Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].N1C=CC=CC=1>CCOCC>[CH3:7][S:8]([O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:10])=[O:9]
Reactant: OC1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CS(=O)(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
A round-bottomed flask (1,000 cc) equipped with a mechanical stirrer was charged with cyclopentyl alcohol (51.2 g, 0.595 mol) and methanesulfonyl chloride (75.1 g, 0.656 mol), followed by the addition of pyridine (200 mL) under ice cooling to form a solution. The solution was stirred for 6 h as it was warmed gradually to room temperature. After completion of the reaction, the reaction mixture was poured into ice water (300 mL) and extraction was conducted with ether (200 mL×3). The organic layers were washed with water, 1N HCl and saturated brine and dried with anhydrous magnesium sulfate. Distilling off the solvent under vacuum gave cyclopentyl methanesulfonate as a colorless oil (75.2 g, 0.458 mol; yield=77.0%). 1H-NMR(CDCl3,TMS,ppm): δ1.54-2.03(8H,m), 3.01(3H,s), 5.19(1H,m).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.ClC1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[C:36]3[N:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[S:39][C:35]=3[CH:34]=[CH:33][CH:32]=2)[CH:25]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C@H:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]3[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]4[C:36]5[N:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[S:39][C:35]=5[CH:34]=[CH:33][CH:32]=4)[CH:25]=3)[CH2:13][CH2:12]2)[CH3:15])=[CH:21][CH:20]=1
Reactant: C[C@H](c1ccc(F)cc1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Nc1nc2c(Oc3cc(Cl)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(N4CCN([C@H](C)c5ccc(F)cc5)CC4)ncn3)cccc2s1

Procedure:
According to the procedures described in Example 21(b), 4-[(1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester, Example 21(a), (0.48 g, 1.6 mmol) and N-[4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide, Example 1(b), (0.512 g, 1.6 mmol) provided the title compound as a white solid. M.p.: 243.8-245.9° C. MS (ESI, pos. ion.) m/z: 493 (M+1).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([C@H](C(C)C)C)[N:3]=1.[CH:16]1([NH:19][C:20]([C:22]2[CH:23]=[C:24]([F:32])[C:25]([CH3:31])=[C:26](B(O)O)[CH:27]=2)=[O:21])[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CC(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>[CH:16]1([NH:19][C:20]([C:22]2[CH:23]=[C:24]([F:32])[C:25]([CH3:31])=[C:26]([C:2]3[N:3]=[CH:4][C:5]([C:6]([NH:8][C@@H:9]([CH3:10])[CH:5]([CH3:6])[CH3:4])=[O:7])=[CH:9][CH:10]=3)[CH:27]=2)=[O:21])[CH2:18][CH2:17]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Reactant: CC(C)[C@H](C)c1nc(Cl)ccc1C(N)=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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)C)cn1
Temperature: 90 °C

Procedure:
6-Chloro-[(S)-(+)-3-methyl-2-butyl]nicotinamide (Intermediate 20, 100 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 6, 100 mg), tetrakis(triphenylphosphine)palladium (10 mg) and aqueous sodium hydrogen carbonate (4 ml) were mixed in propan-2-ol (8 ml) and heated at 90° C. under nitrogen for 18 hrs. The solvents were evaporated from the cooled reaction under vacuum and the residue dissolved as far as possible in ethylacetate. The solution was applied to an SPE (SCX, 10 g) and washed with ethyl acetate. The product was eluted from the column with methanol/0.880 ammonia, and the solvents evaporated in vacuo. The residue was redissolved in ethyl acetate and filtered through an SPE (silica, 0.5 g). The filtrate was reduced to dryness under vacuum and triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2-dimethylpropyl]-3-pyridinecarboxamide.
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]2[CH2:10][CH2:11][CH2:12][C:6]=12
Reactant: O=[N+]([O-])c1cnc2c(c1O)CCC2
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Yield: 52 %

Procedure:
A solution of 3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-ol (1.424 g, 7.904 mmol) in POCl3 (11.0 mL) was heated at 110° C. in a sealed flask under N2 for 2 h. The crude mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 50% NaOH to pH 7. The resulting mixture was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the crude sub-title compound as a brown solid (0.82 g, 52%), which was used without further purification. LCMS calc. for C8H8N2O2 (M+H)+: m/z=199.0. Found: 199.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]([NH:28]O)=[NH:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCC(=N)NO)CCC2c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N2C(CCCC(=N)N)CCC2c2ccc(F)cc2)cc1
Yield: 76.6 %

Procedure:
(2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-butyramidine (1.1 g, 2.62 mmol) was dissolved in EtOH (50 ml) and acetic acid (5 ml) and hydrogenated on Ra—Ni at room temperature for 2 h. The catalyst was filtered off, the filtrate evaporated and the crude product crystallized from saturated NaHCO3 solution to give (2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-butyramidine (0.81 g, 76%) as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:11][N:10]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([NH2:15])=[CH:13][C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:11][N:10]=1
Reactant: COc1ccccc1-c1cnc(-c2ccccc2OC)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1-c1cnc(-c2ccccc2OC)c(N)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 2,5-bis(2-methoxyphenyl)-3-nitropyridine (97.3 mg, 0.29 mmol) in EtOAc (5.0 mL) was added tin(II) chloride dihydrate (0.33 g, 1.45 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 65° C. After 2 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH (15 mL), water (15 mL), and brine (15 mL). After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as mostly 2,5-bis(2-methoxyphenyl)-3-pyridinamine. Mass Spectrum (pos.) m/e: 307.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:3]1.[N+:19]1([O-])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.CS(NC1C=CC(CC(O)=O)=CC=1)(=O)=O.CC1(C)OC(=O)CC(=O)O1>C(OC(=O)C)(=O)C>[O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)/[C:3]/1=[C:20]1/[NH:19][C:28]2[C:23]([CH:22]=[CH:21]/1)=[CH:24][CH:25]=[CH:26][CH:27]=2
Reactant: CS(=O)(=O)Nc1ccc(CC2=NNC(=O)C2)cc1
Reactant: [O-][n+]1cccc2ccccc21
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)Nc1ccc(CC2=NNC(=O)/C2=C2/C=Cc3ccccc3N2)cc1

Procedure:
The tile compound was synthesized using N-(4-((5-oxo-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)methanesulfonamide and quinoline N-oxide in acetic anhydride according to the procedure described in Example 23. The N-(4-((5-oxo-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)methanesulfonamide was synthesized using 2-(4-(methylsulfonamido)phenyl)acetic acid and Meldrum's acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.91 (s, 3H) 4.08 (s, 1H) 4.43 (s, 1H) 7.10 (d, J=3.79 Hz, 2H) 7.24-7.37 (m, 2H) 7.46 (d, J=6.06 Hz, 1H) 7.67-7.77 (m, 2H) 7.82-7.94 (m, 2H) 8.17-8.29 (m, 1H) 9.60 (s, 1H) 11.40 (s, 1H); ESI-MS: m/z calc'd for C20H18N4O3S 394.45. found 395.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[N:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccncc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccncc3)ccn2c1=O
Yield: 70 %

Procedure:
Methyl 8-(pyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and pyridin-4-yl-boronic acid (253 mg, 2.05 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (400 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(C)ccc1F
Yield: 82.1 %

Procedure:
Heat a mixture of 2-fluoro-5-methyl-benzoic acid (1.0 g, 6.48 mmol), iodomethane (1.38 g, 9.73 mmol), and potassium carbonate (2.68 g, 19.44 mmol) in acetone (20 mL) at reflux overnight. Cool the reaction and filter through Celite®. Concentrate the filtrate under reduced pressure to provide the title compound as a colorless gum (0.895 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 2.32 (s, 3H), 3.89 (s, 3H), 6.95-7.10 (m, 1H), 7.20-7.30 (m 1H), 7.75-7.80 (m, 1H); TLC Rf=0.45 (2:1 Hexanes/Ethyl Acetate).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:23])[CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([O:19][CH3:20])[CH3:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:24]O>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:23][CH3:24])[CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])([CH3:21])[CH3:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(C)(C)CCCC(C)CCC(O)c1ccc(C(C)C)cc1
Reactant: CO
Product: COC(CCC(C)CCCC(C)(C)OC)c1ccc(C(C)C)cc1

Procedure:
Crude 1-(p-isopropylphenyl)-4,8-dimethyl-8-methoxy-1-nonanol (1.1 g) and "Amberlyst A-15" resin (50 mg) in methanol (20 ml), as the acidic lower alkanol, was refluxed for 2 days. GC analysis showed the consumption of the alcohol and appearance of the dimethoxy compound. Material was recovered quantitatively. "Amberlyst A-15" resin used in this methoxylation reaction is a commercially available solid acidic ion exchange resin with pendant sulfonic acid groups.
Reaction SMILES: [C:1]1([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]4)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C[Si](C([Si](C)(C)C)(C(F)(F)F)C(N)=O)(C)C>O1CCOCC1.C(OCC)(=O)C>[C:1]1([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]4)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Agent: C[Si](C)(C)C(C(N)=O)(C(F)(F)F)[Si](C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one (295 mg, 0.865 mmol, in 3.5 mL of 1,4-dioxane was added DDQ (216 mg, 1.1 equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (998 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 60 mg (20%) of the title compound as a white solid. mp 199°-201° (decomp.) FDMS m/e=339. α[D]589 =+35.98 (c=0.67, chloroform).
Reaction SMILES: [CH3:1][CH:2]([C:6](Cl)=O)[C:3](Cl)=[O:4].[C:9]([CH:12]([C@@H:14]1C[CH2:17][CH2:16][NH:15]1)C)(O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+].Cl>ClCCl>[CH3:1][CH:2]1[C@H:6]2[N:15]([CH2:14][CH2:12][CH2:9]2)[CH2:16][CH2:17][C:3]1=[O:4]
Reactant: CC(C(=O)O)[C@@H]1CCCN1
Reactant: CC(C(=O)Cl)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C(=O)CCN2CCC[C@@H]12
Reaction time: 0.25 h
Yield: 171.6 %

Procedure:
2.01 ml (18.7 mmol) of methyl malonyl chloride were added dropwise to a stirred, ice-cooled mixture of a solution of 2.43 g (17.0 mmol) of (2S)-2-(1-carboxyethyl)pyrrolidine [prepared as described in Tetrahedron Lett., 40, 2891–2894 (1999)] in 60 ml of dichloromethane and 2.61 ml (18.7 mmol) of triethylamine. After stirring the resulting mixture at the same temperature for 15 minutes and then at room temperature for 30 minutes, a saturated aqueous solution of sodium hydrogencarbonate was added. Subsequently, the resulting mixture was adjusted to pH 2 with concentrated hydrochloric acid and then extracted with a 4:1 by volume mixture of dichloromethane and isopropanol. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to afford 4.47 g (yield: quantitative) of the title compound as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([B:7]([OH:9])[OH:8])[S:5][CH:6]=1.[NH:10]([CH2:14][CH2:15]O)[CH2:11][CH2:12]O>>[CH3:1][C:2]1[CH:3]=[C:4]([B:7]2[O:9][CH2:15][CH2:14][NH:10][CH2:11][CH2:12][O:8]2)[S:5][CH:6]=1
Reactant: Cc1csc(B(O)O)c1
Reactant: OCCNCCO
Product: Cc1csc(B2OCCNCCO2)c1
Yield: 88 %

Procedure:
The title compound (88%, oil) was prepared from 4-methylthiophen-2-boronic acid and diethanolamin.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:17][CH2:18][O:19][CH3:20])=[CH:6][C:7]([O:13][CH2:14][O:15][CH3:16])=[C:8]([CH:12]=1)[C:9](O)=[O:10])([CH3:3])[CH3:2].C(Br)C1C=CC=CC=1.O.[NH2:30][NH2:31]>O1CCCC1>[CH:1]([C:4]1[C:5]([O:17][CH2:18][O:19][CH3:20])=[CH:6][C:7]([O:13][CH2:14][O:15][CH3:16])=[C:8]([CH:12]=1)[C:9]([NH:30][NH2:31])=[O:10])([CH3:3])[CH3:2]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)O
Reactant: NN
Agent: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)NN
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
5-isopropyl-2,4-bis-methoxymethoxy-benzoic acid (IM3-a: 2.84 g, 10 mmol), N,N′-carbonyldiimidazole (1.62 g, 10 mmol) and tetrahydrofuran 100 mL were placed in a 300 mL eggplant shaped flask and stirred at room temperature for 4 hours. The reaction mixture was mixed with benzylbromide (1.19 mL, 10 mL), stirred at room temperature for further 4 hours and then mixed with hydrazine mono hydrate (0.63 mL, 13 mmol) and stirred at room temperature overnight. After completing the reaction, most of the reaction mixture was removed under reduced pressure, and the residue was mixed with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate and saturated sodium chloride solutions, dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was purified by silica gel column chromatography to obtain the title compound (IM4-a: 2.44 g, 82%).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:21]1([CH3:28])[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>CN(C)C=O>[ClH:27].[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:23]2[CH:22]=[C:21]([CH3:28])[CH:26]=[CH:25][CH:24]=2)=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: Cc1cccc(Cl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)c1

Procedure:
Using a procedure similar to that described above in Example 58A, 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 8 g. of sodium methoxide in 200 ml. of N,N-dimethylformamide under an atmosphere of nitrogen and then 8 g. of m-toluyl chloride was added to produce 3-hydroxy-4-(m-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride. This salt was converted to the free base which was treated with acetic acid to yield 11.5 g. of the acetate salt, m.p. 170°-175° C. By treating a slurry of this salt in 100 ml of N,N-dimethylformamide with 40 g. of methanesulfonic acid there was obtained 10.6 g. of the corresponding methanesulfonate salt, m.p. >250° C. (uncorr.). This methanesulfonate (10 g.) was catalytically hydrogenated, using a procedure similar to that described above in Example 30B, to yield 5.4 g. of 3-hydroxy-4-(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 165°-168° C. (uncorr.).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1)[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@@H](O)CNC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@H](N)c1ccc([C@@H](O)CNC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
78 mg of the compound [6-1] was dissolved in 2 mL of chloroform, then 2 mL of trifluoroacetic acid was added thereto, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, dissolved in methanol, and passed through a weak ion exchange resin to remove the trifluoroacetic acid. The solvent was distilled off to obtain 55 mg of (1R)-1-{4-[(1S)-1-aminoethyl]phenyl}-2-(tert-butylamino)ethanol [11-3] as a white solid. The compound [11-3] (hereinafter, referred to as the compound [11-3]) was used in the subsequent reaction without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:13][CH:12]=1.O.[NH2:25][NH2:26]>CCO>[N:17]1([C:14]2[CH:15]=[CH:16][C:11]([C:10]3[C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:3](=[O:2])[NH:26][N:25]=3)=[CH:12][CH:13]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: NN
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(-n2ccnc2)cc1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccc(-n3ccnc3)cc2)c2ccccc12

Procedure:
A solution of methyl-2-[4-(1H-imidazol-1-yl)benzoyl]benzoate (1.3 g, 4.25 mmol) in 15 mL of EtOH is treated with hydrazine monohydrate (0.26 g, 5.20 mmol) and heated to reflux for 1 day. The white solid which precipitates is filtered and recrystallized from EtOH to give 4[4-(1H-imidazol-1-yl)phenyl]-1-oxo-1,2-dihydrophthalazine. M.P. 309.5°-311° C.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH3:14])[CH:3]([OH:13])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:6]([O:5][CH2:4][CH:3]1[O:13][C:24](=[O:26])[NH:1][C:2]1([CH3:15])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)C(O)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)OC1COCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
To a cold, 0° C., solution of 3-amino-1-(benzyloxy)-3-methylbutan-2-ol (2 g, 9.6 mmol) and triethylamine (3.3 mL, 24 mmol) in 95 mL of anhydrous dichloromethane was added triphosgene (3.1 g, 10.5 mmol). The reaction was stirred at 0° C. for 3.5 hr and at RT for 1.5 hr. A solution of saturated sodium bicarbonate (95 mL) was added and the mixture was stirred for 15 min, then the organic layer was isolated and washed successively with 0.25N HCl, sat. NaHCO3, and brine. The organic layer was dried over sodium sulfate, concentrated to a residue and purified by column chromatography (30 to 75% ethyl acetate in hexanes) to give the title compound (1.8 g, 7.4 mmol, 78%). 1H NMR (CDCl3, 400 MHz) δ 1.27 (s, 3H), 1.40 (s, 2H), 1.90 3.67-3.76 (m, 2H), 4.37-4.41 (t, J=6.4 Hz, 1H), 4.56-4.64 (dd, J=9.6, 12 Hz, 2H), 5.27 (s, H), 7.28-7.40 (m, 5H). LRMS (ESI/APCI) m/z 236 [M+H]+.
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[C:5](=[O:14])[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[NH3:19]>>[OH:13][C:6]12[NH:19][CH:2]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=31)[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]2=[O:14]
Reactant: O=C1C(=O)c2ccccc2C(Br)c2ccccc21
Reactant: N
Product: O=C1c2ccccc2C2NC1(O)c1ccccc12
Temperature: -40 °C
Reaction time: 1 h

Procedure:
10 g of 5-bromo-10,11-dihydro-[5H]-dibenzo (a,d) cycloheptene-10,11-dione was added to 250 ml of ammonia cooled to -40° C and then stirred for 1 hour at -40° C. The ammonia was distilled off and after adding 100 ml of 5 N hydrochloric acid thereto, the mixture was heated at 60°-65° C for 30 minutes. The mixture was cooled, made alkaline with addition of 110 ml of ammonium hydroxide and extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was crystallized from ether, vacuum filtered and dried to obtain 7.4 g of 10-hydroxy-10,11-dihydro-5,10-imino-[5H]dibenzo (a,d) cycloheptene-11-one dl melting at 214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH2:12]Br.C(N(CC)CC)C>ClCCl>[F:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH2:12][S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: Sc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(F)c(CSc2ccc(Cl)cc2)c1
Reaction time: 2 h
Yield: 75.6 %

Procedure:
4-Chlorothiophenol (3.6 g, 0.025 mol) in dichloromethane (100 mL) was treated with 2,5-difluorobenzyl bromide (5.17 g, 0.025 mol) and triethylamine (3.9 ml, 0.028 mol). The reaction was stirred for 2 hours then diluted with dichloromethane (250 mL) and washed with water (100 mL) and brine (100 mL). The separated organic layer was dried (MgSO4), evaporated to dryness, and the product purified by passing down a plug of silica eluting with hexane-ethyl acetate mixtures to give 4-chlorophenyl 2,5-difluorobenzyl sulfide (5.12 g). 1H NMR CDCl3 7.23 (4H, s), 6.69–6.86 (3H, m) and 4.04 (2H, s).