Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:39][C:40]([NH:42][CH2:43][CH3:44])=[O:41]>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:43]([NH:42][C:40](=[O:41])[CH2:39][N:27]1[CH2:28][CH2:29][CH:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([CH3:30])[N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:25][CH2:26]1)[CH3:44]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: CCNC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)CN1CCC(c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 54.3 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (150 mg, 0.35 mmol) in DCM (2 mL) was added triethylamine (107 μL, 0.77 mmol). The resultant mixture was stirred for 10 minutes before the addition of 2-chloro-N-ethyl-acetamide (46 mg, 0.38 mmol) and tetrabutylammonium iodide (13 mg, 0.04 mmol). The reaction was stirred at RT for 4 days before the reaction was washed with sodium hydrogen carbonate solution (sat. aq.). The aqueous phase was extracted with 10% MeOH in DCM (×3) and the combined organic layers dried (Na2SO4) then concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM) affording 276 (91 mg, 0.19 mmol, 55%). LCMS: RT=2.75 min, [M+H]+=478. 1H NMR δ (ppm) (CDCl3): 8.43 (1H, d, J=8.29 Hz), 7.59 (1H, s), 7.16 (1H, s), 7.00 (1H, dd, J=8.34, 1.81 Hz), 6.88 (1H, d, J=1.76 Hz), 5.91-5.80 (1H, m), 4.48-4.44 (2H, m), 4.42-4.37 (2H, m), 3.37-3.26 (2H, m), 3.06-2.88 (4H, m), 2.57-2.47 (1H, m), 2.38 (3H, s), 2.30 (2H, s), 1.87 (2H, d, J=12.74 Hz), 1.76 (2H, s), 1.54 (6H, d, J=6.65 Hz), 1.15 (3H, t, J=7.26 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[NH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CCCCCC>[C:22]1([S:28]([N:10]2[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1ccc(-c2c[nH]c3ccncc23)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccc(F)cc2)c2cnccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
106 mg (0.5mM) of the product of Step 3, above, in 5 ml of absolute THF is cooled to -78°. 0.328 ml (0.525mM) of 1.6M n-butyllithium in hexane is added and the mixture stirred for 1 hour whilst allowing the temperature to rise to 0°. The mixture is then re-cooled to -60° and 97mg (0.55mM) of benzenesulfonyl chloride is added. After allowing to warm to RT overnight, the mixture is quenched with aqueous NaHCO3 and extracted with ethyl acetate. After washing with NaHCO3 the mixture is dried over Na2SO4 and evaporated to dryness. The residue is triturated with ether and the solids produced precipitated and dried to produce the title product of this step.
Reaction SMILES: Cl.[N:2]([O-:4])=O.[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14](=[O:23])[CH2:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCO>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14](=[O:23])[CH:15]([NH:2][OH:4])[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(=O)CC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C(NO)C(=O)c1c(Cl)cccc1Cl

Procedure:
Slowly bubble N2O3 gas (generated by the dropwise addition of concentrated HCl into an aqueous solution of sodium nitrite) into a stirred solution of ethyl 4-(2,6-dichlorophenyl)-2,4-dioxobutanoate (14.4 g, 50 mmol) in EtOH (300 mL) until the reaction is complete (as determined by TLC). Remove the EtOH by evaporation under reduced pressure and partition the residue between EtOAc and water. Dry the organic extract over MgSO4 and evaporate in vacuo to obtain the title compound which is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.254 min, m/z=477.21; 1H NMR (CDCl3) 1.55 (d, 3H), 2.01 (m, 1H), 2.15-2.34 (m, 5H), 2.46 (m, 1H), 2.96 (m, 1H), 4.00 (s, 3H), 5.66 (m, 1H), 5.80 (s, 1H), 6.19 (s, 1H), 6.86 (d, 1H), 7.03 (m, 4H), 7.23 (m, 2H), 7.79 (dd, 1H), 8.36 (s, 1H).
Reaction SMILES: S([C:5]1C=C[C:8](C)=[CH:7][CH:6]=1)([O-])(=O)=O.[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-:29].[K+].[K+]>C(#N)C>[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:5][CH2:6][C@@H:7]([OH:29])[CH3:8])[CH2:24][CH2:25]3)=[N:18][O:19][C:15]=2[CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: [K+]
Solvent: CC#N
Product: C[C@H](O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
(S)-Hydroxybutyl rosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of the tosylate (6.8 g, 28.0 mmol) in acetonitrile (150 ml) was added 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (6.2 g, 28.0 mmol) followed by milled potassium carbonate (5.8 g, 42.0 mmol) at room temperature under nitrogen. The reaction mixture was warmed to reflux for 3 hours and allowed to cool to room temperature. The solids were removed via filtration through a pad of Celite and were washed with EtOAc. The combined filtrates were concentrated to give the crude product. Purification via flash column chromatography (silica gel, 0-10% MeOH/EtOAc) afforded 5.5 g (67%) of the desired product as an oil which solidified on standing, m.p.=84°-86° C.
Reaction SMILES: C([Cl:4])(=O)C.[Cl:5][C:6]1[CH:43]=[CH:42][CH:41]=[CH:40][C:7]=1[C:8]([NH:10][C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([N:22]3[CH2:27][CH2:26][CH2:25][C:24]4([CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH2:23]3)=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)=[O:9]>C(O)C>[ClH:4].[CH2:23]1[C:24]2([CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)[CH2:25][CH2:26][CH2:27][N:22]1[C:20]([C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][C@H:11]2[NH:10][C:8](=[O:9])[C:7]2[CH:40]=[CH:41][CH:42]=[CH:43][C:6]=2[Cl:5])=[CH:15][CH:16]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(C(=O)c3ccc4c(c3)[C@H](NC(=O)c3ccccc3Cl)CC4)C2)CC1
Reactant: CC(=O)Cl
Solvent: CCO
Product: Cl
Product: O=C(N[C@@H]1CCc2ccc(C(=O)N3CCCC4(CCNCC4)C3)cc21)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Acetyl chloride (5 eq.) was added to an ice-cold solution of (R)-tert-butyl 2-(3-(2-chlorobenzamido)-2,3-dihydro-1H-indene-5-carbonyl)-2,9-diazaspiro[5.5]undecane-9-carboxylate (0.652 mmol, 1 eq.) in ethanol. The reaction mixture was then stirred at room temperature overnight. The solvent was concentrated in vacuo and the residue was dissolved in ethanol/acetone (1:3, 5 ml) and diethyl ether (100 ml) was added. The white solid was filtered out, washed with diethyl ether and dried in vacuo. Yield: 82%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:23]([O:24][CH3:25])=[C:22]([CH3:26])[C:21]([CH3:27])=[C:20]([CH:28]([OH:30])[CH3:29])[C:19]=2[CH3:31])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[C:28]([C:20]1[C:19]([CH3:31])=[C:18]([C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:23]([O:24][CH3:25])=[C:22]([CH3:26])[C:21]=1[CH3:27])(=[O:30])[CH3:29]
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)O)c(C)c(C)c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)=O)c(C)c(C)c1OC
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A solution of methyl (R)-7-(4-fluorophenyl)-7-[3-(1-hydroxyethyl)-6-methoxy-2,4,5-trimethylphenyl]heptanoate (4.1 g, 9.5 mmol) in dichloromethane (10 ml) was added to a solution of pyridinium chlorochromate (3.3 g, 15.2 mmol) in dichloromethane (20 ml) at room temperature. The mixture was stirred for 2 hours at the same temperature. To the mixture was added diethyl ether. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to give methyl (R)-7-(3-acetyl-6-methoxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)heptanoate (3.9 g). Physico-chemical properties and spectral data are shown in [Table 5].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:17]([CH2:16][CH2:15][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[CH:9]=[CH:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCOc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (0.5 g, 2.9 mmol) and 1-(2-bromoethoxy)benzene (0.74 g, 3.7 mmol) in DMF (15 mL) was added K2CO3 (1.2 g, 8.6 mmol). After stirring at room temperature for 16 hr, the mixture was heated to 55° C. for 5 hr then cooled to room temperature and diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was subjected to flash chromatography (20% ethyl acetate/hexane, then ethyl acetate) to provide 0.63 g (75%) of methyl 1-(2-phenoxyethyl)-1H-indole-6-carboxylate. 1H NMR (300 MHz, DMSO) δ 8.26 (d, 1H, J=1.0 Hz), 7.67-7.62 (m, 3H), 7.23 (td, 2H, J=7.6 Hz, J=1.0 Hz), 6.92-6.84 (m, 3H), 6.55 (dd, 1H, J=3.0 Hz, J=0.6 Hz), 4.66 (t, 2H, J=4.9 Hz), 4.28 (t, 2H, J=4.9 Hz), 3.86 (s, 3H).
Reaction SMILES: C(S[C:4](=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:5])C.[C:13]([NH:21][NH2:22])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C(O)CCC>[CH3:5][C:4]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:21][N:22]=1
Reactant: CCSC(C)=Nc1ccccc1
Reactant: NNC(=O)c1cccnc1
Solvent: CCCCO
Product: Cc1nnc(-c2cccnc2)n1-c1ccccc1
Yield: 42 %

Procedure:
First, into a 100-mL three-neck flask were placed 3.64 g of N-[1-(ethylsulfanyl)ethylidene]aniline, 20 mL of 1-butanol, and 2.78 g of nicotinic acid hydrazide, and the mixture was stirred at 130° C. for 22 hours. After the stirring, this reaction solution was concentrated under reduced pressure to give an oily substance. This oily substance was washed with ethyl acetate, and subjected to suction filtration to give a solid. This solid was purified by alumina column chromatography using ethyl acetate as a developing solvent. The obtained fraction was concentrated to give a solid. This solid was washed with a mixed solvent of ethyl acetate and hexane, so that 3-methyl-4-phenyl-5-(3-pyridyl)-4H-1,2,4-triazole (abbreviation: HMpytz) was obtained (a white solid, 42% yield). The synthesis scheme of Step 1 is illustrated in the following (a-1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br>>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1cccc(F)c1CBr
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1c(F)cccc1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,6-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([S:16][CH2:17][C:18]#[N:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+].Br[CH2:23][CH2:24]Br>CN(C)C=O.CCOCC.O>[C:10]1([S:16][C:17](=[C:8]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:24][CH2:23][S:9]2)[C:18]#[N:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CCSc1ccccc1
Reactant: BrCCBr
Reactant: S=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#CC(Sc1ccccc1)=C1SCCN1c1ccccc1
Reaction time: 1 h
Yield: 60.1 %

Procedure:
18.9 g (140 mmols) of phenylisothiocyanate and 20.9 g (140 mmols) of phenylthioacetonitrile dissolved in 50 ml of dimethylformamlde were added dropwise with stirring at room temperature to a suspension of 11.5 g of sodium hydride (60% oil, 287 mmols) in 200 ml of dimethylformamide. The mixture was stirred for 1 hour, and 28.9 g (154 mmols) of 1,2-dibromoethane was added dropwise at room temperature. Then the mixture was stirred for 3 hours. To the reaction mixture were added 300 ml of water and 100 ml of ether, followed by stirring. The precipitated crystals were collected by filtration, giving 26.1 g of the title compound as colorless crystals (yield 60%).
Reaction SMILES: [N:1]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])CCCC.[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18]C.C1([O:26]C2C=CC=CC=2)C=CC=CC=1>>[C:10]1(=[O:26])[C:11]2[C:8](=[CH:9][CH:14]=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:13][C:12]3=2)[CH:7]=[CH:6][NH:1]1
Reactant: CCCCCC
Reactant: CCCCN(CCCC)CCCC
Reactant: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ccc2ccc3ccccc3c12

Procedure:
A solution of n-Bu3N (1.3 ml) in diphenyl ether (5 ml) was heated at 230° C. A solution of the compound prepared in Reference Example 2 in diphenyl ether was added to the solution dropwise. After cooling, hexane was added to the reaction solution. The solids deposited were gathered by filtration. The solids were washed with hexane, and dried to give the title compound (655 mg) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][O:14][CH3:15].CN(C)CCN(C)C.C([Li])CCC.[CH2:29]1[O:39][C:32]2([CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]2)[O:31][CH2:30]1.Cl>C1COCC1.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][O:12][C:3]1[CH:4]=[C:5]([O:8][CH2:9][O:10][CH3:11])[CH:6]=[CH:7][C:2]=1[C:35]1([OH:38])[CH2:36][CH2:37][C:32]2([O:39][CH2:29][CH2:30][O:31]2)[CH2:33][CH2:34]1
Reactant: COCOc1ccc(Br)c(OCOC)c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2(O)CCC3(CC2)OCCO3)c(OCOC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A round bottomed flask, equipped with magnetic stirrer, under an argon atmosphere was loaded with 1-bromo-2,4-bis(methoxymethoxy)benzene (2.00 g, 7.2 mmol) and THF (50 mL). N,N,N′,N′-Tetramethylethylene diamine (2.3 ml, 15.2 mmol) was added in one portion via syringe and the stirred solution was cooled to −78° C. n-Butyl lithium (9.5 ml, 15.2 mmol, 1.6M in hexane) was added dropwise via syringe. The resulting yellow solution was stirred for 1 hr at −78° C. and 1,4-cyclohexanedione monoethylene ketal (1.35 g, 8.7 mmol) was added as a solution in THF (25 ml) slowly, via syringe. The resulting solution was stirred at −78° C. for 1 hr and then allowed to warm to room temperature overnight. Hydrochloric acid (20 ml, 2M) was added and the reaction mixture stirred vigorously for 15 min. Ethyl acetate (100 ml) was added and the mixture poured into a separating funnel. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine (20 ml), dried over anhydrous magnesium sulphate, filtered and concentrated affording an orange oil which was purified by flash column chromatography (SiO2, ethyl acetate/petroleum ether, 45:55, v/v). The title product (1.42 g, 56%) was isolated as a colourless oil. m/z (ES30) 337 (M−H2O+H+); δH (CDCl3) 1.61-1.64(2H, m), 2.00-2.18(6H, m), 3.44(3H, s), 3.48(3H, s), 3.90-3.97(4H, m), 5.11(2H, s), 5.24(2H, s), 6.64(1H, dd), 6.82(1H, d), 7.20(1H, d).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[H-].[Na+].[C:34](=[O:48])([O-:47])[O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1CCl.O.[CH2:50]1COCC1>>[N+:42]([C:39]1[CH:40]=[CH:41][C:36]([O:35][C:34](=[O:48])[O:47][CH2:50][N:28]2[C:29]3[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]4[CH2:12][CH2:11][N:10]([C:6]5[C:3]6[CH:4]=[CH:5][S:1][C:2]=6[CH:9]=[CH:8][CH:7]=5)[CH2:15][CH2:14]4)[CH:30]=3)[CH:25]=[CH:26][C:27]2=[O:31])=[CH:37][CH:38]=1)([O-:44])=[O:43]
Reactant: O=C([O-])Oc1ccc([N+](=O)[O-])cc1CCl
Reactant: C1CCOC1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccc([N+](=O)[O-])cc1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one (2.0 g) was suspended in anhydrous THF (40 ml) under a nitrogen atmosphere, and sodium hydride (about 55% oil) (0.22 g) was added. The mixture was refluxed for 30 min under a nitrogen atmosphere. The obtained solution was cooled to was cooled to −70° C., and a solution (20 ml) of chloromethyl-4-nitrophenyl carbonate (1.50 g) in anhydrous THF with cannula. The reaction mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated by filtration. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the component (Rf value: 0.62, ethyl acetate, 0.67 g) as a pale-yellow amorphous compound. The obtained compound was used for the next reaction step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH:15]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](OC(C)(C)C)=[O:23])[OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH2:37][CH2:38][C:39]([N:41]2[CH2:48][CH2:47][CH2:46][C@H:42]2C(O)=O)=[O:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH:15]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:23])[C@@H:48]2[CH2:47][CH2:46][CH2:42][N:41]2[C:39](=[O:40])[CH2:38][CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc(OCc2ccccc2)cc1
Product: O=C(CCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(OCc2ccccc2)cc1
Yield: 81.1 %

Procedure:
By the same procedure as in Example 26-D), while using (2S)-2-{2-[4-(benzyloxy)phenoxy]-1-hydroxyethyl}-1-(tert-butoxycarbonyl)pyrrolidine (1.71 g) and N-(3-phenylpropionyl)- L-proline (1.10 g), there was obtained 1.82 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:16][S:22]([C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23]
Reactant: Nc1cccc2cc(-c3ccccn3)[nH]c12
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cc(-c3ccccn3)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a mixture of 2-(pyridin-2-yl)-1H-indole-7-amine (0.35 g) and pyridine (6 mL) was added thiophene-2-sulfonyl chloride (0.38 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.50 g, yield 82%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 161-162° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:32]=[C:33]4[N:37]([CH:38]=3)[C:36]3[CH:39]=[CH:40][C:41]([O:43][CH2:44][CH2:45][N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[CH:42][C:35]=3[S:34]4)=[CH:27][CH:26]=2)=[O:23])[CH:17]=1)([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[CH3:15][C:13]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[N:32]=[C:33]4[N:37]([CH:38]=3)[C:36]3[CH:39]=[CH:40][C:41]([O:43][CH2:44][CH2:45][N:46]5[CH2:47][CH2:48][O:49][CH2:50][CH2:51]5)=[CH:42][C:35]=3[S:34]4)=[CH:29][CH:30]=2)=[O:23])[CH:17]=1)([CH3:14])[CH:12]=[O:11]
Reactant: CC(C)(CO)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C=O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Alternatively, 1-[5-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-4a) is prepared in the following manner. To a stirred mixture of dimethyl sulfoxide (1 equivalent) in anhydrous dichloromethane at −78° C. under an argon atmosphere is added dropwise oxalyl chloride (0.5 equivalents). After stirring for a further 20 to 40 min, compound 1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1) (0.3 equivalents) is added and the mixture is stirred at −78° C. Triethylamine (1-2 equivalents) is added, and the mixture is allowed to warm to rt, then the mixture is filtered through Celite and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 1-[5-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-4a).