Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH:10]1[CH:19](O)[C:18]2[C:13](=[CH:14][C:15]([CH3:21])=[CH:16][CH:17]=2)[O:12][CH2:11]1)=[O:8].C(OC(=O)C)(=O)C.FC(F)(F)C(O)=O>C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH3:21])=[CH:16][CH:17]=2)[O:12][CH2:11]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NC1COc2cc(C)ccc2C1O
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(Cl)cc1C(=O)NC1COc2cc(C)ccc2C1

Procedure:
7.7 g (22 mmol) of 3-(5-chloro-2-methoxybenzamido)-7-methylchroman-4-ol were hydrogenated in a mixture of 80 ml of glacial acetic acid, 7.5 ml of acetic anhydride and 0.5 ml of trifluoroacetic acid with 0.5 g of Pd/C (10 %) at 25° C. under atmospheric pressure for about 3 hours. The catalyst was filtered off and the filtrate was concentrated to a small volume in vacuo. The residue was introduced into ice/water and the mixture was extracted several times with methylene chloride. The combined methylene chloride extracts were washed with sodium bicarbonate solution and water, dried and concentrated and the residue was recrystallized from diisopropyl ether. The 3-(5-chloro-2-methoxybenzamido)-7-methylchroman had a melting point of 97° C.
Reaction SMILES: [N+](C1C=CC([C:10]2[CH:22]=[C:21]([C:23]([O-])=[O:24])[C:20]3[C:19]4[C:14](=[C:15]([Cl:26])[CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:12]=3[C:11]=2[O:35][CH3:36])=CC=1)([O-])=O.[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH2:44].[H-].[Na+]>CN(C=O)C>[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH:44][C:23]([C:21]1[C:20]2[C:19]3[C:14](=[C:15]([Cl:26])[CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:12]=2[C:11]([O:35][CH3:36])=[CH:10][CH:22]=1)=[O:24]
Reactant: COc1c(-c2ccc([N+](=O)[O-])cc2)cc(C(=O)[O-])c2c3cccc(Cl)c3n(Cc3ccc(F)cc3)c12
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cccc(Cl)c3n(Cc3ccc(F)cc3)c12
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of 4-nitrophenyl-8-chloro-9-(4-Fluorobenzyl)-1-methoxy-9H-4-carbazole carboxylate (100 mg, 0.1982 mmoles) and 3,5-dichloro 4-amino pyridine (32.3 mg, 0.1982 mmoles) in dry DMF (7 mL), at 25° C. under nitrogen atmosphere, sodium hydride 55% (10.3 mg, 0.2576 mmoles) was added and stirred for 1 hr. The reaction mixtre was quenched in ice cold water (25 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with bicarbonate (2×25 mL), followed by 1N HCl (2×25 mL) and with brine (25 mL), dried over sodium sulphate and concentrated to give the 70 mg of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CO.C1COCC1>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:20])=[O:3])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)#[N:19]
Reactant: CCOC(=O)CC1CCN(c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(N2CCC(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (1.38 g) obtained in the above (2) is dissolved in a mixture of methanol (20 ml) and THF (10 ml), and thereto is added an aqueous sodium hydroxide solution (NaOH; 2.1 g, water; 10 ml), and the mixture is stirred at room temperature for 30 minutes. The pH value of the mixture is adjusted to pH 1 with conc. hydrochloric acid, and the reaction mixture is concentrated under reduced pressure. To the residue is added isopropanol, and the mixture is stirred at room temperature for one hour, and the precipitates are removed by filtration. The filtrate is concentrated under reduced pressure to give the title compound (1.20 g) as a powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:16]=2[CH:17]=[CH:18][CH:19]=1)=O.O>O1CCCC1>[OH:8][CH2:9][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=1)(=[O:22])=[O:21]
Reactant: COC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CO)cccc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
The suspension of 1.9 g of lithium-aluminum hydride in 165 ml of tetrahydrofuran cooled to 0° C. is proportionately mixed with 16.45 g of 1-tosylindole-4-carboxylic-acid-methylester. After 30 minutes 1.9 ml of water, 1.9 ml of 15% soda lye and 5.7 ml of water are carefully and sequentially dripped in. After 20 minutes, the precipitate is filtered off, washed out with acetic-acid-ethylester and the filtrates are concentrated. The raw product (15.97 g) is crystallized out of diisopropylether. 13.15 g of 4-hydroxymethyl-1-tosylindole with a m.p. of 125°-126° C. is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH2:20][C@@H:21]([OH:39])[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[C:31]=2[CH3:38])[CH2:25][CH2:24]1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([NH:19][CH2:20][C@@H:21]([OH:39])[CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[C:31]=3[CH3:38])[CH2:25][CH2:24]2)=[O:14])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)COc1cccc(C(=O)O)c1
Reactant: Cc1c(OC2CCN(C[C@H](O)CN)CC2)ccc(Cl)c1Cl
Product: Cc1c(OC2CCN(C[C@H](O)CNC(=O)c3cccc(OCC(=O)OC(C)(C)C)c3)CC2)ccc(Cl)c1Cl

Procedure:
Prepared as for Example 15 Step 2 using 3-(2-tert-butoxy-2-oxoethoxy)benzoic acid [WO 00/78317 A1] and (2R)-1-amino-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]propan-2-ol to yield the subtitle compound as a white solid (0.11 g).
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]1=2
Reactant: Brc1ccccc1I
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccccc1-n1c2ccccc2c2cnccc21
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A mixture of 84.1 g (500 mmol) of 5H-pyrido[4,3-b]indole [244-69-9], 147.1 g (520 mmol) of 2-bromoiodobenzene [583-55-1], 103.7 g (750 mmol) of potassium carbonate, 31.8 g (500 mmol) of copper powder and 300 g of glass beads (diameter 3 mm) in 800 ml of DMF is stirred at 130° C. for 24 h. After cooling, the mixture is filtered through a short Celite bed, the bed is rinsed with DMF, and the latter is removed in vacuo. The residue is dissolved in 1500 ml of dichloromethane, and the solution is washed three times with 500 ml of concentrated ammonia solution each time and dried over magnesium sulfate. After removal of the dichloromethane in vacuo, the oily residue is distilled in a short-path evaporator (p=5×10−3 mbar, T=120° C.). Yield: 56.1 g (173 mmol), 35%; purity: 98% (1H-NMR).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.[OH:12]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(O)(=O)C>[OH:12][C:7]12[CH2:9][CH:3]3[CH2:4][CH:5]([CH2:10][CH:1]([C:2]3=[O:11])[CH2:8]1)[CH2:6]2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: O=O
Solvent: CC(=O)O
Product: O=C1C2CC3CC1CC(O)(C3)C2
Yield: 48 %

Procedure:
A mixture of 0.1 mol of 2-adamantanone, 10 mmol of N-hydroxyphthalimide, 0.33 mmol of acetylacetonatovanadium V(AA)3, 0.17 mmol of acetylacetonatomanganese Mn(AA)2, and 250 ml of acetic acid was stirred at 85° C. in an oxygen atmosphere (1 atm) for 10 hours. The resulting reaction mixture was concentrated and was then extracted with ethyl acetate. A portion of an organic layer was concentrated and was then cooled for crystallization to yield 5-hydroxy-2-adamantanone (yield: 48%). The conversion rate from 2-adamantanone was 74%.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])=[O:3].C(O)C.C(OCC(O)COC1C=CC([NH:27][C:28](=[O:32])[CH2:29][CH2:30]Cl)=CC=1)C>[OH-].[Na+]>[C:2]([NH:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6][S:7][CH2:30][CH2:29][C:28]([NH2:27])=[O:32])(=[O:3])[CH3:1]
Reactant: CCOCC(O)COc1ccc(NC(=O)CCCl)cc1
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)NC(CSCCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A 1.63 g quantity of L-acetylcysteine was dissolved in 0.80 g of sodium hydroxide and 50 ml of a 70% aqueous solution of ethanol with ice cooling. To the solution was added 3.02 g of N-[4-(3-ethoxy-2-hydroxypropoxy)phenyl]-3-chloropropionamide. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was adjusted to a pH of 3 with diluted hydrochloric acid, washed with chloroform and extracted with ethyl acetate. The ethyl acetate layer was dewatered with Glauber's salt and was concentrated. The residue was purified with acetone-ether, giving 3.95 g of N-] 4-(3-ethoxy-2-hydroxypropoxy)phenyl]-3-(2-acetylamino-2 carboxyethylthio)propionamide in a yield of 92.1 %. ##STR5##
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][CH:32]4[CH3:36])[N:19]=3)[CH2:14][CH2:13]2)=[N:7][CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][OH:3])[CH:6]=[N:7][C:8]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:21]=[C:20]([N:31]3[CH2:35][CH2:34][CH2:33][CH:32]3[CH3:36])[N:19]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)CC2)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(CO)cc3Cl)CC2)n1
Temperature: -78 °C

Procedure:
Dissolve 5-chloro-6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (595 mg, 1.13 mmol, prepared in Example 1-B, step 5, above) in DCM and cool to −78° C. using a dry ice/acetone bath. Add diisobutylaluminum hydride (4.53 mL, 1N in hexanes) dropwise and continue stirring for 1 h at −78° C. Add excess Na2SO4.10H2O, stir at −78° C. for 5 min and then remove the cooling bath and allow to come to room temperature. Filter the mixture through celite washing with DCM then concentrate under reduced pressure. The resulting oil is purified using flash chromatography (30-50% EtOAc/hexanes eluent) to afford the title compound as a white foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)([OH:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[CH:24]1([C:7]2([OH:23])[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=3)[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:6]2[C:4]([OH:5])=[O:3])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)(C1CCCCC1)C(C(=O)O)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.7 %

Procedure:
1-Cyclohexyl-1-hydroxy-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (20 mg, 0.051 mmol) prepared in Example 6 was dissolved in THF, and an excess amount of sodium hydroxide dissolved in aqueous ethanol was added thereto in such a way not to cause layer separation. The mixture was stirred for 24 hrs at RT, and the pH was adjusted to 3˜4 using 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure, to obtain 15 mg of the titled compound (yield: 80%).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH:14]=[O:15])[CH3:2].[BH4-].[Na+]>CCO>[CH2:1]([N:3]([CH2:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][CH2:22]1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:5]=1[CH2:14][OH:15])[CH3:2]
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl [trans-4-({ethyl[2-formyl-4-(trifluoromethyl)phenyl]amino}methyl)cyclohexyl]acetate (Step A; 153 mg; 0.38 mmol) in EtOH (1 mL) was added sodium borohydride (7.3 mg; 0.19 mmol). The reaction stirred at room temperature for 1 h and was concentrated in vacuo. The residue was redissolved in EtOAc (10 mL) and washed with sat. NH4Cl (10 mL). The aqueous layer was re-extracted with EtOAc (2×10 mL) and the combined organic layers were washed with H2O and brine (10 mL each), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford ethyl [trans-4-({ethyl[2-(hydroxymethyl)-4-(trifluoromethyl)phenyl]amino}methyl)cyclohexyl]acetate as a yellow oil. LCMS=402.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.56-7.54 (m, 2 H), 7.29-7.26 (m, 1 H), 4.85 (s, 2 H), 4.13 (q, J=7.1 Hz, 2 H), 3.10-3.02 (m, 2 H), 2.91-2.85 (m, 2 H), 2.17 (d, J=6.9 Hz, 2 H), 1.84-1.70 (m, 4 H), 1.57-1.44 (m, 2 H), 1.39-1.31 (m, 1 H), 1.26 (t, J=7.1 Hz, 3 H), 1.08-1.04 (m, 3 H), 1.01-0.93 (m, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=2)[CH2:7][CH2:6]1)=[O:4].C(OCC)(=O)C>C(O)C>[CH3:1][O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:18])[CH:10]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C1(Oc2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4.49 g (17.6 mmol) 1-(3-fluoro-4-nitro-phenoxy)-cyclopropanecarboxylic acid methyl ester in 50 mL ethanol 0.5 g 10% palladium on charcoal was added and the suspension stirred for 8 h at room temperature under an atmosphere of hydrogen (1.7 bar). After the addition of 100 mL ethyl acetate the catalyst was filtered off, the filtrate evaporated and dried under high vacuum to give the title compound as a brown oil (98%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[C:6]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10](OC)=[O:11])#[N:2].CO.[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1>[F:23][C:16]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=1[C:6]1[C:5]([CH2:4][CH2:3][C:1]#[N:2])=[CH:14][C:9]([CH2:10][OH:11])=[CH:8][N:7]=1
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(CCC#N)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(CO)cc2CCC#N)c1
Yield: 85.1 %

Procedure:
To a mixture of methyl 5-(2-cyanoethyl)-6-(2-fluoro-5-methoxyphenyl)nicotinate (548 mg), methanol (2 mL) and THF (10 mL) was added sodium borohydride (208 mg), and the mixture was refluxed for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (425 mg) as a colorless oil.
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[C:9]([CH3:26])[N:8]=1)([OH:3])=[O:2].ClC1C=C(C=CC=1)C(OO)=[O:32].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([CH2:4][CH:5]=[CH:6][C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[C:9]([CH3:26])[N+:8]=1[O-:32])([OH:3])=[O:2]
Reactant: CCCCCCCCCCCCOc1ccc(C)nc1/C=C/CC(=O)O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C)[n+]([O-])c1C=CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine (2.15 g, 5.95 mmol) was dissolved in dry CH2Cl2 (20 mL) and cooled to 0∞C; 85% m-chloroperoxybenzoic acid (1.45 g, 7.14 mmol) was added and the reaction was stirred at 0∞C for 30 minutes and at room temperature for 16 hours. The reaction solution was poured into sainted aqueous NaHCO3 (20 mL). The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the combined CH2Cl2 extracts were washed with H2O (20 mL) and brine and dried (MgSO4). The crude pale yellow solid was used directly in the next step without further purification: 1H NMR (250 MHz, CDCl3): δ 8.23 (d, J=16.2 Hz, 1H, olefin), 7.58 (d, J=16.2 Hz, 1H, olefin), 7.13 (d, J=8.8 Hz, 1H, 5- pyridyl), 6.79 (d, J=8.8 Hz, 1H, 4-pyridyl), 4.06 (t, J=6.6 Hz, 2H, OCH2), 3.81 (s, 3H, CO2CH3), 2.45 (s, 3H, CH3), 1.92-0.85 (m, 23H, aliphatic); MS (CI): 378.2 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=O)=O)[S:9][CH:10]=1.FC(F)(F)C([O-])=O.[NH4+:28].O>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([C:11]2[NH:28][C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=2)[S:9][CH:10]=1
Reactant: [NH4+]
Reactant: O=C(NC1CCCCC1=O)c1nc(-c2ccco2)cs1
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: c1coc(-c2csc(-c3nc4c([nH]3)CCCC4)n2)c1
Yield: 28.2 %

Procedure:
4-(2-Furyl)-N-(2-oxocyclohexyl)thiazole-2-carboxamide (239 mg, 0.823 mmol) obtained in Step 2 and ammonium trifluoroacetate (1.00 g, 7.63 mmol) were stirred at 140° C. for 2 hours, and water and ethyl acetate were added thereto, then the mixture was extracted. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give a title compound (63.0 mg, 28%).
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.[NH2:7][C:8]1[C:9](Br)=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1.[C-]#N.[Na+].O>C1C=CC=CC=1>[C:2]([C:9]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=[CH:13][C:8]=1[NH2:7])#[N:1]
Reactant: c1ccncc1
Reactant: Nc1cccc(C(F)(F)F)c1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1c(N)cccc1C(F)(F)F

Procedure:
To 21 g. of dry pyridine is added slowly with stirring 23 g. (0.26 mol.) of cuprous cyanide. The mixture rapidly solidifies and is then heated to 125°. Excess pyridine is boiled off and the temperature is decreased to 110°. 3-Amino-2-bromobenzotrifluoride (48 g., 0.20 mol.) is added with stirring and the reaction mixture is heated to 165°-170° for 75 minutes. The mixture is then cooled to 90° and a solution of 75 g. (1.05 mol.) of sodium cyanide in 75 ml. of water is added followed by 250 ml. of benzene. The resulting mixture is stirred for one hour, the layers are separated and the benzene layer is washed with water, dried and evaporated to give 2-cyano-3-trifluoromethylaniline.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1)[C:12]([OH:14])=O.[NH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34](=[N:36]O)[NH2:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(C1C=CC(S(N)(=O)=O)=CC=1)#N.CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:14][N:36]=[C:34]([C:31]3[CH:30]=[CH:29][C:28]([S:25]([NH2:24])(=[O:26])=[O:27])=[CH:33][CH:32]=3)[N:35]=2)[CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1
Reactant: COc1cc(C(=O)O)ccc1-c1cscc1C
Reactant: NC(=NO)c1ccc(S(N)(=O)=O)cc1
Agent: N#Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc(-c3ccc(S(N)(=O)=O)cc3)no2)ccc1-c1cscc1C

Procedure:
Oxalyl chloride (123 mL; 1.45 mmol), Intermediate 8 (120 mg; 0.48 mmol), 4-(aminosulfonyl)-N′-hydroxybenzenecarboximidamide, prepared as described in WO 2006/013104 A1 from 4-cyanobenzene-1-sulfonamide (ABCR; CD10716), (104 mg; 05 mmol, 1 eq.) and DIEA (250 mL; 1.45 mmol) were reacted according to the procedure described for Example 38. Purification by recrystallisation from DCM/n-pentane afforded the title compound as a white solid. LC/MS (Method A): 426.3 (M−H)−. HPLC (Method A) Rt 4.93 min (purity 89.2%).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:15][C:14]([C:16]#[N:17])=[CH:13][CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].CS(Cl)(=O)=O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:46]=[CH:45][C:35]([O:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:34][CH:33]=1>C(#N)C.CN(C)C=O.[Cl-].[Na+].O.C(N(CC)CC)C>[C:1]([C:3]([C:11]1[S:15][C:14]([C:16]#[N:17])=[CH:13][CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:42]1[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][O:36][C:35]2[CH:45]=[CH:46][C:32]([F:31])=[CH:33][CH:34]=2)[CH2:44][CH2:43]1)#[N:2]
Reactant: Fc1ccc(OCCN2CCNCC2)cc1
Reactant: CC(C)C(C#N)(CCCO)c1ccc(C#N)s1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2ccc(F)cc2)CC1)c1ccc(C#N)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexanol, 273 mg 1.10 mmol, was dissolved in acetonitrile 5.00 ml and cooled at 0° C. Triethylamine 0.16 ml and methane sulfonyl chloride 0.10 ml 1.21 mmol were added thereto and the temperature was raised to room temperature. After 1 hour, the mixture was partitioned by adding ether and brine. The organic layer was washed with aqueous saturated sodium bicarbonate, dried over magnesium sulfate anhydride and evaporated. A half about 0.55 mmol of the residues was dissolved in N,N-dimethylformamide 5.00 ml, and 500 mg 3.34 mmol of sodium iodide, 76.0 mg 0.55 mmol of potassium carbonate, and 202 mg 0.90 mmol of 1-[2-(4-fluorophenoxy)ethyl]piperazine were added thereto, and the mixture was heated at 60° C. Brine was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate anhydride, and evaporated. The residue was purified by Chromatorex NH silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound, 215 mg 0.47 mmol, 86.0%, was obtained as a yellow syrup.