Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)CCCCCCCO.FC1C(F)=C(F)C=CC=1CBr.[F:22][C:23]1[C:39]([F:40])=[C:38]([F:41])[CH:37]=[CH:36][C:24]=1[CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35].FC1C(F)=C(F)C=CC=1COCCCCCCCC(O)=O.Cl.Cl.[CH2:65]([O:72][C:73](=[O:81])[CH2:74][C@@H:75]([NH2:80])[CH2:76][N:77]([CH3:79])[CH3:78])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>>[CH2:65]([O:72][C:73](=[O:81])[CH2:74][C@@H:75]([NH:80][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][C:24]1[CH:36]=[CH:37][C:38]([F:41])=[C:39]([F:40])[C:23]=1[F:22])[CH2:76][N:77]([CH3:78])[CH3:79])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: OCCCCCCCCOCc1ccc(F)c(F)c1F
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: Fc1ccc(CBr)c(F)c1F
Agent: O=C(O)CCCCCCCOCc1ccc(F)c(F)c1F
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1F

Procedure:
The title compound, m/e=432.5 ([M+H]+), was produced in analogy with intermediate 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 2,3,4-trifluorobenzyl bromide, leading to 8-(2,3,4-trifluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(2,3,4-trifluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(2,3,4-trifluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[C:18]1([CH:24](OC(=N)C(Cl)(Cl)Cl)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl.C1CCCCC1>[C:18]1([CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=2)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)COc1cccc(CCCCO)c1
Reactant: N=C(OC(c1ccccc1)c1ccccc1)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCCCC1
Solvent: CCOCC
Product: COC(=O)COc1cccc(CCCCOC(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of methyl 3-(4-hydroxybutyl)phenoxyacetate (372 mg) and diphenylmethyltrichloroacetoimidate (771 mg) in chloroform (4 ml) and cyclohexane (8 ml) was added a catalytic amount of boron trifluoride etherate at 0° C. After being stirred for 30 min at 0° C., the mixture was quenched by addition of a saturated aqueous solution of sodium bicarbonate and extracted with ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (343 mg) having the following physical data.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[C:6]1([N:12]2[C:20](=[O:21])[C:19]3[C@@H:18]4[C:22]([CH3:24])([CH3:23])[C@@:15]([CH3:25])([CH2:16][CH2:17]4)[C:14]=3[NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH:5]1([CH2:4][N:13]2[C:14]3[C@:15]4([CH3:25])[C:22]([CH3:24])([CH3:23])[C@@H:18]([CH2:17][CH2:16]4)[C:19]=3[C:20](=[O:21])[N:12]2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Reactant: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2)n1CC1CC1
Temperature: 100 °C
Yield: 48.5 %

Procedure:
A mixture of (bromomethyl)cyclopropane (263 μL, 2.75 mmol), (4R,7S)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 184 mg, 0.69 mmol) and tetra-n-butylammonium iodide (1.02 g, 2.75 mmol) in N,N-dimethylformamide (4.3 mL) was heated in an oil-bath at 100° C. for 16 h. The solvent was evaporated and dichloromethane (100 mL) and water were added. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and then with sodium thiosulfate solution (100 mL). The solvent was evaporated and the residue purified on an Isco 120 g column, eluting with 33-100% ethyl acetate/hexanes to give (4R,7S)-1-(cyclopropyl)methyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (108 mg, 49%) as an off-white/tan oil. APCI-MS (M+H) 323.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH3:20][O:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH:25]3[CH2:32][C:33](O)=[O:34])[CH2:23]1)[CH2:29]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:20][O:21][C:22]12[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH:25]3[CH2:32][C:33]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:34])[CH2:31]1)[CH2:29]2
Reactant: COC12CC3CC(C1)C(CC(=O)O)C(C3)C2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC12CC3CC(C1)C(CC(=O)N1CC4CC[C@](C)(C1)C4(C)C)C(C3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 29.3 μl was added to a methylene chloride 1 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 33.7 mg and stirred at 0° C. for 30 min. 5-methoxy-2-adamantyl acetic acid 36.2 mg and WSC 40.3 mg were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 20.5 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(5-methoxy-2-adamantylacetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 3 ml solution of lithium aluminum hydride 7.4 mg and refluxed under heating for 1.5 hours. The reaction mixture was cooled, then water was added thereto and then insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=20:1-10:1) to obtain the product.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]([C:13]1[C:21]2[CH:20]=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1)[OH:12].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.O.O1CCCC1>[F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([C:13]1[C:21]2[CH:20]=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1)=[O:12]
Reactant: O=[N+]([O-])c1cccc(C(O)c2c[nH]c3ncncc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1cccc([N+](=O)[O-])c1F)c1c[nH]c2ncncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To (2-fluoro-3-nitro-phenyl)-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol (37, 0.699 g, 2.42 mmol), 52 mL of tetrahydrofuran was added, followed by sodium bicarbonate (2.04 g, 24.2 mmol) and Dess-Martin periodinane (1.03 g, 2.42 mmol). The reaction was allowed to stir at room temperature for 30 minutes and 25 mL of saturated sodium thiosulfate and 30 mL of water were added, followed by 50 mL of ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 20-80% ethyl acetate in hexanes (with 4% acetic acid). Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (38, 581 mg). MS (ESI) [M+H+]+=287.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:10]1[C:15]([N+:16]([O-])=[O:17])=[CH:14][C:13]([CH3:19])=[CH:12][N:11]=1)=[CH:6]N(C)C)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:5]1[C:10]2=[N:11][CH:12]=[C:13]([CH3:19])[CH:14]=[C:15]2[N:16]([OH:17])[CH:6]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)c1ncc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cn(O)c2cc(C)cnc12

Procedure:
A solution of 3-Dimethylamino-2-(5-methyl-3-nitro-pyridin-2-yl]-acrylic acid ethyl ester (6.2 g, 0.022 mol) in ethanol (50 mL) is hydrogenated over 10% Pd-C at 50 psi for 48 h. The catalyst is removed by filtration through a pad of celite, and the solvent evaporated under vacuum. The residue is chromatographed over silica gel eluting with 7% MeOH-DCM containing few drops of NH4OH to afford 1-Hydroxy-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid ethyl ester 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J=6.6 Hz, 3H), 4.21 (q, J=6.6 Hz, 2H), 7.59 (s, 1H), 8.15 (s, 1H), 8.29 (s, 1H); LRMS Calcd 220.2; found 221.12.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:23]=[C:9]2[CH:10]=[C:11]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:13]([C:14]([NH2:16])=[O:15])[N:8]2[N:7]=1)[CH3:2].CO[C:27](OC)([N:29](C)C)[CH3:28].Cl.NO.[OH-].[Na+]>CC(N(C)C)=O.O>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[N:23]=[C:9]2[CH:10]=[C:11]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:13]([C:14]3[O:15][N:29]=[C:27]([CH3:28])[N:16]=3)[N:8]2[N:7]=1)=[O:24])[CH3:2]
Reactant: COC(C)(OC)N(C)C
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(N)=O)n2n1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3nc(C)no3)n2n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2-(3-Ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid amide, which may be prepared as in Example 16, (200 mg, 0.62 mmol) was suspended in DMA (8 mL) and preheated to 90° C. Dimethylacetamide-dimethylacetal (0.45 mL, 3.07 mmol) was added and the solution was heated at 90° C. for 30 minutes. The reaction was allowed to cool, diluted with water (100 mL), then extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 fractions were washed with water (3×50 mL), brine (50 mL), and dried (Na2SO4). The mixture was filtered under reduced pressure. The resultant oil was dissolved in a mixture of dioxane and acetic acid (3 mL of a 1:1 mixture). Hydroxylamine hydrochloride (64 mg, 0.92 mmol) and 2 M NaOH solution (0.46 mL, 0.92 mmol) were added and the mixture was stirred at 90° C. for 2 h. The reaction mixture was allowed to cool, concentrated under reduced pressure and diluted with water (50 mL) to afford a precipitate. The precipitate was collected by filtration, then purified by chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give the desired product, 1-ethyl-3-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea (27) as a solid mp. 298-301° C.
Reaction SMILES: [C:1]1(/[CH:11]=[CH:12]/[C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[S:16][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:31][C:32]1[N:36]([CH2:37][C:38]([OH:40])=O)[N:35]=[C:34]([C:41]([F:44])([F:43])[F:42])[CH:33]=1>>[CH3:31][C:32]1[N:36]([CH2:37][C:38]([N:21]2[CH2:22][CH2:23][CH:18]([C:15]3[S:16][CH:17]=[C:13](/[CH:12]=[CH:11]/[C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[N:14]=3)[CH2:19][CH2:20]2)=[O:40])[N:35]=[C:34]([C:41]([F:44])([F:43])[F:42])[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(/C=C/c3cccc4ccccc34)cs2)CC1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(/C=C/c3cccc4ccccc34)cs2)CC1

Procedure:
tert-Butyl 4-{4-[(E)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IV-2, 171 mg) is deprotected analogously to Example II-2 and then reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (100 mg). After chromatographic purification, this gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[(E)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (180 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[NH:12]1[C:20]2[C:15](=[C:16]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:15]=3[CH:14]=[CH:13][N:12]4[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]([F:11])([F:10])[F:9])[CH2:23][CH2:24]2)[CH:29]=1)=[O:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: FC(F)(F)c1ccccc1I
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccccc3C(F)(F)F)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2-(trifluoromethyl)benzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12]([C:22]([O:24]C2C=CC=CC=2)=O)C(=O)OC2C=CC=CC=2)[CH:7]=1.[N:50]1([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C)C=O>[F:48][C:45]1[CH:44]=[CH:43][C:42]([NH:41][C:40]([C:37]2([C:35]([NH:34][C:33]3[CH:32]=[CH:31][C:4]([O:5][C:6]4[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:22]([N:58]5[CH2:59][CH2:60][CH:55]([N:50]6[CH2:54][CH2:53][CH2:52][CH2:51]6)[CH2:56][CH2:57]5)=[O:24])[CH:7]=4)=[CH:3][C:2]=3[F:1])=[O:36])[CH2:38][CH2:39]2)=[O:49])=[CH:47][CH:46]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) was added 4-(pyrrolidin-1-yl)piperidine (46.3 mg), followed by stirring at room temperature for 16 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with diethyl ether:hexane=1:3 and dried under aeration to provide the titled compound as white powder (36.9 mg, 81.4%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]#[N:19].O.[OH-].[Li+]>CS(C)=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[C:18]#[N:19])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N#Cc1ccsc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccsc1Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 44.9 %

Procedure:
Combine 2,4-difluoro-1-nitro-benzene (5.24 g, 32.94 mmol), 2-aminothiophene-3-carbonitrile (4.09 g, 32.94 mmol), and DMSO (30.0 ml). Add lithium hydroxide monohydrate (2.76 g, 65.88 mmol) all at once and then stir the mixture at 55° for 22 hours. Cool the mixture to ambient temperature and then pour it onto ice chips. Extract with ethyl acetate and then wash (brine), dry (sodium sulfate), and evaporate the organic to residue. Purify the residue on silica gel using hexanes/dichloromethane (35:65) to give 3.89 g (45%) of the title compound as a red solid: mass spectrum (ion spray): m/z=262.0 (M−1).
Reaction SMILES: [C:1]([C:3]1([CH2:8][O:9]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[Cl:20][C:21]1[CH:22]=[CH:23][C:24](O)=[C:25]([CH:28]=1)[CH:26]=[O:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:9][CH2:8][C:3]2([C:1]#[N:2])[CH2:4][CH2:5][CH2:6][CH2:7]2)=[C:25]([CH:26]=[O:27])[CH:28]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2(C#N)CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1(COc2ccc(Cl)cc2C=O)CCCC1
Temperature: 100 °C

Procedure:
To a solution of the crude toluene-4-sulfonic acid 1-cyano-cyclopentylmethyl ester in DMF (70 mL) was added 5-chloro-2-hydroxy-benzaldehyde (12.48 g, 80 mmol) and K2CO3 (13.25 g, 96 mmol). After heated at 100° C. for 3 h, the reaction mixture was poured into water. The solution was diluted with EtOAc (200 mL), washed with water, dried and concentrated to give the title compound as a yellow oil (17.4 g). The oil was used for next step reaction directly without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.CCCCCC.[CH2:35]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:36]#[CH:37].BrC1C=C2C(NC=C2CCN)=CC=1>N1CCCCC1.C(OCC)(=O)C.[Cu]I.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[CH2:39]([O:38][CH2:35][C:36]#[C:37][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Reactant: C#CCOCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: N#Cc1ccccc1
Solvent: CCCCCC
Product: CN(C)CCc1c[nH]c2ccc(C#CCOCc3ccccc3)cc12
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A Schlenk flask is charged with CuI (19 mg, 0.1 mmol), Pd(PhCN)2Cl2 (39 mg, 0.1 mmol), piperidine (28 mL), and [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) (2.70 g, 10 mmol). The mixture is degassed, and then 0.4 mL of a solution of P(tBu)3 in hexane (0.2 mmol) is added. The stirred yellow solution is warmed to 50° C., and a solution of benzyl propargyl ether (2.65 g, 20 mmol) in piperidine (2 mL) is added during a 5 hour period. The yellow reaction mixture is left stirring for another 15 hours when HPLC indicates complete conversion of the 5-bromotryptamine. The mixture is diluted with ethyl acetate, washed with brine (4 times 10%, 3 times saturated), and dried. After removal of the solvent, the residue is triturated with 20 mL hexane/O(i-Pr)2 (1:1). The crystals which form are filtered off, washed with 4 mL of the same solvent mixture and dried in vacuo. Yield of the title compound: 2.70 g (75%), mp.=93-95° C. 1H-NMR (CDCl3, 300 MHz) δ 2.36 (s, 6, N(CH3)2); 2.63-2.70 (m, 2, CH2NMe2); 2.90-2.97 (m, 2, Indol-CH2); 4.46 (s, 2, CH2-alkin); 4.72 (s, 2, CH2Ph); 6.94 (d, 1, J=2.2 Hz, H-2); 7.18 (dd, 1, J=8.4 Hz, J=0.7 Hz, H-7); 7.26 (dd, 1, J=1.4 Hz, H-6); 7.32, 7.37, 7.41 (m, 5, Ph p-, m-, o-H); 7.76 (d, 1, H-4); 8.63 (br s, 1, NH). 13C-NMR (CDCl3, 75 MHz) δ 23.89 (indole-CH2); 45.73 (N(CH3)2); 58.55 (CH2CC); 60.48 (CH2NMe2); 71.90 (CH2Ph); 82.69 (CH2CC); 88.57 (CH2CC); 111.45 (C-7); 113.15 (C-5); 114.64 (C-3); 122.90 (C-2); 123.21 (C-4); 125.79 (C-6); 127.53 (C-9); 128.02, 128.40, 128.64 (Ph p, m, o-C); 136.34 (C-8); 137.90 (Ph ipso-C).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:17]=2[S:18][CH2:19][CH3:20])=O)=[CH:7][C:6]([C:25]([F:28])([F:27])[F:26])=[CH:5][N:4]=1.CN(C=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:19]([S:18][C:17]1[CH:16]=[C:15]([C:21]([F:24])([F:23])[F:22])[N:14]=[CH:13][C:12]=1[C:10]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:25]([F:28])([F:27])[F:26])[CH:7]=[C:8]2[N:9]=1)[CH3:20]
Reactant: CCSc1cc(C(F)(F)F)ncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCSc1cc(C(F)(F)F)ncc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of 786 mg of 4-ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 704 mg of p-toluenesolufonic acid-hydrate, 2.5 ml of DMF and 0.5 ml of toluene was heated and stirred at 150° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 716 mg of 2-(4-ethylsulfanyl-6-trifluoromethylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 12).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[CH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:21]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]#[CH:11]
Reactant: C#CCCCCCCCCCBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCCCCCCCCCOc1ccccc1C=O

Procedure:
To an ice-cold solution of 11-hydroxyundecyne (10 g, 59.4 mmoles) in 400 ml of methylene chloride under argon was added in one portion carbon tetrabromide (40.5 g, 0.1224 mole). The reaction mixture was stirred at 0° C. for 5 minutes and triphenylphosphine (29.43 g, 0.1122 mole) was added. The reaction was kept at 0° C. for an additional 15 minutes and stirred at room temperature for 3 hours. The methylene chloride was removed in vacuo. The residue was treated with hexane and the combined organic extract was concentrated in vacuo. The crude product was purified by flash chromatography on silica, eluting with straight hexane, to give 7.2 g (52%) of 11-bromoundecyne as a colorless oil. Following the procedures of Examples 20 and 39(a), a mixture of salicylaldehyde, 11-bromoundecyne and potassium carbonate in dimethylformamide is reacted to furnish 2-(10-undecynyloxy)benzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][CH2:13]1)=[O:5])[CH3:2].C(N(CC)CC)C.[Br:29][CH2:30][CH2:31]Br>CO>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]([CH2:31][CH2:30][Br:29])[CH2:10][CH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCNCCC1COc2ccccc2C1
Reactant: BrCCBr
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN(CCBr)CCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
29.1 g (0.1 mol) of N-(3-ethoxycarbonylpropyl)-N-[2-(chroman-3-yl)ethyl]-amine are dissolved in 200 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 18.8 g (0.1 mol) of 1,2-dibromoethane are added to the solution. The reaction mixture is stirred for 16 hours at room temperature and then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. N-(3-ethoxycarbonylpropyl)-N-(2-bromoethyl)-N-[2-(chroman-3-yl)ethyl]amine is thus obtained in the form of an oil which can be used further in the crude state.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:16])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].[ClH:17]>C(Cl)Cl>[ClH:17].[CH3:1][O:2][C:3]([C:5]1([CH3:16])[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1(C)CNC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of INT 13 (1.66 g, 7.24 mmol) in CH2Cl2 was added HCl (2.0 M in Et2O, 36.2 mL, 72.4 mmol). The reaction mixture was stirred at room temperature for 20 hours. The mixture was concentrated to afford INT 14.