Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][C:7]1[NH:11][N:10]([CH3:12])[C:9](=[O:13])[CH:8]=1.Cl[CH:20]([F:22])[F:21]>O.O1CCOCC1>[Cl:3][C:4]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][C:7]1[N:11]([CH:20]([F:22])[F:21])[N:10]([CH3:12])[C:9](=[O:13])[CH:8]=1
Reactant: FC(F)Cl
Reactant: Cn1[nH]c(Cc2cccc(Cl)c2Cl)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(=O)cc(Cc2cccc(Cl)c2Cl)n1C(F)F

Procedure:
A solution of 19 g (0.48 mol) of sodium hydroxide in 165 ml of water was added to a solution of 24.5 g (95.3 mmol) of 5-(2,3-dichlorobenzyl)-1,2-dihydro-2-methyl-3H-pyrazol-3-one in 200 ml of dioxane. The mixture was subsequently heated to 60—65° C. and gaseous chlorodifluoromethane was passed through until the starting material had been completely consumed (after about 2 hours). The reaction mixture was then poured into 500 ml of water. The product was extracted with methyl tert-butyl ether. The organic phase was finally dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1:1). Yield: at first 11.5 g of compound Ic.1 and thereafter 5.8 g of compound IIIc.1;
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[C:17]([CH3:18])=[C:16]([CH2:19][C:20]#[N:21])[C:15]([CH3:22])=[C:14]([C:23](=[O:25])[CH3:24])[C:13]=2[CH3:26])[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].[OH-:28].[Na+]>>[C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[C:17]([CH3:18])=[C:16]([CH2:19][C:20](=[O:28])[NH2:21])[C:15]([CH3:22])=[C:14]([C:23](=[O:25])[CH3:24])[C:13]=2[CH3:26])[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c(CC#N)c(C)c(C(C)=O)c2C)CC1=O
Reactant: [OH-]
Agent: [Na+]
Product: CCC(=O)C1=C(O)CC(c2c(C)c(CC(N)=O)c(C)c(C(C)=O)c2C)CC1=O
Yield: 65 %

Procedure:
A solution of 2-propionyl-3-hydroxy-5-(3-acetyl-5-cyanomethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.67 g, 1.83 mmol) in 5% aqueous sodium hydroxide (12 ml) was refluxed for 30 min. The solution was then cooled, acidified and extracted with ethylacetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbon solution, further water then dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure to yield 2-propionyl-3-hydroxy-5-(3-acetyl-5-carbamoylmethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a colourless solid (0.49 g, 65%). The compound was characterized by proton magnetic resonance spectroscopy (CDCl3 ; δ in ppm): 1.14 (3H,t); 2.13 (3H,s); 2.22 (3H,s); 2.32 (3H,s); 2.46 (3H,s); 2.4-3.9 (7H, m); 3.61 (2H,s); 5.48 (1H,brs); 6.10 (1H,brs); 18.00 (1H,brs). The sodium hydrogen carbonate solution washings were acidified and extracted with ethylacetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to yield 2-[3-(4-propionyl-5-hydroxycyclohex-3-one-4- enyl)-5-acetyl-2,4,6-trimethylphenyl]acetic acid (0.11 g, 16%) as a colourless solid.
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[N:19]4[N:20]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=6[OH:35])[CH:26]=[CH:27][CH:28]=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:36])[C:15]=3[C@H:37]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:38]([O:40][CH3:41])=[O:39])[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:47](O)[CH:48]=[CH2:49].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[N:19]4[N:20]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=6[O:35][CH2:49][CH:48]=[CH2:47])[CH:26]=[CH:27][CH:28]=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:36])[C:15]=3[C@H:37]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:38]([O:40][CH3:41])=[O:39])[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: C=CCC1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6ccccc6O)c5)nn34)cc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c4ccc5c(c4)C(CC=C)CCO5)n3n2)c1
Reaction time: 2 h
Yield: 105.8 %

Procedure:
A solution of (2S)-methyl 2-(7-(4-allylchroman-6-yl)-2-(2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.350 g, 0.567 mmol) in dry THF (12 ml) was treated sequentially with allyl alcohol (0.116 ml, 1.700 mmol), Ph3P (0.446 g, 1.700 mmol) and DEAD (0.269 ml, 1.700 mmol), and the reaction was stirred for 2 h. The reaction was concentrated, and the residue was purified by biotage (24 g SiO2, 0% (3 CV), 0-60% (15 CV), 60% (2 CV), EtOAc in hexane). The residue after concentration was taken up in Et2O (20 mL) and washed with water (2×20 mL) to remove residual allyl alcohol, then dried (MgSO4), filtered, and concentrated, affording the desired product (0.4 g, 0.6 mmol, quant.) as a viscous clear oil. 1H NMR (500 MHz, CDCl3) δ 8.11-8.04 (m, 1H), 7.90-7.84 (m, 1H), 7.58-7.36 (m, 5H), 7.35-7.29 (m, 1H), 7.06 (t, J=7.4 Hz, 1H), 7.02-6.93 (m, 2H), 6.90 (s, 1H), 6.04-5.91 (m, 1H), 5.90-5.78 (m, 1H), 5.37-5.30 (m, 4H), 5.27-5.13 (m, 4H), 5.12-5.02 (m, 2H), 4.55 (d, J=4.9 Hz, 2H), 4.30 (br. s., 2H), 3.82 (s, 3H), 2.68-2.63 (m, 3H), 1.01-0.93 (m, 9H). LCMS (M+H)=658.6.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][OH:37])=[CH:34][CH:33]=1>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]([O:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: COc1ccc(CO)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Cl)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
2,4-Dichloroquinoline (4.48 g, 25 mmol) was dissolved in dry THF (100 ml) and treated with sodium hydride (60% dispersion in oil, 5.62 g 25 mmol) under an argon atmosphere portion-wise over a period of 20 min. After a further 30 min the reaction mixture was treated with 15-crown-5 (5.62 g, 25 mmol) followed by 4-methoxybenzyl alcohol (3.44 g, 23 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then evaporated to low volume, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. Chromatography on Kieselgel 60 eluting with 10% ethyl acetate in hexane afforded the title compound as a white solid (2.67 g, 39%); δH (CDCl3) 5.20 (2H, s), 6.83 (1H, s), 6.97 and 7.43 (4H, 2×d, J=8.6 Hz), 7.49 (1H, t, J=8.1 Hz), 7.70 (1H, t, J=8.2 Hz), 7.94 (1H, d, J=8.3 Hz), 8.17 (1H, d, J=8.2 Hz); MS (ES+) 300 (MH+, 10%). 121 (100).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[I:20]I>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[N:11]=[C:12]([I:20])[S:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)OCc1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1csc(I)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a −78° C. solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole (106.4 mg, 0.465 mmol) in THF (5 mL) was added dropwise a solution of n-BuLi (465 μL of a 1.6M solution in hexanes, 0.744 mmol). The reaction was stirred at −78° C. for 30 minutes, and then a solution of iodine (295 mg, 1.16 mmol) in THF (5 mL) was added by cannula. The reaction was warmed to room temperature for 15 minutes and then quenched by pouring into aq. NaHSO3 (20 mL). The mixture was extracted with EtOAc (60 mL) and the organic layer was washed with brine, saturated NaHCO3, and brine (20 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography (15% EtOAc/hexanes) afforded 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole. Rf=0.55 (15% EtOAc/hexanes). LCMS=356.0 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.16 (s, 1H), 4.86 (s, 2H), 0.93 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18](B(O)O)[CH:19]=1.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=2[F:23])[CH:11]=1
Reactant: Clc1cc(Cl)c2cccnc2n1
Reactant: OB(O)c1cc(Cl)ccc1F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 9.95 g (50.0 mmol) 2,4-dichloro-[1,8]naphthyridine (described by Koller, Chemische Berichte 60: 407 (1927)), 8.72 g (50.0 mmol) 5-chloro-2-fluorophenylboronic acid und 5.04 g (60.0 mmol) sodium hydrogencarbonate in 100 ml DMF und 50 ml water was heated to 80° C. under nitrogen. 701 mg (1.0 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and the mixture was stirred for 16 hrs at 80° C. Water was added to the reaction mixture and the precipitate was filtered off, dried in vacuum and recrystallized from 2-propanol. This yielded 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine as yellowish crystals; HPLC-MS: 2.49 min, [M+H] 293.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1>>[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([N:10]4[CH2:9][CH2:8][N:7]([CH2:6][C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[CH2:12][CH2:11]4)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: c1csc(CN2CCNCC2)c1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)N1CCN(Cc2cccs2)CC1

Procedure:
Reaction of N-(2-thienylmethyl)piperazine and 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid (2 g) analogously to the procedure of Example 4 gave the title compound after suspending in methanol as the dihydrochloride salt; yield 3.50 g (95%), m.p. 244°-245° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][N:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:23])[NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][CH:9]=1)=[O:4].[OH-].[Na+:25]>C(O)C>[CH3:1][O:2][C:3]([NH:5][N:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:23])[NH:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][CH:13]=1)=[O:4].[Na+:25]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C=NNC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)NN=Cc1ccc(NC(=O)NCC(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5.15 g (15.98 mmol) of ethyl (3-(4-(methoxycarbonylaminoiminomethyl)phenyl)ureido)acetate are dissolved in 200 ml of ethanol and treated with 7.99 ml (15.98 mmol) of a 2N NaOH and the mixture is stirred at room temperature for 24 h. It is then concentrated in vacuo and the residue is freeze-dried.
Reaction SMILES: C([N:3]([C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])[C:4](=[O:8])[C:5]([O-:7])=O)C.[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[C:13]3[C:26]([CH3:27])=[C:9]([NH:3][C:4](=[O:8])[C:5](=[O:7])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=3[O:16][CH2:15]2)=[CH:18][CH:19]=1)([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CCN(C(=O)C(=O)[O-])c1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)C(=O)C(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a solution of ethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate (100 mg, 0.25 mmol) obtained in Example 15 in THF (3 ml) was added dropwise at 0° C. under an argon atmosphere tert-butylmagnesium chloride (2.0 M THF solution, 0.26 mL, 0.5 mmol) and the mixture was stirred for 30 minutes. After the reaction solution was stirred at room temperature for 1 hour, the reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to obtain 29 mg (yield: 28%) of the title compound. Melting point: 142-143° C.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33]([F:32])([F:45])[F:44])[CH:24]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)N(NC(=O)C1CCCCC1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)C1CCCCC1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 62.3 %

Procedure:
A solution of cyclohexanecarboxylic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (310 mg, 0.75 mmol) in DME (3 ml)/2M Na2CO3 (1.3 ml, 2.62 mmol) was treated 2-trifluoromethoxybenzeneboronic acid (231 mg, 1.12 mmol) and Pd[PPh3]4 (172 mg, 0.15 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 30-80% ethyl acetate/hexanes gradient to afford the product as a solid (232 mg, 63%). MS m/e 497.53 (M+H+)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:21].Cl.[NH2:23][CH2:24][CH2:25][O:26][NH2:27].N1C=CC=CC=1>C(O)C>[ClH:21].[ClH:21].[NH2:23][CH2:24][CH2:25][O:26][N:27]=[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 4-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-butanone (5.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (3.17 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180: 19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 3.1 g (42%) of product, mp 207°-208C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:14].[Na+].Cl>O>[OH:13][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][C:11]([OH:12])=[O:14]
Reactant: [OH-]
Reactant: O=C1CCC(c2ccc(F)cc2)O1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC(O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
Commercial γ-(p-fluorophenyl)-γ-butyrolactone, 18.0 g. (0.10mole) was added to a solution of 14.0 g. (0.35 mole) of sodium hydroxide in100 ml. of water and the mixture heated at reflux for 40 minutes. After cooling to 0° C., 70 ml. of 6 N hydrochloric acid was added at 0°-15° C. for one hour. The white solid which formed was filtered, washed with pentane and air dried to afford racemic-4-hydroxy-4-(p-fluorophenyl)butyric acid, 18.43 g., (93% yield). When heated to temperatures of about 100° C., the hydroxy acid was converted back to the starting lactone.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=2)(O)=[O:2].C(Cl)(=O)C(Cl)=O.C[N:28](C=O)C.C([O-])(=O)C.[NH4+]>C(Cl)Cl>[C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=2)(=[O:2])[NH2:28]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Solvent: ClCCl
Product: NC(=O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 2-carboxy-6-benzyloxy-1H-indole (0.125 g; 0.468 mmol), oxalyl chloride (0.5 mmol) and DMF (0.2 ml) in CH2Cl2 was stirred at room temperature for 2 hours. After evaporation to dryness, the residue was redissolved in acetone; ammonium acetate (0.074 g; 0.95 mmol) was added to the solution and the mixture was stirred at room temperature for 1 hour. After evaporation, the residue was purified by flash chromatography eluting with CH2Cl2/acetone 80/20 to give 2-carbamoyl-6-benzyloxy-1H-indole.
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(NO)(C)(C)C.C(=O)(O)[O-].[Na+].[H-].[Na+].[C:24]([C:28]1[S:32]/[C:31](=[N:33]\[C:34](=[O:46])[C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=2F)/[N:30]([CH2:47][C@H:48]2[CH2:52][CH2:51][CH2:50][O:49]2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:1]([NH:5][O:6][C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:42])([F:44])[F:43])=[CH:40][C:35]=1[C:34](/[N:33]=[C:31]1\[S:32][C:28]([C:24]([CH3:27])([CH3:25])[CH3:26])=[N:29][N:30]\1[CH2:47][C@H:48]1[CH2:52][CH2:51][CH2:50][O:49]1)=[O:46])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CC(C)(C)c1nn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)NOc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)nn1C[C@H]1CCCO1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-tert-butylhydroxylamine (145 mg, 1.62 mmol) (prepared from commercially available N-tert-butylhydroxylamine acetate (Aldrich) by adding saturated sodium bicarbonate solution and extracting the free base with ethyl ether) in anhydrous THF (10 mL) was added sodium hydride (58.4 mg, 1.46 mmol). The mixture was stirred at 0° C. for 20 minutes. A solution of Example 153A (350 mg, 0.81 mmol) in THF (4 mL) was added and the mixture was stirred at 0° C. for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 using an Analogix® Intelliflash280™ (Hexanes-EtOAc: 0-50% gradient) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (s, 9H), 1.42 (s, 9H), 1.74-1.89 (m, 1H), 1.88-2.08 (m, 3H), 3.74-3.84 (m, 1H), 3.89-4.00 (m, 1H), 4.29 (dd, J=12.0, 4.7 Hz, 1H), 4.45-4.63 (m, 2H), 5.73 (s, 1H), 7.59 (dd, J=8.8, 3.1 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H); MS (ESI) m/z 501 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:19])=[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1.O.C(O)(=O)C(O)=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:19])=[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:32]3[CH2:31][CH2:30][CH:29]([C:26]4[C:25]5[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=5[O:28][N:27]=4)[CH2:34][CH2:33]3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2sc(C)c(C(=O)CCCCl)c2C1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: O
Product: CC(=O)N1CCc2sc(C)c(C(=O)CCCN3CCC(c4noc5cc(F)ccc45)CC3)c2C1
Yield: 23.2 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.6 g of 5-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine and 1.4 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.6 g of 5-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil, m.p. 116°-118° C. as an oxalate monohydrate thereof.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl.[CH2:20](O)[CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH2:20][CH3:21])=[O:11])=[CH:17][CH:18]=1
Reactant: CCO
Reactant: O=C(O)c1ccccc1CCc1ccc(Br)cc1
Agent: Cl
Product: CCOC(=O)c1ccccc1CCc1ccc(Br)cc1

Procedure:
A solution of 40 g. (0.131 mole) of 2-(4-bromophenethyl)-benzoic acid in 250 ml. of absolute ethanol is stirred and heated to refluxing while hydrogen chloride is introduced into the solution for 2 hours. After standing at room temperature for 2 1/2 days, the mixture again is stirred at reflux for 12 hours and, during this period, hydrogen chloride is passed into the solution for 1 hour. The two-phase mixture is evaporated to dryness under reduced pressure and the residue partitioned between benzene and water. The combined benzene layers are extracted with 5% aqueous sodium hydroxide and then washed thoroughly with water and dried over anhydrous sodium sulfate. Evaporation of the solvent and distillation of the residue in vacuo gives the product as the oily distillate, b.p. 142°/0.2 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.O[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[O:9][CH2:18][CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:23](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:25])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCOC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Yield: 56.3 %

Procedure:
A mixture of (4-Bromo-phenyl)-(4-chloro-phenyl)-methanol (2.3 g, 7.73 mmol), N-(2-hydroxyethyl)phthalimide (1.4 g, 7.36 mmol) and para-toluenesulphonic acid monohydrate (560 mg, 2.94 mmol) in toluene (50 ml) was heated to reflux under Dean-Stark conditions for 17 hours. Upon cooling, the solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was then dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (SiO2), eluting with ethyl acetate/petroleum ether (1:4), to yield the title compound (1.95 g). LC/MS. (PS-B3) Rt 4.07 no observable mass ion.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:17][C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccncc1
Product: COc1ccc(C=Cc2ccncc2)cc1

Procedure:
By the procedure described in Ex. 1, 4-methoxybenzaldehyde (17 g) and 4-picoline (9.3 g) 4.76 g were reacted to obtain 4-(4-methoxystyryl)pyridine.