Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][O:36][C:37](Cl)=[O:38]>ClCCl>[CH3:35][O:36][C:37](=[O:38])[NH:2][C@H:3]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10]([C:11]2[C:12]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)=[O:27])[CH2:5][CH2:4]1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was suspended in dichloromethane (2 ml) under nitrogen at room temperature and triethylamine (153 μl, 1.09 mmol) was added followed by methylchloroformate (31 μl, 0.4 mmol). The reaction was stirred at room temperature for 1.5 h and the mixture was quenched with sat. sodium bicarbonate solution (3 ml). The organic phase was separated and the aqueous phase was washed with dichloromethane (2×3 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) and the product was triturated with diethylether (3 ml) to give (cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-carbamic acid methyl ester (64 mg) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=O.C1N(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)C1.[OH:35][C:36]([CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H:50]2[C@@H:45]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:43]1)=[O:37].N[C@@H](C(O)=O)C>CN(C=O)C.C(N(CC)CC)C>[CH3:1][NH:2][CH2:3][C:4]([CH:38]([CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H:50]2[C@@H:45]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:43]1)[C:36](=[O:35])[OH:37])=[O:6]
Reactant: CNCC(=O)O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: C[C@@H](N)C(=O)O
Agent: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O

Procedure:
The N-methyl glycine-linked DOTA-biotin conjugate was prepared by an analogous method to that used to prepare D-alanine-linked DOTA-biotin conjugates. N-methyl-glycine (trivial name sarcosine, available from Sigma Chemical Co.) was condensed with biotin-NHS ester in DMF and triethylamine to obtain N-methyl glycyl-biotin. N-methyl-glycyl biotin was then activated with EDCI and NHS. The resultant NHS ester was not isolated and was condensed in situ with DOTA-aniline and excess pyridine. The reaction solution was heated at 60° C. for 10 minutes and then evaporated. The residue was purified by preparative HPLC to give [(N-methyl-N-biotinyl)-N-glycyl]-aminobenzyl-DOTA.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[CH2:7]([C:10]1([S:13]([N:16]2[C:20]3[C:21]4[O:25][CH:24]=[CH:23][C:22]=4[C:26]([F:29])=[C:27]([F:28])[C:19]=3[N:18]([C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=3[F:37])C2=O)(=[O:15])=[O:14])[CH2:12][CH2:11]1)[CH:8]=[CH2:9].C(OCC)(=O)C>C1COCC1.CCCCCC>[CH2:7]([C:10]1([S:13]([NH:16][C:20]2[C:21]3[O:25][CH:24]=[CH:23][C:22]=3[C:26]([F:29])=[C:27]([F:28])[C:19]=2[NH:18][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])(=[O:15])=[O:14])[CH2:12][CH2:11]1)[CH:8]=[CH2:9]
Reactant: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c(F)c4ccoc4c32)CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(F)c(F)c3ccoc23)CC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
Potassium trimethyl silanolate (0.105 g, 0.82 mmol) was added to a solution of 1-(1-allylcyclopropylsulfonyl)-4,5-difluoro-3-(2-fluoro-4-iodophenyl)-1H-benzofuro[6,7-d]imidazol-2(3H)-one (0.230 g, 0.4108 mmol) in THF (5 mL) at 0° C. The reaction mass was stirred for 4 hours at 20-40° C. The reaction was monitored by TLC (10% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford the crude compound. Purification by column chromatography on silica gel (10% ethyl acetate in hexane) afforded 0.177 g of the product (78% yield). 1H NMR (CDCl3, 300 MHz): δ 7.54 (d, 1H), 7.40 (dd, 1H), 7.25 (s, 1H), 7.05 (bs, 1H), 6.99 (d, 1H), 6.32-6.39 (m, 1H), 6.22 (s, 1H), 5.65-5.75 (m, 1H), 5.19 (s, 1H), 5.10 (d, 1H), 2.88 (d, 2H), 1.15 (t, 2H), 0.75 (t, 2H). LCMS: 96.32%, m/z=548.8 (M+1). HPLC: 97.19%.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Li+].[OH-].O.Cl>O1CCCC1>[N:1]1([CH2:7][C:8]2[C:17]([C:18]([F:19])([F:21])[F:20])=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Temperature: 40 °C

Procedure:
Methyl 4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-5-(trifluoromethyl)benzoate (may be prepared as described in Description 49; 248 mg, 0.61 mmol) was dissolved in tetrahydrofuran (4 ml). LiOH (43.8 mg, 1.83 mmol) and water (1 ml) were added and the mixture heated at 40° C. for 2 hours. The mixture was cooled and 2M hydrochloric acid (0.96 ml, 1.91 mmol) was added and the solvent removed in vacuo to give the title compound. 240 mg.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]([N:34]1[CH2:35][CH2:36][N:31]([C:29]2[S:28][N:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:30]=2)[CH2:32][CH2:33]1)=[O:19]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cn1c(NC(=O)OCC(Cl)(Cl)Cl)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)nc2ccccc21
Yield: 46.8 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (1-methyl-1H-benzimidazol-2-yl)carbamate (238 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and 145 mg (46.8%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH3:7].[CH3:8][I:9]>CCOCC>[I-:9].[CH3:1][NH+:2]1[CH:6]=[CH:5][N:4]([CH3:8])[CH:3]1[CH3:7]
Reactant: CI
Reactant: Cc1nccn1C
Solvent: CCOCC
Product: CC1N(C)C=C[NH+]1C
Product: [I-]

Procedure:
To 20 g of 1,2-dimethylimidazole dissolved in 100 ml of ether there is added 20 ml of methyl iodide. On standing the product precipitates and is filtered off. Two crystallizations from ethanol-ether furnish the pure product, melting point 315°-318° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:14](=[O:15])[O:13][CH2:12][CH2:11][N:10]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.COC(=O)C(N)C1C=CC(F)=CC=1.FC(F)(F)C(O)=O>C(OC(C)C)(=O)C>[CH2:16]([N:10]1[CH:11]=[CH:12][O:13][C:14](=[O:15])[C@@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Agent: COC(=O)C(N)c1ccc(F)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
To a solution of 3-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-4-fluorophenyl-1,4-oxazin-2-one) (10 g) in isopropyl acetate (110 ml) at room temperature was added a solution of (-)-3-bromocamphor-8-sulphonic acid ((-)-3BCS) (12 g) in acetonitrile (24 ml). Crystallisation began after 2-3 min. The slurry was stirred for 1 h at room temperature. Trifluoroacetic acid (7 ml) was added and the mixture stirred at 65° C. for 3 days. The mixture was cooled to 0-5° C., aged for 1 h. and the solid collected, washed with isopropyl acetate and dried in vacuo at 40° C., to give the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 17.24 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 79%(R), 21%(S). The liquors were stirred at 65° C. for 3 days, then cooled to 0-5° C. The solid was collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 0.84 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 64%(R), 36%(S). The liquors were stripped in vacuo and the residue was dissolved in isopropyl acetate (20 ml) containing trifluoroacetic acid (1 ml) and stirred at 65° C. for 20 h. The mixture was cooled to 0-5° C. for 1 h and the solid collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 2.2 g, ee 99.2% (S) isomer. Total weight of (-)-3BCS salt: 20.28 g, 97% yield. A sample (0.5 g) of the (-)-3BCS salt was retained and the remainder converted back to free base. The salt was partitioned between isopropyl acetate (50 ml) and water (100 ml) containing 0.88 ammonia soln. (3 ml). The layers were separated and the aqueous phase extracted with isopropyl acetate (25 ml). The combined organic phases were washed with water (25 ml). The organic phase was concentrated to residue and flushed with isopropyl acetate to give the 3-(S)-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one) as the free base: yield 8.7g, 93% recovery, ee 98.4% (S) isomer.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1.[O-]S(C(F)(F)[F:36])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C.O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([F:36])=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:24]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: c1ccc(N2CCN(c3nc(N4CCOCC4)cc(N4CCOCC4)n3)CC2)cc1
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: ClCCl
Solvent: O
Product: Fc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. 4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine (380 mg, 0.926 mmol) was dissolved in dichloromethane (5 ml), and N-fluoro-2,4,6-trimethylpyridinium triflate (402 mg, 1.39 mmol) was added. After agitation for 30 minutes at room temperature, water was added and extraction was done with dichloromethane. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=4:1), and 122 mg of 4,6-dimorpholino-5-fluoro-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained (yield 31%). The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 82 are shown below.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]=1[CH3:30])=[O:15].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C.CCCCCC>C(OCC)C>[CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([O:13][S:33]([CH3:32])(=[O:35])=[O:34])[C:6]([Cl:11])([Cl:12])[C:7]([F:8])([F:10])[F:9])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19]=1[CH3:30])=[O:15]
Reactant: Cc1c(COC(=O)C2C(C(O)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cc1c(COC(=O)C2C(C(OS(C)(=O)=O)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 406 mg (0.855 mmol) of (2-methyl-3phenylphenyl)methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 3, in 2 ml of diethyl ether, 0.079 ml (1.0 mmol) of methanesulfonyl chloride and 0.143 ml (1.0 mmol) of triethylamine, were added, and the mixture was stirred at room temperature for 1 hour. After an addition of 5 ml of hexane to the mixture, the precipitated inorganic salt was filtered off, and the filtrate was concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/1) to obtain 458 mg of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-methanesulfonyloxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11](=O)[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8]C.C(O)(=O)C.Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[C:6]([CH3:10])[C:7]=1[OH:8]
Reactant: COc1c(C)cc(C(=O)CCC(=O)O)cc1C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(CCCC(=O)O)cc(C)c1O

Procedure:
A mixture of 4-(3,5-dimethyl-4-methoxyphenyl)-4-oxobutyric acid (13 g), zinc amalgam [prepared from zinc (15 g) and mercuric chloride (1.5 g)], glacial acetic acid (70 ml), water (70 ml) and concentrated hydrochloric acid (170 ml) was heated at reflux for 12 hr. The cooled mixture was filtered and the filtrate was poured into water (1 liter). The mixture was extracted with ethyl acetate and the organic fraction was washed four times with water. The dried (MgSO4) organic fraction was evaporated to give 4-(3,5-dimethyl-4-hydroxyphenyl)butyric acid as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.79-2.64 (6H,m); 2.22 (6H,s); 6.79 (2H,s); 7.6 (2H,brs).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2].[CH2:27]([SH:31])[CH2:28][CH2:29][SH:30].B(F)(F)F.CCOCC>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:22])[CH3:21])[S:31][CH2:27][CH2:28][CH2:29][S:30]1)[CH3:2]
Reactant: SCCCS
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)CCCCC1(CCCCC(C)(C)C(=O)OCC)SCCCS1
Reaction time: 3 h
Yield: 80.4 %

Procedure:
Under N2 atmosphere, to a solution of 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid diethyl ester (1.0 g, 2.70 mmol) and 1,3-propanedithiol (361 mg, 361 L, 3.24 mmol) in dichloromethane (20 mL; dried with Aluminum oxide, activated, neutral, Brockmann I) was added boron trifluoride diethyl etherate (100 L) at rt. The reaction mixture was stirred for 3 h, diluted with dichloromethane (100 mL), and extracted with 5% NaOH solution (100 mL) and water (75 mL). The organic phase was dried over MgSO4, concentrated in vacuo, and dried in high vacuo to furnish 6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid ethyl ester (1.0 g, 80%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): (ppm): 4.11 (q, 4H, J=7.1), 2.79 (t, 4H, J=5.6), 1.94 (m, 2H), 1.84 (m, 4H), 1.54 (m, 4H), 1.39 (m, 4H), 1.24 (t, 6H, J=7.1), 1.30-1.20 (m, 4H), 1.16 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm): 178.08, 60.33, 53.32, 42.27, 40.69, 38.28, 26.14, 25.67, 25.28, 24.71, 14.41. HRMS (LSIMS, nba): Calcd. for C24H45S2O4 (MH+): 461.2759. found 461.2774.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](NCC)=[CH:24][CH:23]=1.[CH3:31][CH2:32][N:33](C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:31][CH2:32][NH:33][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)=[CH:26][CH:27]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CCNc1ccc(OC)cc1
Product: COc1ccc(CCNC2=NC(=O)/C(=C/c3ccc4ncccc4c3)S2)cc1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 4-methoxy-phenyl-ethyl amine and DIEA to give 2-[2-(4-methoxy-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:18]=[CH2:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cccc2c1CN(Cc1ccccc1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1CN(Cc1ccccc1)C2
Temperature: 100 °C

Procedure:
A solution of 2-benzyl-4-bromoisoindoline (16.7 g, 58.0 mmol) and tributyl(vinyl)tin (20.3 mL, 69.6 mmol) in PhMe (400 mL) was degassed by bubbling nitrogen gas through the solution for 0.25 h. Tetrakis(triphenylphosphine)palladium (0) (1.30 g, 1.16 mmol) was added, and the resulting solution heated in a 100° C. oil bath under nitrogen for 24 h. The contents of the reaction flask were cooled, evaporated and subjected to flash column chromatography eluting with hexane/EtOAc 95/5 to give after evaporation the title compound as a pale oil that turned pink on standing. LRMS (ESI) m/z 236 [(M+H)+; calcd for C17H18N: 236].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:28][C@H:29]([CH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[C@H:30]([CH3:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(C(C)(C)C)(C)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.C1(C)C=CC=CC=1>[OH:28][C@H:29]([CH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[C@H:30]([CH3:41])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:3]=2)=[CH:34][CH:33]=1
Reactant: NC(=O)Nc1cccc(Br)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
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: Cc1ccccc1
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cccc(NC(N)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 120 °C
Yield: 61.5 %

Procedure:
Prepared according to the method described in Example 12b) from 3-bromophenylurea (0.215 g), ethanol (1 ml), toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.2 g, Example 11)), and tetrakis(triphenylphosphine)palladium (0) (0.02 g) with heating at 120° C. for 4 hours. After work-up, the residue was purified by normal-phase HPLC eluting a gradient of 0-25% ethanol in dichloromethane to give the title compound as a solid (0.116 g).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:11]=2[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([CH2:23][CH2:24][C:25](Cl)=[O:26])([O:21][CH3:22])=[O:20].CCOCC.Cl>N1C=CC=CC=1.O>[C:19]([CH2:23][CH2:24][C:25]([O:12][C:11]1[CH:10]=[C:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:26])([O:21][CH3:22])=[O:20]
Reactant: Oc1cc(-c2ccccc2)sc1-c1ccccc1
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCC(=O)Oc1cc(-c2ccccc2)sc1-c1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred, ice-cooled solution of 2,5-diphenyl-3-hydroxythiophene (0.12 g, 0.5 mmol) in dried pyridine (5.0 ml) under a nitrogen atmosphere was added 3-carbomethoxypropionyl chloride (0.1 g, 0.66 mmol) over ca. 20 seconds. The mixture was allowed to stir cold for 15 minutes and then at ambient temperatures for 4 hours. The mixture was added in portions to a stirred mixture of ether, ice, water, and 2N hydrochloric acid (40 ml), the ether layer washed 2 times with water, dried over sodium sulfate, filtered and concentrated to 0.18 g of oily (I). M.S.: M+ =366; NMR: consistent. ##STR26##
Reaction SMILES: [NH3:1].CO.[S:4]1[CH:8]=[CH:7][C:6]2[C:9]([NH:13][C:14]3[N:15]=[C:16]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]4[NH:32]C(OC(C)(C)C)=O)[N:17]=[N:18][C:19]=3[C:20](OCC)=[O:21])=[CH:10][CH:11]=[CH:12][C:5]1=2>>[NH2:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:16]1[N:17]=[N:18][C:19]([C:20]([NH2:1])=[O:21])=[C:14]([NH:13][C:9]2[C:6]3[CH:7]=[CH:8][S:4][C:5]=3[CH:12]=[CH:11][CH:10]=2)[N:15]=1
Reactant: CCOC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc2sccc12
Reactant: N
Solvent: CO
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 7 M ammonia-methanol solution (2 ml) was added to ethyl 5-(benzo[b]thiophen-4-ylamino)-3-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 2 (71.8 mg), and then the reaction solution was allowed to react in a microwave reactor at 130° C. for 1 hour. The solvent was evaporated under vacuum, then trifluoroacetic acid (0.5 ml) was added to the resultant residue, and the reaction solution was stirred at room temperature for 5 minutes. The solvent was evaporated under vacuum, and then the resultant residue was purified by column chromatography on basic silica gel (developing solvent:hexane/ethyl acetate) to obtain the titled compound as a white solid.