Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([NH:15][CH:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH:16]1([NH:15][C:13](=[O:14])[CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:24])[C:3]([OH:25])=[O:2])=[CH:10][CH:9]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)C(=O)c1ccc(OCC(=O)NC2CCCCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(COc1ccc(C(=O)C(=O)O)cc1)NC1CCCCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
A solution of 4-[2-(cyclooctylamino)-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.4 g) in methanol (40 mL) was treated with 1N sodium hydroxide solution (1.3 mL), and the mixture was stirred at room temperature for 15 minutes. After the solvents were evaporated under reduced pressure, water (20 mL) was added and the solution was acidified with 3N hydrochloric acid, then the aqueous layer was extracted with a mixture of dichloromethane-tetrahydrofuran (30 mL; 2:1). The organic layer was dried (MgSO4), evaporated and the resulting oil was crystallized from diethyl ether-hexane to yield 0.084 g of 4-[2-(cyclooctylamino)-2-oxoethoxy]-alpha-oxobenzeneacetic acid, mp 139°-140 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[C:5]([Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: OCc1cncc(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)c1ncc(Br)cc1CO
Reaction time: 1 h

Procedure:
To a solution of 5-bromopyridin-3-ylmethanol (Chem. Pharm. Bull. 1990, 38, 2446) (29 g, 154 mmoL) and tert-butylchlorodiphenylsilane (47.5 g, 173 mmoL) in CH2Cl2 (500 mL) at r.t., there was added imidazole (15.8 g, 232 mmoL). The mixture was stirred for 1 hr. and filtered. The filtrate was evaporated and the residue chromatographed on silica gel, eluting with a 1:7 mixture of EtOAc and hexane, to afford the product as a colorless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[C:4]([C:12]([NH:14][CH:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:13])[CH:3]=1.CC1(C)COB([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)OC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:9]1[CH:10]=[CH:11][C:7]([C:5]2[S:6][C:2]([C:39]3[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=3)=[CH:3][C:4]=2[C:12]([NH:14][CH:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:13])=[CH:8]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: CC(C)(C)OC(=O)NCC(Cc1ccccc1)NC(=O)c1cc(Br)sc1-c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)Cc2ccccc2)c(-c2ccoc2)s1
Reaction time: 4 h

Procedure:
1,1-dimethylethyl [2-({[5-bromo-2-(3-furanyl)-3-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (140 mg, 0.277 mmol), 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (54 mg, 0.277 mmol), Pd(PPh3)4 (16 mg, 13.8 μmol) and K2CO3 (153 mg, 1.11 mmol) in dioxane (2.3 mL) and H2O (462 uL) were combined in a sealed tube. After 4 h at 80° C., additional 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (54 mg, 0.277 mmol) and Pd(PPh3)4 (16 mg, 13.8 μmol) were added. After an additional 12 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly: LCMS (ES) m/z=507 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]1C(OCC)=O.[OH-].[Na+].Cl>O1CCOCC1.O>[O:1]=[C:2]1[CH2:3][CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a solution 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (429.1, 19.0 g, 66.6 mmol, 1.00 equiv) in 1,4-dioxane (190 mL) was added dropwise sodium hydroxide (4.00 g, 100 mmol, 1.50 equiv) in water (100 mL). The resulting mixture was stiffed at room temperature overnight. The pH was then adjusted to 4-5 with hydrogen chloride (aq. 3 M) and the resulting solution was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:3) as eluent to furnish 11.0 g (77%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[C:5]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH3:12])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Cc1cc(Cl)ccc1-2
Reactant: CCCCCCBr
Product: CCCCCCC1(CCCCCC)c2cc(Cl)ccc2-c2ccc(Cl)cc21
Yield: 91 %

Procedure:
2,7-Dichloro-9,9-di(1-hexyl)fluorene is prepared from 2,7-dichlorofluorene and 1-bromohexane following the procedure of Example 1 as colorless crystals (recrystallized from hexane) in 91 percent yield, melting point 66° C. to 67° C. HPLC analysis shows that the sample is 99 percent or greater pure and the spectral data confirms the title structure.
Reaction SMILES: Cl.Cl.C[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[BrH:17]>>[BrH:17].[BrH:17].[OH:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: Cl
Product: Oc1ccc(N2CCNCC2)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
1-(4-Hydroxyphenyl)piperezine dihydrobromide may be prepared in the following manner: a 47% aqueous solution of hydrobromic acid (720 cc) is added, over 30 minutes and at a temperature of about 20° C., to 4-(4-methoxyphenyl)piperazine dihydrochloride (70 g). The mixture is heated at boiling point for 4 hours then cooled to a temperature of about 20° C. Stirring is continued for 15 hours at this temperature, then the mixture is concentrated at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residual oil is redissolved in acetonitrile (300 cc). The precipitate formed is separated by filtration, washed with acetonitrile (2 x 50 cc) and diisopropyl ether (2 x 100 cc). 4-(4-Hydroxyphenyl)piperazine dihydrobromide (85.2 g) (m.p. greater than 260° C.) is obtained and used in the crude state in the subsequent syntheses.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:18][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[O:17][N:16]=1
Reactant: Cc1cc(CCCCO[Si](C)(C)C(C)(C)C)on1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(CCCCO)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a solution of 5-[4-(tert-butyldirnethylsilanyloxy)butyl]-3-methylisoxazole (350 mg in 5 mL dry tetrahydrofuran) at 0° C. was added 1.62 mL of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran and the mixture stirred while warming to room temperature. After 16 hours, the mixture was concentrated in vacuo and the residue purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:3, then 1:1) to give the title compound (147 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].Br[CH2:14][C:15](=O)[CH2:16][CH3:17]>C1(C)C=CC=CC=1.O1CCOCC1>[CH2:16]([C:15]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=2)[O:7][CH:14]=1)[CH3:17]
Reactant: COc1cc(C(N)=O)ccc1O
Reactant: CCC(=O)CBr
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCc1coc(-c2ccc(O)c(OC)c2)n1
Temperature: 125 °C
Yield: 63.4 %

Procedure:
To a solution of the amide prepared in Example 171 (460 mg, 2.75 mmol) in toluene (3 mL) and 1,4-dioxane (3 mL) was added 1-bromo-2-butanone (623 mg, 4.13 mmol), and the solution was heated to 125° C. for 18 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc:hexane (v/v)=4:1) gave 382 mg (73%) of the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 7.78 (s, 1H), 7.39 (d, 1H), 7.36 (dd, 1H), 6.83 (d, 1H), 3.79 (s, 3H), 2.45 (m, 2H), 1.18 (t, 3H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:6]>CO>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:13]([NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:5]([OH:6])=[O:4])=[O:23])=[CH:16][CH:17]=1
Reactant: COC(=O)c1sccc1NC(=O)Cc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(=O)Nc2ccsc2C(=O)O)cc1
Temperature: 25 °C

Procedure:
A 3M lithium hydroxide solution (80 mL) was added to methyl-3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate (7.30 g, 23.91 mmol) dissolved in methanol. The reaction mixture was refluxed for 2 h, cooled to room temperature and then partitioned between ethyl acetate and H2O. The aqueous layer with acidified with conc HCl, filtered and washed with H2O. The precipitate that formed was collected by filtration (8.55 g, quantitative) and used in the next step without further purification. Method [7] m/z 291.9 (M+H); retention time=3.827. 1H-NMR (CD3OD) δ 8.0 (d, J=5.3 Hz, 1H), 7.61 (d, J=5.3 Hz, 1H), 7.26 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 3.76 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][S:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:3]([OH:5])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[CH3:13][C:2]1([CH3:1])[CH2:6][S:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:3]1=[O:5]
Reactant: CC(C)(CSc1cccs1)C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: CC1(C)CSc2sccc2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 2,2-dimethyl-3-(2-thienylthio)propanoic acid (53.65 g, 0.25 m), diatomaceous earth (54 g) and phosphorus pentoxide (87 g) in toluene (870 ml) was vigorously stirred and heated at 100° C. After 2 hours, additional phosphorous pentoxide (87 g) was added and the mixture was heated for 3 hours more. After filtering the hot mixture, the solid was washed with hot toluene (3×500 ml) and the combined filtrate and washings were concentrated under reduced pressure to afford 33.17 g (67%) of crude product. This material was combined with 2.89 g of crude product from a previous reaction and distilled to yield 25.07 g (46%) of pure product boiling at 96°-100° C./0.4 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[CH2:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:7][C:6]=12.C1(O)C=CC=CC=1.[BrH:27]>C(O)(=O)C>[BrH:27].[CH3:1][C:2]1[S:3][CH:4]=[C:5]2[CH2:9][NH:8][CH2:7][C:6]=12
Reactant: Cc1ccc(S(=O)(=O)N2Cc3csc(C)c3C2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: Cc1scc2c1CNC2
Temperature: 90 °C
Yield: 27 %

Procedure:
A mixture of 3.1 g (10.6 mmol) of 1-methyl-5-tosyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole and 3.1 g (32.9 mmol) of phenol in 43 ml of a 33% solution of hydrobromic acid in acetic acid, placed in a sealed tube, is heated at 90° C. in a water bath for 3 hours. The reaction mixture is then filtered and poured into 150 ml of water and then extracted with three times 150 ml of diethyl ether. The aqueous phase is evaporated to dryness and the residue washed with acetone. There is obtained 0.64 g of a pasty solid. Yield 27%.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([CH2:18][OH:19])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][O:19][C:2]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:17][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: OCC1CC1
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and cyclopropyl-methanol. The crude material was purified by flash chromatography to yield the title compound as a white solid. MS (m/e): 269.1 ([M−H]−, 100%).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[C:20]([CH:23]=1)[C:21]#[N:22].[H-].[Na+].Cl>CN(C)C=O>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=[C:2]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)=[C:20]([CH:23]=3)[C:21]#[N:22])[CH:12]=[C:6]12
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (31 mg, 0.153 mmol) and 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (49.4 mg, 0.168 mmol) in N, N-dimethylformamide (DMF) (1.5 mL), was added NaH (18.36 mg, 0.459 mmol). The reaction mixture was stirred at rt for 30 min. Aqueous HCl solution was added to adjust pH to ˜7. Purification by Mass Directed AutoPrep (MDAP) afforded the title compound as a white solid (35 mg, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1([NH2:31])[CH2:30][O:29][CH2:28]1>>[CH3:26][C:27]1([NH:31][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])[CH:16]=2)=[O:22])[CH2:30][O:29][CH2:28]1
Reactant: CC1(N)COC1
Reactant: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NC1(C)COC1
Yield: 32 %

Procedure:
As described for example 107, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.28 mmol) was converted, using 3-methyl-3-oxetanamine instead of 2-amino-2-methyl-1-propanol, to the title compound (39 mg, 32%) which was obtained as a white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:15][C:14](=[O:16])[NH:13][CH:12]2[CH2:17][OH:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1.Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[O:15][C:14](=[O:16])[NH:13][CH:12]2[CH2:17][O:18][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(C2OC(=O)NC2CO)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC1NC(=O)OC1c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
Compound (H) (200 mg; 0.84 mmols) has been dissolved in anhydrous pyridine (3 ml). The thus obtained solution has been cooled to 0° C. and added with freshly distilled methanesulfonyl chloride (0.06 ml). The solution has been maintained at 0° C. overnight and then diluted with an aqueous solution of hydrochloric acid (stoichiometric amount with respect to pyridine) and ice. After extraction with ethyl acetate, the organic extract has been dried over sodium sulfate and evaporated in vacuo to afford crude (J); yield, 85-90%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([O:14][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NN1CC[C@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
(S)-1-(tert-Butoxycarbonylamino)-3-hydroxypyrrolidine (40 g, 0.21 mol) was dissolved in anhydrous methylene chloride (400 mL), in the presence of N,N-diisopropyl-ethylamine (73 mL, 0.42 mol, 2 equiv.) and cooled using an ice bath. This solution was treated with methanesulfonyl chloride (18 mL, 0.23 mol, 1.1 equiv.) over a 30 min. period and was then allowed to stir at room temperature for 4 h. The solution was concentrated and the residue dissolved in ethyl acetate (250 mL). The resulting organic solution washed with 5% NaHCO3 and then with brine. The organic extract was dried over magnesium sulfate, filtered and concentrated to give (S)-1-(tert-butoxycarbonyl-amino)-3-methanesulfonyloxypyrrolidine as a dark oil (39 g) which was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: Brc1ccccc1I
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccccc1-c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
2-Bromoiodobenzene (640 μL, 5.0 mmol) was added to a suspension of Pd(PPh3)4 (305 mg, 0.26 mmol) in DME (100 mL) at room temperature under argon. After 15 min at room temperature, a solution of 2-methoxyphenylboronic acid (760 mg, 5.0 mmol) in ethanol (2 mL) was added, followed by aqueous Na2CO3 (2.0 M, 5 mL, 10 mmol). The reaction vessel was fitted with a reflux condenser and heated to reflux under argon for 22.5 h. The reaction mixture was then cooled to room temperature and filtered through Celite. The filter cake was washed with ether and water, and the filtrate was concentrated in vacuo. The resulting aqueous residue was diluted with brine and extracted with ether. The ethereal layer was dried (MgSO4), filtered and concentrated. The crude residue was purified by flash chromatography on silica gel to afford 823 mg (63%) of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:38])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:38])[CH3:22])=[CH:29][CH:28]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CN(C)c1ccc(CNc2ccccc2)cc1
Product: CN(C)c1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccccc2)cc1
Yield: 80.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.57 g) and [(4-dimethylaminophenyl)methyl]phenylamine (0.61 g) as starting materials, 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-phenyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.80 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound, N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-phenyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.083 g) was obtained. melting point: 138-143° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]=4)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.C([O:35][CH:36](OCC)/[CH:37]=[CH:38]/B1OC(C)(C)C(C)(C)O1)C.C(=O)([O-])[O-].[Na+].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCOC.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]=4)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](/[CH:38]=[CH:37]/[CH:36]=[O:35])=[CH:4][N:3]=1
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2coc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Yield: 36.9 %

Procedure:
A mixture of N-[4-(4-amino-7-iodofuro[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-benzimidazole-2-carboxamide (1.50 g, 2.78 mmol) in 1,2-dimethoxyethane (30 mL) and water (15 mL) was reacted 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.42 g, 5.56 mmol), sodium carbonate (1.17 g, 11.12 mmol) and tetrakis triphenylphosphine palladium (0) (0.19 g, 0.17 mmol) at 80° C. for 18 hours. Additional 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 3.90 mmol), sodium carbonate (0.508 g, 4.80 mmol) and tetrakis triphenylphosphine palladium (0) (0.19 g, 0.17 mmol) was added and the mixture was heated for another 24 hours. Additional tetrakis triphenylphosphine palladium (0) (0.32 g, 0.27 mmol) was added and the mixture was heated for another 24 hours after which time all starting material was consumed. The solvent was removed in vacuo and the residue was triturated with water (30 mL) for 3 hours. The solid was collected by filtration and dried in vacuo. The crude product was suspended in acetone (60 mL) and water (8 mL) and reacted with p-toluenesulfonic acid monohydrate (0.10 g, 0.52 mmol) at ambient temperature for eighteen hours. The acetone was removed in vacuo and the precipitate was filtered, washing with water. The precipitate was triturated with 2-propanol (30 mL) for 1 hour. The solvent was removed an the residue was partitioned between dichloromethane (20 mL) and water (40 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the title compound (0.48 g, 31%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.19 (s, 1H), 9.64 (d, 1H), 8.52 (dd, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.86 (d, 1H), 7.75-7.82 (m, 2H), 7.47 (t, 1H), 7.39 (t, 1H), 7.32 (d, 1H), 7.21 (dd, 1H), 6.93 (dd, 1H), 4.25 (s, 3H), 4.04 (s, 3H), 1.86 (s, 3H); RP-HPLC (Conditions g) Rt 12.21 min.; MS: MH+ 468.