Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[CH:38]=O)[C:29]#[N:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:29]([C:28]1[CH:31]=[CH:32][C:33](/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[C@H:38]2[O:21][CH2:20][C@H:19]([S:18][C@H:16]([CH3:17])[C@:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])([OH:24])[CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:22][O:23]2)=[C:26]([F:25])[CH:27]=1)#[N:30]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Yield: 66.8 %

Procedure:
In the same manner as that described in Example 1(iii) above, a reaction was carried out using 1.02 g (2.84 mmol) of (2R,3R)-2-(2,5-difluorophenyl)3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Step 8(vi) above], 571.6 mg (2.84 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile and 594.5 mg (3.13 mmol) of p-toluenesulfonic acid monohydrate and the reaction product was purified by chromatography on a silica gel (75 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give 1.03 g (yield 66%) of the title compound as a colorless non-crystalline solid.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][NH:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[Br:18])[CH3:9]
Reactant: CNCC=CC#CC(C)(C)C
Reactant: BrCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C/C=C/C#CC(C)(C)C)Cc1ccccc1Br
Yield: 56.4 %

Procedure:
The procedure described in Example 1 was repeated, except that N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine (1.96 g; 13.0 mmol), potassium carbonate (1.44 g; 13.6 mmol), and 2-bromobenzylbromide (3.25 g; 13.0 mmol) were used, to thereby yield 2.35 g of the target compound (yield: 56.5%).
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[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C@H:25]([CH2:27][OH:28])[CH3:26]>>[OH:28][CH2:27][C@H:25]([NH:24][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][O:10][CH:11]=2)=[CH:20][N:19]=1)=[O:23])[CH3:26]
Reactant: C[C@H](N)CO
Reactant: O=C(O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Product: C[C@H](CO)NC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Yield: 47 %

Procedure:
As described for example 17b, 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (80 mg, 0.24 mmol) was converted, using L-alaninol instead of D-alaninol, to the title compound (44 mg, 47%) which was obtained as a white solid. MS: m/e=389.0 [M+H]+.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C[O:13][C:14](=O)[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17].B(OB=O)=O>CO>[C:1]([NH:10][NH:11][C:14](=[O:13])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: COC(=O)c1ccccc1O
Reactant: NNC(=O)c1ccccc1O
Agent: O=BOB=O
Solvent: CO
Product: O=C(NNC(=O)c1ccccc1O)c1ccccc1O
Reaction time: 3 h
Yield: 85 %

Procedure:
152 parts by weight salicyclic acid hydrazide was heated with 152 parts by weight salicylic-acid methyl ester and 3 parts by weight boron trioxide in 230 parts by weight paraffin (viscosity at 60° C.: 100 m Pa s) to 140° to 150° C. while stirring vigorously. Methanol produced during the reaction was distilled off by a column. After about 3 hours, the reaction was completed. The now viscous reaction mixture was cooled down to 50° to 60° C., treated with alcohol (methanol or ethanol) and the mixture was stirred very vigorously at about 50° to 60° C. The yellow-colored alcohol phase was decanted from the viscous paste and the process was repeated until discoloration was complete. After separating the washing alcohol, drying in a vacuum at about 100° C. was performed. 460 parts by weight of a colorless viscous paste was obtained, consisting of 230 parts by weight N,N'-bis(salicyloyl)hydrazine (85% yield) and 230 parts by weight paraffin. By dissolving the paraffin with methylene chloride and boiling-out the solid matter with methanol, N,N'-bis(salicyloyl)hydrazine with a melting and decomposition range of 305° to 310° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11]C(C)([O-])C.[K+].CI>O1CCCC1.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2ccc(Cl)cc21
Reaction time: 1 h
Yield: 67 %

Procedure:
A mixture of 6-chloroindole (22.0 g, 0.145 mole) and potassium t-butoxide (KOt-Bu) (20.0 g 0.179 mole) in tetrahydrofuran at room temperature is treated dropwise with methyl iodide (11.2 mL, 0.179 mole), allowed to stir at ambient temperatures for about 1 hour and diluted with a mixture of pet ether and water. The phases are separated. The organic phase is washed with 1 N HCL and water, dried over Na2SO4 and concentrated to a brown oil. After chromatography (silica gel/4:1 hexanes:ethyl acetate), the oil is distilled to afford the title product as a colorless oil, 16.25 g (67% yield), bp 110°-115° C./4 mm Hg, identified by IR, 1HNMR, 13CNMR, mass spectral and microanalyses.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:32][CH3:33])=[CH:22][C:23]=3[O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[N:18]=[CH:17][N:16]=2)[CH:10]=[CH:11][C:12]=1[F:13].C([N:37]([CH2:41][CH3:42])[CH:38]([CH3:40])C)(C)C.N1CCCC1>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:32][CH3:33])=[CH:22][C:23]=3[O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:3](=[O:4])[CH2:2][N:37]3[CH2:38][CH2:40][CH2:42][CH2:41]3)[N:18]=[CH:17][N:16]=2)[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(OC[C@@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: O=C(Cl)CCl
Solvent: C1CCNC1
Solvent: ClCCl
Product: COc1cc(OC[C@@H]2CCCN2C(=O)CN2CCCC2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reaction time: 0.67 h
Yield: 61 %

Procedure:
Chloroacetyl chloride (21 μl) was added in one portion to a stirred solution of N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (96 mg) (obtained as described in Example 1, preparation of starting materials) and N,N-diisopropylethylamine (83 μl) in DCM (3 ml) at room temperature. The reaction mixture was stirred for 40 minutes and then pyrrolidine (80 μl) was added in one portion and the reaction mixture was stirred for 15 hours 30 minutes under a nitrogen atmosphere. The reaction mixture was diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate and water. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow oil, which was purified by column chromatography using 0-10% methanol in DCM as eluent to give the title compound as a white solid (75 mg, 61%); NMR Spectrum (DMSO-d6) 9.90 (s, 1H), 8.40 (s, 1H), 8.10 (dd, 1H), 7.72-7.62 (m, 1), 7.39 (t, 1H), 6.82 (d, 1H), 6.78 (d, 1H), 4.62-4.54 (m, 1H), 4.34 (dd, 1H), 4.16 (dd, 1H), 3.90 (s, 3H), 3.58-3.48 (m, 2H), 3.28-3.16 (m, 2H), 2.48 (br s, 4H), 2.10-1.82 (m, 4H), 1.6 (br s, 4H); Mass spectrum MH+ 514.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Al].[H][H].[CH3:12][S:13]SC.Cl>C1CCCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:13][CH3:12])[CH:3]=1
Reactant: CSSC
Reactant: Oc1ccc(Cl)cc1
Reactant: [H][H]
Agent: Cl
Agent: [Al]
Solvent: C1CCCCC1
Product: CSc1cc(Cl)ccc1O
Temperature: 152 °C

Procedure:
A mixture of para-chlorophenol (100 grams, 0.78 moles) and cyclohexane (50 ml) was distilled free of cyclohexane to remove any residual water in the para-chlorophenol. The para-chlorophenol was heated at 160° to 180° C. and aluminum turnings (1.5 grams, 0.06 moles) were slowly added. After cessation of hydrogen evolution, methyldisulfide (46 ml) was added to the mixture and heated at reflux (ca. 152° C.) overnight. The temperature was then increased to 180° C. for 2 additional hours. The mixture was hydrolyzed by the addition of b 1N HCl, extracted with diethyl ether and dried over sodium sulfate. Concentration and distillation through a packed column gave, after removal of the para-chlorophenol, 52.25 grams of 4-chloro-2-(methylthio)-phenol product. The result was confirmed by NMR analysis, the overall yield being 55 percent.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>C(O)C>[ClH:2].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCO
Product: Brc1cccc(Nc2ncnc3[nH]c4ccccc4c23)c1
Yield: 66 %

Procedure:
4-Chloroindolo[2,3-d]pyrimidine hydrochloride (240 mg, 1 mmol) and 3-bromoaniline (0.33 mL, 3 mmol) in ethanol (3 mL) are heated under reflux for 2 h. The solids are collected by suction filtration, washed with ethanol and dried to give 4-(3-bromoanilino)indolo[2,3-d]pyrimidine hydrochloride (248 mg, 73%). 1H NMR (DMSO) δ1H, s) , 9.02 (1H, s),8.51 (1H, s), 8.42 (1H, d, J=7.7 Hz), 8.08 (1H, t, J=1.9 Hz), 7.82 (1H, d, J 8.0 Hz), 7.53 (1H, d, J=7.9 Hz), 7.46 (1H, dt, Jd=1.0 Hz, Jt=7.6 Hz), 7.36-7.27 (3H, m).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].[N-:21]=[N+]=[N-].[Na+]>C(#N)C.C1COCC1.C(OCC)(=O)C>[NH2:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: Cc1ccccc1OCCCCCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccccc1OCCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound 22 (0.506 g) was dissolved in 50 ml of acetonitrile. Sodium azide (0.395 g) was then added to that, and 29-hour reaction was carried out by refluxing, followed by 95-hour reaction at room temperature. After the resultant was cooled down to room temperature, the solid components were removed by filtration. The solvent of the filtrate was then distilled away under reduced pressure, and 0.313 g of a transparent, viscous liquid was obtained. This liquid was dissolved in 15 ml of THF distilled from calcium hydride in a nitrogen atmosphere, and was cooled in an ice bath. Lithium aluminum hydride (0.054 g) was then dissolved in 20 ml of dried THF, and was dripped. After the resultant was stirred in an ice bath for one hour, 80 μl of ion-exchange water, 80 of 15 wt % of aqueous potassium hydride solution, and 240 μl of ion-exchange water were added so as to stop the reaction. The precipitate generated was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. The solid obtained was then dissolved in ethyl acetate (30 ml), and was washed twice with 30 ml of ion-exchange water. The organic phase was then collected, and was dehydrated with magnesium sulfate. The desiccant agent was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. In this manner, 0.2 g of (11-aminoundecyl)tolylether 23, which was a white solid, was obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:28])[CH2:6][C:7](=[O:27])[C@H:8]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1.O.CO>COC(C)(C)C>[CH3:3][O:4][C:5](=[O:28])[CH2:6][C@@H:7]([OH:27])[C@H:8]([N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1
Reactant: COC(=O)CC(=O)[C@@H](Cc1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CO
Product: COC(=O)C[C@@H](O)[C@@H](Cc1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
Sodium borohydride (0.227 g, 6 mmol) is added to the stirred solution of (R)-4-(tert-butoxy-carbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-3-oxo-pentanoic acid methyl ester (4) in tert-butyl methyl ether at 18-22° C. Water (3 ml) is added over a period of approx. 20 minutes at 18-22° C., then stirring is continued for approx. 15 minutes. Methanol (3 ml) is added over a period of approx. 30 minutes at 18-22° C., then stirring is continued for approx. 30 minutes to give a solution of (3R,4R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-3-hydroxy-pentanoic acid methyl ester (5), which is used as such in the next step.
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].O>C1(C)C(C)=CC=CC=1>[C:1]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:18]([OH:20])=[O:19])[NH2:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCC(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 81.9 %

Procedure:
Lysine octanoate (35.0 g) was suspended in 300 ml of xylene using a 600-milliliter reaction vessel. The suspension was boiled through heating, and water formed through azeotropic distillation was removed outside the system. After it was identified that a stoichiometric amount of water was removed (reaction time 3 hours), the residue was cooled. Crystals precipitated were separated through filtration, and washed with 100 ml of a 50% ethanol solution. The crystals were recrystallized from a sulfuric acid aqueous solution to obtain 26.9 g of Nε-octanoyl lysine (yield 81.9%). This is designated Derivative B.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([S:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:18]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[S:19][C:13]=2[N:12]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:11]1=[O:43].C(=O)(O)[O-].[Na+]>CO.O1CCCC1.O>[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([S:31]([CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:2])=[C:18]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[S:19][C:13]=2[N:12]([CH2:39][CH:40]([CH3:41])[CH3:42])[C:11]1=[O:43]
Reactant: O=S(=O)([O-])O[O-]
Reactant: COC(=O)CCCSc1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)CCCS(=O)c1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 1 h
Yield: 315.3 %

Procedure:
Potassium peroxymonosulfate (0.163 g) was added to a stirred suspension of methyl 4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoate (0.246 g) in methanol (3 ml), tetrahydrofuran (3 ml) and water (3 ml). After 1 hour, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2×20 ml) The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography eluting with hexane:ethyl acetate (1:1) followed by trituration with ethyl acetate/hexane to give the title compound (0.80 g)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][C@@H:29]1[CH2:38][CH2:37][C:36]2[C:31](=[C:32]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH:33]=[CH:34][C:35]=2[CH2:39][O:40][CH3:41])[CH2:30]1>CN(C)C=O>[NH3:4].[CH3:41][O:40][CH2:39][C:35]1[CH:34]=[CH:33][C:32]([N:42]2[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]2)=[C:31]2[C:36]=1[CH2:37][CH2:38][C@@H:29]([NH:28][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:15][CH:14]=1)[CH2:30]2
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: COCc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](N)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COCc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](NC(=O)c1ccc(N3CCOCC3)cc1)C2
Product: N
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 152.7 %

Procedure:
4-Morpholinobenzoic acid (54 mg, 0.26 mmol) was dissolved in dry N,N-dimethylformamide (1 mL) and 1,1′-carbonyldiimidazole was added. The reaction mixture was stirred at 75° C. for 1.5 h and cooled to room temperature. A solution of (R)-2-amino-5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (72 mg, 0.25 mmol) in dry N,N-dimethylformamide (3 mL) was added. The reaction mixture was stirred at room temperature for 15 h. The solvent was evaporated giving 160 mg of a crude product. Purification by preparative TLC using chloroform/methanol/conc. NH3 (95:5:0.5) as the eluent afforded 95 mg (80% yield) of the title compound as a white solid: mp 200° C. (dec); EIMS (70 eV) m/z (relative intensity) 478 (7, M+); [α]21D 46° (c 0.12, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:36]1[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[CH2:37]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:36]4[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[CH2:37]4)[CH:22]=[CH:23][CH:24]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)C1CNC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 149.8 %

Procedure:
To a solution of 3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylbenzaldehyde (D74) (120 mg), acetic acid (0.022 mL) and sodium acetate (31.9 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (90 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (137 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (D88) (226 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C26H29ClN2O3S requires 484. found 485.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1)=[N:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:42][O:43][CH2:44][CH2:45]Br.O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:45][CH2:44][O:43][CH3:42])=[N:15][CH:14]=[CH:13]2)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4)nccc3c2)c(OC)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CCCC1c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3nccs3)ccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
N-(2,4-dimethoxybenzyl)-1-(pyrrolidin-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.050 g, 0.080 mmol) and potassium carbonate (0.055 g, 0.400 mmol) were dissolved in DMF (0.800 ml). 2-Bromoethyl methyl ether (9.03 μl, 0.096 mmol) was added and the reaction was stirred for three hours at 70° C. Water was added followed by ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 20% MeOH:EtOAc with 5% triethylamine modifier) to afford N-(2,4-dimethoxybenzyl)-1-(1-(2-methoxyethyl)pyrrolidin-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as an off white solid. m/z (ESI) 569.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:38])[C:5]([CH3:37])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:33]C(=O)C)=[C:17]([CH:32]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:31]=[CH:30][NH:29][N:28]=3)=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.ClCCl.O>[CH3:1][O:2][C:3]1[C:4](=[O:38])[C:5]([CH3:37])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:33])=[C:17]([CH:32]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:31]=[CH:30][NH:29][N:28]=3)=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(-c4cc[nH]n4)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(-c4cc[nH]n4)cc3)c2)=C(C)C1=O
Yield: 59.4 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-(1H-pyrazol-3-yl)aniline (0.090 g, 0.175 mmol) was dissolved in a mixed solvent of methanol (2 ml) and dichloromethane (1 ml), and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from a mixed solvent of ethyl acetate and hexane (1:1) to obtain the titled compound (0.049 g, 0.104 mmol, 59%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41]C(F)=CC=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1.Cl.FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1[O:53]C1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1>>[CH:37]1([CH2:36][C:35]([NH:34][C:32]([NH:31][C:6]2[CH:7]=[CH:8][C:9]([O:10][C:11]3[C:16]4=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)=[CH:19][N:15]4[N:14]=[CH:13][N:12]=3)=[C:4]([F:3])[CH:5]=2)=[O:53])=[O:44])[CH2:42][CH2:41]1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)NC(=O)CC4CC4)cc3F)c12

Procedure:
Prepared in a similar manner as Example 264 using Compound B of Example 45 and Compound A of Example 279 (21.0 mg, 81%). 1H NMR (CD3OD) δ 7.81 (s, 1H), 7.74 (d, 1H, J=5.5 Hz), 7.25 (m, 3H), 4.18 (t, 2H, J=5.5 Hz), 3.35 (t, 2H, J=1.7 Hz), 2.90 (t, 2H, J=5.5 Hz), 2.74-2.54 (m, 4H), 2.45 (s, 3H), 2.33 (t, 4H, J=2.8 Hz), 1.12 (m, 1H), 0.67-0.64 (m, 2H), 0.29-0.25 (m, 2H); MS(ESI+) m/z 529.3 (M+H)+.