Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH2:25][CH2:26][O:27][CH3:28])=[C:10]([C:22](=[O:24])[CH3:23])[C:11]([O:18][CH2:19][O:20][CH3:21])=[CH:12][C:13]=2[O:14][CH2:15][O:16][CH3:17])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C)C=O>[CH2:35]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH2:25][CH2:26][O:27][CH3:28])=[C:10]([C:22](=[O:24])[CH3:23])[C:11]([O:18][CH2:19][O:20][CH3:21])=[CH:12][C:13]=2[O:14][CH2:15][O:16][CH3:17])[CH:5]=[CH:6][CH:7]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COCCc1c(C(C)=O)c(OCOC)cc(OCOC)c1-c1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1c(C(C)=O)c(OCOC)cc(OCOC)c1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
1-[3-(3-hydroxyphenyl)-2-(2-methoxyethyl)-4,6-bis(methoxymethoxy)phenyl]ethanone (25 mg, 0.064 mmol) obtained in Example 134 was dissolved in N,N-dimethylformamide (1.0 mL), and potassium carbonate (35 mg, 0.25 mmol) and benzyl bromide (0.02 mL, 0.17 mmol) were added thereto and stirred at room temperature for 1 hour. Water was added to the reaction solution, and extracted twice with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/n-hexane=1/4 to 1/2) to obtain 1-[3-(3-benzyloxyphenyl)-2-(2-methoxyethyl)-4,6-bis(methoxymethoxy)phenyl]ethanone (30 mg, 97%).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow foam (35%).
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)C>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:13][C:12]([C@H:9]2[CH2:8][CH2:7][C@H:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[O:14])=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOc1ccc(O)cc1
Reactant: CCC/C=C/[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCC/C=C/[C@H]1CC[C@H](C(=O)Oc2ccc(OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 800 mg of trans-4-(trans-1-pentenyl)cyclohexanecarboxylic acid, 675.64 mg of p-ethoxyphenol, 1.01 g of dicyclohexylcarbodiimide and 49.79 mg of 4-(dimethylamino)pyridine was suspended in 14.5 ml of methylene chloride and stirred at room temperature for 20 hours. The mixture was subsequently diluted with diethyl ether, the precipitated urea was filtered off and the filtrate was concentrated. The residue was taken up in hexane and washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The aqueous phases were back-extracted twice with hexane. The organic phases were dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting residue on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 1.080 g (83.8%) of trans-4-(trans-1-pentenyl)cyclohexanecarboxylic acid p-ethoxyphenyl ester. After recrystallization from 40 ml of hexane, there were finally obtained 880 mg of product in the form of transparent crystals; m.p. (C--N) 57.2° C., cl.p. (N--I) 93.1° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[N:3]=1.Cl.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33])(=[O:28])=[O:27].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[N:3]=1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: O=C1CCc2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)ccc2N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1cccc(CNc2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2C(F)(F)F)c1
Temperature: 100 °C
Yield: 53.3 %

Procedure:
6-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3,4-dihydro-1H-quinolin-2-one (50 mg, 0.145 mmol) was added to 0.5 ml NMP and 3-Methanesulfonyl-benzylamine mono hydrochloride salt (32 mg, 0.145 mmoles) and triethylamine (0.060 ml, 0.435 mmoles) were added the reaction was heated to 100° C. for one hour. The reaction was cooled to room temperature and 0.5 mL NMP was added. The reaction was then filtered and purify by preparative reverse phase HPLC 30×50 mm XTerra C18 prep column, fifteen minute gradient 15-60% (0.1% NH4OH in Acetonitrile) and (0.1% NH4OH in water)), flow rate 40 mL/min. The desired product eluted (retention time 8.41 minutes) and was concentrated to a solid (38 mg, 54% yield). 1H NMR (Methanol-d4, 400 MHz) δ 2.52 (m, 2H), 2.80 (m, 2H), 2.99 (s, 3H), 4.80 (s, 2H), 6.73 (d, J=9 Hz; 1H), 7.22 (d, J=9 Hz; 1H), 7.37 (s, 1H), 7.57 (t, J=8 Hz; 1H), 7.64 (d, J=8 Hz;1H), 7.80 (m, 1H), 7.90 (s, 1H), 8.12 (s, 1H). HPLC ret. time: 5.390, LRMS (M+) 492.12.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].OS(O)(=O)=O.[CH2:13](O)[CH3:14]>C1C=CC=CC=1>[C:1]([O:7][CH2:13][CH3:14])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: CCO
Reactant: C=CCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: C=CCCC(=O)OCC
Reaction time: 15 h

Procedure:
To a solution containing 4-pentenoic acid (20.73 g, 207 mmol) in ethanol (100 mL) and benzene (200 mL) was added H2SO4 (250 μL). The solution was refluxed and monitored by GC (50° C., 1 min to 250° C. at 10° C./min; DB-5; tR of acid 4.4 min, ester 3.8 min). After 15 h, the reaction was complete; about 1/2 of the solvent was removed under reduced pressure and diluted with 150 mL ether. This was extracted with H2O (1×150 mL), saturated NaHCO3 (2×150 mL), H2O (1×150 mL), and brine (1×100 mL). The organic layer was dried over K2CO3, the solvent was removed under water aspirator vacuum, and the residue was distilled to yield ethyl 4-pentenoate, a compound, having the following structure: ##STR11## (20.79 g, 162 mmol, 78%; bp760 144° C.): 1H-NMR (200 MHz, CDCl3) δ 1.25 (t, J=7.2 Hz 3 H, CH3), 2.36 (m, 4 H, CH2CH2), 4.14 (q, J=7.2 Hz, 2 H, OCH2), 4.95-5.13 (m, 2 H, H2C=). 5.81 (m, 1 H, =CH); 13C-NMR (50 MHz, CDCl3) δ 14.2 (CH3), 28.6, 33.5 (C--H2CH2), 115.3 (H2C=), 136.5 (=CH), 172.8 (C=O).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)[C:3]([O:5][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@@H](O)CC1CCC1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H](O)CC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
A mixture of 1.05 g (7.3 mmol) of 2-(S)-hydroxy-3-(cyclobutyl)propanoic acid (from Step D), 40 mL (10.0 mmol) of TEA and 1.20 mL (10.0 mmol) of benzyl bromide in 8 mL of DMF was stirred at rt for 2 h. The mixture was partitioned between 200 mL of ether and 100 mL of H2O and the layers were separated. The organic layer was washed with 100 mL of 2.0 N HCl, 100 mL of sat'd NaHCO3, 2×100 mL of H2O, 100 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 60 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 1.20 g (70%) of the title compound: 1H NMR (500 MHz) δ 1.58-1.70 (m, 2H), 1.72-1.82 (m, 2H), 1.84-1.92 (m, 2H), 1.98-2.10 (m, 2H), 2.46-2.58 (m, 1H), 2.63 (br s, 1H), 4.15 (dd, J=7.5, 3.0), 7.33-7.40 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH3:18])[C:3]=1[O:20][CH2:21][CH2:22][CH3:23].[CH3:24][CH2:25][O:26][C:27]([CH:29](P(OCC)(OCC)=O)[F:30])=[O:28].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:18])=[C:29](/[F:30])\[C:27]([O:26][CH2:25][CH3:24])=[O:28])[C:3]=1[O:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1c(/C(C)=C(/F)C(=O)OCC)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-8-isopropyl-5,5-dimethyl-3-propoxy-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-113, 202 mg, 0.53 mmol) and triethyl 2-fluoro-2-phosphonoacetate (516 mg, 2.12 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 1.33 mL, 2.12 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][C@@:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17]Br)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][N:3]2[CH2:4][CH2:5][CH2:6][C@@:2]2([CH3:1])[C:7]([OH:9])=[O:8])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: C[C@@]1(C(=O)O)CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CCN2CCC[C@@]2(C)C(=O)O)cc1
Yield: 73.6 %

Procedure:
A mixture of (S)-2-methylproline (1.47 g) (prepared by the method of D. Seebach et al., JACS, 105, 5390 (1983)), 4-methoxyphenethyl bromide (1.72 g) and sodium carbonate (2.12 g) in ethanol (30 ml) was heated under reflux for 48 hours, adjusted to pH8 with 2M hydrochloric acid, treated with glacial acetic acid to pH7, filtered and evaporated under reduced pressure. The residue was triturated with ethanol, filtered and evaporated under reduced pressure to give the title compound as a brown gum, (1.55 g), which was used directly in Preparation 10 without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[C:3]=1[Br:16]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc2nc[nH]c2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.08 g of 5-aminobenzimidazole in 20 mL of glacial acetic acid are added 2.68 g of sodium acetate. To this solution is added dropwise 0.4 mL of bromine. The resulting brown precipitate is stirred at room temperature for 2 hours. The reaction mixture is rotary evaporated and the residue is diluted with water and ethyl acetate. The mixture is basified with 1 N sodium hydroxide and decanted. The organic layer is washed with water followed by brine. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 12.5 to 16.5% methanol/methylene chloride followed by recrystallization from hexanes/ethyl acetate to provide 887 mg of 5-amino-4-bromobenzimidazole as a pale brown solid.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1([NH2:35])[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>>[C:25]1([NH:35][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: Nc1cccc2c1CCCC2
Product: CCCCCCCCCCCc1noc(-c2ccc(CNc3cccc4c3CCCC4)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 5,6,7,8-tetrahydronaphthalen-1-ylamine gave the title compound as an oil. M+(LC/MS(ESI)): 460.4. HPLC (Condition A), Rt: 6.36 min (HPLC purity: 73.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][C:13](O)=O>>[CH3:12][C:13]1[NH:11][S:8](=[O:9])(=[O:10])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CC(=O)O
Reactant: Nc1ccccc1S(N)(=O)=O
Product: CC1=Nc2ccccc2S(=O)(=O)N1
Yield: 91 %

Procedure:
2-Aminobenzenesulfonamide (17.2 g; 100 mmol) was refluxed in AcOH for 5 days. The precipitate formed was isolated by filtration and washed with water to give 17.8 g (91%) of 3-methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide. 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was transformed by Method A (using dimethylamine as amine). M.p. 260-261° C.
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26](C=O)=[C:25]([Cl:29])[N:24]=[C:23]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])C.Cl.C(O)C>O>[Cl:29][C:25]1[N:24]=[C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:10]3[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:19]=2)[CH:26]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccccc1-c1ccc(Cn2cc(Cl)nc2-c2ccccc2)cc1
Yield: 0 %

Procedure:
9.2 g of 4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acid dimethylaminomethylenamide (Example 11a), 95 ml of a saturated aqueous HCl solution and 95 ml of ethanol are refluxed for 2 h. After cooling, the mixture is diluted with 500 ml of water and extracted twice using 500 ml of EA each time and the organic phase is washed twice using 100 ml of a saturated aqueous NaCl solution each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. The product mixture is recrystallized from 200 ml of EA and 6.2 g of 4′-(4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl)biphenyl-2-sulfonamide (compare Example 11b) are obtained. The solvent of the mother liquor is removed in vacuo and the residue is chromatographed on silica gel using MTB/DIP 1:1.40 mg of a colorless oil are obtained.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]([O:30][C:31]([NH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:32])([CH3:29])[CH3:28]>C1COCC1>[C:27]([O:30][C:31](=[O:32])[NH:33][CH:34]1[CH2:39][CH2:38][N:37]([S:14]([C:13]2[C:7]3[O:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:8]=3[CH:10]=[CH:11][C:12]=2[Cl:18])(=[O:16])=[O:15])[CH2:36][CH2:35]1)([CH3:29])([CH3:26])[CH3:28]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Yield: 54 %

Procedure:
Following the general procedure for the synthesis of sulfonylamides outlined in example 51, 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (5.05 g, 16.4 mmol), triethylamine (4.57 mL, 32.8 mmol), and 4-N-Boc-aminopiperidine (3.288 g, 16.4 mmol) were reacted in THF (125 mL) to afford the title compound (4.18 g, 54%). 1H NMR (DMSO-d6) • 7.98 (d, 1H, J=8.48 Hz), 7.63 (d, 1H, J=8.47 Hz), 3.73 (d, 2H), 3.35 (bs, 2H), 2.92 (m, 2H), 1.75 (d, 2H), 1.35 (s, 10H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([O:8][OH:9])([CH:6]=[CH2:7])[CH3:5].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>O>[C:10]([O:9][O:8][C:4]([CH3:5])([CH:6]=[CH2:7])[CH3:3])(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=CC(C)(C)OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CC(C)(C)OOC(=O)C(C)(C)C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a stirred mixture cooled at 10° C. of 10 g of demineralized water, 17.3 g of a 45% by weight-potassium hydroxide solution in water (0.139 moles) and 12.9 g of 2-methyl-3-buten-2-yl hydroperoxide (0.120 moles) there were added over a period of 25 minutes 14.5 g of pivaloyl chloride (0.120 moles); the temperature of the reaction mixture was kept at 10°-12° C. Stirring was continued for 1 hour, after which the organic layer was isolated. It was washed successively with an aqueous solution of 10% by weight-KOH (15 min, 10° C.), an aqueous bisulphite/acetate buffer (20 min., 10° C.) and a dilute solution of sodium bicarbonate in water (2x). Finally, the organic layer was dried with MgSO4 and the product was isolated by filtration. There were obtained 17.3 g of colourless oil containing 97.7% of peroxy ester, which corresponds to a yield of 75.6 %. The identity of the product was confirmed by IR and NMR spectroscopy (1H and 13C).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[F:29][C:30]([F:35])([F:34])[CH2:31][NH:32][CH3:33].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:33][N:32]([CH2:31][C:30]([F:35])([F:34])[F:29])[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:26]
Reactant: CNCC(F)(F)F
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)CC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1.5 mL) were added 2,2,2-trifluoro-N-methylethanamine hydrochloride (60 mg, 0.40 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a light yellow solid.
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[C:5]([C:9]1[CH:13]=[C:12](CO)[NH:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6].S(Cl)(Cl)=O>ClCCl>[C:5]([C:9]1[CH:13]=[C:12]([CH2:1][Cl:4])[NH:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)c1cc(CO)[nH]n1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(CCl)[nH]n1

Procedure:
To a chloroform (20 mL)-dichloromethane (10 mL) mixed solution of [3-(tert-butyl)-1H-pyrazol-5-yl]methanol (617 mg, 4.00 mmol), thionyl chloride (577 μL, 8.01 mmol) was added at room temperature and the resultant solution was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product (931 mg) of the title compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[NH2:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:15]=[CH:14][C:13]=1[C:24]([O:26]C1C=CC=CN=1)=S>O1CCCC1>[NH2:11][C:12]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[N:15]=[CH:14][C:13]=1[C:24](=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cccc(Br)c1
Reactant: Nc1c(C(=S)Oc2ccccn2)cnn1-c1ccc(F)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an oven dried flask containing magnesium turnings (0.408 g, 17 mmol) and tetrahydrofuran (10 ml) was added 3-bromoanisole (3.1 g, 17 mmol )and the reaction mixture was heated at reflux. After 2 h, the reaction mixture was cooled to room temperature and 5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (1.5 g, 4.8 mmol) was added and the stirring was continued for 1 h. The reaction mixture was quenched with water and the product was extracted into ethyl acetate. The organic layer was washed with aqueous ammonium chloride and brine and dried over sodium sulfate. The organics were removed in vacuo and the residue was filtered and washed with hexane to give 5-amino-1-(4-fluoro-phenyl)-4-(3-methoxybenzoyl)pyrazole (1.20 g).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]([CH2:18][O:19][C:20]4[C:24]([CH:25]=O)=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OP([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[C:1]1([C:7]2[O:8][C:9]([CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]([CH2:18][O:19][C:20]4[C:24](/[CH:25]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
To a mixture of 3-[{4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), ethyl diethylphosphonoacetate (0.27 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) under ice-cooling. The mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (2E)-3-[3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]-2-propenoate as colorless crystals (0.51 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:10]=[C:9]([OH:19])[N:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:20]N1C(=O)CCC1=O>CN(C)C=O>[Br:20][C:12]1[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][C:9]([OH:19])=[N:10][C:11]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCc1cc(CCCCCC)nc(O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCCCc1nc(O)nc(CCCCCC)c1Br
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 20.3 %

Procedure:
4,6-dihexylpyrimidin-2-ol (31.2 g, 118 mmol) was dissolved in 375 mL of dimethylformamide, and 21.0 g (118 mmol) of N-bromo-succinimide was added at 3° C., and the mixture was stirred for 2.5 hours. Ice water (500 g) was added, and the mixture was extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate and concentrated. The concentrate was purified by re-crystallization from ethanol, and the purity thereof was enhanced by a silica gel column (hexane•ethyl acetate) to obtain 8.4 g (24 mmol) of 5-bromo-4,6-dihexylpyrimidin-2-ol.