Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:7][CH2:6][C@@H:4]([OH:5])[C@@H:2]1[OH:3].C1OC[C@H](O)[C@H]1O.Cl[C:16]1[N:25]=[C:24](Cl)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[H-].[Na+].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C.O1CCOCC1>[OH:5][C@@H:4]1[CH2:6][O:7][CH2:1][C@H:2]1[O:3][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:25]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: O[C@@H]1COC[C@H]1O
Reactant: C1CNCCN1
Agent: O[C@H]1COC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O[C@@H]1COC[C@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 1,4-anhydro-D-threitol [prepared from D-threiol (manufactured by Fluka Co.) in the same manner as in the preparation of 1,4-anhydro-L-threitol (cf. J. Am. Chem. Soc., 74, 5336 (1952)] (11.43 g) and 2,4-dichloroquinazoline (16.8 g) in dimethylformamide (78 ml) is added gradually 60% sodium hydride (in oil) (4.39 g) with stirring under ice-cooling, and the mixture is stirred under ice-cooling for 15 minutes and further at room temperature for 30 minutes. The reaction mixture is diluted with ethyl acetate and washed with water 5 times. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is briefly purified by medium pressure liquid column chromatography [eluent, chloroform] to give a crystalline substance. The crystalline substance is dividedly added to a solution of piperazine (20.7 g) in dioxane (95 ml) with stirring at 55° C., and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The resulting solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure column chromatography (eluent, chloroform:methanol=10:1, 5:1, v/v) to give 4-[(3R,4R)-(4-hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline (5.83 g) as crystals. A part thereof is crystallized from ethanol-ether for obtaining the following physical data.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.CCCCCC.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C:20](=[O:26])[CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>CCOCC>[O:4]1[CH:5]=[CH:6][C:2]([C:20]2([OH:26])[CH:21]3[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]3)[CH2:19]2)=[CH:3]1
Reactant: O=C1CN2CCC1CC2
Reactant: Brc1ccoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1(c2ccoc2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.8 %

Procedure:
A stirred solution of 3-bromofuran (5.0 g of technical grade, 0.034 mole) in dry ether (130 ml) at -60° C. under nitrogen was treated with 1.6M n-butyllithium in hexane (18.7 ml, 0.030 mole) and then stirred for 5 minutes. A solution of 1-azabicyclo[2.2.2]octan-3-one (3.37 g, 0.027 mole) in dry ether (10 ml) was added and the resulting mixture stirred for 40 minutes at -60° C., then allowed to warm to room temperature. The mixture was treated with potassium carbonate solution (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on basic alumina eluting with ethyl acetate. The pale yellow oil obtained crystallised on standing. This material was recrystallised from acetone to give the title compound (D20) as a white solid (1.40 g, 21%) m.p. 130°-133° C.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: O=c1cc(OCc2ccc(F)cn2)cn[nH]1
Product: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(F)cn2)cc1=O
Yield: 91 %

Procedure:
5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1c employing 5-(5-fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:13]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:15]([CH2:29][CH3:30])[N:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH3:31][C:32]([S:35]([N:37]=[C:38]1[CH2:41][O:40][CH2:39]1)=[O:36])([CH3:34])[CH3:33]>O1CCCC1>[CH2:29]([N:15]1[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][C:13]([C:9]2[CH:8]=[C:7]([C:38]3([NH:37][S:35]([C:32]([CH3:34])([CH3:33])[CH3:31])=[O:36])[CH2:41][O:40][CH2:39]3)[CH:12]=[CH:11][CH:10]=2)=[N:14]1)[CH3:30]
Reactant: CCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
A solution of n-butyllithium in hexanes (2.50 M, 1.3 mL, 3.2 mmol, 1.5 equiv) was added to a solution of -(3-bromophenyl)-1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazole (1.32 g, 3.21 mmol, 1.5 equiv) in tetrahydrofuran (18 mL) at −78° C. The reaction mixture was stirred at −78° C. for 20 minutes, and then a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (375 mg, 2.14 mmol, 1 equiv) in tetrahydrofuran (2 mL) was added via syringe. The reaction mixture was stirred at −78° C. for 5 minutes, then the cooling bath was removed. After stirring for an additional 15 minutes, saturated aqueous ammonium chloride solution was added, and the crude product was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (10% ethyl acetate-hexanes, grading to 100% ethyl acetate, then flushing with 10% methanol-dichloromethane) to afford N-[3-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (894 mg, 82%). Calc'd (M+1)+: 508.2. Found: 507.9.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].Cl[Si:19]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[O:20][Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>N1C=CC=CC=1>[OH:3][C@@H:2]1[C@@H:4]2[O:5][Si:19]([CH:29]([CH3:31])[CH3:30])([CH:32]([CH3:34])[CH3:33])[O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:23])[CH3:24])[O:8][CH2:7][C@H:6]2[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12]
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: c1ccncc1
Product: CC(C)[Si]1(C(C)C)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
Uridine (15, 100.0 g, 409.5 mmol) was co-evaporated to dryness with anhydrous pyridine (600 mL) and re-suspended in anhydrous pyridine (700 mL). To this stirred fine suspension was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (135.7 g, 482.5 mmol) over 60 min at ambient temperature. After stirring the fine suspension for 17 h at ambient temperature, the reaction was quenched by adding methanol (20 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1.5 L) and water (2 L). The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL), dried over solid sodium sulfate (50 g), filtered and concentrated under reduced pressure to the crude product, ca 250 g. The residue was subjected to a filtration column using silica gel (1.75 kg) and a gradient of ethyl acetate in hexanes 20-65%. The pure product fractions as judged by a homogenous TLC (Rf 0.55 in 1:1 hexanes-ethyl acetate) were combined and concentrated under reduced pressure and dried (40° C., 0.2 mm Hg, 24 h) to afford 145.5 g (76%) of 16 as a white foam solid. An additional fraction (35 g) of slightly impure 16 was also collected. 1H NMR (DMSO-d6) δ (ppm) 11.35 (s, 1H, NH), 7.66 (d, 1H, J=7.6 Hz, H-6), 5.57 (d, 1H, J=4.8 Hz, 2′-OH), 5.50-5.49 (m, 2H, l′-H and H-5), 4.14-4.18 (m, 3H, 2′, 3′, 4′-H), 3.97-3.87 (m, 2H, 5′-Ha and Hb), 1.02-0.95 (m, 28H, CH(CH3)2).
Reaction SMILES: [OH-:1].[Na+:2].[Si:3](=[O:5])=[O:4].[OH2:6]>>[Si:3]([O-:6])([O-:1])([O-:5])[O-:4].[Na+:2].[Na+:2].[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: O
Reactant: O=[Si]=O
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
Namely, a proper amount of sodium hydroxide (manufactured by Nacalai Tesque Co., Ltd.) of a guaranteed reagent was dissolved into 1 liter of ion-exchanged water. 300 g of silicon dioxide (#200, manufactured by Aerosil Co. Ltd) which is commercially available was added to the dissolution and was stirred. Sodium silicate was obtained by calcining the dispersion for 5 hours at 700° C.
Reaction SMILES: O[Li].O.[CH:4](=[C:6]1[CH2:10][CH:9]([C:11]([O:13]CC)=[O:12])[CH:8]([C:16]([O:18]CC)=[O:17])[CH2:7]1)[CH3:5]>O.C1COCC1>[CH:4](=[C:6]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH:8]([C:16]([OH:18])=[O:17])[CH2:7]1)[CH3:5]
Reactant: CC=C1CC(C(=O)OCC)C(C(=O)OCC)C1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC=C1CC(C(=O)O)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of LiOH.H2O (5.1 g, 120 mmol) in 130 ml of water is added dropwise at 0° C. to a solution of the compound from Example VIII (13.1 g, 54.5 mmol) in 70 ml of THF. The solution is stirred at room temperature for 20 h, the THF is stripped off in vacuo and the residue is extracted once with 40 ml of ether. The aqueous phase is brought to pH 2 with 10% strength hydrochloric acid and extracted three times with 200 ml of ethyl acetate each time. The combined ethyl acetate phases are dried over Na2SO4 and the solvent is stripped off in vacuo.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH2:28])[C:22]=1[NH2:29].[CH3:30]N(C=O)C>>[CH3:20][C:21]1[C:22]2[N:29]=[C:18]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH3:30])[CH2:2][CH2:3]4)[CH:17]=3)[NH:28][C:23]=2[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: O=Cc1ccnc(OCCCCC2CCNCC2)c1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c(N)c(N)c1
Product: Cc1cc(C)c2nc(-c3ccnc(OCCCCC4CCN(C)CC4)c3)[nH]c2c1

Procedure:
4,6-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole. To a stirred solution of 2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile (440 mg, 1.61 mmol, 1.0 equiv) in toluene (5.0 mL) at 0° C. was added 1.0 M diisobutylaluminum hydride in toluene (2.41 mL, 2.41 mmol, 1.5 equiv). After 3 h, methanol (8 mL) and 1.0 M H2SO4 (5 mL) were added. The mixture was stirred for 30 min, and then 1.0 M NaOH (10 mL) was added, followed by satd. aq. sodium potassium tartrate (40 mL) and dichloromethane (100 mL). After stirring for 30 min, the mixture was extracted with chloroform (3×50 mL) and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was partially purified by Method 2 to afford 318 mg of a mixture of 2-(4-piperidin-4-yl-butoxy)-pyridine-4-carbaldehyde and several other unidentified products. A portion of the crude of 2-(4-piperidin-4-yl-butoxy)-pyridine-4-carbaldehyde (100 mg), 3,5-dimethyl-benzene-1,2-diamine (70 mg), and Na2S2O5 (93 mg) were stirred in DMF (3 mL) at 90° C. for 18 h. The reaction mixture was loaded directly on silica gel and purified according to Method 2, which afforded 38 mg of the title compound. MS (electrospray): mass calculated for C24H32N4O, 392.26; m/z found 393.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.25 (d, J=5.3 Hz, 1H), 7.62 (dd, J=4.5, 1.0 Hz, 1H), 7.48 (s, 1H), 7.24 (s, 1H), 6.95 (s, 1H), 4.34 (t, J=6.6 Hz, 2H), 2.91-2.83 (m, 2H), 2.58 (s, 3H), 2.43 (s, 3H), 2.25 (s, 3H), 2.07-1.95 (m, 2H), 1.86-1.69 (m, 5H), 1.57-1.18 (m, 6H).
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:11][C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][CH2:4][C:5]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CC1(C[N+](=O)[O-])CCCCC1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1

Procedure:
A solution of 5 g (0.017 mol) of benzyl 1-(nitromethyl)cyclohexyl-acetate in 50 ml of methanol is added to a mixture of 0.5 g of prehydrogenated palladium, 10% on activated carbon in 50 ml of methanol. This mixture is hydrogenated at room temperature under atmospheric pressure until the calculated hydrogen is consumed, then the catalyst is filtered off, the filtrate is concentrated to about 15 ml and 30 ml of tetrahydrofuran is added to precipitate the title compound. Yield: 1.5 g (51%). Mp: 168° C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C@@H:9]([OH:36])[CH2:10][C@@H:11]([NH:25]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.CO.O1CCOCC1.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:10][C@H:9]([OH:36])[C@@H:8]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2cccnc2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccc(-c2cccnc2)cc1
Reaction time: 18 h

Procedure:
The product from Example 148B (0.170 g, 0.29 mmol) was dissolved in a mixture of ethyl acetate (1.5 mL) and methanol (1.5 mL) and 20% Pd(OH)2 on carbon (0.080 g) and a solution of HCl in dioxane (0.070 mL, 4 N) were added, and the reaction was stirred under an atmosphere of hydrogen (balloon pressure) for 18 hours. The mixture was filtered through celite® and the solvent was evaporated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10])=O.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]=3[C:9](=[O:10])[N:22]3[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[C:23]=23)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCCNC1
Reactant: COc1ccc(C(=O)Cl)c(C(=O)c2cccc(F)c2)c1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)C(=O)CCC3

Procedure:
To a mixture of 2-(3-fluorobenzoyl)-4-methoxybenzoyl chloride (3.36 g) and piperidin-3-one hydrochloride (1.88 g) in 54 ml of toluene was added 2,6-lutidine (4.01 ml). The reaction was heated at reflux (3:10 pm) for 24 h, then partitioned between EtOAc and 400 mL of 1 N HCl. The aqueous solution was extracted twice more with EtOAc. The combined organic solutions were dried (MgSO4) and concentrated. Flash chromatography (40-100% EtOAc/hexanes) to gave the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:31][CH2:32][CH2:33][OH:34].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:31][CH2:32][CH2:33][OH:34])=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)ccc1F
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
5-[(2,5-Difluorophenyl)[(4-fluoro-3-methylphenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (300 mg, 0.69 mmol), 2-aminoethanol (60 μl, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1.0 mmol), 1-hydroxybenzotriazole (93 mg, 0.69 mmol), and triethylamine (292 μl, 2.1 mmol) were dissolved in methylene chloride (60 ml), and the solution was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (developed with 5% methanol/methylene chloride, eluted with 30% methanol/methylene chloride), to obtain the title compound (190 mg, 0.39 mmol, 58%) as a white amorphous substance.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:7]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:6]([CH3:41])[N+:5]=1[O-])([CH3:3])[CH3:2].[C:43]([O:46]C(=O)C)(=[O:45])[CH3:44]>>[C:43]([O:46][CH2:41][C:6]1[C:7]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:9]([CH2:10][O:11][Si:12]([C:25]([CH3:26])([CH3:28])[CH3:27])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]=1)(=[O:45])[CH3:44]
Reactant: CCCCCc1c(-c2ccc(F)cc2)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C(C)C)[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Product: CCCCCc1c(COC(C)=O)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Temperature: 100 °C
Yield: 90 %

Procedure:
A mixture of the intermediate obtained in Example 199, Step B (4.8 g, 7.97 mmol) and acetic anhydride (20 mL) was heated to 100° C. for 20 min. The mixture was poured onto ice and the aqueous phase extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution (3×50 mL), and saturated aqueous sodium chloride solution (3×50 mL). Silica gel chromatography provided a yellow oil (4.4 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.40 (m, 6H), 7.31 (m, 4H), 7.06 (m, 4H), 5.29 (s, 2H), 4.26 (s, 2H), 3.14 (sept, 6.8 Hz, 1H), 2.2 (m, 2H), 2.18 (s, 3H), 1.2 (m, 2H), 1.16 (d, 6.6 Hz, 6H), 1.05 (m, 4H), 0.99 (s, 9H), 0.77 (t, 6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([CH3:4])[CH3:3].[H-].[Na+].Br[CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH3:26])[CH:19]=2)[C:14]1=[O:27].O>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:16][CH2:17][CH:13]([N:7]3[CH:8]=[CH:9][C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[N:6]3)[C:14]2=[O:27])=[CH:19][C:20]=1[O:25][CH3:26]
Reactant: COc1cc(N2CCC(Br)C2=O)ccc1Cl
Reactant: CC(C)(C)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(n3ccc(C(C)(C)C)n3)C2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(1,1-dimethylethyl)-1H-pyrazole (0.22 g, 1.8 mmol) in N,N-dimethylformamide (20 mL) under nitrogen at room temperature was added 60% sodium hydride in mineral oil (79 mg, 2.0 mmol). After the addition, the mixture was stirred at room temperature for ˜15 minutes, and then 3-bromo-1-(4-chloro-3-methoxyphenyl)-2-pyrrolidinone (0.5 g, 1.6 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight and then poured into water (˜100 mL). The aqueous layer was extracted twice with ethyl acetate (˜50 mL each). The organic extracts were combined, washed twice with water (˜100 mL each), dried over MgSO4 and filtered. The filtrate was concentrated. The residue was purified by medium pressure liquid chromatography (silica gel) using as eluant methylene chloride and then 10:1 (by volume) ethyl acetatemethylene chloride to give the title compound, a compound of this invention, as a solid (186 mg) melting at 128–130 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-])=O)[C:3]=1[OH:15]>CCO>[Br:1][C:2]1[C:3]([OH:15])=[C:4]([NH2:12])[C:5](=[C:9]([Br:11])[CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1c(Br)cc(Br)c(O)c1[N+](=O)[O-]
Solvent: CCO
Product: Nc1c(O)c(Br)cc(Br)c1C(=O)O
Yield: 67.3 %

Procedure:
4,6-Dibromo-3-hydroxy-2-nitrobenzoic acid (4.09 g, 12 mmol) and PtS2 (160 mg, 0.62 mmol) in EtOH (150 mL) was hydrogenated at atmospheric pressure and room temperature for 45 h. Filtration and evaporation of the filtrate gave a crude product (3.69 g) which was purified by flash chromatography (SiO2, toluene-EtOAc). Treatment with activated charcoal in MeOH and crystallization from MeOH/H2O gave the title compound (2.51 g). Mp: 162°-164.5° C. 1H NMR (DMSO-d6): δ6.96 (s, 1H). 13C NMR (DMSO-d6): δ167.69, 140.56, 139.95, 121.81, 117.23, 112.53, 110.45. MS (EI, 70 ev): m/z (rel. int.) 309, 311, 313 (M+, 36, 72, 34).
Reaction SMILES: [CH3:1][C:2](=[CH:8][C:9]1[CH:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:11][C:10]=1[CH3:17])[C:3](OCC)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][C:2](=[CH:8][C:9]1[CH:13]([CH:14]([CH3:15])[CH3:16])[CH2:12][CH2:11][C:10]=1[CH3:17])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)=CC1=C(C)CCC1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(=CC1=C(C)CCC1C(C)C)CO
Yield: 95.5 %

Procedure:
40 g of ethyl 2-methyl-3-(2-methyl-5-isopropyl-cyclopent-1-en-1-yl)-prop-2-enoate in 100 ml cooled ether were added under stirring to a suspension of 4 g of LiAlH4 in 50 ml ether. After addition of water to the thus obtained suspension, the separated organic phase was dried and evaporated to dryness. There was thus obtained 31.4 g (yield 95%) of the desired alcohol; bp. 75°-80°/0.01 Torr.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].[C:23]1([CH2:29][CH2:30][CH:31]=[CH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:32]=[CH:31][CH2:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1-c1nc2c(I)cccc2c(=O)[nH]1
Reactant: C=CCCc1ccccc1
Product: CCCOc1ccccc1-c1nc2c(C=CCCc3ccccc3)cccc2c(=O)[nH]1
Yield: 49.9 %

Procedure:
The title compound is prepared analogously to the method of Example 2, starting with the compound from Example III and 4-phenyl-1-butene.