Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[C:26]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C1CCCCCC1
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCCCCC3)CC2)nc1
Temperature: 50 °C
Reaction time: 96 h
Yield: 72.1 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess cycloheptanone (1.48 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol provided 0.41 g (72%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC(C)C)=O.[CH:30]1([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][NH2:41])[CH2:34][CH2:33][CH2:32][CH2:31]1>C(N(CC)CC)C.O>[CH:30]1([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][NH:41][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:14]([CH3:17])(=[O:16])=[O:15])[C:10]([O:12][CH3:13])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(OC)c(S(C)(=O)=O)cc1C(=O)O
Reactant: NCC1CCCN1C1CCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(S(C)(=O)=O)cc1C(=O)NCC1CCCN1C1CCCC1
Reaction time: 0.67 h

Procedure:
91 g of 2,4-dimethoxy-5-methylsulphonyl benzoic acid, 400 ml of acetone, 130 ml of water and 48.6 ml of triethylamine are placed in a liter flask fitted with an agitator, a thermometer and a dropping funnel. 47.6 g of isobutyl chloroformate is dripped into the solution obtained, at about 10° C. It is agitated for 40 minutes, then 58.8 g of 1-cyclopentyl-2-aminomethyl-pyrrolidine is poured in drop by drop at about 0° C. A precipitate appears after 30 minutes of agitation at room temperature. It is allowed to react then the precipitate is filtered off, washed with water and dried. 74 g of a crude version of the product is obtained, melting at 198° C.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:17]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]3[CH2:12][N:13]([S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(S(=O)(=O)c3ccccc3)CCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (50 mg, 0.17 mmol) in chloroform (2 mL) were sequentially added pyridine (0.5 mL) and benzenesulfonyl chloride (43 mg, 0.24 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from diisopropyl ether to obtain the title compound (27 mg, yield 37%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH2:14]([Si:21]1(C2C=CC=CC=2)[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:14]([Si@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([O:13][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([F:1])[CH:3]=2)=[O:28])[CH2:25][CH2:26]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Reactant: Oc1ccc(OC(F)(F)F)c(F)c1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2ccc(OC(F)(F)F)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3-fluoro-4-trifluoromethoxyphenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[OH-].[Na+].O.S(OCC)(O[CH2:17][CH3:18])(=O)=O>O1CCCC1>[CH2:17]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[CH3:18]
Reactant: CCOS(=O)(=O)OCC
Reactant: c1ccc2[nH]cnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cnc2ccccc21
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a flask were added 100 g benzimidazole, 44 g sodium hydroxide, 320 ml water and 480 ml tetrahydrofuran and the mixture was stirred under nitrogen. 157 g Diethyl sulfate were added slowly, maintaining a temperature of 40 C. After 2 hrs at 40 C, the reaction was quenched with slow addition of 100 ml concentrated hydrochloric acid. After washing with 150 ml hexane, the mixture was basified with 50 g sodium hydroxide and extracted with 275 ml ethyl acetate, then 225 ml ethyl acetate. The solvent was removed, leaving an orange oil, which was distilled under full vacuum to give 109.4 g clear colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:34](=[O:35])[O:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:4]2[C:5]([CH3:13])=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]([CH3:1])=[N:3]2)=[CH:19][CH:18]=1)(=[O:32])=[O:31]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCOC(=O)NS(=O)(=O)c3ccccc3Cl)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethanol (step 1 of Example 2) and 2-chlorobenzenesulfonyl isocyanate: 1H-NMR (CDCl3) δ 8.21 (1H, d, J=7.5 Hz), 7.55-7.20 (12H, m), 4.30 (2H, t, J=6.8 Hz), 2.91 (2H, t, J=6.8 Hz), 2.34 (3H, s), 2.28 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([C:12]2[CH2:16][CH:15]=[CH:14][CH:13]=2)[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH3:17][C:18]([CH3:20])=O.N1CCCC1>CO>[CH3:1][C:2]1([C:12]2[CH:16]=[CH:15][C:14](=[C:18]([CH3:20])[CH3:17])[CH:13]=2)[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:9]1[CH2:10]3)[CH2:11]2
Reactant: CC(C)=O
Reactant: CC1(C2=CC=CC2)C2CC3CC(C2)CC1C3
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)=C1C=CC(C2(C)C3CC4CC(C3)CC2C4)=C1
Yield: 88.2 %

Procedure:
A flask containing 19.45 grams (90.74 mmol) of 2-methyl-2-adamantylcyclopentadiene was charged with 30 mL acetone, 100 mL methanol, and 10 mL pyrrolidine (120 mmol). The solution formed a yellow precipitate over 96 hours which was collected by suction filtration and rinsed with 50 mL methanol. The material was dried in vacuo to provide 20.36 grams of product as a yellow powder (88.2%).
Reaction SMILES: C(O[O:4][CH2:5][CH:6]1[C:11]([CH3:12])=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][CH2:7]1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.[O:56]1CCO[CH2:58][CH2:57]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:57]([O:56][C:5]([CH:6]1[CH:11]([CH3:12])[CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[C:9]([C:50]2[CH:51]=[CH:52][C:47]([O:46][CH3:45])=[CH:48][CH:49]=2)=[CH:8][CH2:7]1)=[O:4])[CH3:58]
Reactant: CCOOCC1CC=C(OS(=O)(=O)C(F)(F)F)C(Cc2ccc(OCCN3CCCCC3)cc2)=C1C
Reactant: COc1ccc(B(O)O)cc1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1CC=C(c2ccc(OC)cc2)C(Cc2ccc(OCCN3CCCCC3)cc2)C1C
Temperature: 8 °C

Procedure:
Into a mixture of trifluoro-methanesulfonic acid 4-ethylperoxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohexa-1,5-dienyl ester (118.5 mg, 0.2219 mmol), Pd (PPh3)4 (6.4 mg, 0.025 eq.) and K3PO4 (70.7 mg, 1.5 eq.) in 1,4-dioxane (5 mL) was bubbled N2 for 10 min. To the reaction mixture was then added 4-methoxy benzene boronic acid (37.1 mg, 0.2441 mmol). The resulting mixture was heated to 8° C. for 16 h, filtered through a plug of silica gel, concentrated and purified on preparative TLC (10% MeOH/DCM) to yield 4-(4-methoxy-phenyl)-6-methyl-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohex-3-enecarboxylic acid ethyl ester as light yellow oil.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:18]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=2[F:40])=[CH:29][CH:28]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C[C@@H](OC1C=CC(Br)=CC=1F)CCCCC.C(C1C=CC(C2C=CC(Br)=CC=2F)=CC=1)CCCCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:36]2[CH:37]=[CH:38][C:33]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:28][CH:29]=3)=[C:34]([F:40])[CH:35]=2)=[CH:12][C:11]=1[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(Br)cc1F
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2F)cc1
Agent: CCCCCCCCc1ccc(-c2ccc(Br)cc2F)cc1
Agent: CCCCC[C@@H](C)Oc1ccc(Br)cc1F
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(OCCCCCCCC)c(F)c3)cc2F)cc1
Yield: 13.9 %

Procedure:
Except that 3.6 g of 4-octyloxy-3-fluorobromobenzene obtained in Example 3 (a) and 2.2 g of 4-octyloxy-2'-fluoro-4'-bromobiphenyl obtained in Example 2 (c) were used in place of 3.4 g of (R) -4-(1-methylhexyl)oxy-3-fluorobromobenzene and 2.2 g of 4-octyl-2'-fluoro-4 '-bromobiphenyl used in Example 1 (e), respectively, the operation was performed in the same manner as in Example 1 (e) to obtain 0.42 g (13.9%) of 4,4"-dioctyloxy-3,3 '-difluoro-p-terphenyl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[NH:4][NH2:5].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[CH:9][CH:8]=1>CO>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:5][NH:4][C:3]([O:2][CH3:1])=[O:6])=[CH:9][CH:8]=1
Reactant: COC(=O)NN
Reactant: O=Cc1ccnc2ccccc12
Solvent: CO
Product: COC(=O)NN=Cc1ccnc2ccccc12
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A mixture of 2.70 gm (0.03 mole) of methylcarbazate, 4.72 gm (0.03 mole) of 4-quinolinecarboxaldehyde and 100 ml of anhydrous methanol is refluxed 8.5 hr. The hot solution is filtered. The filtrate is diluted with water until cloudy. The mixture is cooled to room temperature then chilled. The crystals are collected, washed with ether and dried to give 5.88 gm (86%) of the title compound, having a melting point of 83.5° C.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br:20]Br.Cl>C(OCC)C>[Br:20][C:10]1[N:11]([CH3:14])[CH:12]=[CH:13][C:9]=1[S:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:8])=[O:7]
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Reactant: BrBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
To a solution of 8.85 g (41 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 200 mL diethyl ether under a nitrogen atmosphere cooled to -78° C. was added dropwise, at such a rate as to keep the temperature below -65° C., 36.0 mL (85 mmol) 2.41M n-butyllithium in hexanes. The reaction was stirred at -78° C. for ca. 15 minutes. To the reaction mixture was added 2.2 mL (41 mmol) of bromine dropwise. The light orange reaction mixture was allowed to warm to room temperature and stir for ca. 2 hours. The reaction mixture darkened as it stirred at room temperature. The reaction mixture was cooled to 0° C. and acidified with 1N HCl. The ether phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica (25% ethyl acetate/80% hexanes) affording 7.11 g of the title compound as an orange oil. 1H NMR (CDCl3, 200 MHz.) δ: 6.73(d,1H), 6.62(d,1H), 3.63(s,3H), 1.24(s,9H).
Reaction SMILES: B.[CH2:2]([C:5]1([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:3]=[CH2:4].[OH-:19].[Na+].OO>O1CCCC1.C(OCC)C.O>[Si:12]([O:11][C:5]1([CH2:2][CH2:3][CH2:4][OH:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: [OH-]
Reactant: C=CCC1(O[Si](C)(C)C(C)(C)C)CCCCC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1(CCCO)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A solution of borane in tetrahydrofuran (1 M, 15.7 mL, 15.7 mmol) was added to a solution of [(1-allylcyclohexyl)oxy](tert-butyl)dimethylsilane (8.00 g, 31.4 mmol) in tetrahydrofuran. After 2 h, water (5 mL) was added dropwise, followed by 3 M NaOH (6 mL), followed by dropwise addition of 30% aqueous hydrogen peroxide (6 mL). The mixture was stirred at rt for 1 h, then was diluted with diethyl ether (100 mL) and water (70 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2×35 mL). The combined organic layers were washed with brine (90 mL), dried over MgSO4, filtered, and concentrated to yield a colorless oil that was purified using HPFC (silica gel, gradient elution with 2-30% ethyl acetate/hexanes) to afford pure 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-ol (6.80 g, 79%).
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])C=C[C:6](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:13][C:14]([F:32])([F:31])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=[CH:25][CH:26]=[N:27]N(C)C)=[O:16].[C:33](OC(=O)C)(=O)[CH3:34]>CC#N.C1(C)C=CC=CC=1.[Pd]>[F:32][C:14]([F:13])([F:31])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:25]2[C:6](=[O:12])[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:10]=3[C:9](=[O:11])[C:26]=2[N:27]=[CH:34][CH:33]=1)=[O:16]
Reactant: CN(C)N=CC=Cc1ccccc1NC(=O)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=CC(=O)c2ncccc21
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C1c2ncccc2C(=O)c2c(-c3ccccc3NC(=O)C(F)(F)F)ccnc21
Yield: 5 %

Procedure:
1 g (6.3 mmol) of quinoline-5,8-dione, 3.59 g (12.6 mmol) of 4-(2-trifluoroacetamidophenyl)-1-dimethylamino-1-aza-1,3-butadiene and 7.5 mL of acetic anhydride in 175 mL of CH3CN are refluxed for 24 hours. After evaporating off the solvent on a rotary evaporator and purifying by filtration on silica (95/5 CH2Cl2/MeOH), the adduct is obtained. This compound is dissolved in 150 mL of toluene, 6.2 g of Pd/C (10%) are added and the reaction medium is refluxed for 12 hours. After filtering off and washing the residue with MeOH and then with CHCl3, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a column of silica (95/5 CH2Cl2/MeOH) to give 0.125 g of compound CRL 8277 in the form of a yellow powder.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[CH:20]=[CH:21][C:22]([NH:24][NH2:25])=[O:23])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[CH3:31][C:30]([C:27]1[CH:26]=[C:19]([CH:20]=[CH:21][C:22]2[O:23][C:1](=[O:2])[NH:25][N:24]=2)[CH:18]=[C:17]([C:14]([CH3:13])([CH3:15])[CH3:16])[C:28]=1[OH:29])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cc(C=CC(=O)NN)cc(C(C)(C)C)c1O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C=Cc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.4 %

Procedure:
Carbonyl diimidazole (0.7 g, 0.004 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-cinnamic acid hydrazide (1.0 g, 0.003 mole) and triethylamine (0.4 g, 0.004 mole) in tetrahydrofuran (12 ml). The mixture is stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stir 45 minutes. The solution is concentrated and the residue dissolved in ether (50 ml) and washed with aqueous 2M HCl. The product is extracted from the organic layer by treatment with aqueous 1M NaOH (20 ml). The aqueous extract is made acidic by treatment with cold aqueous 2M HCl and the product is extracted with ether. The organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration provided a solid which was recrystallized from ethyl acetate/hexane to give 1.0 g (1.1 g theor., 94%) of 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3, 4-oxadiazole-2(3H)-one, mp >260° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:14])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(F)ccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol), iodomethane (13.5 g, 95.4 mmol), and potassium carbonate (16.7 g, 159 mmol) in acetone (80 mL) was heated to reflux for 4 hours. The mixture was cooled and evaporated under vacuum, and the residue was dissolved in ethyl acetate (200 mL) and washed with water (3×250 mL), dried (MgSO4), and evaporated, providing 5.25 g, in 97% yield: 1H NMR (CDCl3) δ 3.97 (s, 3H), 6.69-6.82 (m, 2H), 7.97 (dd, J=8.9 Hz, J=6.0 Hz, 1H).
Reaction SMILES: [C:1](O)(C(F)(F)F)=[O:2].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][NH:24][S:23](=[O:27])(=[O:26])[NH:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:28][C:29]([C:31]2[N:32](COCC[Si](C)(C)C)[CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1>C(Cl)Cl.CCO>[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][NH:24][S:23](=[O:26])(=[O:27])[NH:22][CH2:21]3)[C:17]([CH2:1][OH:2])=[CH:16][C:15]=2[NH:28][C:29]([C:31]2[NH:32][CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2cc(CO)c(C3CNS(=O)(=O)NC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
TFA (0.3 mL) was added to a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide (as prepared in Example 5, step (d), 21 mg, 0.030 mmol) in DCM (1 mL) and EtOH (30 μL). The resulting mixture was stirred at RT for 2 h and concentrated in vacuo. The residue obtained was purified on silica (20-50% EtOAc-hexane) to obtain the title compound (8.0 mg, 46%): 1H-NMR (CD3OD; 400 MHz): δ 8.10 (s, 1H), 8.05 (s, 1H), 7.11 (s, 1H), 5.78 (br s, 1H), 4.7 (ABq, 1H, J=16 Hz), 4.48 (ABq, 1H, J=16 Hz), 4.3 (m, 1H), 3.87 (m, 1H), 3.52 (m, 1H), 3.6 (m, 1H), 3.18 (m, 1H), 2.62 (br s, 1H), 2.22-2.34 (m, 4H), 1.72-1.90 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H24N6O4S, 439.1 (M−H2O+H). found 439.2.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:8][N:7]=1)C.O1CCCC1.[OH-].[Na+:30]>CC(O)C>[CH2:16]([O:15][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O-:23])=[O:3])=[N:7][CH:8]=1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+:30]
Reactant: CCOC(=O)Cc1ccc(NC(=O)OCc2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C([O-])Cc1ccc(NC(=O)OCc2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of ethyl(5-(((benzyloxy)carbonyl)amino)pyridin-2-yl)acetate (1.0 g) obtained in Step A of Example 363 in a mixed solvent of tetrahydrofuran (20 mL) and 2-propanol (5.0 mL) was added 2 M aqueous sodium hydroxide solution (6.4 mL) in an ice bath, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was collected by filtration to give the title compound (2.6 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.ClC[C:10]1[CH:11]=[N:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:14]=1.[CH3:23]N(C=O)C>>[Cl:22][C:17]1[CH:16]=[C:15]([N:13]2[CH:14]=[C:10]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[C:11]([CH3:23])=[N:12]2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: c1c[nH]cn1
Reactant: ClCc1cnn(-c2ccc(Cl)c(Cl)c2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1nn(-c2ccc(Cl)c(Cl)c2)cc1-n1ccnc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Sodium hydride (0.24 g of a 55% dispersion in mineral oil, 5.5 mmol) was slowly added to a solution of imidazole (0.19 g, 2.8 mmol) in DMF: (15 ml). After 30 min at 60° C. the mixture was cooled in an ice bath and 4-chloromethyl-1-(3,4-dichloro-phenyl)-1H-pyrazole (0.50 g, 1.9 mmol) was added in one portion. The resulting mixture was stirred for 1 h at 20° C. After evaporation of the solvent the residue was dissolved in AcOEt, washed with H2O, dried (Na2SO4) and chromatographed [silica, elution with gradient CH2Cl2 to 30% (CH2Cl2/MeOH/aq. NH4OH=90:10:1)] to obtain 0.23 g (41%) of the title compound. Mp. 103-104° C. (iPr2O), MS: m/e=293 (M+H+)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Si:9]([CH3:19])([CH3:18])/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14]CCC.[CH3:20][CH2:21][CH2:22]C#CCCC.C[SiH](C)C1C=CC=CC=1COC1CCCCO1.C#CCCCCCC>>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Si:9]([CH3:18])([CH3:19])/[C:10](=[CH:11]/[CH2:12][CH2:13][CH3:14])/[CH2:20][CH2:21][CH3:22]
Reactant: CCCC#CCCC
Reactant: CCCCCC/C=C/[Si](C)(C)c1ccccc1CO
Agent: C#CCCCCCC
Agent: C[SiH](C)c1ccccc1COC1CCCCO1
Product: CCC/C=C(\CCC)[Si](C)(C)c1ccccc1CO
Yield: 81 %

Procedure:
The same operation as in the production of the compound 1a was carried out except that 4-octyne (0.22 g, 2.0 mmol) was used instead of 0.55 g and 2.2 mmol of dimethyl[2-(2-tetrahydro-2H-pyranoxymethyl)phenylsilane (R2 and R3 in (5): methyl group) and 1-octyne, thereby (E)-(2-(hydroxymethyl)phenyl)dimethyl(4-octene-4-yl)silane (0.45 g, yield of 81%) as a colorless oil. Rf: 0.25 (hexane-ethyl acetate=10:1). 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J=7.2, 1.2 Hz, 1H), 7.47 (dd, J=7.2, 1.2 Hz, 1H), 7.40 (td, J=7.3, 1.4 Hz, 1H), 7.29 (m, 1H), 5.80 (t, J=7.2 Hz, 1H), 4.70 (s, 2H), 2.12-2.06 (m, 4H), 1.38 (m, 2H), 1.28-1.18 (m, 2H), 0.90 (t, J=7.4 Hz, 3H), 0.83 (t, J=7.2 Hz, 3H), 0.40 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 146.6, 142.8, 140.2, 136.7, 135.3, 129.6, 128.0, 126.9, 65.2, 32.1, 30.8, 23.4, 22.6, 14.5, 14.0, −1.2; Anal. Calcd for C17H28Osi; C, 73.85; H, 10.21. Found: C, 73.67; H, 10.06.