Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14](I)[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.[Cu][C:35]#[N:36]>CN(C=O)C.CCOCC>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14]([C:35]#[N:36])[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(I)ccc3-4)CC21
Reactant: N#C[Cu]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(C#N)ccc3-4)CC21
Temperature: 110 °C

Procedure:
The product from Example 102A (24.7 mg, 0.044 mmol) was treated with copper(I) cyanide (27.5 mg, 0.307 mmol) in DMF (0.5 mL) heated at 110° C. overnight, cooled, diluted with Et2O (25 mL), washed with water (2×20 mL), washed with brine, dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eluting with hexane:EtOAc (2:1, 1:1, 4:1) to provide the title compound. MS (M+H)+ m/z 463.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][N:13]1[C:17]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:16][C:15]([C:23]([F:26])([F:25])[F:24])=[N:14]1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH3:12][N:13]1[C:17]([C:18]2[S:19][C:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][N:22]=2)=[CH:16][C:15]([C:23]([F:26])([F:24])[F:25])=[N:14]1
Reactant: Cn1nc(C(F)(F)F)cc1-c1nccs1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc(-c2cc(C(F)(F)F)nn2C)s1
Reaction time: 1.5 h

Procedure:
An n-butyl lithium-n-hexane solution (1.6 M) was added to a mixture of 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole and THF at −50° C. or below, followed by stirring at −50° C. or below for 90 minutes. Ethyl chloroformate was added to the reaction solution at −20° C. or below. After stirring at −20° C. or below for 15 minutes, it was subjected to purification in the usual way to give ethyl 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylate. This was hydrolyzed with a base in the usual way to give 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11].O>CN(C)C=O>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: Nc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CNc1ncccn1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A solution of 2-aminopyrimidine (1.9 g.) in dried dimethylformamide (8 ml.) was dropwise added to a suspension of 50% sodium hydride (1.25g.) in dried dimethylformamide (2 ml.) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. Bromoacetaldehyde diethyl acetal (4.3 g.) and dried dimethylformamide (2 ml.) were added thereto, and the mixture was stirred for 2 hours and 20 minutes at ambient temperature and for 2.5 hours at 80° C. The reaction mixture was cooled to at ambient temperature and to the mixture was added water, and then the mixture was extracted 3 times with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution in turn, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residual oil was purified by column chromatography on silica gel (25 g.) using chloroform as developing solvent to give 2-pyrimidinylaminoacetaldehyde diethyl acetal (1.4 g.), oil. This oil was allowed to stand to give crystals.
Reaction SMILES: NN=C([C:10]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3N(N)[C:14]=2[CH:13]=[CH:12][C:11]=1[CH2:26][C:27]1C=CC=CC=1)C1C=CC=CC=1.[ClH:33].N1CCC(=O)CC1.S(=O)(=O)(O)O.[NH3:46]>O.C(O)C>[ClH:33].[CH:27]1[N:46]2[C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[CH:18]=[CH:19][C:20]3=[C:10]2[C:11](=[CH:12][CH:13]=[CH:14]3)[CH:26]=1
Reactant: N
Reactant: NN=C(c1ccccc1)c1c(Cc2ccccc2)ccc2c1CCc1ccccc1N2N
Agent: Cl
Agent: O=C1CCNCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: C1=Cc2cccc3ccn(c23)-c2ccccc21
Reaction time: 0.67 h

Procedure:
A mixture of 24.6 g of N-aminoiminodibenzyl (5-amino-10,11-dihydro-5H-dibenz[b,f]azepine) and 14.8 g of 4-piperidone hydrochloride in 250 ml. ethanol was heated on a steam bath for 15 minutes 1,2,3,4,4cooled; 8,9,14a-octahydropyridoof 20 g. indoloconcentrated sulfuric acid in 250 ml. ethanol was added. The resulting mixture was reheated on the steam bath for an additional 40 minutes; the solution which formed was cooled, basified with ammonia, and diluted with 1 liter of water. The crude, semisolid material which separated was taken up in ether, and the aqueous mother liquors were extracted with additional portions of ether. The combined ethereal extracts were concentrated to 500 ml. and treated, under an atmosphere of nitrogen and with vigorous stirring, with 50 ml. of 5N hydrochloric acid. The resulting precipitate was filtered off, washed with ether and C (dec). 1N hydrochloric acid, and dried in vacuo at 100° to yield 1,2,3,8,9-hexahydropyrido[4',3':2,3]=indolo[1,7ab][1]benzazepine hydrochloride, m.p. 309°, a salt only very slightly soluble in water. Dissolving the above salt in aqueous acetic acid, basifying with ammonia, filtering off the crude product and recrystallizing it from benzene regenerated the free 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine, m.p. 134°-136° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]([NH2:18])[C:11]3=[CH:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:4]([Cl:28])[CH:3]=1.CCN(CC)CC.[Br:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:36][CH2:37][CH2:38][CH2:39][C:40]([NH:18][CH:17]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[Cl:28])=[C:9]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH:10]=2)[O:14][C:15]([CH3:20])([CH3:19])[CH2:16]1)=[O:41]
Reactant: CC1(C)CC(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Reactant: O=C(Cl)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(NC(=O)CCCBr)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 7-(4-bromo-2-chlorophenyl)-6-(4-chloro-phenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine (303 mg, 0.63 mmol) and NEt3 (221 μL, 1.6 mmol) in 10 mL of CH2Cl2 was added 4-bromobutyryl chloride (110 μL, 0.95 mmol). After stirring at rt for 16 h, the reaction mixture was combined with saturated aq NaHCO3 (20 mL). The aq layer was separated and extracted with CH2Cl2 (3×20 mL). The organic layers were combined, dried over MgSO4, and concentrated to afford the product.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([C:12]1[C:13]([NH:19][CH2:20][CH3:21])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:11].[Cl:25][CH2:26][C:27](Cl)=[O:28]>N1C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([C:12]1[C:13]([N:19]([CH2:20][CH3:21])[C:27](=[O:28])[CH2:26][Cl:25])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:11]
Reactant: O=C(Cl)CCl
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCN(C(=O)CCl)c1nc(C)ccc1C(=O)c1cccc(Cl)c1

Procedure:
To a DMF solution of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine were added chloroacetyl chloride and pyridine, followed by reaction at room temperature. Thereafter, the whole was worked up and purified in a usual manner to obtain N-[3-(3-chlorobenzoyl)-6-methylpyridin-2-yl]—N-ethylchloroacetamide. To an acetonitrile solution of the compound were added N-tert-butoxycarbonylpiperazine and potassium carbonate, followed by reaction under heating. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 2-[4-tert-butoxycarbonylpiperazin-1-yl]—N-[3-(3-chlorobenzoyl)-6-methylpyridin-2-yl]-N-ethylacetamide. The resulting compound was reacted with sodium methoxide in methanol under heating. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 3-(1 -tert-butoxycarbonylpiperazin-4-yl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one. NMR1: 4.73 (2H, q, J=7.3 Hz), 3.15-3.35 (2H, m), 1.38 (9H, s).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:15]([O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:21][CH:22]=1)[CH3:14]
Reactant: CC(=O)CCC(=O)c1ccccc1
Reactant: CCOc1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOc1ccc(-n2c(C)ccc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-phenyl-1,4-pentanedione (1.06g, 6.0 mmol) and toluene (50 mL) was added p-phenetidine (0.78 mL, 6.0 mmol) and 5 drops of glacial acetic acid. The mixture was heated at reflux overnight. After cooling to rt, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (15-25% EtOAc/hexanes) to give 1-(p-ethoxyphenyl)-5-methyl-2-phenyl-pyrrole as a yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.17-7.13 (m, 2H), 7.10-7.05 (m, 5H), 6.89-6.84 (m, 2H), 6.35 (d, 1H), 6.08 (d, 1H), 4.04 (q, 2H), 2.13 (s, 3H), 1.44 (t, 3H); MS (ESI) 278 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.CN(C)CCCN=C=NCC.[NH2:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([NH:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[O:33])=[C:30]([O:44][CH3:45])[CH:29]=1>O>[CH2:40]([N:37]([CH2:38][CH3:39])[CH2:36][CH2:35][NH:34][C:32](=[O:33])[C:31]1[CH:42]=[CH:43][C:28]([NH:27][C:10](=[O:12])[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:29][C:30]=1[O:44][CH3:45])[CH3:41]
Reactant: O=C(O)COCc1ccccc1
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1OC
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCNC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
664 mg (4 mmol) of benzyloxyacetic acid is introduced into 20 ml of methylene chloride, mixed with 768 mg (4 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDG), and stirred for 0.5 hour at 4° C. Then, 1.06 g (4 mmol) of 4-amino-N-(2-diethylamino-ethyl)-2-methoxy-benzamide in a total of 12 ml of methylene chloride is added to the batch and stirred for 48 hours at room temperature. After 30 ml of water is added, it is extracted twice with 30 ml each of methylene chloride. The organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on 20 g of Isolute NH2 (50 μm) with methylene chloride. The correspondingly combined fractions are concentrated by evaporation and chromatographed again on 20 g of Isolute NH2 (50 μm) with a gradient from cyclohexane to cyclohexane:methylene chloride 50:50 as an eluant, and 348 mg (27% of theory) of N-(2-diethylamino-ethyl)-4-(2-benzyloxy-acetylamino)-2-methoxy-benzamide is obtained as an oil.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.FC(F)(F)S(O)(=O)=O.[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:17]([C:5]1[C:6]([OH:7])=[C:1]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[C:3]([CH3:8])[CH:4]=1)=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(O)cc1
Reactant: C=Cc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1cc(C=Cc2ccccc2)c(O)c(C=Cc2ccccc2)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a one liter round-bottomed flask equipped with a stirrer, thermometer, and addition funnel was charged 151.3 grams (1.4 moles) of p-cresol. The mixture was heated to 70° C., followed by the addition of 5 μL of trifluoromethane sulfonic acid via a 100 μL syringe. Under a nitrogen blanket, 284.5 grams (2.73 moles) of styrene was placed into the funnel and then added dropwise, with stirring, over a period of three hours. During styrene addition, the pot temperature did not exceed 80° C. Stirring was continued at a pot temperature of 70° C. for a period of 1.5 hours after all the styrene had been added. The resultant styrenated p-cresol composition analyzed as follows:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:24][CH2:25][CH3:26])([CH3:23])[CH3:22])[C:15]=1[NH2:16]>C(Cl)Cl>[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:24][CH2:25][CH3:26])([CH3:23])[CH3:22])[C:15]=1[NH:16][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: CCOC(C)(C)c1cccc(C)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(C)(C)c1cccc(C)c1NC(=O)CCl
Reaction time: 8 h

Procedure:
In this example 1.45 g (1.03 ml) of chloroacetyl chloride was added dropwise to a solution containing 1.44 g (2 ml) of triethylamine and 0.0129 mole of 2-methyl-6-(1-ethoxy-1-methylethyl)aniline in methylene chloride at about but below 20° C. The mixture was then refluxed and then allowed to stand overnight at room temperature. Another 0.51 ml of chloroacetyl chloride and 1 ml of triethylamine was then added dropwise. The mixture was then again refluxed and allowed to stand overnight at room temperature. The mixture was then washed with saturated aqueous sodium bicarbonate, dried and evaporated affording the title compound as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[CH3:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.[Li]C(C)(C)C.CN([CH:30]=[O:31])C>C1COCC1>[CH3:21][C:16]1[N:15]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:7]=2[N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:30]=[O:31])[C:19]([CH3:20])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C)n1-c1cncc(Br)c1N1CCN(C)CC1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cncc(C=O)c1N1CCN(C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-[3-bromo-5-(2,5-dimethylpyrrol-1-yl)-4-pyridyl]-4-methyl-piperazine (1250 mg, 3.579 mmol) in THF (35.79 mL) was cooled to −78° C. and t-BuLi (2.105 mL of 1.7 M, 3.579 mmol) was added dropwise. The mixture was stirred for 30 mins at −78° C. before DMF (261.6 mg, 277.1 μL, 3.579 mmol) was added dropwise. The mixture was stirred for 2 h at −78° C. The reaction was quenched with MeOH (5 mL) and allowed to warm to room temperature. The reaction was washed with an aqueous saturated solution of ammonium chloride (50 mL) and extracted with EtOAc (100 mL and 50 mL). The combined organics were dried (MgSO4) and evaporated to leave an orange oil. Purification by column chromatography (EtOAc to EtOAc:MeOH 20%) yielded 5-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(4-methylpiperazin-1-yl)nicotinaldehyde as a pale yellow crystalline solid. MS (ES+) 299.2.
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C(O)C.[I-:29].[K+]>O>[I-:29].[CH3:1][CH:2]([N+:14]([CH3:16])([CH3:15])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N(C)C
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1=CCCC(C)(C)C1/C=C/C(C)[N+](C)(C)Cc1ccc(Cl)cc1
Yield: 131.7 %

Procedure:
A mixture of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2-(trans)propenyl]dimethylamine (2.2 g), α,4-dichlorotoluene (0.8 g) and ethanol (30 cc) was refluxed for 1 hour, and thereto were added water (100 cc) and potassium iodide (5.0 g). The reaction mixture was extracted with chloroform, and the chloroform layer was dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol to give crystals (3.1 g) of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethyl(4-chlorobenzyl)ammonium iodide.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10]([OH:12])=[O:11].[C:16](O)([CH3:19])([CH3:18])[CH3:17].N1C=CC=CC=1.Cl>C(Cl)Cl>[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10]([O:12][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: CC(C)(C)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Oxalyl chloride (87.3 g, 0.68 mol) was added to a solution of TFMAA (15.0 g, 0.11 mol) in methylene chloride (90 mL) in a dropwise manner at room temperature under a nitrogen atmosphere. The solution was heated to reflux for 5 hours, and the solvent and excess reagent were removed on a rotary evaporator. The resulting acid chloride was added to a stirred solution consisting of t-butanol (44 g, 0.59 mmol) and pyridine (33.6 g, 0.42 mol) in dichloromethane at 0° C. over a 10 min period. After stirring overnight at room temperature, the solution was neutralized with diluted aqueous HCl and washed with saturated aqueous sodium bicarbonate. The organic phase was removed, and the aqueous phase was extracted with pentane. The combined organic solvents were reduced to a small volume by distillation and then the residue was chromatographed on a column of silica gel. The product was re-purified by distillation to give 14.0 g of TBTFMA as a colorless liquid (70%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13](F)=[C:12]([F:19])[C:11]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29]([O:33][C:34](=[O:41])[NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]>C(#N)C>[CH2:1]([O:8][C:9](=[O:21])[C:10]1[C:11]([F:20])=[C:12]([F:19])[C:13]([N:38]2[CH2:39][CH2:40][C@H:36]([NH:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:41])[CH2:37]2)=[C:14]([F:17])[C:15]=1[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(OCc1ccccc1)c1c(F)c(F)c(F)c(F)c1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(F)c(C(=O)OCc3ccccc3)c(F)c2F)C1
Yield: 63.6 %

Procedure:
A solution of 2,3,4,5,6-pentafluorobenzoic acid benzyl ester (Example 1d, 8.05 g, 26.6 mmol), triethylamine (26 mL, 186 mmol), and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (5.6 g, 30 mmol) in acetonitrile (150 mL) is stirred at room temperature for 24 hours. The solvent is removed under vacuum and the residue dissolved in chloroform, washed with NaHCO3 and then brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a solid. The solid is then purified by column chromatography (1:1:6 ethyl acetate/chloroform/hexanes) to yield the title compound as a solid (7.92 g). 1H NMR (CDCl3): δ 7.48–7.30 (m, 5H), 5.35 (s, 2H), 4.77–4.50 (m, 1H), 4.37–4.19 (m, 1H), 4.01–3.63 (m, 3H), 3.59–3.46 (m, 1H), 2.29–2.09 (m, 1H), 2.01–1.82 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])N1C(OCC)=O>C1COCC1>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][N:1]1[C:8](=[O:7])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCCCO
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCO
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of 4-aminobutan-1-ol (18 g, 201.94 mmol, 1.00 equiv), ethyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (44.5 g, 203.02 mmol, 1.01 equiv) and TEA (28 g, 276.71 mmol, 1.37 equiv) in 500 mL of THF was heated to reflux overnight. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EtOAc (10:1 to 1:1) to give 30 g (68%) of 2-(4-hydroxybutyl)-2,3-dihydro-1H-isoindole-1,3-dione as a white solid. MS (ES): m/z 220 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.N1C=CC=CC=1.[I-].[K+].Br[CH:36]([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O1CCCC1>[CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[O:20][CH2:42][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)c2c(C)nn(C)c2O)c(C)c2c1S(=O)(=O)CCC2(C)C
Reactant: CCOC(=O)C(C)Br
Agent: [I-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCOc1c(C(=O)c2cc(C)c3c(c2C)C(C)(C)CCS3(=O)=O)c(C)nn1C
Temperature: 25 °C
Yield: 44.3 %

Procedure:
1.0 Gram (2.7 mmol) of the 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide obtained in Preparation Example 6 was dissolved in 10 ml of tetrahydrofuran, and further, 0.27 g (3.5 mmol) of pyridine and 90 mg of potassium iodide were added. Then, 0.63 g (3.5 mmol) of ethyl 2-bromopropionate was added, and the mixture was refluxed under heat for 7 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The resultant residue was extracted by adding ethyl acetate, and the extract was consecutively washed with 10% hydrochloric acid, with a saturated sodium bicarbonate aqueous solution and with a saturated sodium chloride aqueous solution, and the solvent was distilled off under reduced pressure to give 0.57 g (yield 45%) of 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-(1-ethoxycarbonyl)ethoxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 40).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([O:7][CH3:8])[O:4][C:3]1([CH3:11])[CH2:9][OH:10].CO>C(N(CC)CC)C>[NH2:1][C@@H:2]1[C@@H:9]([OH:10])[C@H:3]([CH3:11])[O:4][CH:5]([O:7][CH3:8])[CH2:6]1
Reactant: COC1CC(N)C(C)(CO)O1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC1C[C@H](N)[C@@H](O)[C@H](C)O1
Reaction time: 1 h

Procedure:
A mixture of 4.524 g (0.028 mole) [2β,2S*,3β)]-3-aminotetrahydro-5-methoxy-methyl-2-furanmethanol, 250 ml methanol, 2.57 g Amberlite CG 120 200-400 mesh (H+ form) and 1.5 g 3A molecular sieves was stirred for 20 hr. then 10 ml triethylamine was added. After 1 hour, the mixture was filtered through diatomaceous earth and filtrate evaporated in vacuo. The reaction was not complete (nmr) so the crude material was stirred with 250 ml methanol and 5.14 g Amberlite CG 120 200-400 mesh (H+ form) for 65 hr., then 15 ml triethylamine added. After stirring for 11/2 hr, the mixture was filtered through diatomaceous earth. The filtercake was stirred 1 hour with 200 ml methanol, 5 ml triethylamine then filtered. The combined filtrates were concentrated in vacuo to give 4.056 g crude product from which 2.189 g methyl 3-amino- 2,3,6-trideoxy-L-arabinohexopyranoside was crystallized from ether as a 2:1 parts by weight mixture (α:β) of anomers as determined by nmr.