Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:19]([CH:25]1[CH2:27][CH2:26]1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C.O>[CH:25]1([CH:19]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:27][CH2:26]1
Reactant: CCOC(=O)C(Br)C1CC1
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc2ccccc12)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of 1-naphthol (170 mg, 1.18 mmol) in anhydrous DMF (10 mL) was added K2CO3 (510 mg, 3.53 mmol) and ethyl α-bromocyclopropaneacetate (295 mg, 1.41 mmol). The mixture was stirred at room temperature for 2 h and then diluted with water (50 mL) and then extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography using a mixture of ethyl acetate and n-hexane (1:9) to furnish ethyl 2-cyclopropyl-2-(1-naphthalenyloxy)acetate (8, R=c-Pr, 296 mg, 93%) as a white solid. The ester (250 mg, 0.92 mmol) was dissolved in 20 mL THF: H2O (2:1) and then 3M NaOH (111 mg, 2.77 mmol) was added. The reaction was heated at 80° C. for 6 h. After cooling, the reaction mixture was quenched with 1N HCL to a pH ˜7 and then extracted with chloroform. The organic extract was dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography eluting with a mixture of ethyl acetate/n-hexane (a gradient of 2:1) to furnish 2-cyclopropyl-2-(1-naphthalenyloxy)acetic acid (41, R=c-Pr) (136 mg, 61%) as a white solid.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][C:6]([NH:10][N:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])=[CH:7][CH:8]=2)[CH:3]=N1.NC1C=C2C(=CC=1)[NH:23][N:22]=C2.C(#N)CC#N.O.[NH2:33][NH2:34]>>[NH:33]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][N:11]=[C:12]3[C:13]([NH2:14])=[N:23][N:22]=[C:15]3[NH2:16])=[CH:7][CH:8]=2)[CH:3]=[N:34]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccc2[nH]ncc2c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc2[nH]ncc2c1
Yield: 63 %

Procedure:
4-[(1H-Indazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 2-[(1H-indazol-5-yl)hydrazono]malononitrile (0.105 g, 0.5 mmol) which was derived from 5-aminoindazole (0.133 g, 1.0 mmol) and malononitrile (1.5 mmol) in a manner similar to that described in Example 2, and hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 0.076 g (63%) of the title compound as a brown solid; 1H NMR (ppm, 200 MHz, DMSO-d6) δ 6.0 (br s, 4H), 7.50 (d, 1H), 7.94 (d, 1H), 8.0 (s, 1H), 8.08 (s, 1H), 10.68 (br s, 1H), 13.08 (s, 1H).
Reaction SMILES: C[C:2]1[N:3]=[C:4]([NH:20][C:21]([N:23]2[CH:27]=[CH:26]N=C2)=[O:22])[S:5][C:6]=1[C:7]1[N:8]=[C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[S:10][CH:11]=1.NCC[C:31]([OH:33])=[O:32].[CH2:34](N(CC)CC)C>CN(C=O)C>[CH3:34][C:7]1([C:6]2[S:5][C:4]([NH:20][C:21]([NH:23][CH2:27][CH2:26][C:31]([OH:33])=[O:32])=[O:22])=[N:3][CH:2]=2)[CH2:11][S:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[N:8]1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(C(=O)N2CCOCC2)n1
Reactant: NCCC(=O)O
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(c2cnc(NC(=O)NCCC(=O)O)s2)CSC(C(=O)N2CCOCC2)=N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
To N-[4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide, prepared as in Step 3 of Example 36, described above (75 mg; 0.19 mmol; 1 eq.), is added DMF (3 ml), Beta-alanine (Aldrich) (18.2 mg; 0.20 mmol; 1.10 eq.) and triethylamine (57 μl; 0.41 mmol; 2.20 eq.). The mixture is stirred 3 days at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (47) as a light yellow solid (17 mg; 22%). 1H NMR (DMSO-d6, 300 MHz) δ 2.41 (s, 3H), 2.49 (m, 4H), 3.31 (m, 6H), 4.33 (m, 2H), 6.71 (br s, 1H), 7.90 (s, 1H), 10.47 (br s, 1H), 12.34 (br s, 1H). M− (ESI): 424.03; M+ (ESI): 426.08. HPLC (method A), Rt: 2.20 min (purity: 98%).
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:4]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][N:12]=[C:13]2[N:17]([CH2:18][CH3:19])[N:16]=[CH:15][C:14]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Product: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Yield: 50 %

Procedure:
(1-Ethylpyrazol-5-ylamino)methylenemalonate diethyl ester (10.0 g, 42.6 mmol) was dissolved in phosphorus oxychloride (50 mL). This solution was heated at reflux for 10 h before the phosphorus oxychloride was removed via evaporation under reduced pressure. The resulting brown residue was diluted with EtOH (5 mL) and extracted with hot hexane (200 mL×3). The combined organic layers were evaporated under reduced pressure to afford the title compound as an oil which formed light green needle shaped crystals upon standing at room temperature (5.4 g, 21.3 mmol, 50% yield). This material is identical to the one obtained in Preparation 3 (1H NMR, 13C, MS, and HPLC).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl[CH2:14][CH:15]([O:18][CH2:19][O:20][CH3:21])[CH2:16]Cl>CS(C)=O.C(OCC)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][CH:15]([O:18][CH2:19][O:20][CH3:21])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: COCOC(CCl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COCOC1CC(C#N)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
Potassium hydroxide (2.57 g) was dissolved in dimethyl sulfoxide (8.0 mL). (4-Chlorophenyl)acetonitrile (1.58 g, 10.4 mmol) and 1,3-dichloro-2-(methoxymethoxy)propane (1.993 g) were dissolved in ethyl ether (3 mL), and this mixture was added dropwise to the vigorously stirred potassium hydroxide solution at room temperature. After stirring at room temperature for one hour, the reaction was quenched by adding ice-cold water (5.5 mL). The mixture was filtered through a pad of celite which was washed with ether (30 mL). The filtrate was added to a separatory funnel, and the aqueous layer was extracted with ether (3×15 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The product was purified by silica gel chromatography to provide 1-(4-chlorophenyl)-3-(methoxymethoxy)cyclobutanecarbonitrile (1.28 g) as a mixture of isomers (ca. 2:1).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCc3ccccc3)cc2)nc1
Reaction time: 18 h

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinamide (0.097 g, 0.4 mmol) in 5 mL of methanol with benzylamine (0.4 mmol), and 1 g of 3 Å molecular sieves. Stir for 18 h. Add sodium borohydride (0.076 g, 2 mmol), and stir for 18 h. Flush the reactions down through a 5 g SCX column, first wash with 1:1 chloroform/methanol, then collect washes with 1:1 chloroform/2 M ammonia in methanol. Adsorb the collected material on silica, then purify via a ISCO® Combiflash 16× system (use a 10 g silica cartridge, and elute with 98:2:2 chloroform/ethanol/ammonium hydroxide, gradient to 90:10:1 chloroform/ethanol/ammonium hydroxide). 1H NMR (DMSO-d6): 8.58 (d, 1H), 8.22 (m, 1H), 8.0 (s, 1H), 7.46 (s, 1H), 7.27-7.38 (m, 6H), 7.20 (m, 1H), 7.02-7.08 (m, 3H), 3.67-3.68 (d, 4H). TLC Rf (90:10:1 chloroform/ethanol/ammonium hydroxide): 0.31.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH2:17][CH:16]1[CH2:25][NH2:26]>>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:26]([CH2:25][CH:16]2[O:15][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH2:17]2)[CH:10]=1
Reactant: NCC1COc2ccccc2O1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1CC1COc2ccccc2O1

Procedure:
According to the method of Example 160, 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide was reacted with 1-(2,3-dihydro-1,4-benzodioxin-2-yl) methanamine to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C1C(=O)N([I:20])C(=O)C1>CN(C=O)C.CCOC(C)=O>[I:20][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
5-nitro-1H-indazole (2 g, 12.26 mmol) was taken up in DMF (40 mL) and NIS (5.52 g, 24.52 mmol) was added. The reaction was stirred at room temperature for 72 h. The reaction mixture was diluted with EtOAc and washed with saturated sodium bisulfite solution, water, and then 2× with brine. The organic layer was dried over Na2SO4, filtered and concentrated to give 3-iodo-5-nitro-1H-indazole (3.4 g) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C@@H:7]([CH3:27])[CH2:6]1)=[O:4].[OH-].[Li+].CO.Cl>O1CCCC1.O>[CH3:27][CH:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[C:15](=[O:26])[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C(F)(F)F)cc2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1CC(C(=O)O)c2ccccc2N1C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.5 %

Procedure:
A round bottom flask with magnetic stirrer was charged with cis-2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (980 mg, 2.60 mmol) in tetrahydrofuran (10.0 mL). To the reaction was added a solution of lithium hydroxide (179 mg, 7.47 mmol) in water (10 mL), followed by methanol (10 mL). The reaction was stirred at room temperature for 18-20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (3×35 mL) and the combined extractions were washed with brine (1×50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield 2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (mixture of cis and trans isomers) as an off-white solid (912 mg, 97%). The mixture was used without purification in subsequent reactions.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6])#[N:2].[Cl:17][C:18]([Cl:24])([S:22]Cl)[CH:19]([Cl:21])[Cl:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:22][C:18]([Cl:24])([Cl:17])[CH:19]([Cl:21])[Cl:20])[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6])#[N:2]
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: N#CCNC(=O)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCN(SC(Cl)(Cl)C(Cl)Cl)C(=O)c1cccc2ccccc12
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 5.0 g (0.024 N-cyanomethyl-1-naphthamide (the product of Example 11) and 6.2 g (0.026 mole) 1,1,2,2-tetrachloroethylsulfenyl chloride in 125 ml methylene chloride, 3.0 g (0.030 mole) triethylamine in 25 ml methylene chloride were dropped in over 40 minutes. The reaction mixture was stirred 30 minutes. The reaction mixture was washed three times with 75 ml portions of water, dried over magnesium sulfate, and stripped down to a volume of 50 ml. The methylene chloride solution was then chromatographed on a column containing about 125 g silica gel, eluting with methylene chloride. The eluate was stripped to give 4.3 g of the above-identified product as an amber glass which tended to crystallize slowly.
Reaction SMILES: S1C2CCCC(=[O:10])C=2C=C1.[Li]C1C=CC=CC=1.C1([C:24]2[CH:35]=[C:34]3[CH:26]([CH2:27][CH2:28][C:29]4[S:30][CH:31]=[CH:32][C:33]=43)[CH:25]=2)C=CC=CC=1.C1(C2CC3C4C=CSC=4CCC=3C=2)C=CC=CC=1>CCOCC>[CH:32]1[C:33]2[C:34]3[CH:26]([CH2:25][C:24](=[O:10])[CH:35]=3)[CH2:27][CH2:28][C:29]=2[S:30][CH:31]=1
Reactant: O=C1CCCc2sccc21
Reactant: C1=C(c2ccccc2)C=C2c3ccsc3CCC12
Agent: C1=C(c2ccccc2)CC2=C1CCc1sccc12
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: O=C1C=C2c3ccsc3CCC2C1
Yield: 30 %

Procedure:
6,7-dihydro-1-benzothiophen-4(5H)-one was obtained with an overall yield of 43% via the acylation of thiophene by succinic anhydride followed by reduction of the ketone formed and by the cyclisation of 4-(2-thienyl)butanoic acid in the presence of the laton's reagent. Next, 4,5,5a,6-tetrahydro-7H-indeno[5,4-b]thiophen-7-one was synthesised from 6,7-dihydro-1-benzothiophen-4(5H)-one with an overall yield of 30%. The latter product was further reacted with one equivalent of PhLi in ether followed by acidification of the reaction medium to give a mixture of 7-phenyl-5,5a-dihydro-4H-indeno[5,4-b]thiophene and 7-phenyl-5,8-dihydro-4H-indeno[5,4-b]thiophene as shown in the scheme below
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH:21]=[C:20]([Si](C)(C)C)[C:11]3[C:12]4[C:13]([NH:19][C:10]=3[C:9]2=[O:26])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=4)=[CH:5][CH:4]=1.[I:29]I>C(O)C.C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[I:29][C:20]1[C:11]2[C:12]3[C:13]([NH:19][C:10]=2[C:9](=[O:26])[N:8]([CH2:7][C:6]2[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:21]=1)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3
Reactant: COc1ccc(Cn2cc([Si](C)(C)C)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Reactant: II
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(Cn2cc(I)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Reaction time: 0.25 h

Procedure:
In a 2 L round bottom flask, 7-(4-methoxybenzyl)-3-methyl-5-trimethylsilyl-7,9-dihydro-8H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-8-one (18.6 g, 47.505 mmol) was suspended in ethanol (1 L) and DCM (150 mL), then cooled in an ice bath. To the cooled mixture was added silver tetrafluoroborate (AgBF4, 10.17 g, 52.255 mmol) and after 15 minutes of stirring, iodine (18.08 g, 71.257 mmol) was added. The reaction was stirred at 0° C. for one hour followed by five hours at ambient temperature. The crude yellow solid was collected by filtration, suspended in 10% wt Na2S2O3 (700 mL) and stirred for 1 h. The solid was collected by filtration and again washed with 10% wt Na2S2O3. The product (light yellow solid) was collected by filtration, washed with water and diethyl ether and dried under high vacuum. The material was taken forward without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.59 (s, 3 H) 3.81 (s, 3 H) 5.26 (s, 2 H) 6.90 (d, J=8.84 Hz, 2 H) 7.34 (d, J=8.59 Hz, 2 H) 7.44 (s, 1 H) 8.51 (s, 1 H) 8.92 (s, 1 H). ESI-MS: m/z 446.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][C:18](=[CH2:21])[CH2:19][NH2:20].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:8]1[CH2:15][CH2:14][C:11]([CH2:12][NH:20][CH2:19][C:18]([CH3:21])=[CH2:17])([OH:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Reactant: C=C(C)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)CNCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 70 °C

Procedure:
A mixture of 6-benzyl-1-oxa-6-azaspiro[2.5]octane (2 g) and 2-methylprop-2-en-1-amine HCl (2 g) and Hunig's Base (3.44 mL) in ethanol (30 mL) was heated at 70° C. for 18 hours. The mixture was cooled to room temperature and the solvent evaporated under reduced pressure. The residue was partitioned between DCM and brine, the aqueous layer was re-extracted with fresh DCM and the combined organics dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 2.70 g.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:7]([O:10]CC)(=[O:9])[CH3:8].[C:13]1([CH:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:22][OH:23]>>[CH3:22][O:23][C:3]1[CH:2]=[C:1]([CH:6]=[CH:5][CH:4]=1)[CH2:13][C@H:14]1[C:8]([C:7]([OH:10])=[O:9])=[CH:17][CH2:16][CH2:15]1.[C:13]1([CH:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCC
Reactant: CO
Reactant: CCOC(C)=O
Agent: CC(N)c1ccccc1
Product: COc1cccc(C[C@@H]2CCC=C2C(=O)O)c1
Temperature: 25 °C

Procedure:
To a n-hexane and ethyl acetate solution (80 ml, 1:1) of the crude carboxylic acid was added (+)-1-phenylethylamine (1.96 g) with stirring at the room temperature. A precipitated colorless powder (3.97 g, mp : 125-131° C.) was collected by filtration and the additional powder (0.20 g, mp : 127-129° C.) was obtained from the filtrate Recrystallization of the combined powder from n-hexane--ethyl acetate (1:1, 100 ml) afforded a pure salt of (-)-5(S)-(3-methoxybenzyl)-1-cyclopentenecarboxylic acid and (+)-1-phenylethylamine as a colorless needles (3.27 g, mp : 135-136° C., [α]D : -21.87° (C=1, MeOH)).
Reaction SMILES: [ClH:1].[C:2]([O:5][C@H:6]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(OC(C)(C)C)=O)=[CH:17][CH:16]=2)[N:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@H:7]1[C:36]1[CH:41]=[CH:40][C:39]([NH:42]C(OC(C)(C)C)=O)=[CH:38][CH:37]=1)(=[O:4])[CH3:3].CCOCC>O1CCOCC1>[ClH:1].[ClH:1].[C:12]([O:11][C@H:10]1[C@H:6]([O:5][C:2](=[O:4])[CH3:3])[C@H:7]([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[CH:40][CH:41]=2)[N:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](c2ccc(NC(=O)OC(C)(C)C)cc2)N(c2ccc(F)cc2)[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](c2ccc(N)cc2)N(c2ccc(F)cc2)[C@H]1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 4 N hydrogen chloride in dioxane (8 mL) was treated with the compound of Example 70B (136 mg, 0.21 mmol) followed by stirring at RT for 2 h. (During this time, the mono-deprotection product started precipitating, and ca. 4 mL of dichloromethane was added to speed the reaction by solublizing the mono-hydrochloride) The mixture was added to excess ether and the product collected by filtration and washed with ether. After drying in a vacuum oven at 50° C. for 18 h, these procedures afforded the title compound (92 mg, 84%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (m, 8 H), 6.81 (t, J=8.9 Hz, 2 H), 6.33 (m, 2 H), 5.63 (m, 2 H), 5.51 (dd, J=5.5, 1.9 Hz, 2 H), 1.79 (s, 6 H).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[CH:35]1([CH2:40][CH2:41][C:42](Cl)=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36]1.O>O1CCCC1>[CH:35]1([CH2:40][CH2:41][C:42]([C:2]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=2[O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)CCC3CCCC3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added to the cooled solution, and the mixture was stirred at −78° C. for 20 min. 3-Cyclopentylpropionyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (9 mg, yield 8%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33](=[O:34])[N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([CH3:22])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNCCc1ccc(NC(C)(C)C(=O)O)cc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCN(CCc1ccc(NC(C)(C)C(=O)O)cc1)C(=O)Nc1ccc(F)cc1F
Yield: 7.7 %

Procedure:
A solution of of 2-[4-(2-heptylamino-ethyl)-phenylamino]-2-methyl-propionic acid (75 mg, 234 μmol), 2,4-difluorophenyl isocyanate (33 μL, 281 μmol), N,N-diisopropylethylamine (82 μL, 468 μmol) and methylene chloride (0.5 mL) was stirred at ambient temperature for 18 h, concentrated under reduced pressure and purified by flash column chromatography (3% methanol/chloroform) to provide 8.6 mg (8%) of 2-(4-{2-[3-(2,4-difluoro-phenyl)-1-heptyl-ureido]-ethyl}-phenylamino)-2-methyl-propionic acid as a white foam.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH:29]4[CH2:35][CH:34]5[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]5)[CH2:30]4)[N:25]=3)=[N:12][CH:13]=[C:14]([S:16]CCC(OC)=O)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].CC([O-])(C)C.[K+].Br[CH2:51][CH2:52][O:53][CH3:54]>C1COCC1>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH:29]4[CH2:30][CH:31]5[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]([CH2:33][CH2:32]5)[CH2:35]4)[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][CH2:51][CH2:52][O:53][CH3:54])[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: COCCBr
Reactant: CCc1ncccc1Oc1cc(SCCC(=O)OC)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ncccc1Oc1cc(SCCOC)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Temperature: 25 °C
Reaction time: 0.01 h
Yield: 92.3 %

Procedure:
tert-Butyl 3-(5-(3-(2-ethylpyridin-3-yloxy)-5-(3-methoxy-3-oxopropylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (115 mg, 0.183 mmol) was dissolved in THF (4 mL) and nitrogen was bubbled through the solution for 3 minutes. Potassium 2-methylpropan-2-olate (51.5 mg, 0.459 mmol) was added and the reaction was stirred at ambient temperature for 30 seconds. 1-Bromo-2-methoxyethane (19.0 μL, 0.202 mmol) was added and the reaction was stirred at ambient temperature for 30 minutes. The reaction was partitioned between EtOAc and aqueous NH4Cl. The organic layer was dried over sodium sulfate, filtered, concentrated and purified on silica gel (80% EtOAc in hexanes) to afford tert-butyl 3-(5-(3-(2-ethylpyridin-3-yloxy)-5-(2-methoxyethylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (101 mg, 0.169 mmol, 91.9% yield).