Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([C@H:12]([OH:16])[CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][NH2:28].Cl>ClCCl>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][NH:28][C:9](=[O:11])[C@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C@H:12]([OH:16])[CH2:13][CH2:14][CH3:15]
Reactant: NOC1CCCCO1
Reactant: CCC[C@@H](O)[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC[C@@H](O)[C@@H](CC1CCCCC1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
(2R,3R)-2-Cyclohexylmethyl-3-hydroxyhexanoic acid (3.00 g, 13.1 mmol) is dissolved in 30 mL of anhydrous dichloromethane. EDC (2.77 g, 14.5 mmol) is added followed by 2-tetrahydropyranyloxyamine (3.08 g, 26.3 mmol). The reaction is stirred at 25° C. for 8 h and is then poured into 200 mL of 1 M hydrochloric acid. The mixture is extracted with two 250-mL portions of dichloromethane. The combined organics are then washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to afford (2R,3R)-2-cyclohexylmethyl-3-hydroxyhexanoic acid 2-tetrahydropyranyloxyamide as a foam (3.60 g, 84% yield).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=[CH:14][C:13]=1[N:12]2[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35]CCO.[Sn].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[C:17]([C:23]([O:25][CH2:26][CH2:27][CH2:33][N:34]([CH3:39])[CH3:35])=[O:24])=[CH:16][CH:15]=[CH:14][C:13]=1[N:12]2[CH2:28][CH:29]=[C:30]([CH3:31])[CH3:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1Nc1ccc(C(=O)c3ccccc3)cc1N2CC=C(C)C
Reactant: CN(C)CCCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Sn]
Solvent: Cc1ccccc1
Product: CC(C)=CCN1c2cc(C(=O)c3ccccc3)ccc2Nc2c(C(=O)OCCCN(C)C)cccc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
In toluene (12 mL) was dissolved ethyl 7-benzoyl-5,10-dihydro-5-(3-methyl-2-butenyl)-1-phenazinecarboxylate (1.26 g, 2.95 mmol.) obtained in Example 2. To the mixture were further added 3-(dimethylamino)-1-propanol (3.50 mL, 29.5 mmol.) and tetra-n-butyl-1-isothiocyanate-3-hydroxydistannoxane (SCN(n-Bu)2SnOSn(n-Bu)2OH; 329 mg, 0.591 mmol.). The mixture was stirred at 100° C. for 24 hours in the stream of gaseous nitrogen. The mixture was further stirred at 100° C. for 24 hours, after addition of 3-(dimethylamino)-1-propanol (1.50 mL) and the above-mentioned tin compound (329 mg, 0.591 mmol.). The reaction mixture was cooled to room temperature and poured into saturated aqueous sodium hydrogencarbonate solution. The aqueous mixture was then extracted with ethyl acetate. The extract was washed with two portions of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The dried extract was placed under reduced pressure to distill the solvent off. The residue was purified by medium pressure column chromatography (CHCl3 /methanol=1/0→95/5), to give the desired compound (142 mg, 10%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16].[O:17]([CH2:24][CH2:25]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16]
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Reactant: BrCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(N2CCN(CCOc3ccccc3)CC2)cc(=O)n(C)c1=O
Yield: 64 %

Procedure:
1.12 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)pyrimidinedione and 1.4 g of phenoxyethyl bromide were dissolved in 5 ml of ethanol, and 1.0 g of triethylamine was then added, followed by heating under reflux for 1 hour. Furthermore, 0.6 g of phenoxyethyl bromide was added, and the solution was heated under reflux for 2 hours. The precipitated crystals were collected by filtration, washed with water, dried and then recrystallized from hexane/ethanol to obtain 1.1 g (yield: 63%) of 1,3-dimethyl-6-[4-(2-phenoxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[BH4-].[Na+]>C1COCC1>[CH2:1]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A solution of 4-(dodecyloxy)-benzaldehyde (10 g, 35 mmol) in THF (80 mL) was added dropwise to a stirred suspension of NaBH4 (2.7 g, 70 mmol) in dry THF (70 mL) at 0° C. The reaction mixture was stirred at room temperature overnight and was quenched with a small amount of water (5 mL). The solid formed was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in CHCl3 (50 mL). The resulting solution was washed with brine (3×20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a white powder (9.56 g, 94%). 1H NMR (400 MHz, CDCl3, δ): 7.29 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.62 (d, J=6.0 Hz, 2H), 3.97 (t, J=6.8 Hz, 2H), 1.79-1.51 (m, 2H), 1.51-1.26 (m, 19H), 0.90 (t, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]1(=[O:29])[N:5]([C@H:6]2[CH2:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][N:8]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]2=[O:23])C(=O)C2=CC=CC=C12.C(O)C.C(N(CC)CC)C.[CH2:40]([O:47]C(Cl)=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O.NN.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:41]1([CH2:40][O:47][C:1]([NH:5][C@H:6]2[CH2:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][N:8]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]2=[O:23])=[O:29])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)CN1Cc2ccccc2C[C@H](N2C(=O)c3ccccc3C2=O)C1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: NN
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CN1Cc2ccccc2C[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (S)-1,3,4,5-tetrahydro-4-phthalimido-3-oxo-2H-2-benzazepine-2-acetic acid, ethyl ester (1.67 g., 4.26 mmol.) in 1.0M hydrazine hydrate in ethanol (9.0 ml., 9.0 mmol.) was stirred at room temperature under argon for 36 hours. The mixture was diluted with an equal volume of ethyl acetate, filtered and filtrate evaporated to dryness. The residue was taken up in toluene and again evaporated to dryness. The colorless, semi-solid residue (1.81 g.) was taken up in dry methylene chloride (20 ml.), placed in an ice bath and treated successively with triethylamine (0.80 ml., 5.8 mmol.) and benzylchloroformate (0.77 ml., 5.4 mmol.). After stirring at 0° C. for 2 hours, the mixture was partitioned between ethyl acetate-5% potassium bisulfate. The organic phase was washed successively with 5% potassium bisulfate, saturated sodium bicarbonate and saturated sodium chloride solutions, dried (sodium sulfate), and evaporated to dryness. Purification of the crude product by flash chromatography on silica gel (Whatmann LPS-1) eluting with ethyl acetate:hexane (1:2) gave 1.0747 g. of product as a colorless foam; Rf =0.52 (ethyl acetate:toluene, 3:7). A sample crystallized from hexane had m.p. 80°-82° C.; [α]D =+87.2° (c=0.53, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[CH:23]=1.[CH3:32][C:33]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])[CH3:34]>N1C=CC=CC=1>[Si:36]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[CH:23]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37]
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1F
Reaction time: 16 h
Yield: 100 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 4f (5.7 g, 12.5 mmol) was dissolved in 50 mL pyridine, followed by addition of TBSCl (2.26 g, 15 mmol) and 4-dimethyl-amino pyridine (305 mg, 2.5 mmol) in turn. The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 200 mL ethyl acetate and washed with saturated copper sulfate solution (50 mL×3). The organic extract was combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 4g (7.14 g, colourless grease), which was used directly without purification in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=O)=[C:4]2[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.Cl.[CH3:35][O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH2:39].C(N(CC)CC)C>CN(C)C=O>[OH:41][CH2:40][C@H:38]([NH:39][C:16]([C:15]1[N:14]=[CH:13][N:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12)=[O:18])[C:37]([O:36][CH3:35])=[O:42]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccsc2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
A suspension of 15.5 g (0.0493 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid in 200 ml of dimethylformamide was treated portionwise with 8.07 g (0.0498 mol) of carbonyidiimidazole while gassing with argon. After completion of the CO2 evolution the mixture was stirred at 65° for 1 hr. After cooling to 0-5° the clear solution obtained was treated with 8.62 g (0.0554 mol) of L-serine methyl ester hydrochloride and with 12.3 ml (0.0554 mol) of triethylamine and stirred at room temperature for 16 hrs. The suspension was completely freed from the solvents. The residue was partitioned between water and ethyl acetate and extracted. The yellow oily residue was chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 17.09 g (95%) of methyl (S)-3-hydroxy-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-ylcarbonylamino)-propionate as a yellowish oil. An analytical sample was recrystallized from ethyl acetate and gave white crystals; m.p. 158-160°. [α]D20 =+3.9° (CHCl3, c=1%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:26](=[O:33])[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)c4ccccc4)ccc32)n1)c1ccccc1
Yield: 52.9 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and benzoyl chloride (14 mg, 0.10 mmol) furnished the product (23 mg, 53%) after chromatography.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][C:10]([C:12]1([NH2:20])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11].[CH:21]1([C:24]2[C:25]([CH3:35])=[CH:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31](Cl)=[O:32])[CH:29]=2)[CH2:23][CH2:22]1>C(#N)C>[CH3:8][O:9][C:10]([C:12]1([NH:20][C:31](=[O:32])[CH2:30][C:28]2[CH:29]=[C:24]([CH:21]3[CH2:22][CH2:23]3)[C:25]([CH3:35])=[CH:26][C:27]=2[CH3:34])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)C1(N)CCN(OC)CC1
Reactant: Cc1cc(C)c(C2CC2)cc1CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1(NC(=O)Cc2cc(C3CC3)c(C)cc2C)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4 g of potassium carbonate and 2.5 g of 4-amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride (preparation example P1, step P1.3) in 10 ml of acetonitrile is added at 0-5° C. a solution of 2.1 g of crude (5-cyclopropyl-2,4-dimethyl-phenyl)-acetyl chloride in 5 ml of acetonitrile. After stirring for 18 hours at room temperature, the solvent is removed in vacuo and the crude residue of 4-[2-(5-cyclopropyl-2,4-dimethyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester (3.2 g) is used without further purification in the next step.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][C:28]=1[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:24][CH3:25])=[CH:21]/[CH2:22][OH:23])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][C:28]=1[CH2:29][O:30][Si:31]([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:32])[CH3:33])[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:24][CH3:25])=[CH:21]/[CH:22]=[O:23])=[CH:17][CH:16]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC/C(=C\CO)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC/C(=C\C=O)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Reaction time: 14 h

Procedure:
2.74 g (5.1 mmol) of (E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}pent-2-en-1-ol are dissolved in 80 mL of dichloromethane and placed under a nitrogen atmosphere. 4.45 g (51 mmol) of manganese dioxide are added and the medium is stirred for 14 hours. After filtration and then evaporation, a yellow oil is obtained. The crude product (2.9 g) is the expected aldehyde, obtained in a quantitative yield.
Reaction SMILES: [CH:1](=[C:8]1/[C:9](=[O:14])[CH2:10][C:11](=[O:13])[NH:12]/1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[CH:1](=[C:8]1/[C:9]([O:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:13])[NH:12]/1)\[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)/C(=C/c2ccccc2)N1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)OC1=CC(=O)N/C1=C\c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 67.0 g of (Z)-5-benzylidene pyrrolidin-2,4-dione cooled to 0° C. in 670 ml of dichloromethane, 40.0 g of butyryl chloride and then 47.1 g of triethyl amine were added and the mixture was stirred another 5 minutes at 0° C. Then the mixture washed twice with 200 ml of 5 percent NaHCO3 solution each and then twice with 200 ml of 0.5M hydrochloric acid each. The aqueous phases were extracted separately with dichloromethane. The combined organic phases were dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue was recrystallized from 230 ml of toluene. The yield of the title compound was 67.25 g (73 percent of theory). The title compound had a melting point of 139.8° to 141.5° C. Other data concerning the title compound was:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(NC(C)C)(C)C.[Li]CCCC.C=O.N1C=CC=CC=1.[CH3:39][C:40]([O:42][C:43](C)=O)=[O:41]>C1COCC1>[C:40]([O:42][CH2:43][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[S:10]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])(=[O:41])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(Cc1ccc(Cl)cc1Cl)c1ccccc1
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC(C)NC(C)C
Product: CC(=O)OCC(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
The crude sulfone (2) (1 eq) in THF was added dropwise via addition funnel to a freshly prepared solution of diisopropylamine (1.3 eq), n-BuLi 2.5 M in hexanes (1.1 eq) and THF under N2 at −78° C. with stirring. After 30 min., the paraformaldehyde was added (2.1 eq). The reaction was stirred for an additional 30 min. at which time the reaction was allowed to warm to room temperature over 4.5 h. The reaction was then quenched with sat. aq. NH4Cl. The aqueous layer was extracted with EtOAc, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the crude sulfonyl hydrin which was used without further purification. The crude sulfonyl hydrin was dissolved in CH2Cl2 (excess) and pyridine (1.2 eq) followed by the addition of Ac2O (1.1 eq). After stirring at room temperature for 14.5 h, the reaction was quenched with sat. aq. NH4Cl. The layers were separated, and the aqueous layer was extracted with Et2O. The combined organic layers were dried (Na2SO4), filtered, and concentrated to give the 2-(2,4-dichlorophenyl)-2-(phenylsulfonyl)ethyl acetate (3) (94% yield) in high purity.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([CH2:22][C:23]3[C:24](=[O:35])[C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[C:27](=[O:30])[C:28]=3[CH3:29])[CH:19]=[CH:18][C:17]=2[O:36][C:37](=[O:39])[CH3:38])=[N:12][CH:13]=1)=[O:7])(C)(C)C>C(O)=O>[OH:7][C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([CH2:22][C:23]3[C:24](=[O:35])[C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[C:27](=[O:30])[C:28]=3[CH3:29])[CH:19]=[CH:18][C:17]=2[O:36][C:37](=[O:39])[CH3:38])=[N:12][CH:13]=1)=[O:5]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cn3)c2)=C(C)C1=O
Solvent: O=CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)O)cn3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
N-(5-tert-Butoxycarbonylpyridin-2-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.170 g, 0.309 mmol) was dissolved in formic acid (3.0 ml) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was concentrated and the obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.109 g, 0.220 mmol, 71%).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8](=[O:15])[NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])([CH3:6])([CH3:5])[CH3:4].S(OC)(O[CH3:20])(=O)=O>O1CCOCC1>[C:3]([O:7][C:8](=[O:15])[NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH3:20])([CH3:6])([CH3:4])[CH3:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
KOH (3.47 g, 61.82 mmol) was added to a solution of (2-Hydroxy-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester (Preparation 253, 3.9 g, 20.6 mmol) in 1,4-dioxane (30 mL) followed by the slow addition of dimethyl sulphate at room temperature. The mixture was further allowed to stir at room temperature for 48 hours. Reaction mass was filtered through a short pad of celite, washed with DCM (3×50 mL). The combined filtrate was washed with water (2×50 mL), brine (30 mL), dried over sodium sulphate and evaporated in vacuo to afford the title compound as yellow oil in 88% yield, 3.7 g.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][N:5]([CH:18]1[CH2:20][CH2:19]1)[C:6]([C:8]1[C:9]([CH:15]([F:17])[F:16])=[N:10][N:11]([CH3:14])[C:12]=1[Cl:13])=[O:7].[C:26]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1.O>[Cl:13][C:12]1[N:11]([CH3:14])[N:10]=[C:9]([CH:15]([F:17])[F:16])[C:8]=1[C:6]([N:5]([CH2:4][C:3]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:2]=1[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1)[CH:18]1[CH2:20][CH2:19]1)=[O:7]
Reactant: Cn1nc(C(F)F)c(C(=O)N(Cc2cc(F)ccc2Br)C2CC2)c1Cl
Reactant: OB(O)C1=CCCCC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nc(C(F)F)c(C(=O)N(Cc2cc(F)ccc2C2=CCCCC2)C2CC2)c1Cl
Temperature: 100 °C
Yield: 51.7 %

Procedure:
To a suspension of 300 mg (0.68 mmol) of N-(2-bromo-5-fluorobenzyl)-5-chloro-N-cyclopropyl-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide in a 10/1 mixture of toluene/water degassed with argon, are successively added 190 mg (1.50 mmol) of cyclohex-1-en-ylboronic acid, 38 mg (0.137 mmol) of tricyclohexylphosphine, 15 mg (0.069 mmol) of palladium (II) acetate and 437 mg (2.06 mmol) of tri-potassium phosphate. The mixture is heated at 100° C. for 1 hour. The reaction mixture is cooled to ambient temperature. 1 mL of water is added to the reaction mixture and the organic phase is filtered over a cake of diatomaceous earth. The cake is washed twice by dichloromethane and the combined organic phases are concentrated under vacuum to give 516 mg of crude material. A purification by column chromatography on silica gel (gradient heptane/ethyl acetate) yields 154 mg (49% yield) of 5-chloro-N-[2-(cyclohex-1-en-1-yl)-5-fluorobenzyl]-N-cyclopropyl-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide: (M+H)=438.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH2:17][Br:18])=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c(-c3ccc(Cl)cc3)onc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2onc3c(CBr)cccc23)cc1
Yield: 57.2 %

Procedure:
A mixture of 15.7 g (0.065 mole) of 3-(4-chlorophenyl)-7-methyl-2,1-benzisoxazole, 11.6 g (0.065 mole) of N-bromosuccinimide, 0.5 g of dibenzoylperoxide and 400 ml of carbon tetrachloride was heated at reflux while being illuminated by a flood lamp for 3 hr. The mixture was filtered and the filtrate was concentrated to give a solid as residue. The solid was recrystallized three times from acetonitrile to yield 12.0 g (58%) of crystals, m.p. 153°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([F:14])[CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([F:14])[CH:3]=1
Reactant: OC(c1ccc(Br)cc1F)C(F)(F)F
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1F)C(F)(F)F
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a solution of 1-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethanol (1.09 g, 3.99 mmol) in ethyl acetate (30 mL) was added 2-iodoxybenzoic acid (2.28 g, 7.97 mmol). The reaction was heated to reflux overnight. The reaction was cooled to room temperature and diluted with heptanes (30 mL). The mixture was filtered through Celite and the filtrate was concentrated to give the title compound (1.03 g, 95%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3, δ): 7.44 (dd, J=10.15, 1.56 Hz, 1H), 7.48 (m, 1H), 7.76 (m, 1H).