Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.C1C=CC=CC=1.Cl[CH2:26][N:27]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=2[CH:39]([CH3:41])[CH3:40])[S:28]1(=[O:30])=[O:29].[N-:44]=[N+:45]=[N-:46].[Na+]>O>[N:44]([CH2:26][N:27]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=2[CH:39]([CH3:41])[CH3:40])[S:28]1(=[O:30])=[O:29])=[N+:45]=[N-:46]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CN=[N+]=[N-])C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A solution of 18-crown-6 ether (0.60 g) and benzene (60 mL) was heated under reflux with a water separator for 1 hour, then cooled to room temperature. 2-Chloromethyl-4-isopropyl-6-methoxysaccharin (3.03 g) and sodium azide (0.65 g) were added, and the mixture was stirred for a week at room temperature, then chromatographed on a column of silica gel (silica gel 60, 83 g) using benzene as eluant. The fractions containing the product, which were identified by thin layer chromatography, were combined and concentrated affording 2-azidomethyl-4-isopropyl-6-methoxysaccharin as a solution in benzene (250 mL).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]1[N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[C:7]([C:30]2[CH:47]=[CH:46][C:33]([O:34][C@H:35]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)=[CH:6][CH:5]=1>C(O)C>[CH3:3][C:4]1[N:8]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:16]=2)[C:7]([C:30]2[CH:47]=[CH:46][C:33]([O:34][C@H:35]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[CH:6][CH:5]=1.[Na+:2]
Reactant: CCCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)cc1
Yield: 52.8 %

Procedure:
Ethanol (3 ml) and a solution of 1N sodium hydroxide in ethanol (0.480 ml) were added to (2R)-2-{4-[5-methyl-1-(4-dodecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoic acid (325 mg, 0.533 mmol) and the mixture was concentrated. To the residue was added ether to give the object compound as a solid. 160 mg (yield: 52.8%)
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C=O)C>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][O:9][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 2,2-diphenylethanol (1 g) in DMF (10 mL) was added 60% sodium hydride (350 mg) at 0° C. under Ar. The solution was stirred for 10 min, and t-butyl bromoacetate (888 uL) was added, and the solution was warmed to RT. After stirring 30 min, the reaction was quenched with water (20 mL), and the aqueous solution was extracted with ether (25 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The organic solution was dried (MgSO4), and silica gel flash chromatography (3% ethyl acetate/hexanes) yielded t-butyl (2,2-diphenylethoxy)acetate. The intermediate was treated with 25% TFA/CH2Cl2 for 1 h. The solvent was removed, and traces of TFA was removed by azeotroping with toluene to yield the title compound. 1H NMR (CDCl3) δ 7.1-7.4 (m, 10H), 4.32 (t, J=8.4 Hz, 1H), 4.0-4.1 (m, 4H).
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][CH2:10][N:11](C=O)[C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.Cl.C(=O)([O-])O.[Na+]>CO.O>[I:1][CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][CH2:10][NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1
Reactant: Cc1c2c(c(C)c3c1OC(C)(CI)C3)N(C=O)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c2c(c(C)c3c1NCC3)OC(C)(CI)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
3,5,6,7-Tetrahydro-2-(iodomethyl)-2,4,8-trimethyl-2H-furo[2,3-f]indole-5-carbaldehyde (3.71 g, 10 mmol) was dissolved in methanol (37 ml). To the solution was added concentrated hydrochloric acid, and stirred for 2 hours at 60° C. under argon atmosphere. The mixture was cooled to 0° C., made weakly basic with a saturated aqueous solution of sodium hydrogen carbonate, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was removed under reduced pressure, and this was subjected to chromatography on a small amount of silica gel with eluting with ethyl acetate. The resultant oil was crystallized from hexane to obtain 3.37 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@:10]1([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][C@H:12]2[C:24](O)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:33]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@:10]1([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:11][C@H:12]2[CH2:24][OH:25])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](N(Cc3ccccc3)Cc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@@]2(c3ccccc3)[C@H](N(Cc3ccccc3)Cc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Reaction time: 16 h
Yield: 75.6 %

Procedure:
(1R*,2R*,5S*,6R*)-2-Dibenzylamino-8-benzyl-6-(hydroxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 21; 400 mg, 0.78 mmol) was dissolved in tetrahydroftiran (10 mL) and treated with lithium aluminium hydride solution (800 μL, 1M, 0.8 mmol) in tetrahydrofuran. The resulting mixture was stirred for 16 hours, then a further portion of lithium aluminium hydride solution (200 μL, 1M, 0.8 mmol) in tetrahydrofuran was added. Stirred at 50° C. for 1 hour, then cooled, and water (40 μL) added, followed by 15% aqueous sodium hydroxide solution (40 μL), then water (120 μL). The suspension formed was filtered and the filtrate taken up in water (10 mL). This mixture was extracted with ethyl acetate (2×10 mL) and the extracts were dried (MgSO4), before being concentrated in vacuo. The gum remaining was purified by silica chromatography to give the title compound (295 mg, 0.59 mmol) as a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:4][CH:3]=1.[O-:41][C:42]#[N:43].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:6][CH:7]=1)[C:42]([NH2:43])=[O:41]
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(N)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(NC(N)=O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 40 °C
Reaction time: 2.3 h
Yield: 56 %

Procedure:
4-(4-Aminophenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (39.2 mg, 0.0730 mmol) was dissolved in acetic acid (1.57 mL) and water (1.57 mL), and the solution was added with aqueous sodium cyanate solution (0.139 mol/L, 1.57 mL, 0.219 mmol), followed by stirring at 40° C. for 2.3 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=10/0.5/0.5) to obtain 4-(4-ureidophenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (23.7 mg, yield 56%).
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.C1(OCCCBr)C2CCCCC=2C=CC=1.CSC1C=CC=CC=1N1CCNCC1.[ClH:58].FC(F)(F)C1C=C(N2CCN(CCCOC3C4CCCCC=4C=CC=3)CC2)C=CC=1.FC(F)(F)C1C=C(N2CCNCC2)C=CC=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:58][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1
Reactant: CSc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3)CC1
Reactant: Cl
Agent: BrCCCOc1cccc2c1CCCC2
Agent: CSc1ccccc1N1CCNCC1
Agent: FC(F)(F)c1cccc(N2CCN(CCCOc3cccc4c3CCCC4)CC2)c1
Product: Clc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3)CC1

Procedure:
4-(2-methylthiophenyl)-1-[3-(5,6,7,8-tetrahydronaphth-1-yloxy)-prop-1-yl]-piperazine from 1-(5,6,7,8-tetrahydronaphth-1-yloxy)-3-bromopropane and 1-(2-methylthiophenyl)-piperazine; yield 64% of theory; m.p. of the hydrochloride 224°-225°C. decomp.); 4-(3-trifluoromethylphenyl)-1-[3-(5,6,7,8-tetrahydronaphth-1-yloxy)-prop-1-yl]-piperazine from 1-(5,6,7,8-tetrahydro-napth-1-yloxy)-3-bromopropane and 1-(3-trifluoromethylphenyl)-piperazine; yield 84% of theory; m.p. of the dihydrochloride: 182°-183°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Cl:49][C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[Cl:49][C:50]1[CH:56]=[CH:55][C:53]([NH:54][C:22](=[O:23])[CH2:21][O:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:26][CH:25]=2)=[CH:52][CH:51]=1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(OCC(=O)Nc4ccc(Cl)cc4)cc3)c2cc1OC
Yield: 79.5 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenoxy}acetic acid (150 mg), WSC.HCl (122 mg), and HOBT.H2O (86 mg) were dissolved in chloroform (5 ml) to prepare a solution. 4-Chloroaniline (65 mg) was then added to the solution, and the mixture was heated under reflux for 5 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with 1 N hydrochloric acid, water, and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (156 mg, yield 79%).
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[CH2:7][CH2:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH2:11]/[CH:12]=[CH:13]\[C:14]([O:23][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])C.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[F:18][C:15]([F:16])([F:17])[C:14]([O:23][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])([C:19]([F:21])([F:22])[F:20])/[CH:13]=[CH:12]\[CH2:11][C:10]([CH3:31])([CH3:32])[CH2:9][CH2:8][CH2:7]/[CH:6]=[CH:5]/[CH2:4][OH:3]
Reactant: CCOC(=O)/C=C/CCCC(C)(C)C/C=C\C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/CO)(C(F)(F)F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of 10.09 g of (2E,9Z)-12,12,12-Trifluoro-7,7-dimethyl-11-triethylsilanyloxy-11-trifluoromethyl-dodeca-2,9-dienoic acid ethyl ester in 100 ml of toluene was added at −78° 40.0 ml of diisobutylaluminiumhydride (1.2 M in toluene) and stirring was continued for 30 min after which time t.l.c. indicated completion of the reaction. The mixture was washed with sat. aqueous NH4Cl-solution and water, the organic layer was dried over MgSO4 and evaporated to give 8.92 g of the pure (t.l.c.) title compound as a pale yellow oil. IR (neat): 3332m, br. (OH), 1669w (C═C).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]>CO.[Pd]>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccco1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCCO1
Reaction time: 48 h
Yield: 91.8 %

Procedure:
Methyl furoate (75 g, 0.595 mole) was dissolved in MeOH (150 ml), and poured into a Parr bottle. Air was replaced with argon, and then 10% Pd/C (2.5 g) was added. The atmosphere was replaced with H2 and methyl furoate was hydrogenated at 40 psi for 48 hours. The reaction was filtered through celite pad, and the pad was washed with ether. The filtrate and the wash were combined and distilled to give the title compound (71 g, 0.546 mole, 59° C./5.1 mmHg, 92%) as a colorless liquid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:17][CH:16]=3)=[CH:9][N:8]2[C:30]=1[CH3:31].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:31][C:30]1[N:8]2[CH:9]=[C:10]([NH:13][C:14](=[O:29])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:19][CH:20]=3)[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[CH2:4][CH2:3][CH2:2][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: Cc1c(CCCO)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12
Product: Cc1c(CCCN2CCOCC2)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12

Procedure:
The compound (20.0 mg) obtained in Example 14 and morpholine (1 mL) were processed in the same manner as in Production Example 46-3 to obtain the entitled compound (13.0 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[NH2:25][CH2:26][C:27]1[CH:39]=[CH:38][C:30]2[O:31][C:32]([CH3:37])([CH3:36])[O:33][C:34](=[O:35])[C:29]=2[CH:28]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:25][CH2:26][C:27]3[CH:39]=[CH:38][C:30]4[O:31][C:32]([CH3:37])([CH3:36])[O:33][C:34](=[O:35])[C:29]=4[CH:28]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)OC(=O)c2cc(CN)ccc2O1
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Solvent: CC(=O)O
Product: CCCCc1ccc(C#Cc2ccc(CNCc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethynyl]benzaldehyde and 6-(aminomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-4-one acetate as a yellow oil (83%). 1H NMR (CDCl3, 300 MHz) δ 7.91 (s, 1H), 7.55 (m, 1H), 7.47 (d, J=7.9 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 7.14 (m, 2H), 6.92 (d, J=8.3 Hz, 1H), 3.80 (s, 2H), 3.77 (s, 2H), 2.61 (m, 2H), 1.72 (s, 6H), 1.65-1.54 (m, 2H), 1.43-1.10 (m, 2H), 0.92 (m, 3H). M+ (ESI): 454.4. HPLC, Rt: 4.23 min (Purity: 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH3:21][O:20][N:19]([CH3:18])[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CNOC
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reaction time: 8 h

Procedure:
2(S)-(tert-Butoxycarbonylamino)hexanoic acid (24.6 g, 0.106 mol), N,O-dimethylhydroxylamine hydrochloride (15.5 g, 0.15 mol), EDC hydrochloride (22.3 g, 0.117 mol) and HOBT (14.3 g, 0.106 mol) were stirred in dry, degassed DMF (300 mL) at 20° C. under nitrogen. N-Methylmorpholine was added to obtain pH 7. The reaction was stirred overnight, the DMF distilled under high vacuum, and the residue partitioned between ethyl acetate and 2% potassium hydrogen sulfate. The organic phase was washed with saturated sodium bicarbonate, water, and saturated brine, and dried with magnesium sulfate. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:21]([C:17]3[O:16][CH:20]=[CH:19][CH:18]=3)=[O:22])[S:10][C:3]=12
Reactant: O=C(Cl)c1ccco1
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccco1)c1cc2nccc(Cl)c2s1
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
To a solution of 2 (100 mg, 0.589 mmol) in THF (6 mL) at −78° C., was added n-BuLi (2.5 M in hexane, 0.259 mL, 8.84 mmol) and the reaction mixture was stirred 15 minutes. 2-Furoyl chloride (0.087 mL, 0.884 mmol) was added drop wise; the mixture was stirred for additional 2 hours and partitioned between DCM and water. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound 239 (35 mg, 23% yield, crude) as a yellow solid, that was used in the next step without additional purification. MS (m/z): 264.0 (100%), 266.0 (40%) (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[N:3]1[CH2:11][C:12]([F:15])([F:14])[F:13].C(Cl)Cl>C([O-])(O)=O.[Na+]>[CH3:1][C:2]1([CH3:16])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:9])([CH3:10])[N:3]1[CH2:11][C:12]([F:14])([F:15])[F:13]
Reactant: CC1(C)CC(O)CC(C)(C)N1CC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(=O)CC(C)(C)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.1 %

Procedure:
To a solution of 2,2,6,6-tetramethyl-1-(2,2,2-trifluoro-ethyl)-piperidin-4-ol (780 mg, 3.25 mmol; J. Phys. Org. Chem., 16(3), 175-182 (2003)) in DCM (50 mL) Dess-Martin periodinane (1.6 g, 3.2 mmol; Adv. Syn. Catalysis, 346, 111-124 (2004)) was added portionwise at 0° C. The resulting mixture was stirred at RT for 48 h, diluted with satd NaHCO3 (50 mL) and was extracted with DCM (3×25 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The resulting oil was chromatographed on silica (10-50% EtOAc/hexane) to obtain the title compound 309 mg, 40%. Mass spectrum (ESI, m/z): Calcd. for C11H18F3N, 238.1 (M+H). found 238.0.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.Br[CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[C:9]1([C:2]2([N:1]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccccc2)(N2CCCC2)CC1
Yield: 49 %

Procedure:
A reaction mixture consisting of the free base from 2.69 gm. (0.01 mole) of 4-amino-4-phenylcyclohexanone, ethylene ketal hydrochloride (prepared in Example 32, above) 2.16 gm. of 1,4-dibromobutane, 2.76 gm. potassium carbonate, and 15.0 ml. ethanol is heated at the reflux temperature, with stirring, for eighteen (18) hours. The volatile components are then substantially removed by evaporation under reduced pressure, and the concentrate thus obtained diluted with water. A precipitate forms which is collected on a filter and dissolved in diethyl ether. The ether solution is treated with an equivalent of 3 N hydrogen chloride in diethyl ether. A precipitate that forms is collected on a filter and recrystallized from a mixture of methylene chloride and ethyl acetate. There is thus obtained 1.57 gm. (49% yield) of 4-phenyl-4-(1-pyrrolidinyl)cyclohexanone, ethylene ketal hydrochloride having a melting range from 238° to 239.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](OC(C)(C)C)(=[O:25])[CH2:21][C:22]([CH3:24])=[O:23].C(OCC)(=O)C.CCCCCC>C1(C)C(C)=CC=CC=1>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:20](=[O:25])[CH2:21][C:22](=[O:23])[CH3:24])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 120 °C
Yield: 31.2 %

Procedure:
A mixture of 3-amino-2-benzoyl-6-chloroindole (Example 1) (850 mg, 4.07 mmol) and tert-butyl acetoacetate (1.3 ml, 8.15 mmol) in xylene (10 ml) was heated at 120° C. for 5 h. The mixture was concentrated and purified by flash column chromatography eluting with hexane/ethyl acetate (2/1) to give a yellow amorphous solid. Recrysalization from ethyl acetate/hexane afforded 450 mg (31%) of the titled compound as a pale yellow solid. m.p.: 170-173° C. 1H-NMR (CDCl3) δ: 10.22 (1H, br s), 8.47 (1H, br s), 8.01 (1H, d, J=8.8 Hz), 7.83-7.77 (2H, m), 7.65-7.50 (3H, m), 7.32 (1H, d, J=1.5 Hz), 7.11 (1H, dd, J=1.5, 8.8 Hz), 3.56 (2H, s), 2.32 (3H, s).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of diisopropylamine (7.7 mL, 54.88 mmol) in dry tetrahydrofuran (23 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5 M solution of n-butyllithium in hexanes (22.0 mL, 54.88 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-bromophenylacetic acid (5.62 g, 26.13 mmol) in dry tetrahydrofuran (23 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). The reaction mixture turned dark in color and was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (5.76 g, 27.44 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified using a 10% aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid (3.88 g, 50%) as a light yellow solid: mp 91-93° C.; EI-HRMS m/e calcd for C14H17BrO2 (Me) 296.0412, found 296.0417.