Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15]C(=O)OCC)[CH2:9][CH2:8]2)[C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[NH:3]1.[BrH:25]>O>[BrH:25].[BrH:25].[NH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:5]3[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=3[NH:3][C:2]2=[O:1])[CH2:8][CH2:9]1
Reactant: CCOC(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: Br
Solvent: O
Product: NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 0.333 parts of ethyl 2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethylcarbamate, 1.65 parts of hydrobromic acid solution 48% and 0.11 parts of water is stirred and refluxed for 2 hours. The hydrobromic acid and water are evaporated. The residue is taken up three times in benzene, while each time the latter is evaporated. The oily residue is crystallized from 2- propanol. The product is filtered off and recrystallized from a small amount of ethanol, yielding 0.27 parts of 1-[1-(2-aminoethyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one dihydrobromide; mp. +300° C(dec).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23](B3OC(C)(C)C(C)(C)O3)[C:18]=2[O:17][CH2:16]1.[F-].[K+]>C(#N)C.O.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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:23]2[C:18]3[O:17][CH2:16][O:15][C:19]=3[CH:20]=[CH:21][CH:22]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: CC1(C)OB(c2cccc3c2OCO3)OC1(C)C
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2cccc3c2OCO3)c(F)c(N)c1Cl
Yield: 68.7 %

Procedure:
Methyl 4-amino-3,6-dichloro-5-fluoropicolinate (1.5 g, 6.28 mmol), 2-(benzo[d][1,3]dioxol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.024 g, 8.16 mmol), potassium fluoride (0.875 g, 15.06 mmol; Note: Related examples utilize cesium fluoride) and bis(triphenylphosphine)palladium(II)chloride (0.440 g, 0.628 mmol) were combined in acetonitrile (13 mL) and water (4.5 mL). The reaction mixture was then irradiated in a microwave at 110° C. in a capped vial for 20 min, with external IR-sensor temperature monitoring from the side of the vessel. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried and concentrated onto 1.2 g of silica gel. This mixture was applied to the top of a silica gel column and the product was eluted with a 7-60% hexane/ethyl acetate gradient solvent system to provide the title compound as a white solid (1.4 g, 68.7%): mp 146-148° C.; 1H NMR (400 MHz, CDCl3) δ 7.16-7.09 (m, 1H), 6.98-6.85 (m, 2H), 6.01 (s, 2H), 4.91 (br s, 2H), 3.98 (s, 3H); ESIMS m/z 325 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].[C-:11]#[N:12].[K+].C(O)(=O)C.OP(O)(O)=O>CO.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:11]#[N:12])[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CSCC1=O
Reactant: [C-]#N
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C1CSCC1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 4-oxotetrahydro thiophene-3-carboxylic acid methyl ester (4 g, 25 mmol) in methanol (7 ml), cooled at 0° C., a solution of potassium cyanide (1.68 g, 30 mmol) in water (10 ml) was added. The mixture was acidified with acetic acid (1.5 ml, 25 mmol) and stirred at 0° C. for 8 hours. Then the mixture was acidified with H3PO4 and diluted with brine (50 ml) and extracted with CH2Cl2 (4×30 ml). The organic layers were dried over sodium sulfate and concentrated to give 4-cyano-tetrahydro thiophene-3-carboxylic acid methyl ester in 75% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH:18]1([S:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:20][CH2:19]1>>[CH:18]1([S:21][CH2:22][C:23]2[CH:24]=[C:25]([NH:26][C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=4[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: Nc1cccc(CSC2CC2)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: COc1cc(F)ccc1-c1nc(Nc2cccc(CSC3CC3)c2)ncc1F

Procedure:
Intermediate 48.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-[(cyclopropylsulfanyl)-methyl]aniline. The batch was purified by chromatography (hexane/ethyl acetate 30%) to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]2[CH2:10][CH2:11][C@:12]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])([CH3:14])[O:13][C:4]=2[C:3]=1[CH3:31].[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>CCCCCC>[CH3:31][C:3]1[C:4]2[O:13][C@@:12]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])([CH3:14])[CH2:11][CH2:10][C:5]=2[C:6]([CH3:9])=[C:7]([O:8][C:32]([CH3:33])=[O:34])[C:2]=1[CH3:1]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude α-tocopherol is treated with 25.0 g of acetic anhydride (corresponding to 244.9 mmol), 25.0 g of pyridine (corresponding to 316.1 mmol) and 1.0 g of 4-dimethyl-aminopyridine (corresponding to 8.2 mmol; catalytic amount) and stirred for one hour at room temperature. The reaction mixture is poured on to 100 g of ice/water (about 1:1), stirred for 30 minutes, treated with 250 ml of n-hexane and washed in succession twice with 150 ml of water each time, twice with 100 ml of 2N sulphuric acid each time, with 150 ml of water, with 150 ml of saturated sodium bicarbonate solution and three times with 150 ml of water each time. Thereafter, the mixture is dried over 3 g of anhydrous magnesium sulphate for 10 minutes while stirring. After filtration, distillation of the solvent at 400 mbar and a bath temperature of 60° C. and subsequent drying for 30 minutes at 15 mbar and a bath temperature of 70° C. there are obtained 29.26 g of α-tocopherol acetate as a yellow oil, α-tocopherol acetate content (GC, internal standard squalane) 87.5%, chemical yield (α-tocopherol acetate) 93.1%. This crude acetate is distilled in a bulb tube oven (250° C./10-1 mbar). There are obtained 26.25 g of α-tocopherol acetate as a slightly yellowish oil which crystallizes slowly upon standing at room temperature. α-Tocopherol acetate content (GC, internal standard squalane) 96.2%, chemical yield 91.8%; stereo-chemical purity: 99.6% R,R,R-α isomer (HPLC of the methyl ether derivative on Chiracel OD, n-hexane); the product is identical with α-tocopheryl acetate according to 1H-NMR, IR, MS and microanalytical data.
Reaction SMILES: C(OC([N:8]([S:13]([O:16][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23])(=[O:15])=[O:14])[CH2:9][CH2:10][O:11][CH3:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:12][O:11][CH2:10][CH2:9][NH:8][S:13]([O:16][N:17]1[C:18](=[O:23])[CH2:19][CH2:20][C:21]1=[O:22])(=[O:15])=[O:14]
Reactant: COCCN(C(=O)OC(C)(C)C)S(=O)(=O)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNS(=O)(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
To a solution of N-(N-t-butoxycarbonyl-N-(2-methoxyethyl)aminosulfonyloxy)succinimide (200 mg) in dichloromethane (2 ml) was added trifluoroacetic acid (2 ml) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. The solution was evaporated in vacuo to give N-(2-methoxyethylaminosulfonyloxy)succinimide as a colorless amorphous powder (149 mg).
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][C@H:19]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:17])([CH3:14])([CH3:13])[CH3:12].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=[CH2:1])[CH2:20][C@H:19]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C[C@H]1C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (248 g, 0.69 mol) in anhydrous toluene (1 L) was added sodium hexamethyldisilazide (258 ml, 0.69 mmol) at 0° C., after addition was completed, the reaction mixture was warmed to room temperature, and stirred at room temperature for 1 hour, then cooled to 0° C. and the solution of (S)-4-oxo-piperidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (intermediate 14, 210 g, 0.63 mol) in anhydrous toluene (0.5 L) was added. The resulting mixture was warmed to room temperature, and stirred at room temperature for 1 hour, added water (500 ml), extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1). (S)-4-Methylene-piperidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester was obtained as colourless oil (120 g), yield:57.4%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:35][CH:36]1[CH2:41][CH2:40][CH:39]([CH3:42])[CH2:38][CH:37]1[C:43]([O:45][CH2:46][CH3:47])=[O:44].[F:48][C:49]1[CH:54]=[CH:53][C:52]([SH:55])=[CH:51][CH:50]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.[Cl-].[Na+].O.CCOCC>[F:48][C:49]1[CH:54]=[CH:53][C:52]([S:55][CH2:35][CH:36]2[CH2:41][CH2:40][CH:39]([CH3:42])[CH2:38][CH:37]2[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:51][CH:50]=1
Reactant: CCOC(=O)C1CC(C)CCC1CO
Reactant: Fc1ccc(S)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C1CC(C)CCC1CSc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cold (0° C.) solution of triphenylphosphine (260 mg, 1.0 mmol) in dimethylformamide (1 mL) was added diisopropyl azodicarboxylate (180 μL, 0.9 mmol) and the reaction mixture was stirred at 0° C. for 10 min. A mixture of (1R/S,3R/S,6R/S)-ethyl 2-(hydroxymethyl)-5-methylcyclohexanecarboxylate and (1R/S,3S/R,6R/S)-ethyl 2-(hydroxymethyl)-5-methylcyclohexanecarboxylate (1:1 mixture, 160 mg, 0.8 mmol) and 4-fluorobenzenethiol (100 μL, 0.9 mmol) in dimethylformamide (1 mL) was added to the diisopropyl azodicarboxylate/triphenylphosphine mixture. The reaction mixture was warmed to room temperature and stirred for 3 h. Ether and brine were added and the aqueous layer was extracted with ether. The combined organic extracts were concentrated in vacuo and the residue was purified by flash chromatography over silica gel (ether/hexanes, 5/95) to afford the product (1R/S,3R/S,6R/S)-ethyl 2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methylcyclohexanecarboxylate and (1R/S,3S/R,6R/S)-ethyl 2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methylcyclohexane-carboxylate as a 1:1 mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18](Cl)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2nc(Cl)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Reactant: COc1ccc(CN)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c3cc(OC)ccc3n2)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
Under argon atmosphere, a solution of 1.75 g of (1R,2S)-N-tert-butoxycarbonyl-2-(2-chloro-6-methoxyquinazolin-4-yl)aminocyclohexylamine and 1.47 g of 4-methoxybenzylamine in 100 mL of anhydrous toluene was combined with 97 mg of palladium acetate, 268 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 1.03 g of sodium tert-butoxide, and stirred at 70° C. for 5 hours. The reaction solvent was concentrated, and then combined with water, extracted with chloroform, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain 1.62 g of the desirable compound.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([OH:16])=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[O:10])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[S:1]1[C:5]([C:6]2[C:7]([O:16][CH3:21])=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[O:10])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C=O)c(O)c1-c1cc2ccccc2s1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C=O)c(OC)c1-c1cc2ccccc2s1
Yield: 97.1 %

Procedure:
Ex-44B: 3-Benzo[b]thiophen-2-yl-2-hydroxy-4-methoxy-benzaldehyde (Ex-44A, 57.4 mg, 0.202 mmol) was dissolved in acetone (5 mL) and potassium carbonate (31 mg, 0.22 mmol) was added. Methyl iodide (25 uL, 0.40 mmol) was added and the solution was heated to reflux for 3.5 h. After cooling, the crude reaction mix was concentrated on the rotavap. The resulting residue was taken up in 10 mL of a 1:9 mix of saturated, aqueous NH4Cl to water and extracted with EtOAc (2×15 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to provide 58.5 mg of 3-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde as an orange, oily residue which was used without further purification, 97% yield. 1H-NMR (CDCl3) δ 10.31 (s, 1H), 7.92 (d, J=9 Hz, 1H), 7.81–7.88 (m, 2H), 7.56 (d, 1H), 7.33–7.39 (m, 2H), 6.88 (d, J=9 Hz, 1H), 3.91 (s, 3H), 3.64 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].C[Al](C)C.[N:14]1([CH2:23][C:24]2[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=O)=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1>>[CH:4]1([N:3]([CH2:1][CH3:2])[C:28](=[O:30])[C:27]2[CH:26]=[CH:25][C:24]([CH2:23][N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:16]=[CH:15]3)=[CH:34][CH:33]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCNC1CCCCC1
Reactant: CCOC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Agent: C[Al](C)C
Product: CCN(C(=O)c1ccc(Cn2cnc3ccccc32)cc1)C1CCCCC1

Procedure:
N-Cyclohexyl-N-ethyl 4-(1H-benzimidazylmethyl)benzamide was prepared by the method of Example 9 starting with N-ethylcyclohexylamine and reacting with trimethylaluminium and ethyl 4-(1H-benzimidazylmethyl)benzoate.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[OH-].[K+].S(O[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)(=O)C>C1(C)C(C)=CC=CC=1>[CH2:16]([O:7][CH:4]([CH2:5][O:6][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:3][N:2]([CH3:8])[CH3:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: CN(C)CC(O)CO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCCCCCC/C=C\CCCCCCCCOCC(CN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Reaction time: 3 h
Yield: 76 %

Procedure:
To a three-necked, 2-liter round bottom flask equipped with a Dean-Stork trap were added 3 -dimethylamino-1,2 -propanediol (6.08 g, 51.1 mmoles), xylene (1300 ml) and KOH (8.0 g). The solution was refluxed for 2 hours while removing water azeotropically via the Dean-Stork trap. Oleyl mesylate (40.0 g, 115.6 mmoles) in 100 ml xylene was added to the reaction mixture drop-wise in 30 minutes. Refluxing was continued for 3 hours and the reaction mixture concentrated to a gum. The gum was triturated with 400 ml hexane and filtered. The solid was washed with 100 ml hexane followed with 200 ml ethyl acetate. The filtrates were combined, concentrated and subjected to f lash chromatography. 2,3-dioleyloxy-1- (N, N-dimethylamino) propane was obtained as a colorless oil in 76% yield, TLC: Rf =0.37 (Silica gel: 5% EtOAc: hexane); IR: 2925, 2850, 1469, 1120, 1040 cm-1 ; HNMR (CDCl3) δ 5.35 (t, 4H) , 4.13 (q, 1H) 3.4-3.65 (m, 6H), 2.35-2.45 (m, 2H) , 2.25 (S, 6H) , 1.95-2.05 (m, 8H) , 1.5-1.65 (m, 4H) , 1.2-1.45 (m, 4H) 0.9 (t, 6H).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Br:16])=[CH:11][C:10]=1[C:17](=[O:28])[N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[CH3:19])C(OC)=O.O[Li].O.Cl>C1COCC1.O>[Br:16][C:12]1[C:13]([Cl:15])=[CH:14][C:9]([CH2:4][C:3]([OH:29])=[O:2])=[C:10]([C:17](=[O:28])[N:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH3:19])[CH:11]=1
Reactant: COC(=O)C(C(=O)OC)c1cc(Cl)c(Br)cc1C(=O)N(C)c1ccccc1OC
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1CC(=O)O
Yield: 37 %

Procedure:
A mixture of 2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-malonic acid dimethyl ester (1.4 g, 2.8 mmol) and LiOH.H2O (0.7 g, 16.7 mmol) was stirred at 60° C. in a mixture of THF (20 mL) and water (2 mL) for 24 hrs, then acidified by 1N HCl to pH 4. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and brine, and was dried over MgSO4. The filtrate was then concentrated and purified by silica gel flash column chromatography eluting with 10% MeOH in DCM to yield 2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-acetic acid (427 mg). MS: [M+H]+413.9/412.0; tR=2.60 min (method 1)
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]2[N:16]([CH:31]([CH3:33])[CH3:32])[C:17]3[C:22]([C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:7][CH:6]=1.[OH-].[Na+].N1CCOCC1>CO.C(OCC)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH:31]([CH3:33])[CH3:32])[C:15]=2/[CH:14]=[CH:13]/[CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:34])[C:3]([OH:35])=[O:2])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)C(=O)c1ccc(OC/C=C/c2c(-c3ccc(F)cc3)c3ccccc3n2C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCN1
Product: CC(C)n1c(/C=C/COc2ccc(C(=O)C(=O)O)cc2)c(-c2ccc(F)cc2)c2ccccc21
Yield: 75.7 %

Procedure:
As in Example 19, (E)-4-[3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propenyloxy]-alpha-oxobenzeneacetic acid methyl ester (0.354 g) in methanol (5 mL) was treated with 1N sodium hydroxide (0.9 mL). The usual work up gave 0.4 g of a oil, which was dissolved in diethyl ether and morpholine (0.07 g) was added. Crystallization was induced and the recovered solid was recrystallized from dichloromethane-ethyl acetate to provide 0.26 g of (E)-4-[3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indole-2-yl]-2-propenyloxy]-alpha-oxobenzeneacetic acid (1:1) morpholine salt as a colorless solid, mp 151°-152° C.
Reaction SMILES: Br[C:2]1[C:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C([Li])CCC.CCCCCC.CN([CH:36]=[O:37])C>C1COCC1>[CH2:16]([C:3]1[C:2]([CH:36]=[O:37])=[CH:11][C:10]2[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CN(C)C=O
Reactant: CCCCCCc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 5.43 g of 3-bromo-2-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 110 ml of THF was cooled to −78° C. with an acetone/dry ice bath and treated dropwise with 14.5 ml of butyllithium 1.6M in hexane (1.5 eq.). The mixture was kept at −78° C. for 1 hour. DMF (2.4 ml) was added at −78° C. The reaction mixture was stirred at −78° C. for 15 min. then was allowed to warm to room temperature for 2 hours. The mixture was quenched with water (100 ml) and the pH was adjusted to 2 with hydrochloric acid 25%. The mixture was extracted with 3 portions of 100 ml of ether. The combined organic extracts were washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo, giving a yellow oil. The product was purified by flash chromatography (SiO2, hexane then 5% ethyl acetate/hexane) yielding 4.41 g of a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9](OC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(C)o1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CCCO)o1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a solution of methyl 3-(5-methyl-2-furanyl)propionate (3.6 g, 20 mmol) in 50 mL of THF at 0° C. was added dropwise under nitrogen 8 mL of diisobutylaluminum hydride (1M in hexane), and the mixture was stirred at room temperature over-night. The resulting solution was diluted with 2 mL of water in 10 mL of THF and brine, and the mixture was stirred for 30 min. The solid was removed by filtration, and the filtrate was diluted with 20 mL of water, extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by passing through MPLC column (ethyl acetate/hexane) to afford 1.11 g of 3-(5-methyl-2-furyl) propan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[F:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:29]2[CH2:30][CH2:31][CH:26]([F:25])[CH2:27][CH2:28]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: FC1CCNCC1
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCCN1CCC(F)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for step D of example 223 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (130 mg, 0.32 mmol) and 4-fluoropiperidine (59.0 mg, 0.38 mmol). The title compound was afforded as a solid (15.0 mg, 10% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.13 (1H, m), 8.41 (1H, s), 4.71 (1H, m), 3.32 (2H, m), 3.20 (2H, m), 2.27 (4H, m), 1.83 (2H, m), 1.65 (4H, m). MS m/z: 493.06, 495.05 [M+H]+.