Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)(=O)=O.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[S:10]1[CH:11]=[CH:12][C:8]([CH2:7][CH2:6][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[CH:9]1
Reactant: CS(=O)(=O)OCCc1ccsc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCc1ccsc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of the above crude 2-(3-thienyl)ethyl methanesulfonate in 400 ml of N,N-dimethylformamide, 12.8 g (69.0 mmol) of potassium phthalimide was added, followed by overnight stirring at 100° C. After cooling to room temperature, the reaction mixture was added to water with vigorous stirring. The resulting precipitate was filtered, washed with water and dried to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1.[Li]CCCC.C(O[K])(C)(C)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:38][CH3:39])=[C:27]([C:29]([CH3:37])([CH3:36])[CH2:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:28]=1>C1COCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:38][CH3:39])=[C:27]([C:29]([CH3:37])([CH3:36])[CH2:30][C:31]([CH2:1][C:2]2[NH:10][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=2)([OH:35])[CH:32]([CH3:33])[CH3:34])[CH:28]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(C)C
Reactant: Cc1cc2cnccc2[nH]1
Agent: CC(C)(C)O[K]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2cnccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.6 %

Procedure:
A solution of 2-methyl-1H-pyrrolo[3,2-c]pyridine (69 mg, 0.52 mmol) in 4 mL of THF was treated with 610 μL of n-BuLi (2.5 M in hexanes) at −78° C. After 5 minutes, tert-BuOK (1 M in THF, 1.0 mL) was added and the mixture was warmed to room temperature for 1.5 hours. The orange reaction mixture was cooled to −78° C. and 5-(5-fluoro-2-methoxyphenyl)-2,5-dimethylhexan-3-one (110 mg, 0.436 mmol) in 2 mL of THF was added dropwise. The mixture was stirred at −78° C. for 30 minutes, warmed to room temperature, quenched with 10 mL of saturated ammonium chloride solution, and diluted with 20 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with two 10 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Chromatography on SiO2 (MeOH in CH2Cl2, gradient, 0% to 10%) afforded 71.4 mg (43% yield) of the product as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[N:10]1([CH:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH3:2])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)c1ccccn1
Reactant: C1CCNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(c1ccccn1)N1CCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ml 11.2 (0.1 moles) of 2-acetylpyridine (commercial product) and ml.16.5 (0.2 moles) of pyrrolidine were dissolved in ml.120 of dry methanol, and the solution was brought to pH 8 by adding HCl dissolved in methanol. Gr.9.4 (0.15 moles) of NaCNBH3 were added in small portions and the reaction mixture stirred 48 hours at room temperature. The mixture was brought to strongly basic pH by adding aqueous 20% NaOH, a small amount of insoluble filtered off, and the filtrate concentrated to small volume i.v. The residue was taken up in ether, the phases separated, and the aqueous layer extracted with ether. The combined ether solutions were washed with 20% aqueous Na OH, saturated aqueous NaCl and finally dried on NaOH pellets and evaporated to dryness i.v. 23 g. of red oil were obtained, and were chromatographed on 120 g. of silicagel, eluting with CH2Cl2 containing increasing amounts of metanol (0.5% to 8%). Gr 16 of oily product were obtained, sufficiently pure for the subsequent step.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH2:15]I)[CH2:13][S:14][C@H:9]12)=[O:6].[CH3:60][N:61]([CH3:71])[C:62]1[S:63][C:64]2[CH:69]=[CH:68][N:67]=[CH:66][C:65]=2[N:70]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>CS(C)=O.CCOCC.C(OCC)(=O)C>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O-:19])=[O:18])=[C:12]([CH2:15][N+:67]4[CH:68]=[CH:69][C:64]5[S:63][C:62]([N:61]([CH3:71])[CH3:60])=[N:70][C:65]=5[CH:66]=4)[CH2:13][S:14][C@H:9]23)=[O:6])[N:36]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CN(C)c1nc2cnccc2s1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4sc(N(C)C)nc4c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31.3 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIa] (466 mg, 0.5 mmole) and 2-dimethylaminothiazolo[4,5-c]pyridine (90 mg, 0.5 mmole) in dry DMSO (1 ml) was stirred at room temperature for 40 minutes, and diluted with a mixture of ether (20 ml) and ethyl acetate (50 ml). The precipitate was collected by filtration to obtain 517 mg of the crude quaternary salt. The salt was mixed with 0.3 ml of anisole and was treated with 95% TFA under ice cooling. The solution was stirred for an hour at room temperature and evaporated. The residue was triturated with iso-propyl ether and the resulting precipitate was collected by filtration to give 367 mg of the crude title compound as a yellow powder. The crude product was purified by chromatography (HP-20 column 90 ml), eluted with water (200 ml), 30% CH3OH (240 ml), and 50% CH3OH (450 ml). The desired fractions were combined, concentrated and lyophilized to give 90 mg of yellow powder, which was further purified by column chromatography by using the packing of PrepPAK/C18 cartridge (50 ml). The column was eluted with water (100 ml) and 30% CH3OH (200 ml). The desired fractions were concentrated and lyophilized to obtain 40 mg of Iu as pale yellow powder (14% yield). Mp. 119°~123° C. (dec.). Estimated purity by HPLC: 65%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].[NH2:11][CH:12]([CH:14](N)[CH3:15])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]1[NH:11][CH:12]([CH3:13])[CH:14]([CH3:15])[N:8]=1
Reactant: Cc1nn(C)c(C#N)c1N
Reactant: CC(N)C(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nn(C)c(C2=NC(C)C(C)N2)c1N
Yield: 91.7 %

Procedure:
A mixture of 7 g (0.05 mol) of 4-amino-5-cyano-1,3-dimethylpyrazole, 5 g (0.057 mol) of 2,3-diaminobutane and 10.5 g (0.055 mol) of p-toluene sulfonic acid hydrate is heated in an oil bath at 180°-200° C. for seven hours. The yellow melt is dissolved in 200 ml of chloroform and stirred with 100 ml of 20% aqueous sodium carbonate solution. The organic layer is separated, dried over MgSO4 and evaporated in vacuo to give 9.5 g of 2-(4-amino-1,3-dimethyl-5-pyrazolyl)-4,5-dimethylimidazoline and characterized as a dihydrochloride salt, mp 250° C. from 20% isopropanolic HCl and ethyl acetate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:12][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([CH3:11])[C:8]=1[C:13](=[O:16])[CH:14]=[CH2:15]
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1c(C)cc(C(C)(C)C)cc1C

Procedure:
5-t-butylmetaxylene (0.5 mL), acryloyl chloride (120 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1.5 mL) at from −40° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (120 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[C:11]1([C:17]#[C:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=O)=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH:6]([CH2:23][C:22]2[CH:26]=[CH:27][C:19]([C:18]#[C:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:20][CH:21]=2)[C:4](=[O:5])[O:3]1
Reactant: O=C(O)c1ccc(C#Cc2ccccc2)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(Cc2ccc(C#Cc3ccccc3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 66 h
Yield: 45.5 %

Procedure:
To a mixture of Meldrum's acid (688 mg) and 4-phenylethynylbenzoic acid (955 mg) in methylene chloride (30 mL) was added a solution of 4-dimethylaminopyridine (830 mg) and N, N′-dicyclohexylcarbodiimide (976 mg) in methylene chloride (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 66 hr. Insoluble material was removed by filtration, and the filtrate was washed with 10% potassium hydrogen sulfate (30 mL) and saturated brine and concentrated under reduced pressure. The residue was dissolved in acetic acid (5 mL), and the solution was cooled to 0° C. Sodium borohydride (408 mg) was added, and the mixture was stirred at room temperature for 6 hr. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL×2). The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was washed with isopropanol, and the resulting precipitate was collected by filtration to give the title compound (654 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C1(N=C=NC2CCCCC2)CCCCC1.[C:28](O)(=[O:32])[C:29]([CH3:31])=[O:30]>ClCCl>[C:28]([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])(=[O:32])[C:29]([CH3:31])=[O:30]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
736 mg (4 mmol) of pentafluorophenol and 825 mg (4 mmol) of dicyclohexylcarbodiimide were added to a stirred solution of 352 mg (4 mmol) of pyruvic acid in 10 ml of dichloromethane at 0° C. under nitrogen. The mixture obtained was diluted with 40 ml of dichloromethane and stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was treated with 5 ml of cold ethyl acetate. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by flash chroma- tography on silica gel using ethyl acetate/dichloromethane (1:8) for the elution to give 802 mg of pentafluorophenyl pyruvate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[NH2:9].[CH:10]([N:13]=[C:14]=[S:15])([CH3:12])[CH3:11].[H-].[Na+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][C:3]2[N:9]=[C:14]([NH:13][CH:10]([CH3:12])[CH3:11])[S:15][C:2]=2[CH:7]=1
Reactant: Nc1cnc(Cl)cc1Cl
Reactant: CC(C)N=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1nc2cnc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
To a solution of 4,6-dichloropyridin-3-amine (0.50 g, 3.07 mmol, 1.0 eq.) and isopropyl isothiocyanate (0.33 mL, 3.10 mmol, 1.0 eq.) in DMF under nitrogen at 0° C. was added NaH (60% in mineral oil, 0.194 g, 4.85 mmol, 1.6 eq.). After 10 min., the cold bath was removed, and the reaction mixture was stirred to room temperature for 10 min. It was then heated at 65° C. for 1 hr and cooled to room temperature. At 0° C., aqueous HCl (1 N), water and EtOAc were added, and the reaction mixture was stirred. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (100:1) as eluent afforded 6-chloro-N-isopropylthiazolo[4,5-c]pyridin-2-amine as a white solid (0.43 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[S:3][C:4]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NS(C)(=O)=O)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine (1.0 mmol, 0.33 g) and methylsulfonyl chloride (2.0 mmol, 0.22 g) in dry DMF (2 mL) was added Et3N (0.28 mL). The reaction mixture was stirred at room temperature for 20 h. After cooling, the mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was evaporated and the residue was purified by preparative RP-HPLC using a gradient from 10-70% MeCN in 0.1% aq CF3COOH over 40 min. The title compound was obtained as an orange solid. Anal. RP-HPLC: tR=17.4 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>97%). 1H-NMR (DMSO-d6) δ: 3.10 (s, 3H, CH3), 3.25 (s, 3H, CH3), 7.05 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.42 (m, 1H, Ph-H), 7.63 (m, 1H, Ph-H), 7.98 (m, 1H, Ph-H), 8.21 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.42 (s, 1H, Ph-H), 9.18 (s, 1H, NH).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(Cc1ccc(OC)cc1)c1ccc(C(F)(F)F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CC(Cc1ccc(O)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
To a solution of ethyl (±)-4-(4-methoxyphenyl)-3-[4-(trifluoromethyl)phenyl]butanoate (450 mg, 1.23 mmole) in CH2Cl2 (5 mL) was added BBr3 (1.5 mL, 1.48 mmole) at −10° C. After 3 hr the mixture was carefully quenched with EtOH (10 mL), and the solution was allowed to warm to RT. The mixture was concentrated, and the residue was chromatographed on silica gel (20% EtOAc/hexanes) to give the title compound (270 mg, 63%) as a yellow oil: TLC (20% EtOAc/hexanes) Rf0.22.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-].[Na+]>O1CCCC1.CO.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OCC)c(OCC)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1OCC
Temperature: 20 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of ethyl 3-(7-{5-[3,4-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D66) (100 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) stirred at room temperature was added a solution of sodium hydroxide (45 mg) in water (10 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The organic solvent was evaporated off and the mixture was acidified with HCl (1 M) solution to pH around 1. The solid was filtered and recrystallized from acetonitrile to afford 3-(7-{5-[3,4-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E41) (71 mg). δH (DMSO-d6, 400 MHz): 1.37-1.41 (6H, m), 2.63 (2H, t), 3.00 (2H, t), 4.15-4.22 (4H, m), 7.21 (1H, t), 7.22 (1H, d), 7.27 (1H, d), 7.81 (1H, d), 7.87 (1H, dd), 7.95 (1H, dd), 10.73 (1H, s), 12.05 (1H, br s). MS (ES): C23H23N3O5 requires 421; found 422.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[CH:32]([N:35]([CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37]Cl)([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([S:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:31])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:37][CH2:36][N:35]([CH:39]([CH3:41])[CH3:40])[CH:32]([CH3:34])[CH3:33])=[CH:28][CH:29]=2)=[O:22])(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)N(CCCl)C(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc(OCCN(C(C)C)C(C)C)cc2)C(=O)O)cc1

Procedure:
The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with 2-diisopropylaminoethyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7 as a solid, mp=121-124° C.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:13]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([N:9]2[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]2)=[N:13]1
Reactant: CCOC(=O)N1CCN(c2nn(-c3ccccc3Cl)c3ccccc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Clc1ccccc1-n1nc(N2CCNCC2)c2ccccc21
Temperature: 25 °C

Procedure:
A stirred mixture of 28.7 g of 4-[1-(2-chlorophenyl)-1H-indazol-3-yl]-1-piperazine carboxylic acid ethyl ester, 450 ml of 2-methoxymethanol, and a solution of 25 g of potassium hydroxide in 250 ml of water, was refluxed for 16 hours, cooled to ambient temperature, concentrated to about one-third of its volume, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to yield 1-(2-chlorophenyl)-3-(1-piperazinyl)-1H-indazole as an oil. The oil was dissolved in anhydrous diethyl ether and treated with ethereal hydrogen chloride to precipitate the hydrochloride salt. The salt was recrystallized from acetonitrile to yield 18.8 g (72%) of 1-(2-chlorophenyl)-2-(1-piperazinyl)-1H-indazole hydrochloride. Recrystallization from isopropyl alcohol-diethyl ether afforded the analytical sample, m.p. 197°-199°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CN(C=O)C.[Br:15][CH2:16][C:17](Br)=[O:18]>O1CCOCC1>[Br:15][CH2:16][C:17]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: N#Cc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A solution of 4-aminobenzonitrile (5.0 g, 42.3 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (8.53 g, 3.7 mL, 42.3 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a pale brown solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 7.78 g (77%) of the title compound as a pale brown solid, mp 166°-168° C.: 1H NMR (DMSO-d6) δ10.81 (s, 1H), 7.81-7.74 (m, 4H), 4.08 (s, 2H); 13C NMR (DMSO-d6) δ165.60, 142.75, 133.39, 119.28, 118.89, 105.60, 30.17; MS (EI, m/z) 238 (M+).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH3:17][C:18]1[CH:19]=[N+:20]([O-])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C([O-])(O)=O.[Na+].ClCCl>[CH3:17][C:18]1[C:19]([NH:1][CH:2]([C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:4][CH3:5])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: Cc1cc2ccccc2[n+]([O-])c1
Reactant: CCCC(N)c1ccc(C(=O)OCC)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Intermediate 2 (22.9 g, 104 mmol) was combined with 3-methylquinoline-N-oxide (Intermediate 3, 17.3 g, 109 mmol) and dichloromethane (414 mL). Diisopropylethylamine (68.0 mL, 389 mmol) was added, followed by bromotripyrrolidinophosphonium hexafluorophosphate (61.0 g, 130 mmol). The solution was stirred at room temperature for 12 h before diluting with sat. aq NaHCO3 (400 mL). The mixture was extracted with ethyl acetate (3×400 mL). The combined organics were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave ethyl(+/−)-4-(1-((3-methylquinolin-2-yl)amino)butyl)benzoate (Intermediate 4). 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.2 Hz, 2H), 7.65-7.58 (m, 2H), 7.56-7.48 (m, 3H), 7.43 (t, J=7.5 Hz, 1H), 7.16 (t, J=7.4 Hz, 1H), 5.50 (q, J=7.2 Hz, 1H), 4.79 (d, J=7.0 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 2.30 (s, 3H), 2.04-1.83 (m, 2H), 1.54-1.39 (m, 2H), 1.37 (t, J=7.1 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][C@@H:11]([CH2:14][OH:15])[C@H:10]([OH:16])[CH2:9]2)C=CC=CC=1>CO.[Pd]>[OH:16][C@H:10]1[C@H:11]([CH2:14][OH:15])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OC[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Agent: [Pd]
Solvent: CO
Product: OC[C@@H]1CCNC[C@H]1O
Yield: 107.6 %

Procedure:
A mixture of (±)-trans-1-(phenylmethyl)-3-hydroxy4-piperidinemethanol (17.8 g, 0.085 mol) (already described in J. Med. Chem., 16, pp. 156-159 (1973)) in methanol (250 ml) was hydrogenated, at 50° C., with palladium on activated carbon (10%, 2 g) as catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, yielding 12 g of (±)-trans-3-hydroxy4-piperidinemethanol (interm. 1-a) (used in next reaction step without further purification). The corresponding cis-isomer is known from J. Org. Chem., 34, pp. 3674-3676 (1969).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CCN(CC)CC.[CH:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[CH:23]1([C:28]([CH:11]2[CH2:12][NH:13][CH2:14][CH2:15][N:10]2[C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N2CCNCC2C(=O)C2CCCC2)cc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
4-Methylphenyl piperazine dihydrochloride (4.20 g, 16.9 mmol) and NEt3 (7.0 mL, 50.2 mmol) were dissolved in DCM (125 mL) at 0° C. Cyclopentanecarbonyl chloride (2.0 mL, 16.5 mmol) was added and the reaction mixture was allowed to warm to room temperature over 16 hours. The reaction mixture was washed with 1M aq Na2CO3 solution (3×100 mL), dried (MgSO4) and concentrated in vacuo to give cyclopentanecarbonyl 4-(methyl)phenyl piperazine (4.42 g, 98%) as a pale brown oil which was used without further purification.