Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:18]([CH3:21])[CH:19]=[CH2:20])=[CH:4][C:5]([CH3:17])=[C:6]2[C:14]=1C(NC)C1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1.[CH2:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])C.C(Cl)(=[O:31])C>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:3]([CH:18]([CH3:21])[CH:19]=[CH2:20])=[CH:4][C:5]([CH3:17])=[C:6]2[C:14]=1[CH:25]([N:24]([CH3:22])[C:27](=[O:31])[CH3:28])[CH:26]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(=O)Cl
Reactant: C=CC(C)c1cc(C)c2c(c1O)C(NC)C1CCCCC21
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(C)c1cc(C)c2c(c1O)C(N(C)C(C)=O)C1CCCCC21

Procedure:
25.00 Grams of 8-hydroxy-5-methyl-9-methylamino-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene was dissolved in 250 ml of chloroform. Under ice-cooling and stirring, to the solution were added 24.4 ml of triethylamine and then 14.95 ml of acetyl chloride, followed by stirring at room temperature for 1 hour. Extraction was carried out with addition of water and the organic layer was concentrated. The resulting residue was dissolved in 250 ml of methanol and thereto was added an aqueous solution containing 1.36 g of sodium bicarbonate in 50 ml of water, followed by refluxing for 2 hours. The reaction mixture was rendered weakly acidic with addition of dilute hydrochloric acid and extracted with chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform:methanol:ethyl acetate=100:1:5). The component of Rf value 0.29 in the eluate was recrystallized from ethanol to obtain 1.66 g of 8-hydroxy-5-methyl-9-(N-methyl-N-acetylamino)-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene (diastereomer B) having a melting point of 143°-145° C. and of colorless powdery crystal and the component of Rf value 0.21 was recrystallized from ethanol to obtain 16.43 g of 8-hydroxy-5-methyl-9-(N-methyl-N-acetylamino)-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene (diastereomer A) having a melting point of 166°-168° C. and of colorless granular crystal.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][C:3]1=[O:29].Cl.[NH2:31][OH:32].C(=O)([O-])O.[Na+]>C(O)C.O.C(OCC)(=O)C>[OH:32][N:31]=[C:8]([C:6]1[CH:5]=[CH:4][C:3](=[O:29])[N:2]([CH3:1])[CH:7]=1)[CH2:9][C@H:10]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1ccccc1[C@H](CC(=NO)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 120 °C
Yield: 97.1 %

Procedure:
To a microwave vial was added (R)-1-methyl-5-(3-(4-(methylsulfonyl)phenyl)-3-o-tolylpropanoyl)pyridin-2(1H)-one (168 mg, 410 μmol), hydroxylamine hydrochloride (85.5 mg, 1.23 mmol) and sodium hydrogencarbonate (103 mg, 1.23 mmol) in ethanol (3 mL) and water (0.2 mL). The vial was capped and heated in the microwave at 120° C. for 15 min. The reaction mixture was diluted with ethyl acetate and poured onto water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afforded the title compound (169 mg, 97%) as a mixture of the E and Z isomers (ratio ca. 85:15). Light yellow foam, MS (ESI+): m/z=425.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Cl[C:17]([N:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:25]=2)[CH2:20]1)=[O:18]>O1CCCC1>[CH:33]1([O:32][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:22][CH2:23][N:19]([C:17]([NH:1][CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)=[O:18])[CH2:20]3)[CH:29]=[CH:28][C:27]=2[O:30][CH3:31])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: NCc1cccnc1
Reactant: COc1ccc(C2CCN(C(=O)Cl)C2)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(C(=O)NCc3cccnc3)C2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
216 mg of 3-(aminomethyl) pyridine and 202 mg of triethylamine were dissolved in 5 ml of tetrahydrofuran. During agitation at a cold temperature, a solution obtained by dissolving 545 mg of 1-chloroformyl-3-(3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine in 3 ml of tetrahydrofuran was added in drops. After dropping, agitation was continued for 6 hours at a room temperature. Thereafter, the agitated solution was poured into ice water and then extracted with ethyl acetate. After organic layers were cleaned by water and dried over magnesium sulfate, it was concentrated under a reduced pressure. The residue was purified by means of the silica gel column chromatography to obtain 432 mg of Compound No. 22 in Table 1.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:32]2[NH:37][CH2:36][CH2:35][O:34][C:33]=2[CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[C:30]1[C:29]([F:28])=[CH:38][C:33]2[O:34][CH2:35][CH2:36][NH:37][C:32]=2[CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Reactant: CC1(C)OB(c2cc3c(cc2F)OCCN3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3cc4c(cc3F)OCCN4)n2n1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (300 mg, 0.613 mmol), 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (prepared according to the procedure described in WO 2009/062285; 205 mg, 0.736 mmol) and 2N Na2CO3 (0.613 mL, 1.226 mmol) in DMF (6 mL) was degassed for 15 min. Tetrakis(triphenylphosphine)palladium(0) (49.6 mg, 0.043 mmol) was added and the degassing was continued for another 5 min. The mixture was then heated at 100° C. for 16 h. At this point LCMS indicated completion of reaction and presence of desired product. After cooling to room temperature, water was added (50 mL) and the mixture was extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried (Na2SO4), filtered and concentrated. The crude was then purified by prep-HPLC to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (approx 10-15% of minor atrope isomer present by LCMS and NMR). 1H NMR (500 MHz, CDCl3) δ 7.11 (s, 1H), 6.74 (dd, J=8.3, 1.8 Hz, 2H), 5.17 (s, 1H), 4.48-4.33 (m, 4H), 4.24 (t, J=7.0 Hz, 2H), 3.83 (br. s., 1H), 3.51-3.41 (m, 2H), 2.70 (s, 3H), 1.43-1.39 (m, 3H), 1.31-1.26 (m, 3H), 1.05 (s, 9H). LCMS (M+H)=515.4.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7].[CH3:35]I>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([CH3:35])[CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: CI
Reactant: Cc1ccccc1C1=CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1C1=CN(C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=497.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-1-one and methyl iodide.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH:5]([CH3:9])[C:4](=[O:10])[O:3]1.[CH2:12](Br)[CH:13]=C.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)C>[CH3:11][C:2]1([CH3:1])[O:3][C:4](=[O:10])[CH:5]([CH2:9][CH:12]=[CH2:13])[C:6](=[O:8])[O:7]1
Reactant: CC1C(=O)OC(C)(C)OC1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=CCC1C(=O)OC(C)(C)OC1=O
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a 500 mL 3-necked round bottomed flask equipped with a stir bar, thermowell and a condenser connected to a nitrogen line was added 10.0 g (0.0632 mole) of 2,2,5-trimethyl-1,3-dioxane-4,6-dione, 7.7 g (0.0632 mol) of allyl bromide, 21 g (0.152 mol) of potassium carbonate and 200 mL of acetone. The mixture was refluxed with stirring overnight at which time it was allowed to cool, diluted with 200 mL of ethyl ether and filtered through a bed of Celite/activated charcoal. The filtrate was washed with water and brine and dried overnight over anhydrous sodium sulfate. The suspension was filtered and the filtrate evaporated on a rotary evaporator to yield 11 g of 2,2-dimethyl-5-allyl-1,3-dioxane-4,6-dione compound as shown in Formula (IV)) as a clear, colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH3:8])(=[O:7])[OH:6].[C:9]([O:14][CH:15]([O:17][C:18](OC1CC(=O)NC1=O)=[O:19])[CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11]>C(#N)C.O>[C:9]([O:14][CH:15]([O:17][C:18]([NH:1][CH2:2][CH2:3][CH2:4][P:5]([CH3:8])(=[O:6])[OH:7])=[O:19])[CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CP(=O)(O)CCCN
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(OC(=O)NCCCP(C)(=O)O)OC(=O)C(C)C

Procedure:
A solution of 3-aminopropylmethylphosphinic acid (137 mg, 1 mmol) and compound (17) (301 mg, 1 mmol) in acetonitrile (5 mL) and water (0.5 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to afford the title compound (111) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.69 (br, 1H), 6.77 (q, 1H, J=5.2 Hz), 3.27 (t, 2H, J=6 Hz), 2.53 (m, 1H), 1.83-1.73 (m, 4H), 1.45 (m, 6H), 1.15 (d, 6H, J=7.2 Hz). MS (ESI) m/z 296.1 (M+H)+, 294.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:3]=1[CH2:9][CH:10]=[O:11].S(=O)(=O)(O)[OH:13].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>CC(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])([CH3:8])[CH2:5][CH2:4][C:3]=1[CH2:9][C:10]([OH:13])=[O:11]
Reactant: CC1=C(CC=O)CCC1(C)C
Reactant: O=S(=O)(O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=C(CC(=O)O)CCC1(C)C
Temperature: 0 °C

Procedure:
A solution was made of β-campholenic aldehyde (150 g) in acetone (2 liters) and cooled to 0° C. Oxidizing agent was prepared from 169 ml conc. sulfuric acid, 736 ml water and 292 g of sodium dichromate (Na2Cr2O7.2H2O). The reagent (375 ml) was added to the solution at 0° C. over a period of 30 minutes. After an additional 15 minutes at 0° C. the acetone was removed by decantation and the residual chromium salts were washed with an additional 200 ml acetone. The combined acetone solution was concentrated, the residue taken up in 10% aqueous sodium hydroxide (1 liter) and the solution washed with CH2Cl2 (2×1 liter). The aqueous phase was acidified with 25% sulfuric acid followed by extraction with CH2Cl2 (2×1 liter). Concentration of the dried CH2Cl2 solution yielded an oil (73 g) which was distilled under reduced pressure to give 53 g of a yellowish liquid; bp 102° C. @ 1.1 mm Hg; crystallized upon standing; analysis: (CW 20M fused silica column, 190° C.) 96% β-campholenic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CN2CCNCC2)nc1

Procedure:
A solution of 0.11 g (0.4 mmol) of the title compound from Step A above in 1 mL dichloromethane and 1 mL trifluoroacetic acid was stirred at ambient temperature for 1 h. All volatiles were removed in vacuo and the crude light brown residue was carried forward without purification. LC/MS: m/z (ES) 178.2 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]([NH:12][C:13]([NH:15][CH3:16])=[O:14])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:23]1SC=C(C2C=CC=CC=2)C=1C(OCC)=O.CN.C(N)C>>[CH2:16]([NH:15][C:13](=[O:14])[NH:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:23]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1NC(=O)NC
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Agent: CCN
Agent: CN
Product: CCNC(=O)Nc1scc(-c2ccccc2)c1C(=O)OCC

Procedure:
In exactly the same manner ethyl 4-phenyl-2-(N'-methylureido)thiophene-3-carboxylate. m.p. 109°-12° C. and ethyl 2-(N'-ethylureido)-4-phenyl-thiophene-3-carboxylate M.p. 129°-33° C. were prepared from ethyl 2-amino-4-phenyl-thiophene-3-carboxylate (Gewald et. al., Chem. Ber. 99, 94 (1966) and methylamine and ethylamine respectively.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[C:17]([OH:19])=[O:18])=[CH:14][C:13]([O:20][CH3:21])=[CH:12][CH:11]=2.[CH3:22]O>>[CH3:22][O:18][C:17]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=2)[N:9]=[CH:8][C:7]=1[OH:6])=[O:19]
Reactant: COc1ccc2ncc(O)c(C(=O)O)c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(O)cnc2ccc(OC)cc12
Temperature: 65 °C
Yield: 97 %

Procedure:
Concentrated sulfuric acid (36N, 50 mL) is added dropwise at room temperature to a stirred suspension of 3-hydroxy-6-methoxyquinoline-4-carboxylic acid (14.5 g, 66.15 mmol, 1.0 eq) in methanol (250 mL) and the resulting mixture is heated at 65° C. for 36 hours. Solvent is then evaporated and the residue is quenched with the dropwise addition at 0° C. of saturated sodium hydrogen carbonate aqueous solution. The resulting precipitate is collected by filtration and dried under vacuum to afford 3-hydroxy-6-methoxyquinoline-4-carboxylic acid methyl ester as an off-white powder (15.0 g, 97% yield).
Reaction SMILES: C1OC2C=CC(C[O:7][C:8](=O)[C@H:9]([N:20]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]4[O:42][CH2:43][O:44][C:38]=4[CH:37]=3)[S:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[C:26]([CH3:33])[C:25]=3[CH3:34])(=[O:23])=[O:22])[C@@H:10]([O:12][Si](CC)(CC)CC)[CH3:11])=CC=2O1.[CH2:50]([O:57][NH2:58])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(OCC)(=O)C.[Pd].C(O)C.O1CCCC1>[CH2:50]([O:57][NH:58][C:8](=[O:7])[C@H:9]([N:20]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]2[O:42][CH2:43][O:44][C:38]=2[CH:37]=1)[S:21]([C:24]1[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[C:26]([CH3:33])[C:25]=1[CH3:34])(=[O:23])=[O:22])[C@@H:10]([OH:12])[CH3:11])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CC[Si](CC)(CC)O[C@@H](C)[C@H](C(=O)OCc1ccc2c(c1)OCO2)N(Cc1ccc2c(c1)OCO2)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Reactant: NOCc1ccccc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)NOCc2ccccc2)[C@H](C)O)c(C)c1C
Reaction time: 0.75 h
Yield: 47.4 %

Procedure:
To a solution of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzene-sulfonyl)amino]-3(S)-(triethylsilyloxy)butyric acid 3,4-methylenedioxybenzyl ester (3.3 g, 4.62 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran (100 mL) was added 10% Pd-C (2 g) and the resulting reaction mixture was hydrogenated at atmospheric pressure for 45 min. The reaction mixture was degassed under argon, the slurry was filtered over Celite, and the Celite pad was washed with ample 80% ethanol-methylene chloride. The filtrate was concentrated and azeotroped with tetrahydrofuran (200 mL) and the residue was dissolved in dimethylformamide (25 mL). O-Benzyl hydroxylamine (2.0 g,16.2 mmol), HOBT (0.71 g, 5.2 mmol), and EDAC (3.1 g, 16.2 mmol) were added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with ethyl acetate and was washed with 2.4 N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The mixture was then dried over magnesium sulfate and concentrated in vacuo to afford crude N-benzyloxy-2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,3,6-trimethylbenzene-sulfonyl)amino]-3(S)-hydroxybutyramide (1.25 g) which was taken directly into the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:27][C@:13]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:14]=[C:15]([NH:18]C(=O)C3C=CC=CC=3)[S:16][CH2:17][C@@H:12]2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>CO>[CH2:1]([O:8][C@H:9]1[CH2:27][C@:13]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:14]=[C:15]([NH2:18])[S:16][CH2:17][C@@H:12]2[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)C[C@H](OCc3ccccc3)CC[C@H]2CS1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@@]2(c3ccccc3F)C[C@H](OCc3ccccc3)CC[C@H]2CS1
Temperature: 25 °C

Procedure:
(±)-N-[(4aR*,7R*,8aS*)-7-Benzyloxy-8a-(2-fluorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in Preparation Example 58-(6) (1.81 g) was dissolved in methanol (60 mL). Then, DBU (1.14 mL, specific gravity: 1.018 g/cm3) was added, and the mixture was stirred with heating under reflux for three hours. Then, the reaction solution was stirred at 64° C. for 14 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (1.20 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)[C@@H:11]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][O:38][CH2:39][C@H:40]([O:42][CH2:43][CH3:44])[CH3:41])=[CH:33][CH:32]=2)[C@H:10]([CH2:45]O)[CH2:9]1)=O)(C)(C)C.[CH3:47][CH2:48][N:49](CC)[CH2:50][CH3:51].OS([O-])(=O)=O.[K+]>CS(C)=O.C(Cl)Cl.O>[CH2:43]([O:42][C@H:40]([CH3:41])[CH2:39][O:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:11]2[C@H:10]([CH2:45][N:49]3[CH2:50][CH2:51][CH2:47][CH2:48]3)[CH2:9][NH:8][CH2:13][C@@H:12]2[O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)=[CH:32][CH:33]=1)[CH3:44]
Reactant: CCN(CC)CC
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CO)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN3CCCC3)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-hydroxymethyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 1a) in 1 ml of DMSO and 5 ml of CH2Cl2 at 0° C. are added 5 mmol of Et3N and 3 mmol of pyridine sulfur trioxide complex. The reaction mixture is allowed to stir for an additional 3 h at this temperature and then allowed to warm to RT and stirred at RT for 5 h, diluted with water and acidified by the addition of 1N KHSO4 and subsequently extracted with Et2O. The organic phases are dried over Na2SO4 and concentrated by evaporation The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[C:5]2C[CH:7]=[CH:8][CH2:9][C:10]=2[C:11](=[O:13])[CH:12]=1.[Cl:15]Cl.CCOC(C)=O.COC1C(=O)C2C(C(=O)C=1)=CC=CC=2.[CH:37]([Cl:40])(Cl)Cl>CCO>[CH3:1][O:2][C:3]1[C:4](=[O:14])[C:5]2[CH:37]([Cl:40])[CH:7]([Cl:15])[CH2:8][CH2:9][C:10]=2[C:11](=[O:13])[CH:12]=1
Reactant: ClC(Cl)Cl
Reactant: COC1=CC(=O)C2=C(CC=CC2)C1=O
Reactant: ClCl
Agent: COC1=CC(=O)c2ccccc2C1=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC1=CC(=O)C2=C(C1=O)C(Cl)C(Cl)CC2

Procedure:
To a solution of 2-methoxy-5,8-dihydronaphthalene-1,4-dione (2.75 g, 14.4 mmol) in CHCl3 (60 mL, pre-treated with silica gel to remove the EtOH stabilizer) there was added a solution of Cl2 (~1.10 g, ~15.1 mmol) in EtOH-free CHCl3 (50 mL) in portions over 30 min. TLC (5% EtOAc/95% EtOH) indicated total consumption of the starting material and the appearance of a major higher Rf product spot (lower Rf impurity spots were also noted). The solvent was removed in vacuo to yield a yellow syrup. The addition of 95% EtOH (10 mL) followed by evaporation in vacuo (performed twice) yielded a yellow solid. Crystallization from 95% EtOH (dissolved in 20 mL, allowed to cool to rt) yielded a yellow solid (2.28 g, 60%, ~90% pure by TLC and 1H NMR, mp 119°-123° C.). Recrystallization from 95% EtOH (dissolved in 12 mL, allowed to cool to rt) yielded a yellow crystalline solid (1.89 g, 83% recovery, 50% total yield, ~95% pure by TLC and 1H NMR with the major impurity being 2-methoxynaphthalene-1,4-dione); mp 123°-128° C. (EtOH); 1H NMR (CDCl3) δ3.11 (m, 4H), 3.83 (s, 3H), 4.67 (m, 2H), 5.94 (s, 1H).
Reaction SMILES: C(O[CH2:7][C:8]1[CH:13]=[CH:12]C=[CH:10][CH:9]=1)(=O)C(C)=C.[C:14]([OH:18])(=O)[CH:15]=[CH2:16].S[CH2:20]CC(OC)=O.N(C(C1CC1)(C)C#N)=NC(C1CC1)(C)C#N.N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH3:10][CH2:9][CH:8]([CH2:13][CH2:12][C:14]([OH:18])([CH2:15][CH3:16])[CH3:20])[CH3:7]
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: C=CC(=O)O
Reactant: COC(=O)CCS
Agent: CC(C#N)(N=NC(C)(C#N)C1CC1)C1CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCC(C)CCC(C)(O)CC
Reaction time: 1 h

Procedure:
To the solution was dropwise added a mixed solution of 85.0 g of benzyl methacrylate, 15.0 g of acrylic acid, 2.0 g of methyl 3-mercaptopropionate and 1.2 g of 2,2'-azobis(2-cyclopropylpropionitrile) (abbreviated as ACPP) over a period of one hour, followed by stirring for one hour. To the reaction mixture was added 0.8 g of ACPP, followed by reacting for 2 hours. Further, 0.5 g of 2,2'-azobis-(isobutyronitrile) (abbreviated as AIBN) was added thereto, the reaction temperature was adjusted to 80° C., and the reaction was continued for 3 hours. After cooling, the reaction mixture was passed through a nylon cloth of 200 mesh to obtain a white dispersion which was a latex of good monodispersity with a polymerization rate of 97% and an average grain diameter of 0.17 μm. The grain diameter was measured by CAPA-500 manufactured by Horiba Ltd. (hereinafter the same).