(C)(C)C)on3)n2)cc1OC
Temperature: 110 °C

Procedure:
To a slurry of (5-L-butyl-isoxazol-3-yl)-(2-chloro-pyrimidin-4-yl)-amine (0.110 g, 0.435 mmol, Step A) in DMSO (0.110 mL) was added 2-methyl-4,5-dimethoxyaniline (0.073 g, 0.435 mmol). The mixture was heated in a sealed tube at 110° C. for 90 min until TLC indicated the disappearance of starting materials. The mixture was taken up in CH2Cl2 (5 mL) followed by the addition of NaHCO3 (aq., sat. 1 mL) and H2O (5 mL). Extraction with CH2Cl2 (5×5 mL), followed by drying with MgSO4 and filtration yielded a crude mixture that was concentrated under reduced pressure. Purification by chromatography (97:3 CH2Cl2:MeOH) on silica gel afforded the title compound as a purple solid. MS m/z=384.2. Calc'd for C20H25N5O3: 383.45.
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14](Br)=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:17])[CH2:4][CH2:3]2.C[Li].[CH2:20](OCC)C.C([Li])(C)(C)C.CCCCC.[CH:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[C:35]([C:14]1[CH:13]=[CH:12][C:11]2[C@:2]3([CH3:1])[C@@H:7]([CH2:8][CH2:9][C:10]=2[CH:15]=1)[N:6]([CH3:20])[C:5](=[O:17])[CH2:4][CH2:3]3)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Br)ccc12
Reactant: CCOCC
Reactant: O=Cc1ccccc1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN1C(=O)CC[C@]2(C)c3ccc(C(=O)c4ccccc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4aR)-(10bR)-10b-methyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one in 25 mL of THF at -78° under an atmosphere of nitrogen was added 330 μL of a 1.4M solution of methyllithium in diethyl ether (0.46 mmol). The reaction mixture turned bright yellow, and after 10 min, 470 μl of a 1.7M solution of t-butyllithium in pentane (0.80 mmol) was added. The reaction mixture was stirred for 10 min before the addition of benzaldehyde (80 μL, 0.79 mmol) as a single aliquot. The reaction was warmed to room temperature and stirred for 30 min before partitioning between diethyl ether and 1N hydrochloric acid. The ether layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to afford 0.1818 g crude product. The material was purified on a Chromatotron (2 mm plate, dry loaded with chloroform, eluted with 5% methanol/chloroform) to give 106 mg of desired product. A portion of this material was triturated with diethyl ether to yield a white solid. mp 116-118; FDMS: m/e =321. α[D]589 =100.39
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CC.[CH2:12](O)CCCCCCC(C)C>>[CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:8])[CH3:12]
Reactant: CC(C)CCCCCCCO
Reactant: CCCCCCCCCCO
Product: CC(C)CCCCCCO

Procedure:
n-decylalcohol, iso-decylalcohol
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]=1[C:14]([NH2:16])=[O:15].[C:21](Cl)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]=1[C:14]([NH2:16])=[O:15])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1csc(N)c1C(N)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Nc1scc(C(C)(C)C)c1C(N)=O
Yield: 80.3 %

Procedure:
21.2 g (0.21 mole) of triethylamine were first added to a suspension of 39.6 g (0.2 mole) of 2-amino-3-aminocarbonyl-4-tert.-butyl-thiophene in 300 ml of toluene, and 16.5 g (0.21 mole) of acetyl chloride were then added dropwise. After the exothermic reaction had ended, the mixture was worked up by filtering off the solid product and washing it with water. 38.6 g of 2-acetylamino-3-aminocarbonyl-4-tert.-butyl-thiophene of melting point 251° C. were obtained in this manner.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:23](O)=[O:24])[C:13]3=[O:30])[CH2:5]1)([CH3:3])[CH3:2].CN(C=O)C.S(Cl)(Cl)=O.[NH2:40][C:41]1[CH:45]=[CH:44][O:43][N:42]=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:23]([NH:40][C:41]2[CH:45]=[CH:44][O:43][N:42]=2)=[O:24])[C:13]3=[O:30])[CH2:5]1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(O[C@H]3CCN(C(C)C)C3)cc2c1=O
Reactant: Nc1ccon1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(O[C@H]3CCN(C(C)C)C3)cc2c1=O

Procedure:
To a stirred slurry of 3-[6-{[(3S)-1-isopropylpyrrolidin-3-yl]oxy}-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.29 g) and DMF (0.05 ml) in methylene chloride (15 ml) at 0° C. was added thionyl chloride (0.15 ml). The resultant solution was stirred at room temperature for 21 hour. To this mixture was added 3-aminoisoxazole (0.316 ml) and the resultant solution was stirred for 18 hours. The reaction mixture was evaporated and the residue was dissolved in methanol and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution. The fraction containing the product was further purified by column chromatography on an ion exchange column (isolute NH2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) eluting with MeOH. After evaporation and the residue was dissolved in ethyl acetate and triturated with ether, the resultant solid was removed by filtration and iso-hexane was added to the filtrate and the resulting solid was filtered and dried to give 3-[6-{[(3S)-1-isopropylpyrrolidin-3-yl]oxy}-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide as light tan solid (114 mg); NMR Spectrum: (DMSOd6) 1.02 (m, 6H), 1.76 (m, 1H), 2.18 (s, 3H), 2.27 (m, 1H), 2.40 (m, 2H), 2.85 (m, 3H), 5.01 (m, 1H), 7.04 (m, 1H), 7.49 (m, 2H), 7.60 (d, 1H), 7.72 (d, 1H), 8.07 (m, 2H), 8.21 (s, 1H), 11.45 (s, 1H); Mass Spectrum: M+H+ 474.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]4[CH2:26][CH2:25]S[CH2:23][CH2:22]4)[CH:16]3[CH2:27][CH2:28][NH:29][C:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[O:31])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:56]([O-:60])([O-])(=[O:58])=S.[Na+].[Na+].C(OC)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]4[CH2:26][CH2:25][S:56](=[O:60])(=[O:58])[CH2:23][CH2:22]4)[CH:16]3[CH2:27][CH2:28][NH:29][C:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:34][CH2:33]3)=[O:31])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCCC2C(Nc3nccc(N4CCCCCC4)n3)CCCN2C2CCSCC2)CC1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCC2C(Nc3nccc(N4CCCCCC4)n3)CCCN2C2CCS(=O)(=O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-[({2-[(2RS,3SR)-3-[(4-azepan-1-ylpyrimidin-2-yl)amino]-1-(tetrahydro-2H-thiopyran-4-yl)piperidin-2-yl]ethyl}amino)carbonyl]piperidine-1-carboxylate (73.5 mg) in dichloromethane (1.5 mL), trifluoroacetic acid (17 μL) and m-chloroperbenzoic acid (40 mg) were added and then stirred at room temperature for 3 hours. The reaction solution was added aqueous sodium thiosulfate solution and excessive tert-butylmethyl ether, extracted with aqueous 2N sodium hydroxide solution and saturated brine and obtained a crude product of the title compound (84 mg). The obtained crude product was purified by silica gel column chromatography (ethyl acetate:methanol:28% aqueous ammonia=1000:10:1→80:20:2) to obtain a more polar compound and a less polar compound of the title compound having the following physical properties.