Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]3[NH:40][C:39]([C@@H:41]5[CH2:45][CH2:44][C@H:43]([CH3:46])[N:42]5C(OC(C)(C)C)=O)=[N:38][CH:37]=3)[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:46][C@@H:43]1[NH:42][C@H:41]([C:39]2[NH:40][C:36]([C:31]3[CH:30]=[CH:29][C:28]4[C:33](=[CH:34][CH:35]=[C:26]([C:23]5[CH:22]=[CH:21][C:20]([C:17]6[NH:16][C:15]([C@@H:10]7[CH2:11][CH2:12][C@H:13]([CH3:14])[NH:9]7)=[N:19][CH:18]=6)=[CH:25][CH:24]=5)[CH:27]=4)[N:32]=3)=[CH:37][N:38]=2)[CH2:45][CH2:44]1
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc(-c4ccc5nc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)OC(C)(C)C)[nH]6)ccc5c4)cc3)[nH]2)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CC[C@@H](c2ncc(-c3ccc(-c4ccc5nc(-c6cnc([C@@H]7CC[C@H](C)N7)[nH]6)ccc5c4)cc3)[nH]2)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 199.7 %

Procedure:
4M HCl (0.2 mL, 0.8 mmol) in dioxane was added to a solution of (2S,5S)-tert-butyl 2-(5-(6-(4-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinolin-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (12.7 mg, 0.018 mmol) in dioxane (1 mL) and the mixture was stirred at rt for 3 d. The reaction mixture was concentrated to yield a crude HCl salt of 2-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-6-(4-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline (18.1 mg) as yellow solid. LC-MS retention time 2.597 min; m/z 504.46 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 9.09 (d, J=9.0 Hz, 1H), 8.66 (s, 1H), 8.54-8.61 (m, 2H), 8.51 (d, J=9.0 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.00-8.08 (m, 4H), 7.99 (s, 1H), 5.14 (t, J=8.5 Hz, 1H), 5.07 (t, J=8.0 Hz, 1H), 3.90-4.04 (m, 2H), 2.52-2.75 (m, 4H), 2.39-2.53 (m, 2H), 1.98-2.14 (m, 2H), 1.59 (dd, J=9.7, 6.7 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH:8]([CH3:10])[CH3:9])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][N:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:1][C:2]1[C:6]([CH2:7][CH:8]([CH3:10])[CH3:9])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][N:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)Cc1c(O)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)Cc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 84.2 %

Procedure:
3-Hydroxy-4-isobutyl-5-phenylisoxazole (217 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) were subjected to reaction and post-treatment in a similar manner to that described in Example l(a) to obtain the title compound (303 mg, 84%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[CH3:8]>ClCCl.[O-2].[Mn+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH:9]=[O:10]
Reactant: Cc1ccc(CO)cc1Br
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
14.4 g (72 mmol) of (3-bromo-4-methylphenyl)methanol are placed in 200 ml of dichloromethane in a round-bottomed flask. 62.6 g (72 mmol) of manganese oxide are added and the medium is stirred at room temperature overnight. The mixture is filtered through Celite and the solvent is evaporated off. 11.8 g (85%) of the expected product are obtained in the form of an oil.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:13][CH2:12][C@@H:11]([CH2:14]O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C(Cl)Cl>[C:1]1([C@H:7]([N:9]2[CH2:13][CH2:12][C@@H:11]([CH2:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](c1ccccc1)N1CC[C@@H](CO)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CC[C@@H](CS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 103.5 %

Procedure:
To a solution of (3R)-1-[(R)-1-phenylethyl]-3-(hydroxymethyl)pyrrolidine (25.2 g, 0.12 mol) in CH2Cl2 (250 mL) was added Et3N (18.8 mL, 0.13 mol). The mixture was cooled to 0° C. and treated dropwise with methanesulfonyl chloride (10.63 mL, 0.13 mol) dissolved in CH2Cl2 (125 mL). The mixture was stirred at 0° for 1.5 hours and then at 25° C. for 4 hours. Water was added and the organic layer was separated, washed with NaHCO3 (2X), dried (MgSO4) and concentrated to provide (3R)-1-[(R)-1-phenylethyl]-3-(methanesulfonyl methyl)-pyrrolidine (2a. 33.2 g); NMR (CDCl3) δ 1.39 (m, 3H), 1.54 (m, 1H), 2.0 (m, 1H), 2.3-2.8 (m, 5H), 2.98 (d, 3H), 3.29 (q, 1H), 4.14 (t, 2H), 7.31 (m, 5H). The material was used directly in the next step.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.CCOCC>[CH2:1]([O:9][C:24](=[O:25])[O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCCc1ccccc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 29.96 g phenethyl alcohol and 30 ml pyridine in 150 ml dichloromethane, 60.5 g benzylchloroformate was dropped in over 1 h 45 min while cooling in an ice-bath. After stirring over night at room temperature, the reaction was diluted with ether, washed with 2N HCl, NaHCO3, and water. After extraction with ether, the combined. organic layers were dried and evaporated to dryness. The residue was purified by silica gel chromatography to yield the product: 52.5 g of a colorless oil.
Reaction SMILES: Cl[C:2](=[CH:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].CN(C=O)C.[SH:14][C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][C:18]=2[N:19]=1>O>[OH:8][CH:7]1[N:19]2[C:15](=[N:16][C:17]3[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][C:18]=32)[S:14][CH:2]1[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)=CO
Reactant: O=C(O)c1ccc2nc(S)[nH]c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1Sc2nc3cc(C(=O)O)ccc3n2C1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Methyl 2-chloro-3-hydroxypropenoate (114 g) was added to DMF (460 ml) solution of 2-mercaptobenzoimidazole-5-carboxylic acid (135 g), and the mixture was stirred overnight at 60° C. After cooling to room temperature, water (3 L) was gradually added to the reaction solution and stirred. The thus precipitated crystals were collected by filtration to obtain crude crystals of 2-methyl hydrogen 2,3-dihydro-3-hydroxythiazolo[3,2-a]benzoimidazole-2,7-dicarboxylate (168 g). Next, the thus obtained crude crystals were suspended in 1,4-dioxane (1.5 L), and the suspension was mixed with 4 M HCl 1,4-dioxane solution (500 ml) and stirred at room temperature for 60 hours. The resulting precipitate was collected by filtration and washed with 1,4-dioxane to obtain crude crystals of 2-methyl hydrogen 2,3-dihydro-3-hydroxythiazolo[3,2-a]benzoimidazole-2,6-dicarboxylate hydrochloride (189 g). The thus obtained crude crystals were slowly added to concentrated sulfuric acid (750 ml) which was heated at 60° C. and stirred at the same temperature for 1 hour. After cooling to room temperature, the reaction solution was poured into ice water, and the thus precipitated crystals were collected by filtration to obtain the title compound (152 g).
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[N:17]=[C:16]2[O:18][CH:19]=[CH:20][C:15]2=[CH:14][C:13]=1[C:21]([OH:23])=[O:22])=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+]>O>[CH:5]([C:4]1([CH3:8])[C:1](=[O:3])[NH:2][C:10]([C:12]2[N:17]=[C:16]3[O:18][CH:19]=[CH:20][C:15]3=[CH:14][C:13]=2[C:21]([OH:23])=[O:22])=[N:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(NC(=O)c1nc2occc2cc1C(=O)O)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution containing 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]furo[2,3-b]pyridine-5-carboxylic acid (3.8 g, 0.012 mol) in aqueous sodium hydroxide 2.4 g, 0.06 mol) in water (40 mL) is stirred at 65° C. for three hours. The reaction mixture is then heated at 75° C. for one hour, allowed to cool, poured into ice, acidified to pH 2-3 and the resulting solid filtered off and dried. Crystallization from an acetone-methanol mixture affords pure 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[2,3-b]pyridine-5-carboxylic acid mp 237°-244° C.
Reaction SMILES: C([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:13])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:14]1([C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]([OH:24])=[O:5])=[O:13])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN1C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To compound 19 (550 mg, 1.7 mmol) was added a solution of TFA in dichloromethane (95:5, v/v) (4.0 mL). The solution was stirred over a period of 4 h at room temperature under an argon atmosphere. The resulting solution was evaporated under reduced pressure and purified by FCC (CH2Cl2/MeOH, 95:5) to give 415 mg (89%) of title compound 20. 1H NMR (acetone-d6) δ: 2.00 and 2.35 (2m, 3.2 H and 0.8 H, 2×CH2 of proline), 3.66 and 3.74 (2m, 1.6H and 0.4H, CH2N of proline), 4.60 and 4.67 (m, 0.2H and 0.8H, NCHCO of proline), 7.57 (broad, m, 2×CH of naphthalene), 7.67 (d, J=8.4 Hz, 1×CH of naphthalene), 7.95 (broad, m, 2×CH of naphthalene), 8.14 (s, 1×CH of naphthalene). LRMS for C16H16NO3 [M+H]+: 270.0 m/z.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:29]1[S:30][CH2:31][C@@H:32]2[CH2:37][CH2:36][CH2:35][C@:33]2([C:38]2[CH:43]=[C:42]([Cl:44])[CH:41]=[C:40](Br)[CH:39]=2)[N:34]=1)C(OC)=O)=O)(C)(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:44][C:42]1[CH:43]=[C:38]([C@:33]23[CH2:35][CH2:36][CH2:37][C@H:32]2[CH2:31][S:30][C:29]([NH2:24])=[N:34]3)[CH:39]=[C:40]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:41]=1
Reactant: COC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Cl)cc(Br)c3)CCC[C@H]2CS1
Reactant: OB(O)c1cccnc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(c3cc(Cl)cc(-c4cccnc4F)c3)CCC[C@H]2CS1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
2-Fluoropyridine-3-boronic acid (55.8 mg), tetrakis(triphenylphosphine)palladium (0) (22.9 mg) and a 1 N sodium carbonate solution (396 μL) were added to a solution of the by-product (±)-N-(t-butoxycarbonyl)-N-(methoxycarbonyl)[(4aR*,7aS*)-7a-(3-bromo-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl]amine obtained in Preparation Example 71-(2) (100 mg) in DMF (5 mL). After replacement with nitrogen, the mixture was stirred at 85° C. for three hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain a crude product. The crude product was further sequentially purified by NH-pTLC and silica gel column chromatography to obtain the title compound (25.6 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15](=[O:19])(=[O:18])[NH:16][CH3:17])[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15](=[O:18])(=[O:19])[NH:16][CH3:17])[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Yield: 11.1 %

Procedure:
A solution of 177 mg (0.326 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-methylsulfamoyl-ethyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with MeOH (300 μL) and TFA (3 mL) at RT for 45 min. MeOH (10 mL) was added, and solvents were evaporated in vacuo. The solid residue was triturated with a minimum amount of acetonitrile with sonication, but further purification was needed. Silica gel chromatography of the solid with 50% EtOAc-hexane also afforded impure material. The solid was purified by RP-HPLC (C18) with 40-100% CH3CN in 0.1% TFA/H2O over 30 min to afford 14.9 mg (11%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 9.38 (s, 1H), 8.27-8.20 (m, 1H), 7.93 (s, 1H), 7.27-7.20 (m, 1H), 7.18-7.14 (m, 1H), 5.89-5.82 (m, 1H), 5.09-5.01 (m, 1H), 3.36-3.26 (m, 2H), 3.08-3.00 (m, 2H), 2.70 (d, 3H, J=5.2 Hz), 2.32-2.25 (m, 4H), 1.90-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H23N5O3S, 414.1 (M+H). found 414.1.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(CC)CC.[Cl:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C(Cl)Cl>[Cl:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([N:2]([CH3:3])[CH3:1])=[O:17]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CNC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cccc(CCl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A solution of dimethylamine (2.91 mL, 5.82 mmol, 2.0M THF), NEt3 (0.885 mL, 6.35 mmol) and CH2Cl2 30 mL was cooled to 0° C. 3-(Chloromethyl)benzoyl chloride (1.0 g, 5.29 mmol) was added as a CH2Cl2 solution (3 mL) and the solution was stirred at 0° C. for 2 hours and then at ambient temperature for 2 hours. The reaction was washed with 1N HCl followed by brine, and the organic layer was dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (EtOAc) to provide 0.745 g (71%) of the product as colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:1][CH2:2][C@@H:3]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:28])[CH3:27]
Reactant: COc1cc2ncnc(N[C@H](CO)c3ccccc3)c2cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc2ncnc(N[C@H](COC(C)=O)c3ccccc3)c2cc1OC
Yield: 90 %

Procedure:
A solution of (S)-4-[α-(hydroxymethyl)benzylamino]-6,7dimethoxyquinazoline (70 mg, 0.21 mmol) in acetic anhydride (2 ml) was stirred at room temperature for 3 h. Then water was added to the reaction mixture, the precipitate was filtered, washed with water and dried under vacuum. Thus pure title compound was obtained in 90% yield (71 mg).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:21]=[C:22]([N:26]5[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]5)[CH:23]=[CH:24][CH:25]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3cccc(N4CC(=O)NS4(=O)=O)c3)cc2)cc1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{3-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.[F:20][C:21]([F:26])([F:25])C(O)=O.N1C=CC=CC=1>ClCCl.CN(C=O)C>[F:13][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][C:10](=[O:12])[C:21]([F:26])([F:25])[F:20])[CH2:6][CH2:7]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)CCC1CCC(F)(F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCC1CCC(F)(F)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
3-(4,4-Difluorocyclohexyl)propionic acid (500 mg, 2.60 mmol) obtained in step 3 of Example 34 was dissolved in dichloromethane (5.0 mL), and the solution was stirred at room temperature for 30 minutes after adding oxalyl chloride (0.430 mL, 5.12 mmol) and DMF (0.010 mL). The solvent was then evaporated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and the mixture was cooled to −10° C., and stirred at room temperature for 2 hours after adding anhydrous trifluoroacetic acid (2.20 mL, 15.8 mmol) and pyridine (1.70 mL, 21.3 mmol). Upon being cooled to −10° C., the mixture was extracted with dichloromethane after gently adding water in a manner that keeps the internal temperature at or below 0° C. The organic layer was washed with 3 mol/L hydrochloric acid and a saturated sodium hydrogen carbonate aqueous solution, and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=70/30) to give 4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (204 mg, yield 35%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([NH2:12])[CH:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26](O)=[O:27].CN(C)CCCN=C=NCC>N1C=CC=CC=1>[NH2:12][C:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]([NH:11][C:26]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][N:20]=1)=[O:27])[CH3:10]
Reactant: O=C(O)c1cnccn1
Reactant: CC(N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: CC(NC(=O)c1cnccn1)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
1,1-bis(4-fluorophenyl)-1,2-propanediamine (94 mg) and pyrazinecarboxylic acid (53 mg) was dissolved in pyridine (1 mL), and to the solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (103 mg). The mixture was stirred at room temperature for 24 hrs. The reaction mixture was concentrated, and the obtained residue was dissolved in chloroform, followed by washing with saturated sodium hydrogen carbonate aqueous solution. The aqueous layer was extracted with chloroform twice, and the combined chloroform layers were dried over magnesium sulfate. After evaporating the solvent in vacuo, the obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1→1:3) to give N-[2-amino-2,2-bis(4-fluorophenyl)-1-methylethyl]-2-pyrazinecarboxamide (112 mg) as the mixture with pyrazinecarboxylic acid methyl ester. The mixture was dissolved in methanol (1 mL), and to the solution was added 2N sodium hydroxide aqueous solution (0.5 mL), and the solution was stirred at room temperature for one hr. The reaction mixture was diluted with chloroform, followed by washing with water. The aqueous layer was extracted with chloroform twice, and the combined chloroform layers were dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give the pure amide compound (95 mg).
Reaction SMILES: C([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1([CH2:15][CH:16]=[CH2:17])[OH:14])C1C=CC=CC=1.[CH:18]1[C:23]([C:24](OO)=[O:25])=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:24]([O:25][CH:17]=[CH:16][CH2:15][C:9]12[O:14][CH:10]1[CH:11]=[CH:12][CH:13]=[CH:8]2)[C:23]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=CCC1(O)C=CC=CC1Cc1ccccc1
Reactant: O=C(OO)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C1=CC2OC2(CC=COCc2ccccc2)C=C1
Reaction time: 96 h
Yield: 70.1 %

Procedure:
5.4 g of o-benzyl-1-allylphenol was added to 600 ml of chloroform solution containing perbenzoic acid prepared from 26.4 g of benzoyl peroxide and the mixture was allowed to stand at about 5° C for 4 days. The reslting mixture was washed with sodium hydroxide solution, water, Mohr's salt solution, then saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue which was distilled under reduced pressure, and there was obtained 4.1 g (yield 70.1%) of o-benzyloxyallylbenzene oxide having a boiling point of 158° to 160° C/5 mmHg as colourless oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][Mg]Br)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CO[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=1>O1CCCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CCCC[Mg]Br)cc1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Solvent: C1CCOC1
Product: CCCCc1ccc(CCCCc2ccccc2C2=NC(C)(C)CO2)cc1

Procedure:
Following the procedures of Example 1(a), (b) and (c), to 4-(4-butylphenyl)butylmagnesium bromide (from 21.47 mmoles of 4-(4-butylphenyl)butyl bromide and 18.96 mmoles of magnesium) in distilled tetrahydrofuran (35 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (16.32 mmoles) in tetrahydrofuran (15 ml). Workup of the reaction mixture furnished 2-[2-(4-(4-butylphenyl)butyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (14.41 mmoles) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 91°-94° C.). To an ice cold solution of the iodide (14.07 mmoles) in methanol was added in portions sodium borohydride (14.30 mmoles). Similar treatment of the reaction mixture resulted in the isolation of the desired benzaldehyde product as an oil.