Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.O.C(Cl)[Cl:16]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([Cl:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 4-tert-butyl-phenol (40.0 g, 0.27 mol) and SO2Cl2 (37.5 g, 0.28 mol) in CH2Cl2 was added MeOH (9.0 g, 0.28 mol) at 0° C. After addition was complete, the mixture was stirred overnight at room temperature and then water (200 mL) was added. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (Pet. Ether/EtOAc, 50:1) to give 4-tert-butyl-2-chloro-phenol (47.0 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>C(NCC)C.C(Cl)CCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCCl
Product: CN1Cc2c(C#C[Si](C)(C)C)ncn2-c2ccc(F)cc2C1=O

Procedure:
67.8 g (190 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 8 hours with 23.4 g (238 mmol) of ethynyltrimethylsilane, 300 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 70 mg of copper(I) iodide in 280 ml of diethylamine and 25 ml of ethylene chloride. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with chloroform/ethyl acetate (3:1). By recrystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-5-methyl-3-[(trimethylsilyl)ethynyl]-6H-imidazo-[1,5-a][1,4]benzodiazepin-6-one of melting point 184°-185°.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]2[N:20]=[C:19]([NH2:21])[C:18]([NH2:22])=[C:17]([NH2:23])[N:16]=2)=[N:6]1.Cl[C:29]([O:31][CH3:32])=[O:30].O>N1C=CC=CC=1>[NH2:23][C:17]1[C:18]([NH:22][C:29](=[O:30])[O:31][CH3:32])=[C:19]([NH2:21])[N:20]=[C:15]([C:7]2[N:8]=[C:9]([C:10]3[S:11][CH:12]=[CH:13][N:14]=3)[N:5]([CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=3[F:1])[N:6]=2)[N:16]=1
Reactant: Nc1nc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)nc(N)c1N
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Nc1c(N)nc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)nc1N
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a suspension of 2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4,5,6-triamine (I-57, 0.31 mmol) in pyridine (2.0 mL) at 0° C. was treated with methyl chloroformate (1 equiv). After 30 min, additional portions of methyl chloroformate (3 equiv) were added and the reaction was stirred for 3 h. The reaction mixture was poured into water and the resultant tan solid was collected by filtration to afford methyl 4,6-diamino-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-5-ylcarbamate (74% yield).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)C=O>O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCOc1ccc(Br)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a dry 100 mL round bottom flask under nitrogen was added 3-(4-bromophenoxy)propan-1-ol (9.0 g, 39.0 mmol), tert-butyldimethylsilyl chloride (7.0 g, 47.0 mmol), imidizole (3.2 g, 47.0 mmol), and 20 mL of N,N-dimethylformamide. The reaction was allowed to stir at room temperature while being monitored by thin layer chromatography. Upon disappearance of the starting material the reaction mixture was poured into a separatory funnel containing 50 mL of cold water. The product was extracted using 3×25 mL ether. The organic layers were combined and washed with 3×25 mL cold water and 3×25 mL saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate, filtered from drying agent, and the solvent was removed under reduced pressure. The material was purified by filtering through a plug of silica gel eluting with 4:6 dichloromethane:hexane. The solvent was removed under reduced pressure (12.1 g, 89.4%). 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J=9.0 Hz, 2H), 6.76 (d, J=9.0 Hz, 2H), 4.00 (t, J=6.0 Hz, 2H), 3.76 (t, J=6.0 Hz, 2H), 1.95 (q, J=6.0 Hz, 2H), 0.87 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:18]([CH:19]=2)=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][N:17]4[CH2:18][CH2:9][CH2:10][CH2:11][CH2:16]4)[CH:15]=2)[CH:10]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Reactant: C1CCNCC1
Agent: Cl
Product: c1cc2cc3ccc(OCCN4CCCCC4)cc3nc2cc1OCCN1CCCCC1

Procedure:
A suspension of 3,6-bis(2-chloroethoxy)acridine hydrochloride in piperidine was heated in a steel bomb at 80° C. for 24 hours. The excess piperidine was removed in vacuo and the residual solution was washed twice with 30 ml portions of saturated aqueous sodium bicarbonate, then dried and filtered. The filtrate was evaporated to a residue, giving 3,6-bis(2-piperidinoethoxy)acridine as yellow crystals, mp 129°-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:28]1[S:29][C:30]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:31]=2[N:32]=1.S1C2C=CC=CC=2N=C1NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(O)=O)=CC=2)=CC=1.FC(F)(F)C([O-])=O>>[Cl:37][C:35]1[CH:34]=[CH:33][C:31]2[N:32]=[C:28]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:4][CH:3]=3)[S:29][C:30]=2[CH:36]=1
Reactant: COC(=O)C(CCN(C)C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Agent: O=C([O-])C(F)(F)F
Product: CN(C)CCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1)C(=O)O
Yield: 16.3 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2-[2-(dimethyl-amino)ethyl]-4-oxobutanoate (60 mg, 0.17 mmol) and 2,6-dichloro-1,3-benzothiazole (51.8 mg, 0.25 mmol)) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 14.1 mg (13%) of the desired product as the trifluoroacetate salt. 1H NMR (400 MHz, CD3OD) δ 8.10 (d, 2 H), 7.70-8.10 (m, 8 H), 7.30 (m, 1 H), 3.60 (m, 1 H), 3.30-3.40 (m, 3 H), 3.10 (m, 1 H), 2.95 (s, 6 H), 2.20 (m, 1 H), 2.00 (m, 1 H). LC-MS m/z 508.1 (MH+), ret. time 2.66 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]([CH:15]2[CH2:17][CH2:16]2)([N:12]=[C:13]=[O:14])[CH2:10]I)[CH:3]=1.C(N(CC)CC)C.C([OH:29])CCC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]2([CH:15]3[CH2:17][CH2:16]3)[CH2:10][O:14][C:13](=[O:29])[NH:12]2)[CH:3]=1
Reactant: CCCCO
Reactant: O=C=NC(CI)(c1cc(Br)ccc1F)C1CC1
Solvent: CCN(CC)CC
Product: O=C1NC(c2cc(Br)ccc2F)(C2CC2)CO1
Reaction time: 8 h

Procedure:
A solution of the crude (RS)-4-bromo-2-(1-cyclopropyl-2-iodo-1-isocyanato-ethyl)-1-fluoro-benzene (6.40 g, 16 mmol) in tent-butanol (200 ml) was treated at 23° C. with triethylamine (2.16 ml, 16 mmol) and the mixture was stirred overnight at reflux. For the workup, the reaction mixture was evaporated at reduced pressure to yield the crude title compound as a yellow oil which was directly used in the next step. Mass (calculated) C12H11BrFNO2 [300.126]; (found) [M+H]+=300, [M+2-H]+=302.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[C:6]2[C:11]=1[S:10](=O)[CH2:9][CH2:8][NH:7]2.C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][NH:7]2
Reactant: O=C(O)c1ccc(Cl)c2c1NCCS2=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cl)c2c1NCCS2
Yield: 19.3 %

Procedure:
A mixture of 8-chloro-3,4-dihydro-2H-1,4-benzothiazine-5-carboxylic acid-1-oxide (2.5 g) and stannous chloride dihydrate (4.51 g) in methanol (20 ml) was refluxed for 21 hours. To the reaction mixture was added ethyl acetate (200 ml), washed with water and dried over anhydrous sodium sulfate. After concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography eluting with dichloromethane-ethanol (9:1) to give the title compound (450 mg, 19.6%). This compound was recrystallized from ethanol to give yellow needles, mp 220° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([NH2:9])=[O:8])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Reaction time: 24 h

Procedure:
The above polymer-bound D-Leu-NH2 (20 g) was treated with CH2Cl2 (150 mL), pyridine (100 mL) and 4-chlorophenylsulfonyl chloride (20.0 g, 94.8 mmol). The mixture was shaken for 24 h, drained, washed with DMF (4×200 mL), CH2Cl2 (4×200 mL) and concentrated to give polymer-bound (R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide as a yellow resin (22 g). The completion of the reaction and the loading of the resin (0.57 mmol/g) were determined by the treatment of 50 mg of the resin with 10% (v/v) TFA/CH2Cl2 (2 mL) to give 8.7 mg of (R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([NH:27][C:28]([C:30]3[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=3)=[O:29])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:34]([C:33]3[CH:32]=[CH:31][C:30]([C:28]([NH:27][C:23]4[CH:22]=[C:21]5[C:26](=[CH:25][CH:24]=4)[NH:18][CH:19]=[CH:20]5)=[O:29])=[CH:37][CH:36]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3[nH]ccc3c2)cc1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5[nH]ccc5c4)cc3)[nH]c2c1

Procedure:
Compound 661 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C25H22N4O3: 427.17; found: 426.99.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[C:24]([Cl:26])[C:23]([O:27][CH2:28][C:29](O)=[O:30])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CN1CCOCC1>C1COCC1>[C:16]([C:20]1[N:25]=[C:24]([Cl:26])[C:23]([O:27][CH2:28][C:29]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:30])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)c(Cl)n1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(Cl)n1
Yield: 28.2 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (21 mg, 0.08 mmol) was reacted with (6-tert-butyl-2-chloro-pyridin-3-yloxy)-acetic acid (1.0 eq, 20 mg) DMTMM (1.2 eq, 27 mg) and NMM (1.5 eq, 14 μl) in THF to give the title compound (10 mg, 28.2%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[S:14][C:13]([NH:15][C:16](=[O:18])[CH3:17])=[N:12][CH:11]=2)=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][C:27](N1C=CC=N1)=[N:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C)C=O>O1CCCC1>[C:16]([NH:15][C:13]1[S:14][C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH:27]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:26][C:24](=[O:25])[O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:3][CH:4]=2)=[CH:11][N:12]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ncc(CCc2ccc(N)cc2)s1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)s1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 48.5 %

Procedure:
N-{5-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (100 mg), —N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (119 mg), N,N-dimethylformamide (1 ml) and tetrahydrofuran (2 ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at 50° C. for 5.5 hours. After cooled to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by preparative silica gel column chromatography with n-hexane/ethyl acetate (1:2) as an eluent to give di-tert-butyl {[(4-{2-[2-(acetylamino)-1,3-thiazol-5-yl]ethyl}phenyl)amino]-methylidene}biscarbamate (93.9 mg) as a colorless solid.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@@H:14]([CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.C(Cl)Cl.CO.[NH4+].[OH-]>>[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@@H:14]([CH2:27][CH:28]4[CH2:29][CH2:30][CH2:31]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:45][CH2:46]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(COC(=O)[C@H](CC2CCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)[C@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Yield: 63.8 %

Procedure:
The title compound was prepared from 25 mg (0.059 mmol) of 2-(S)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 92, Step C) and 14.3 mg (0.059 mmol) of 4-(3-phenylpropyl)piperidine.HCl using a procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F to 18.4 mg (64%) of the title compound: RF: 0.48 (90:10:1 v/v/v CH2Cl2/MeOH/NH4OH); 1H NMR (300 MHz, CD3OD) δ 0.99-3.67 (m, 33H), 6.96-7.23 (m, 10H); ESI-MS 489 (M+H); HPLC A: 2.69 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCc1ccc(OC)c(O)c1
Reactant: BrCc1ccccc1
Product: CCOC(=O)CCc1ccc(OC)c(OCc2ccccc2)c1

Procedure:
In substantially the same manner as in Reference Example 92, ethyl 3-(3-hydroxy-4-methoxyphenyl)propionate was reacted with benzyl bromide to yield ethyl 3-(3-benzyloxy-4-methoxyphenyl)propionate. The product was recrystallized from hexane to give colorless needles, m.p.49.5-50.5° C.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([O:35][CH2:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:20]1[C:21]2[N:8]([CH2:7][CH2:6][O:5][C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH:30]([O:35][CH2:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:28]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(Cc1ccc(O)cc1)C(=O)OC
Reactant: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)OC
Temperature: 80 °C
Reaction time: 12 h
Yield: 390.1 %

Procedure:
A mixture of 2-(phenoxazin-10-yl)ethyl methanesulfonate (1.75 g, 5.0 mmol), methyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate (1.5 g, 0.68 mmol) and potassium carbonate (3.16 g) in dry dimethylformamide (20 mL) was stirred for 12 h at 80° C. The reaction mixture was cooled to room temperature (ca. 25° C.). Water (30 mL) was added and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4) and evaporated. The residue was chromatographed using a mixture of ethyl acetate and pet. ether (1:9) to afford the title compound (1.15 g, 47%) as a white solid. mp 89-90° C. 1H NMR data matches with the desired product (see above).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[OH:15])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:16]I.[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CI
Reactant: CCOC(=O)COc1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
Ethyl 4-hydroxyphenoxyacetate (1.5 g, 7.6 mmol) was reacted with SO2Cl2 (1.5 mL) to give ethyl 3-chloro-4-hydroxyphenoxyacetate (700 mg, ˜80% pure) as a white powder. To a solution of ethyl 3-chloro-4-hydroxyphenoxyacetate (700 mg, 3.0 mmol) and MeI(0.280 mL, 4.5 mmol) in DMF (5 mL) at 0° C. was added 10M aq. NaOH (0.320 mL, 3.2 mmol). The mixture was stirred at r.t. for 12 h, then diluted with H2 O and extracted with EtOAc to give ethyl 3-chloro-4-methoxyphenoxyacetate (700 mg).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][CH2:28][CH:29]([OH:32])[CH:30]=[CH2:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C)C=O>[CH2:11]([O:27][CH2:28][CH:29]([O:32][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:30]=[CH2:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C=CC(O)COCCCCCCCCCCCCCCCC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(COCCCCCCCCCCCCCCCC)OCc1ccccc1
Yield: 49 %

Procedure:
To stirred suspension of 3.35 g of 50% sodium hydride and 10.92 g of benzyl bromide in 75 ml of dimethylformamide was added a solution of 19 g of 1-(hexadecyloxy)-3-buten-2-ol in 75 ml of dimethylformamide. The mixture was stirred overnight, then water was added and the mixture was extracted with ether. The ether extract was dried over magnesium sulfate and activated charcoal and the solvent removed giving an oil. This oil was purified by HPLC [hexane: chloroform (8:1)] and the solvent removed giving 12 g of the desired compound as an oil.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>CN(C)C=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: BrCCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: BrCCCCn1ccc2ccccc21
Reaction time: 15 h

Procedure:
0.96 g (17.07 mmol) of sodium hydroxide is added in small portions to a solution, cooled by a bath of ice-cold water, of 2 g (17.07 mmol) of 1H-indole and of 1.15 ml (51.22 mmol) of 1,4-dibromobutane in 80 ml of dimethylformamide. The bath is removed and stirring is continued at ambient temperature for 15 hours.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I-].[K+].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29]O)=[CH:23][CH:22]=1)(=[O:20])=[O:19].O>CO>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH2:31][CH:32]([CH3:33])[CH3:34])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCCO)cc2)c(C)c1
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCCN3CCOCC3)cc2)c(C)c1
Temperature: 150 °C

Procedure:
To a microwave vial was added morpholine (5.10 μL, 0.058 mmol), potassium iodide (19.26 mg, 0.116 mmol), [Cp*IrCl2]2 (0.639 mg, 0.580 μmol), N-(2,4-dimethylphenyl)-4-[(2-hydroxyethyl)oxy]-N-(2-methylpropyl)benzenesulfonamide (43.8 mg, 0.116 mmol), a stirrer bar and water (0.1 mL). The vial was then sealed and the mixture was heated to 150° C. by microwaves (Biotage Initiator) for 3 hours. Reaction mixture was then diluted with methanol (1 mL) and passed down a pre-conditioned sulfonic acid (SCX) solid phase extraction (SPE) cartridge, eluting with methanol and then 2N methanolic ammonia. The fractions from the methanolic ammonia wash were concentrated in vacuo and the residue purified by mass-directed autoprep, using a formic acid modifier. Product containing fractions were evaporated under a stream of nitrogen to provide product, 2.6 mg. LCMS [LCMS1] Rt 1.01 min, m/z (ES+) 447 (M+H).
Reaction SMILES: [C:1]([CH:4]1[CH:17]2[CH2:18][CH:6]([CH:7]3[CH:16]2[C:15]2[CH2:19][CH:8]3[CH:9]3[C:14]=2[CH:13]2[CH2:20][CH:10]3[CH2:11][CH2:12]2)[CH2:5]1)([OH:3])=[O:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:2][C:1]([CH:4]1[CH:17]2[CH2:18][CH:6]([CH:7]3[CH:16]2[C:15]2[CH2:19][CH:8]3[CH:9]3[C:14]=2[CH:13]2[CH2:20][CH:10]3[CH2:11][CH2:12]2)[CH2:5]1)=[O:3]
Reactant: O=C(O)C1CC2CC1C1C3=C4C5CCC(C5)C4C(C3)C21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(OC1CCCCO1)C1CC2CC1C1C3=C4C5CCC(C5)C4C(C3)C21
Yield: 72.6 %

Procedure:
Next, 2.1 g of the 12-carboxyhexacyclo[6.6.1.13,6.110,13.02,7.09,14]heptadecene and 1.71 g of 3,4-dihydro-2H-pyran were dissolved in 50 ml of tetrahydrofuran, into which 0.03 g of p-toluenesulfonic acid were added. The resultant mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with 100 ml of ethyl ether, followed by the successive washing with a 3% aqueous solution of Na2CO3, 3% aqueous solution of sodium chloride, and water. An organic layer was dried over MgSO4. The ethyl ether and unreacted 3,4-dihydro-2H-pyran were distilled off under reduced pressure by an evaporator, whereby 2 g of 12-tetrahydropyranyloxycarbonylhexacyclo[6.6.1.13,6.110,13.02,7.09,14]heptadecene were obtained as a viscous liquid.