Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH2:11])=[N:5][N:4]=[N:3]1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH:11][C:14]([NH:13][CH3:12])=[S:15])=[N:5][N:4]=[N:3]1
Reactant: CN=C=S
Reactant: Cn1nnnc1SCCCN
Solvent: CCO
Product: CNC(=S)NCCCSc1nnnn1C
Yield: 32.8 %

Procedure:
3-(1-Methyl-1,2,3,4-tetrazol-5-yl)thiopropylamine (1.5 g) is dissolved in ethanol (5 ml), and thereto is added dropwise a solution of methyl isothiocyanate (0.8 g) in ethanol (5 ml) with stirring under ice-cooling, and the mixture is refluxed for 1 hour. Ethanol is distilled off, and then the residue is purified by column chromatography (Kieselgel 60), followed by eluting with chloroform-methanol (50:1) to give 1-[3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiopropyl]-3-methylthiourea (0.7 g) which is recrystallized from ethanol-ligroin, pale yellow granules, m.p. 99°-101° C.
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:5]=1[OH:36])(=[O:3])[CH3:2].[OH-].[K+].S(OC)(O[CH3:43])(=O)=O.C(OCC)C.O>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH:33]2[CH2:34][CH2:35]2)[C:5]=1[O:36][CH3:43])(=[O:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCCc1c(OCCCOc2ccc(C(C)=O)c(O)c2CC2CC2)ccc2c1OC(C(=O)OC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OC)c2CC2CC2)ccc2c1OC(C(=O)OC)CC2
Yield: 99.3 %

Procedure:
Methyl 7-[3-[4-acetyl-2-(cyclopropylmethyl)-3-hydroxyphenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate (0.69 g, 1.39 mmol) was stirred in 15 mL THF with 0.20 g (3.57 mmol) potassium hydroxide and 0.34 mL (3.59 mmol) dimethyl sulfate at room temperature for 3.5 hr. The mixture was poured into ethyl ether/water, and the ether layer was washed with brine, dried over sodium sulfate, and concentrated. Flash chromatography on silica gel using 10:1 to 5:1 hexane/ethyl acetate as eluant provided the product (0.705 g, 1.38 mmol, 99% yield). High resolution mass spectrum, m/e 510.2612 (calculated for C30H38O7, 510.2617).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][N:11]=[N+:12]=[N-:13])([O:3]C(C)(C)C)=O.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].C(Cl)(=O)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1>O1CCOCC1.O>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([C:1]([NH:8][C@H:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][N:11]=[N+:12]=[N-:13])=[O:3])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])c1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1ccc(C(=O)N[C@@H](CN=[N+]=[N-])c2ccccc2)cc1
Temperature: -15 °C
Yield: 85.9 %

Procedure:
(R)-2-(Boc-amino)-2-phenylethyl azide (47.8 g, 0.182 mole) was added to trifluoroacetic acid (500 mL) with stirring and ice-water bath cooling. The cooling bath was removed, the reaction was allowed to stir 1 h, and the solvent was removed in vacuo at 35° C. water bath temperature. The residue was co-evaporated with toluene to give a weight of 75.0 g. The residue was dissolved in 1,4-dioxane (500 mL) and water (500 mL), with ice-water bath cooling, and then potassium carbonate (113.5 g, 0.82 mol), and anisoyl chloride (37.3 g, 0.219 mol) were added. Another portion of 1,4-dioxane (300 mL) was added to facilitate stirring. After stirring over the weekend, water (1 L) was added. The mixture was cooled to −15° C., and vacuum filtered to collect a white solid. The solid was washed with water, air dried, and then dried under vacuum at 50° C. for 4 h to afford 46.3 g (86%) of the title compound.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[C:12]([NH:16][NH2:17])([CH3:15])([CH3:14])[CH3:13].Cl.N>O.CO>[NH2:6][C:5]1[N:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:17]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: CC(C)(C)NN
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)(C)n1ncc(N=O)c1N
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 2.70 g (21 mmol) of t-butylhydrazine hydrochloride with a purity of 97% by weight, 1.4 ml of water, 6 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 60 to 62° C. for 3 hours. After completion of the reaction, 5 ml of water was added to the mixture and the mixture was cooled up to 10° C. Then, 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 1.2 ml of cold water and 1.2 ml of cold methanol, and dried under reduced pressure to obtain 1.93 g of 5-amino-1-t-butyl-4-nitrosopyrazole (Isolation yield: 55.2%) as reddish orange solid with a purity of 96.2% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@@H:10]([CH3:24])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CNCCN1C(=O)OCc1ccccc1

Procedure:
A solution of 4.3 g (S)-2-Methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester in 20 ml dichloromethane was stirred in the presence of 10 ml TFA for 16 h. The solution was concentrated and the residue codistilled twice with toluene to give the crude hydrotrifluoroacetate. Yield: 6.4 g.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OCC)(=O)C>C(#N)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CNCCN(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)CCN(C)CC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
A solution of N,N,N′-trimethylethylenediamine (899 mg, Tokyo Kasei Kogyo) in acetonitrile (31 ml) was cooled to 0° C., added with potassium carbonate (2.21 g, and then slowly added dropwise with tert-butyl bromoacetate (1.56 g, Wako Pure Chemical Industries), and the mixture was stirred at the same temperature for 12 hours. The reaction mixture was added with ethyl acetate, and the insoluble solids were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (methanol:chloroform=1:10) to obtain the title compound (1.25 g).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].I[C:14]1[CH:15]=[C:16]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:14]2[CH:15]=[C:16]([C:21]3[NH:25][C:24]4[CH:26]=[C:27]([CH2:30][N:31]5[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]5)[CH:28]=[CH:29][C:23]=4[N:22]=3)[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Reactant: C#Cc1ccc(NC(C)C)nn1
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1ccc(NC(C)C)nn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]-imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The intermediate compound N-isopropyl-6-ethynylpyridazin-3-amine was made as for Example 1 (Step 1 to 3) with the spectra below: 1H NMR (300 MHz, CDCl3) δ: 7.26-7.29 (1H, d, J=9.0 Hz), 6.54-6.57 (1H, d, J=9.0 Hz), 5.00 (1H, s), 3.97-4.04 (1H, m), 3.25 (1H, s), 1.29 (3H, s), 1.27 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[N+:41]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[C:30]([OH:37])[CH:29]=3)=[CH:23][CH:22]=2)([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1.[K+].[Br-]>>[NH2:41][C:40]1[CH:39]=[CH:38][C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([OH:37])[CH:29]=4)=[CH:25][CH:26]=3)([C:17]([F:18])([F:19])[F:20])[C:13]([F:15])([F:16])[F:14])=[CH:8][CH:7]=2)=[CH:3][C:2]=1[OH:1]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(c3ccc(Oc4ccc([N+](=O)[O-])c(O)c4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1O
Agent: [Br-]
Agent: [K+]
Product: Nc1ccc(Oc2ccc(C(c3ccc(Oc4ccc(N)c(O)c4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1O
Yield: 81.7 %

Procedure:
2,2-Bis(4-(4-amino-3-hydroxyphenoxy)phenyl)hexafluoropropane was synthesized in a manner analogous to Example 2 from 2,2-bis(4-(3-hydroxy-4-nitrophenoxy)phenyl)hexafluoropropane. Yield: 81.7%; mp 178˜181° C.; IR (KBr): 3380, 3250, 1599, 1500 cm−1; MS (EI) m/z 550 (M+, 100); Elemental Anal. Calcd. for C27H20F6N2O4: C, 58.91; H, 3.64; N, 5.09. Found: C, 58.73; H, 3.72; N, 5.00.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[O:20])=[N:14]1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[O:20])=[N:14]1
Reactant: COC(=O)c1ccc(Cl)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Cl)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-chloro-3-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]benzoate (for a preparation see Intermediate 23)(0.95 g, 2.34 mmol) in methanol (20 ml) was added sodium hydroxide (2.4 ml, 4.80 mmol). The reaction was stirred for 4 h, under nitrogen, at ambient temperature. The solvent was evaporated in vacuo, and the residue partitioned between diethyl ether (60 ml) and 2N aqueous HCl (50 ml). The residue was insoluble and the diethyl ether was removed in vacuo. The aqueous suspension was filtered through a hydrophobic frit, and the residue washed with ether and dried under vacuum to give the title compound as a white solid (0.651 g);
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([CH2:18][C:17]2[CH:22]=[CH:23][C:14]([F:13])=[CH:15][CH:16]=2)[O:20][CH3:21])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (2.45 g, 12.9 mmol) in dichloromethane (15 ml) was added dropwise over 10 minutes to a cold (0-5° C.) mixture of N-4-fluorobenzyl-O-methyl-hydroxylamine (2.0 g, 12.9 mmol) and pyridine (2.1 ml, 25.7 mmol) in dichloromethane (50 ml). The cooling bath was then removed and the solution was stirred at 22° C. for 30 minutes. The reaction mixture was then quenched by the addition of water and ethyl acetate. The organic phase was washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (toluene-ethyl acetate, 8:2) gave 3.72 g (93% yield) of the title amide as white crystals after recrystallization from ethyl acetate/hexanes. Differential scanning calorimetry shows a sharp endotherm at 107° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s), 3.68 (3H, s), 4.79 (2H, s), 6.38 (1H, s), 7.0 (2H, m), 7.34 (2H, m). 13CNMR 100 MHz (CDCl3) δ (ppm): 26.81, 48.43, 63.03, 94.48, 114.22, 115.31, 115.56, 130.47, 132.03, 146.95, 161.21, 162.46, 163.65, 164.43. 19FNMR 377 MHz(CDCl3) δ (ppm): 114.97. Anal. calcd for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52; Found: C, 58.33; H, 5.38; N, 4.51.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>CCOC(C)=O.CC1C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Clc1ncnc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: Clc1ncnc2c1ncn2C1CCCCO1
Temperature: 90 °C
Yield: 99.4 %

Procedure:
A suspension of 6-chloro-9H-purine (25.36 g, 164 mmol) and 4-methylbenzenesulfonic acid (0.565 g, 3.28 mmol) in EtOAc (250 mL) was treated with 3,4-dihydro-2H-pyran (44.9 mL, 492 mmol). The mixture was heated at 90° C. and the solid slowly dissolved over 1 h. The flask was removed from the oil bath and the cloudy, yellow solution was filtered and concentrated in vacuo. The pale yellow residue was dissolved in DCM and purified by flash chromatography (50% EtOAc/hexane) (1 L silica/4 L solvent) to give 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (38.90 g, 99.3% yield) as a colorless oil which slowly crystallized. MS (ESI, pos. ion) m/z: 239.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=1.[Br:18]N1C(=O)CCC1=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[Cl:17][C:6]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([O:15][CH3:16])[CH:12]=[CH:13][C:14]=2[Br:18])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1cccc(Oc2c(Cl)ncnc2Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(Br)c(Oc2c(Cl)ncnc2Cl)c1

Procedure:
By brominating 4,6-dichloro-5-(3-methoxyphenoxy)-pyrimidine with N-bromosuccinimide in acetic acid/acetic anhydride at 100° C. there was obtained 4,6-dichloro-5-(2-bromo-5-methoxyphenoxy)pyrimidine; therefrom with p-tert-benzenesulfonamide K there was obtained N-[5-(2-bromo-5-methoxyphenoxy)-6-chloropyrimidin-4-yl]-4-tert-butyl -benzenesulfonamide and therefrom with Na ethylene glycolate there was obtained p-tert-butyl-N-[5-(2-bromo-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>ClCCl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 176.8 %

Procedure:
To a solution of tert-butyl 4-{[(3,4-dichlorophenyl)amino]carbonyl}piperidine-1-carboxylate (3.0 g) in dichloromethane (15 mL) was added 4M HCl in dioxane (15 mL). The mixture was stirred at room temperature for 1 hour and then filtered to give the title compound as a white solid (2.2 g, 100%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:9][C:10]3[O:15][C:14](=[O:16])[CH:13]=[CH:12][C:11]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)(C)C>[CH:1]1([O:6][C:7]2[C:8]([O:18][CH2:19][CH2:20][CH2:21][N:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)=[CH:9][C:10]3[O:15][C:14](=[O:16])[CH:13]=[CH:12][C:11]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCCOc1cc2oc(=O)ccc2cc1OC1CCCC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: O=c1ccc2cc(OC3CCCC3)c(OCCCN3CCN(c4ccccc4)CC3)cc2o1
Yield: 68 %

Procedure:
Method B (25 h at 40° C.); starting materials: 6-(cyclo-pentyloxy)-7-[3-(methanesulfonyloxy)propoxy]-2H-1-benzopyran-2-one (example 72) and 1-phenylpiperazine; yield 68%; fusion point 101°-103° C. (from TBME and isopropanol). Fumarate: method E; yield 88%; fusion point 171°-173° C. (from acetone).
Reaction SMILES: [C:1]([Si:5]([C:8]([OH:11])(C)[CH3:9])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Si](Cl)(C)C)(C)(C)C.C(OC=C[Li])C>CC(C)=O>[C:8]([Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])(=[O:11])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)C(C)(C)O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]C=COCC
Solvent: CC(C)=O
Product: CC(=O)[Si](C)(C)C(C)(C)C
Yield: 41 %

Procedure:
Following the general procedure for the preparation of acetylsilanes (see Example 1) tert-butyl(1-hydroxy-1-methylethyl)dimethylsilane was prepared from tert-butylchlorodimethylsilane (5.00 g, 33.2 mmol) and ethoxyvinyl lithium (prepared from ethyl vinyl ether (3.11 g, 43.1 mmol) and tert-butyl lithium (1.9 M in pentane, 22.7 ml, 43.1 mmol) in THF (50 ml)). The crude material was hydrolysed with acetone/1 N HCl (2:1, 60 ml), and purified by silica-gel chromatography (silica-gel 40-63 μm, hexane/EtOAc, 9:1) to afford 2.13 g (41% over 2 steps) of acetyl(tert-butyl)dimethylsilane, of which 1.44 g, (9.10 mmol) was reacted according to Example 1 with methyl lithium (1.6 M in Et2O, 28.4 ml, 45.4 mmol) to provide after purification by silica-gel flash chromatography (silica-gel 15-40 μm, hexane/EtOAc, 9:1) 590 mg (37%) of the odoriferous title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCO.OS(O)(=O)=O>[Br:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[N:14]=[CH:15]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)NC=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(Br)cc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
To a mixture of ethyl-3-(4-bromophenyl)-2-formamidopropanoate (23.5 g, 78 mmol) in DCM (200 mL) was added (CO)2Cl2 (8 ml, 84 mmol). The reaction mixture was stirred at r.t. for 30 mins. Then the reaction solution was cooled to 0° C. and FeCl3 (16 g, 98 mmol) was added into the solution, followed by stirring at r.t overnight. After the solution was extracted by CH2Cl2, the combined organic layers were concentrated in vacuo to afford a black oil. The oil was dissolved in the EtOH (100 ml), and concentrated H2SO4 was added into the solution and refluxed at 80° C. overnight. The solution was poured into saturated NaHCO3 and extracted by EA. After drying with anhydrous Na2SO4, the solution was concentrated in vacuo, and the residue was purified by silica gel chromatography (PE/EA=8:1 to 5:1) to afford ethyl 7-bromoisoquinoline-3-carboxylate as a yellow solid (5.2 g, yield: 23.8%).
Reaction SMILES: C(O)(=O)C.[ClH:5].Cl.[C:7]([NH:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:17]([OH:32])[CH:16]=1)=[O:14])([CH3:10])([CH3:9])[CH3:8]>CN(C)C=O>[ClH:5].[OH:32][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][C:22](=[O:31])[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH:13]([OH:14])[CH2:12][NH:11][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccc(C(=O)Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Oc2ccc(C(O)CNC(C)(C)C)cc2O)cc1

Procedure:
Using a procedure similar to that described above in Example 58A, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 16 g. of sodium methoxide in 300 ml. of N,N-dimethylformamide under an atmosphere of nitrogen and then 17 g. of p-anisoyl chloride was added to produce 3-hydroxy-4-(p-anisoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride. This salt was converted to the free base which was treated with acetic acid to yield 35 g. of the acetate salt, m.p. 170°-175° C.(dec.)(uncorr.). By treating this salt in N,N-dimethylformamide with concentrated hydrochloric acid there was obtained 28 g. of the hydrochloride salt, m.p. >235° C.(dec.)(uncorr.). When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C@H:15]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:14][CH2:13][C@H:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C@H:15]([CH2:22][C:23]([OH:25])=[O:24])[CH2:14][CH2:13][C@H:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2cccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](CC(=O)O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of lithium hydroxide (11.2 mg, 0.468 mmol) and ethyl 2-((5S,6S,9S)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetate (27.8 mg, 0.060 mmol) in tetrahydrofuran (3 mL) and water (0.3 mL) was stirred at room temperature for 24 h. The solvent was removed via high vacuum and the crude product (MS(ESI)[M+H+]=433.17) was used as is in the next step.
Reaction SMILES: Br[CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4]Br.[CH3:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:21]>>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]2[CH2:12][CH:11]3[C:10](=[O:21])[C:9]([CH3:8])([C:18]=2[CH:17]=1)[CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2]3
Reactant: COc1ccc2c(c1)C(C)C(=O)CC2
Reactant: CC(C)(CBr)CBr
Product: COc1ccc2c(c1)C1(C)CC(C)(C)CC(C2)C1=O

Procedure:
By treating 1,3-dibromo-2,2-dimethyl propane and 1-methyl-7-methoxy-2-tetralone in the manner described in Example 1, one may prepare the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(C)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and p-toluenesulfonyl chloride.