Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:38])[C:10](=[C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([N+:35]([O-])=O)=[CH:34][C:28]=3[NH:27]2)[C:11]([C:13]2[CH:14]=[C:15]([S:19]([NH:22][C:23](=[NH:25])[CH3:24])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>[Pd].C(OCC)(=O)C>[NH2:35][C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26](=[C:10]([C:9]([C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)=[O:38])[C:11]([C:13]3[CH:14]=[C:15]([S:19]([NH:22][C:23](=[NH:25])[CH3:24])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)=[O:12])[NH:27][C:28]=2[CH:34]=1
Reactant: CC(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccc([N+](=O)[O-])cc3N2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccc(N)cc3N2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 83.6 %

Procedure:
10% Pd—C (85 mg) was added to an ethyl acetate (150 mL) suspension of N-({3-[3-(3,5-difluorophenyl)-2-(5-nitro-1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)ethanimidamide (845 mg), followed by stirring at room temperature for 22 hours under hydrogen atmosphere (1 atm). The insoluble matter was separated by filtration, washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[2-(5-amino-1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3,5-difluorophenyl)-3-oxopropanoyl]phenyl}sulfonyl)ethanimidamide (667 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[CH:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CCN(CC)CC.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[C:28][C:38]([N:37]([CH3:41])[CH3:36])=[O:39])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C12CC3CC(CC(C(=O)NC(CC#CC(=O)N(C)C)C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound from Step A of Example 49 (0.389 g, 1 mmol) was dissolved in dry DMF (5 mL) with dichlorobis(diphenylphosphine)palladium (II) (0.02 eq), Cul (0.02eq), Et3N (0.4 eq, 3 mL), and N,N-dimethylcarbamyl chloride (1.0 eq, 92 μL). The reaction mixture was stirred overnight at room temperature and then at 70° C. for 1 hour. The mixture was filtered through a pad of Celite and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc/hexanes, 2:3) to afford the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][CH3:17])[C:9](O)=[O:10]>CCOCC>[CH3:7][CH:8]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][CH3:17])[CH2:9][OH:10]
Reactant: CCC(C)CCCC(C)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC(C)CCCC(C)CO
Yield: 79.9 %

Procedure:
First, 1.9 g (0.05 mol) of lithium aluminum hydride was suspended in 50 ml of dried ether while being cooled on an ice bath. Then, 8.6 g (0.05 mol) of 2,6-dimethyl octanoic acid was dripped into the resultant mixture, while the mixture was being stirred, and was reacted with the mixture for 20 hours, thereby obtaining 6.32 g of 2,6-dimethyl-1-octanol (V) at yield of 80%. This reaction is described as follows: ##STR6##
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]2[CH2:14][CH:13]2[C:15]#[N:16])=[O:11])=[CH:6][CH:5]=1.[Cl-].[NH4+].C(OCC)C>C(O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:11])[CH:12]2[CH2:14][CH:13]2[C:15]#[N:16])=[CH:8][CH:9]=1
Reactant: N#CC1CC1C(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N#CC1CC1C(O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
736 mg (19.5 mmol) of sodium borohydride were added to 4.85 g (17.7 mmol) of the compound from Example 74A in 73 ml of ethanol and 18 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 2 h. The reaction mixture was added to saturated aqueous ammonium chloride solution and diethyl ether, the phases were separated, the aqueous phase was extracted twice with diethyl ether, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethanol 9/1) to result in 2.79 g (76% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:14])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: O=C(O)CCC(=O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A mixture of fluorobenzene (104.4 g, 1.09 mol, Aldrich) and succinic anhydride (93.5 g, 0.93 mol) in 1,2-dichlorobenzene (530 mL) was heated to 50° C. Aluminum chloride (245 g, 1.84 mol) was added portionwise keeping the temperature below 60° C. After 4 h at 60° C. followed by 5 h at 80° C., the reaction mixture was poured into a mixture of concentrated HCl (200 mL) and ice water (2 L). The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was dried and concentrated in vacuo. The residue was poured into hexane (2 L) and the resulting solid was filtered and washed with pentane to give 164.1 g (89%) of 3-(4-fluorobenzoyl)propionic acid as a white solid. m.p., 102°-104.5° C. (lit J. Org. Chem. 26, 2667, 1961; m.p., 102.5°-103.5° C.)
Reaction SMILES: C(N(C(C)C)C(C)C)C.[C:10]([OH:16])(=O)[C:11]([CH3:14])([CH3:13])[CH3:12].[NH2:17][C:18]1[C:19]([C:24]([NH:26][NH2:27])=O)=[N:20][CH:21]=[CH:22][N:23]=1.CC1C=CC(S(Cl)(=O)=O)=CC=1>C(#N)C>[C:11]([C:10]1[O:16][C:24]([C:19]2[C:18]([NH2:17])=[N:23][CH:22]=[CH:21][N:20]=2)=[N:26][N:27]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: NNC(=O)c1nccnc1N
Reactant: CC(C)(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)c1nnc(-c2nccnc2N)o1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (47.7 g, 148.69 mmol) was added portionwise over 15 minutes to a stirred suspension of N-ethyl-N-isopropylpropan-2-amine (70.6 mL, 405.51 mmol), pivalic acid (17.08 mL, 148.69 mmol) and 3-aminopyrazine-2-carbohydrazide (20.7 g, 135.17 mmol) in acetonitrile (350 mL) and the reaction mixture was stirred at 80° C. for 20 minutes (a solution was obtained). The reaction mixture was cooled to 0° C. and N-ethyl-N-isopropylpropan-2-amine (70.6 mL, 405.51 mmol), followed by 4-methylbenzene-1-sulfonyl chloride (77 g, 405.51 mmol) were added over a period of 15 minutes. The reaction mixture (yellow suspension) was brought to reflux (solubilisation) and then allowed to stir at room temperature for 14 hours affording a dark orange solution. The solution was concentrated. The residue was diluted with dichloromethane, washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 40% ethyl acetate in dichloromethane. The solvent was evaporated to dryness. The resulting mixture was triturated with ether (100 mL), filtered, washed with the minimum of ether and dried to afford 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (20.8 g, 70.2%) as a pale yellow soild: 1H NMR Spectrum; (CDCl3) 1.53 (9H, s), 1.58-1.68 (2H, m), 6.67 (2H, s), 8.13 (2H, dt); Mass Spectrum [M+H]+=220.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[CH2:10]([O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH:22]=2)[NH:17][CH:16]=1)=[O:14])[CH3:11].[OH-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:10]([O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][C:25]([OH:27])=[O:26])[CH:22]=2)[NH:17][CH:16]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)Cc1ccc2[nH]cc(C(=O)OCC)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCOC(=O)c1c[nH]c2ccc(CC(=O)O)cc12

Procedure:
Generally, Scheme 1 illustrates a synthetic route to the indole-containing fused ring compounds of the present invention. An ethyl 2-(4-aminophenyl)acetate is iodinated with a reagent such as, for example, iodine monochloride, to afford the corresponding ethyl 2-(4-amino-3-iodophenyl)acetate. This amine is treated with a 3-oxoacetate to produce the desired ethyl 3-(phenylamino)but-2-enoate. Formation of the indole is then achieved upon treatment with a catalyst, such as, for example, palladium acetate. The resulting ethyl 2-[3-(ethoxycarbonyl)indol-5-yl]acetate is saponified with a base such as potassium hydroxide to afford the 2-[3-(ethoxycarbonyl)indol-5-yl]acetic acid. The acid is subsequently converted to the amide by treatment with an amine and a suitable coupling agent, such as, for example, N,N′-carbonyldiimidazole or dicyclohexylcarbodiimide. Cyclization of the amide (e.g., in the presence of phosphorous oxychloride via the Bischler-Napieralske reaction) affords the dihydroisoquinoline, which is then treated with, for example, oxomethyl 2,2-dimethylpropanoate to produce the corresponding trihydroisoquinoline-2-carbaldehyde-ene. This compound is further cyclized and subsequently reduced to form the 6,11,12,13,12a,6a-hexahydroisoquinolino[2,1-b]pyrrolo[2,3-h]isoquinoline. The R4 group (as found in Formula I) can be present on the starting ethyl 2-(4-aminophenyl)acetate or introduced at various steps of the scheme (such as depicted in Scheme 1), depending on the nature of the group. The indole nitrogen can also be alkylated with various procedures known in the art.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[CH:4]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[O:20]1[CH2:2][CH:1]1[C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2nonc2c1
Solvent: ClCCl
Product: c1cc2nonc2cc1C1CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-ethenyl-2,1,3-benzoxadiazole (1.80 g, 12.3 mmol) in DCM (20 mL) was slowly added m-CPBA (3.8 g, 22 mmol) at 0° C. The flask was warmed to room temperature; the mixture was then stirred for 12 hours. TLC as well as LC indicated that reaction had gone to completion. The mixture was washed with aqueous Na2S2O3, NaHCO3, and water. The organic layers was washed with brine and then concentrated. The residue was purified over silica gel to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH:10]=[C:9]([CH3:11])[C:7]([NH2:8])=[N:6][C:4]1=[O:5])[CH3:2].[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C(NC1C=CC(S(NC2C(C)=CN(CC)CN=2)(=O)=O)=CC=1)(=O)C>N1C=CC=CC=1>[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([S:20]([NH:8][C:7]2[C:9]([CH3:11])=[CH:10][N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]=2)(=[O:22])=[O:21])=[CH:18][CH:17]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCn1cc(C)c(N)nc1=O
Agent: CCN1C=C(C)C(NS(=O)(=O)c2ccc(NC(C)=O)cc2)=NC1
Solvent: c1ccncc1
Product: CCn1cc(C)c(NS(=O)(=O)c2ccc(NC(C)=O)cc2)nc1=O

Procedure:
A mixture of 1.53 g. of 1-ethyl-5-methylcytosine, 2.34 g. of N-acetylsulfanilyl chloride and 10 ml. of pyridine was stirred overnight, diluted with 100 ml. of cold water, filtered with a little Hyflo to remove turbidity and acidified by addition of 19 ml. of 6N hydrochloric acid. The product was allowed to crystallize for several hours at room temperature before filtering, washing with water, and drying in a vacuum desiccator over potassium hydroxide to obtain 1.78 g. of N4 -acetyl-N1 -(1-ethyl-1,2-dihydro-5-methyl-4-pyrimidinyl)-sulfanilamide, melting at 235°-239°.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[N:11]=[C:10]([C:25]2[CH:26]=[N:27][C:28]([C:31]([C@H:33]3[CH2:38][CH2:37][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:35][CH2:34]3)=O)=[CH:29][CH:30]=2)[CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(OCC)(=O)C.O>[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][N:16]=2)[N:11]=[C:10]([C:25]2[CH:26]=[N:27][C:28]([C:31]([C@H:33]3[CH2:34][CH2:35][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:37][CH2:38]3)=[CH2:1])=[CH:29][CH:30]=2)[CH:9]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)c2ccc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)cn2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(c1ccc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)cn1)[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask was added methyltriphenylphosphonium bromide (444 mg, 1.24 mmol) and THF (3.1 mL). The mixture was cooled to 0° C., and potassium tert-butoxide (1.0 M in THF, 1.39 mL, 1.39 mmol) was added. The mixture was stirred at 0° C. for 30 minutes. A solution of methyl trans-4-[(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)carbonyl]cyclohexanecarboxylate (310 mg, 0.622 mmol) in THF (2 mL) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The reaction was diluted with ethyl acetate and water, and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (0-60%) to afford methyl trans-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)ethenyl]cyclohexanecarboxylate as a white solid. MS ESI calcd. for C27H28F3N4O2 [M+H]+ 497. found 497.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:13][C:14]1[CH:15]=[C:16]([Pb+3])[CH:17]=[CH:18][C:19]=1[Cl:20].[OH:22][C:23]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][N:31]=2)[NH:26][C:25](=[O:33])[CH:24]=1>CN(C)C1C=CN=CC=1.CS(C)=O.C(OCC)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:24]2[C:25](=[O:33])[NH:26][C:27]3=[N:28][CH:29]=[CH:30][N:31]=[C:32]3[C:23]=2[OH:22])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Clc1ccc([Pb+3])cc1Cl
Reactant: O=c1cc(O)c2nccnc2[nH]1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2nccnc2c(O)c1-c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 27.1 %

Procedure:
A mixture of 3,4-dichlorophenyl lead triacetate (1.63 g), 8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (0.254 g) and 4-dimethylaminopyridine (DMAP) (0.549 g) in anhydrous dimethylsulfoxide (10 mL) under a nitrogen atmosphere was heated to 60° C. for four hours. The reaction mixture was then allowed to cool to ambient temperature and stored at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate. The mixture was washed with aqueous hydrochloric acid (1M) and water, and the organic layer concentrated to give 7-(3,4-dichlorophenyl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (0.13 g) which was used without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:24][CH2:25][CH2:26]Cl)[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[I-].[Na+].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>CN(C=O)C.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:24][CH2:25][CH2:26][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(CCCCl)C(C(=O)OC)C(C)C)cc1
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(CCCN(CC)CC)C(C(=O)OC)C(C)C)cc1
Temperature: 80 °C
Yield: 90.2 %

Procedure:
To a solution of 0.45 g (1.08 mmol) of methyl 2-[{[4-(2-butynyloxy)-phenyl]-sulfonyl}(3-chloropropyl)amino]-3-methylbutanoate in 5.0 mL of DMF was added 0.163 g (1.08 mmol) of sodium iodide and 0.34 mL (3.24 mmol) of diethylamine. The reaction was heated to 80° C. for 3 h and then cooled to room temperature. The mixture was then diluted with water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.441 g of methyl 2-{{[4-(2-butynyloxy)-phenyl]sulfonyl}[3-(diethylamino)propyl]amino}-3-methylbutanoate as a brown oil. Electrospray Mass Spec 453.5 (M+H)+
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2O)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:19]1([C:18]2[O:25][C:14]3[C:15]4[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=4[CH:11]=[CH:12][C:13]=3[N:17]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)NCCC1CCc2ccc(NC(=O)c3ccccc3)c(O)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC(=O)NCCC1CCc2ccc3nc(-c4ccccc4)oc3c21
Yield: 82 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}benzamide (100 mg, 0.257 mmol) and pyridinium p-toluenesulfonate (12.9 mg, 0.0513 mmol) were heated under reflux in xylene (5 mL) for 2.5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=30/70→60/40) and recrystallized (ethyl acetate/diisopropyl ether) to give the title compound (67.5 mg, yield 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:16])[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[K].CCSC(N(CC(C)C)CC(C)C)=O.CO>CC(O)(CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Agent: CCSC(=O)N(CC(C)C)CC(C)C
Agent: [K]
Solvent: CCC(C)(C)O
Solvent: CO
Product: CC1(c2cccc(Br)c2)COCC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of (RS)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (5.36 g, 17 mmol) in 2-methyl-2-butanol (100 ml) was treated in one portion with potassium tent-butylate (6.66 g, 58 mmol). Initially, the temperature rose to 30° C.; the reaction mixture was left to cool to room temperature and stirring was continued for one hour. For the workup, the reaction mixture was treated with methanol (50 ml), then evaporated at reduced pressure. The residue was purified by chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 75/25 as the eluent. There were obtained 4.18 g (88% of theory) of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one as a white solid. Mass (calculated) C11H12BrNO2 [270.128]; (found) [M+H]+=270, [M+2-H]+==272.
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])[CH3:2].Cl.[NH2:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:34][C:33]1[CH:32]=[C:31]([CH3:35])[NH:30][C:29](=[O:36])[C:28]=1[CH2:27][NH:26][C:7](=[O:8])[C:6]1[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N:3]([CH2:1][CH3:2])[CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[C:5]=1[CH3:17]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 23 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, 580 mg, 1.68 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one HCl salt (477 mg, 2.53 mmol) in DMSO (6 mL) was added PyBOP (1.57 g, 3.02 mmol) and hunig base (650 mg, 5.04 mmol). The reaction mixture was stirred at 23° C. for 20 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=25/1) to give the titled compound as a white amorphous (386 mg, 48% yield). 1HNMR (400 MHz, CDCl3) δppm; 7.31 (s, 1H), 7.27 (s, 1H), 7.18 (t, J=5.7 Hz, 1H), 5.95 (s, 1H), 4.55 (d, J=5.9 Hz, 2H), 3.17 (dq, J=6.4, 3.3 Hz, 2H), 3.08 (q, J=7.0 Hz, 2H), 2.81 (m, 2H), 2.70 (m, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.78-1.93 (m, 2H), 1.70 (m, 2H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M+H] 479.2, [M+Na] 501.3; HPLC 96.8% purity.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:6]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(C=O)cc1
Reaction time: 6 h
Yield: 83.9 %

Procedure:
As shown in the following Reaction 7, 250 mg (1.19 mmol) of 4-trimethylsilylethynyl benzaldehyde obtained in A of Example 1-2 was melted in 10 mL of methylenechloride and 10 mL of methanol at room temperature, and 1.25 g (9.04 mmol, 7.6 eq) of potassium carbonate was added thereto, and then the reaction solution was stirred for 6 hours. Next, the reaction solution was extracted with ether 2 times and with 1M sodium chloride aqueous solution 1 time. The organic solvent layer was dehydrated with magnesium sulfate, filtered, and then distilled under reduced pressure. The compound distilled under reduced pressure was purified with a column chromatography (mobile phase volume ratio; ethylacetate:n-hexane=1:10) to obtain 130 mg of 4-ethynylbenzaldehyde with the yield of 93%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 10,02 (s, 1H), 7.83 (d, 2H), 7.63 (d, 2H), 3.27 (s, 1H)].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[C:20]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:24]1)(=[O:22])[CH3:21]>>[C:20]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([NH:19][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH:14]5[CH3:18])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:34])=[CH:36][CH:37]=2)[CH2:24]1)(=[O:22])[CH3:21]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: CC(=O)N1CCCC(c2ccc(C(=O)O)cc2)C1
Product: CC(=O)N1CCCC(c2ccc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cc2)C1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(1-acetyl-piperidin-3-yl)-benzoic acid. MS: 489.3 (M+H).