Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31]S(C)(=O)=O)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)(=O)C.O>C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Reaction time: 8 h

Procedure:
(+,-) cis Methanesulfonic acid 4-(7-benzyloxy-3-phenyl-chroman-4-yl)-phenyl ester (35 g, 71.9 mmol) was added to a solution of potassium hydroxide (350 g) in ethanol (2500 ml) and refluxed for 90 min. The reaction mixture was cooled, acetic acid (350 ml) was slowly added, and the resulting mixture was stirred overnight. Water (1.5 l) was added dropwise over 60 min, stirring was continued for 120 min, and the precipitated product was filtered. The precipitate was vacuum dried with sicapent (Merck) at 45° C. for 4 days.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4].I[CH3:17]>CCCCCC.O1CCCC1>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:15][CH3:17])([CH3:14])[CH3:13])[CH:7]=1)[CH3:4]
Reactant: CI
Reactant: CCOc1cccc(C(C)(C)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1cccc(C(C)(C)OC)c1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
Sodium hydride (3.261 g, 81.54 mmol, 60% in mineral oil, Aldrich) was washed twice with hexane, and tetrahydrofuran (60 mL) was added. To this suspension was added 2-(3-ethoxy-phenyl)-propan-2-ol (4.9 g, 27.18 mmol). The mixture was stirred at 45° C. for 1.5 h until the bubbling subsided. It was cooled down to 0° C. and iodomethane (5.08 mL, 81.54 mmol, Aldrich) was added. After 4 h of stirring at room temperature, another portion of iodomethane (5.08 mL, 81.54 mmol) was added. The mixture was stirred at room temperature for 4 d then quenched at 0° C. with cold 20% solution of ammonium chloride. The product was extracted with ethyl acetate (2×1 L). The organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 1-ethoxy-3-(1-methoxy-1-methyl-ethyl)-benzene (5.15 g, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C1CCCCC1)C1CCCCC1.[C:34]([O:38][CH3:39])(=[O:37])[CH:35]=[CH2:36]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[CH:18]=[CH:17][C:16](/[CH:36]=[CH:35]/[C:34]([O:38][CH3:39])=[O:37])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ccc(Br)cc1
Reactant: C=CC(=O)OC
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 150 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a degassed solution of (S)-2-(4-bromo-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (44.0 g, 128 mmol) in 1,4-dioxane (500 mL) in a sealed pressure vessel was sequentially added N-methyldicyclohexylamine (32.9 mL, 154 mmol), (t-Bu)3HBF4 (1.19 g, 4.10 mmol), methyl acrylate (34.8 mL, 385 mmol) and Pd2(dba)3 (1.19 g, 1.29 mmol). The reaction mixture was heated to 150° C. in a sealed pressure vessel for 4.5 h then cooled in ice bath and placed in refrigerator for 16 h. The reaction mixture was filtered through a Celite pad, the filter cake was washed with 250 mL ethyl acetate, and the combined organics were concentrated in vacuo to a yellow oil. The oil was taken up in 20% ethyl acetate in heptane, sonicated and filtered, and the filtrate was concentrated again in vacuo. The residue was dissolved in ethyl acetate and the organic solution was washed sequentially with 10% citric acid, sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography (ethyl acetate/heptane) or recrystallized from 20% ethyl acetate in heptane. Total recovery is 42.1 g (99% yield).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.C(O)(C(F)(F)F)C(F)(F)F.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[C:22]([O:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][C:31]=1[NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)=[O:43])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][C:31]=1[NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([CH:3]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:2]([OH:6])=[O:5])=[CH:46][CH:45]=1)=[O:43])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(B(O)O)cc1
Reactant: O=CC(=O)O
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C(C(=O)O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Glyoxilic acid monohydrate (0.042 g, 0.456 mmol) was suspended in DCM (2.1 mL)/HFIP (0.2 mL) and pyrrolidine (0.038 mL, 0.456 mmol) and [4-({[2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]boronic acid (0.2 g, 0.456 mmol) were added. The reaction was stirred at room temperature overnight. The mixture was transferred to a microwave vial and heated to 120° C. for 30 minutes in the microwave. The solvent was removed in vacuo and the residue triturated in methanol to give the desired product as a pale yellow powder. 1H NMR (DMSO-d6, 600 MHz) δ 9.95 (s, 1H), 8.74 (br s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.79 (d, J=1.8 Hz, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.49 (m, 2H), 7.43 (d, J=2.4 HZ, 1H), 7.11 (dd, J=5.4 and 3.6 Hz, 1H), 4.33 (s, 1H), 3.06 (m, 2H), 2.79 (m, 2H), 1.84 (m, 4H), 1.43 (s, 9H). MS: cal'd 522 (MH+), exp 522 (MH+).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>>[O:6]=[C:1]1[CH2:5][CH2:4][CH:3]([N:11]2[C:7](=[O:17])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:12])[CH2:2]1
Reactant: O=C1C=CCC1
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)C1

Procedure:
In Scheme II, Step A, cyclopentenone (8) is reacted with phthalimide in a Michael addition to give (±)-2-(3-oxo-cyclopentyl)-isoindole-1,3-dione (9). The reaction is performed in methanol/2N Na2CO3 in a ratio of 10/1 by volume preferably at ambient temperature using conditions similar to those described by O. Nowitzki, et. al. in Tetrahedron 1996, 52, 11799-11810. The product is isolated by addition of water and (9) obtained as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=[O:15])[N:2]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>O.C(OCC)(=O)C.CN(C=O)C>[CH2:19]([N:12]1[C:13]2[CH:1]=[N:2][C:3]([C:14]([O:16][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:15])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cc2c3ccccc3n(Cc3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Compound 17 (2.12 g, 10 mmol) was mixed with DMF (50 ml). After stirring the mixture at room temperature for 30 minutes, NaH (1.6 g, 40 mmol) was added and stirred until the solution became clear. After that, benzyl bromide (5 ml) was added. The mixture was stirred and reacted at room temperature for 1 h. The reaction mixture was poured into cold water (200 ml) and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with water and brine, then the organic phase was evaporated in reduced pressure, the residue was dissolved in anhydrous ethanol, and then the mixture was adjusted to pH 4 with concentrated HCl, and evaporated and recrystallized with acetone/ethyl ether, light yellow solids were obtained. The light yellow solids were dissolved in a mixed solution of water and ethyl acetate. The pH was adjusted to 8 with saturated NaHCO3 solution. The organic phases were isolated. The aqueous layer was extracted with ethyl acetate. After drying, decolorization with activated carbon, filtration, concentration, and recrystallization with ethyl ether, white solids (2.3 g, 57%) were obtained, mp 169-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH2:10][CH:12]1[CH2:13][O:14]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(OCC2CO2)cc1Cl

Procedure:
The title compound was prepared from 3,4-dichloro-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)=[O:12].O>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (412 mg) and 2-bromo-4'-cyanoacetophenone (677 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one hour. Water (100 ml) was added and the collected solid was crystallised from ethyl acetate to give the title pyrimidinone (375 mg,); m.p. 236°-240°; λmaxEtOH 248 nm (ε 26140), 289 nm (ε 2130), λinf 254 (ε 22800).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[O:14]=[C:15]([NH:30][CH2:31][C:32](=O)[NH:33][C@@H:34]1[CH2:38]CNC1)[CH2:16][NH:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl.CCOC(C)=O>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:33]2[CH2:34][CH2:38][C@@H:31]([NH:30][C:15](=[O:14])[CH2:16][NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:32]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC(=O)N[C@@H]1CCNC1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(O)(c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a mixture of 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanone (0.075 g, 0.38 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide (0.10 g, 0.317 mmol) in 2% AcOH/CH2Cl2 (10 mL) was added NaB(OAc)3H (0.134 g, 0.634 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed [EtOAc to MeOH/EtOAc (1:9) then to 5% MeOH/EtOAc/Et3N (1:9:0.5)] to give 0.141 g of the title compound in 90% yield. MS (EI) calcd: (M+H)+=497.2; found: 497.3.
Reaction SMILES: C1(S([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:15][CH:14]=2)(=O)=O)C=CC=CC=1.O[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:23]1([S:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][O:10][C:30]3[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=3)=[CH:18][CH:17]=2)(=[O:21])=[O:22])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(OCCc1ccc(OS(=O)(=O)c2ccccc2)cc1)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)c3ccccc3)cc2)cc1
Yield: 65.4 %

Procedure:
20 g (48 mmole) 4-[phenylsulfonyloxy]phenethyl 1-benzenesulfonate, 11.7 g (95 mmole) p-hydroxybenzaldehyde and 13.27 g (96 mmole) potassium carbonate in 100 ml acetonitrile were refluxed over night. The precipitate was filtered off and the filtrate was evaporated in vacuo. Dichloromethane was added, the solid material was filtered off and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate:petroleum ether (1:2) as eluent to give 12 g (yield 65%) of 4-[2-(4-formylphenoxy)ethyl]phenyl 1-benzenesulfonate.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=CC(S(O)(=O)=O)=C[CH:3]=1.[CH3:13][O:14][C:15]([O:18]C)([CH3:17])[CH3:16].O.C1(C)C(S(O)(=O)=[O:28])=CC=CC=1>CC(C)=O>[CH3:16][C:15]1([CH3:17])[O:18][CH2:7][C:2]([CH3:12])([CH2:3][OH:28])[CH2:13][O:14]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: COC(C)(C)OC
Solvent: O
Solvent: CC(C)=O
Product: CC1(CO)COC(C)(C)OC1

Procedure:
Alternative Procedure: 4-Toluenesulfonic acid monohydrate (51.3 g) in acetone (275 mL) was stirred with 2,2-dimethoxy propane (75 mL) and toluenesulfonic acid monohydrate (1.3 g) for 18 hr at room temperature, and worked up in a similar manner as indicated in the procedure above, 52.12 g (76% yield), b.p. 72-75° C./0.65 mmHg. Mass spec: m/z 161, (M+1)+. Anal Calcd for C8H15O3: C, 59.98; H, 10.07%. Found: C, 59.62; H, 10.07%. 1H NMR (CDCl3) δ ppm: 0.83 (s, 3H), 1.40 (s, 3H), 1.44 (s, 3H), 3.59-3.69 (m, 6H). 13C NMR: 17.69, 20.25, 27.41, 34.86, 65.90, 66.43, 98.1 (7 sp3C).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[ClH:32]>C(O)(C)C.O1CCOCC1>[ClH:1].[ClH:32].[N:26]1([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:2]3[N:11]=[C:10]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:25][CH:24]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Clc1nc(Nc2ccccc2)c2ccccc2n1
Reactant: Nc1ccc(N2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: c1ccc(Nc2nc(Nc3ccc(N4CCCCC4)cc3)nc3ccccc23)cc1

Procedure:
A mixture of 2-chloro-4-phenylamino-quinazoline (0.18 g) and N-(4-aminophenyl)-piperidine (0.164 g) is heated for 3 min to produce a melt which is dissolved in isopropanol (4 ml). 4 N HCl in dioxane (1 ml) is added. Recrystallization from ethanol and diethylether yields 2-[4-(piperidin-1-yl)-phenylamino]-4-phenylamino-quinazoline dihydrochloride, Rf (A1) 0.64, FAB-MS: (M+H)+=396. m.p.: (decomposition).
Reaction SMILES: [Cl-].COC(C1C=C(C=CC=1)C[NH3+])=O.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=C=O)=[CH:18][CH:17]=1)#N.CO[C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=2)=[O:37])[CH:29]=1.[CH3:48][N:49](C=O)[CH3:50]>>[C:45]([C:42]1[CH:41]=[CH:40][C:39]([NH:38][C:36](=[O:37])[NH:35][CH2:34][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([NH:22][C:19]2[CH:18]=[C:17]3[C:16]([CH2:14][CH2:48][NH:49][CH2:50]3)=[CH:21][CH:20]=2)=[O:47])=[CH:44][CH:43]=1)#[N:46]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: COC(=O)c1cccc(CNC(=O)Nc2ccc(C#N)cc2)c1
Reactant: CN(C)C=O
Agent: COC(=O)c1cccc(C[NH3+])c1
Agent: [Cl-]
Product: N#Cc1ccc(NC(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CNCC4)c2)cc1
Reaction time: 1 h
Yield: 91 %

Procedure:
3-Methoxycarbonyl-benzyl-ammonium chloride (605 mg, 3.0 mmol) was dissolved in 6 mL DMF in a reaction vial. Si-dimethylamine (silica-bound dimethylamine; 3.3 g, 5 mmol) was added and the mixture was agitated for 1 hour. Subsequently, p-cyanophenylisocyanate (403.5 mg, 2.8 mmol) was added and the mixture was agitated overnight. SCX (strong cation exchanger; silica-bound benzenesulfonic acid; (568 mg, 0.5 mmol) was added and the mixture was agitated for 30 minutes. The solids were filtered, and the filtrate was evaporated to provide 843 mg (91% yield) of the desired urea, 3-[3-(4-cyano-phenyl)-ureidomethyl]-benzoic acid methyl ester, which was used directly. The intermediate urea was dissolved in 7 mL THF. A solution of lithium hydroxide (410 mg, 10 mmol) in 3 mL water was added. The resulting mixture was heated at 50° C. for 2 hours then cooled to room temperature. The organic phase was evaporated, and the remaining aqueous solution was neutralized. 3-[3-(4-Cyano-phenyl)-ureidomethyl]-benzoic acid (118 mg, 0.4 mmol) was isolated as a white solid by filtration (710 mg; 93% yield) and was used directly. The intermediate acid (118 mg, 0.4 mmol), EDC (115 mg, 0.6 mmol), and HOBt (67.6 mg, 0.5 mmol) were combined in a reaction vial and DMF (1 mL) then N-methylmorpholine (0.066 mL, 0.6 mmol) were added. The reaction mixture was agitated for 1 h, then 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (104.3 mg, 0.42 mmol) was added. Shaking was continued overnight. The reaction mixture was diluted to 6 mL with dichloromethane, washed with 1N HCl (3×2 mL), NaHCO3 (satd. aq., 3×2 mL), and brine (1×2 mL), dried, and the solvents were evaporated to give 220 mg of the intermediate 7-{3-[3-(4-cyano-phenyl)-ureidomethyl]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, which was treated directly with a solution of TFA (0.6 mL) in dichloromethane (2 mL). The reaction mixture was stirred for 2 h, and then the solvents were evaporated. The residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient. The title compound was collected as a solid (137 mg, 77%-2 steps) following evaporation of the solvent; MS analysis electrospray, 426 (M+H).
Reaction SMILES: [ClH:1].[C:2]1([NH:8][C:9]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([C:19](=[NH:23])OCC)=[CH:15][N:14]3[CH:24]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](N)[CH2:26][NH2:27]>C(O)C>[ClH:1].[NH:27]1[CH2:26][CH2:25][N:23]=[C:19]1[C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:24]=[C:11]([C:9]([NH:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[N:12]=2)[CH:15]=1
Reactant: CCOC(=N)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: NCCN
Agent: Cl
Solvent: CCO
Product: O=C(Nc1ccccc1)c1cn2cc(C3=NCCN3)ccc2n1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
A suspension of 296 mg of ethyl 2-phenylcarbamoylimidazo[1,2-a]pyridine-6-carboximidate hydrochloride (1:1) in 10 mL of ethanol is cooled to 0° C., followed by addition of 144 μL of ethylenediamine. The reaction mixture is refluxed for 16 hours and then stirred at room temperature for 60 hours. The precipitate is filtered off by suction and washed with ethanol and then recrystallized from methanol to give 64 mg of 6-(4,5-dihydro-1H-imidazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide hydrochloride (1:2) in the form of a white solid. The filtrate is concentrated to dryness and taken up in water. The insoluble matter is filtered off by suction, washed with methanol and then dried to give 99 mg of 6-(4,5-dihydro-1H-imidazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide hydrochloride (1:1) in the form of a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH2:19][CH2:20][C:21]([OH:23])=O)[C:7]=1[CH2:24][N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35])[CH2:2][CH2:3][CH3:4].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH2:19][CH2:20][C:21](=[O:23])[N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:7]=1[CH2:24][N:25]1[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNC1
Reactant: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CCC(=O)O)c(=O)c2cc(Cl)c(Cl)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CCC(=O)N2CCCC2)c(=O)c2cc(Cl)c(Cl)cc12
Yield: 52.6 %

Procedure:
A solution of 3-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)isoquinolinyl]propionic acid (1.03 g, 2.4 mmol), pyrrolidine (0.20 ml, 2.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g, 2.4 mmol) and 1-hydroxybenzotriazole (0.37 g, 2.4 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-diisopropyl ether to give 2-[[4-butoxy-6,7-dichloro-1-oxo-2-[3-oxo-3-(1-pyrrolidinyl)propyl]-1,2-dihydro-3-isoquinolinyl]-methyl]-1H-isoindole-1,3(2H)-dione (0.72 g, 66.1%) as crystals.
Reaction SMILES: [H-].[Na+].CCCCCC.[OH:9][CH2:10][CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O>[CH2:19]([O:9][CH2:10][CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)OC[C@H](CCO)O1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC1(C)OC[C@H](CCOCc2ccccc2)O1
Yield: 88.4 %

Procedure:
Sodium hydride (1.33 g, 33.3 mmol, 60% in oil) was loaded under argon circumstance in three-necked flask and hexane (20 ml) was added thereto. After stirring for a while, it was allowed to stand and the supernatant was removed by syringe. By repeating this procedure three times, the oil of sodium hydride was removed. After drying in vacuo, anhydrous N,N-dimethylformamide (DMF) (5 ml) was added and the mixture was cooled at 0° C. (S)-4-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (4.42 g, 30.25 mmol) in DMF (8 ml) was dropped to the mixture over a one hour period by taking care of the temperature and then the mixture was stirred for 1 hour. Benzyl chloride (3.83 ml, 33.3 mmol) in DMF (3 ml) was dropped to the solution over a one hour period in the range of 0° C. and 5° C. and then the solution was stirred for 4 hours. After stirring water (20 ml) was added to the solution and the solution was extracted with ethyl acetate. The extract was washed with water (40 ml) twice and with saturated brine once, dried on sodium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-4-(2-benzyloxyethyl)-2,2-dimethyl-1,3-dioxolane (6.32 g, yield 88%).