Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>ClCCl>[CH2:1]([C:3]1[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylamine (step 4 of EXAMPLE 3, 1.72 g, 5.9 mmol) and triethylamine (2.0 mL, 14.8 mmol) in dichloromethane (60 mL) was added phenyl chloroformate (900 μL, 7.0 mmol) at ambient temperature. After 1 h, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 3:1 to 1:1) to afford 2.0 g (83%) of the title compound as colorless amorphous: MS (ESI) m/z 412 [M+H]+, 1H-NMR (CDCl3)δ1.27 (3H, d, J=7.5 Hz), 2.73 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.1 Hz,) 3.59 (2H, t, J=7.0 Hz), 5.12 (1H, br), 7.12 (2H, d, J=7.5 Hz), 7.18-7.25 (2H, m), 7.29-7.41 (8H, m) 7.80 (2H, dd, J=8.3, 1.3 Hz).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH:13]=[CH:14][CH:15]=[N:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>[Pd].C1COCC1>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][NH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3cccnc3nc2-c2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Reaction time: 61 h

Procedure:
A suspension of 2,3-diphenylpyrido[3,2-b]pyrazine (Intermediate D) (49.1 g, 143 mmol), triethylamine (20 ml, 143 mmol) and 10% palladium on carbon (19.5 g) in dry THF (410 ml) was placed under an atmosphere of hydrogen (100 mbar) at room temperature for 61 h. After 24 h and 48 h additional palladium catalyst was added (2×4.9 g). The reaction mixture was filtered and the catalyst was washed with THF. The filtrate was concentrated in vacuo and the crude product was dissolved in warm EtOAc (1500 ml) and washed with sat. Na2CO3 solution (400 ml). The aqueous portion was extracted with EtOAc (200 ml) and the combined organic extracts were washed with water (150 ml), brine (300 ml), dried over sodium sulfate and concentrated in vacuo. This crude product was purified by chromatography on silica eluting with neat DCM followed by DCM (1% MeOH) to afford the title product;
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][N:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:21][CH:22]=1
Reactant: Cc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)C2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
To a solution of 9a (0.7 g, 2.3 mmol) in CH2Cl2 (15 mL), TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was neutralized with aqueous NaOH solution and extracted with CH2Cl2 (2×15 mL). The organic layer was washed with brine, dried and concentrated to give the crude product. The crude product was purified with column chromatography to afforded 10a (0.33 g, 70%). 1H NMR (CDCl3): δ 1.62-1.87 (m, 6H), 2.63 (s, 3H), 2.77 (m, 2H), 3.16-3.22 (m, 2H), 3.33 (m, 1H), 7.27 (d, J=8.4 Hz, 1H), 8.12 (dd, J=8.1, 2.4 Hz, 1H), 9.04 (d, J=2.4 Hz, 1H).
Reaction SMILES: ICC.Br[CH:5]([CH2:10][CH3:11])[C:6](OC)=O.BrC1C=C(Cl)C(O)=C(Cl)C=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:6][CH:5]2[CH2:11][CH2:10]2)=[C:25]([F:30])[CH:24]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CCC(Br)C(=O)OC
Agent: Oc1c(Cl)cc(Br)cc1Cl
Solvent: CCI
Product: Fc1cc(Br)ccc1OCC1CC1

Procedure:
The title compound was prepared analogously to Step 1 in Example A(52), where iodoethane was substituted instead of methyl α-bromobutyrate and 4-Bromo-2,6-dichloro-phenol was substituted instead of 4-Bromo-2-fluorophenol of that example.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCC>[Cu].CO.O>[C:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:14][CH:15]=1)([OH:22])=[O:21]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Solvent: CO
Product: O=C(O)Cc1ccc(Nc2ccc(Cl)cc2C(=O)O)cc1
Temperature: 10 °C
Yield: 35 %

Procedure:
To a 100 ml round bottomed flask was added 2,5-dichlorobenzoic acid (1.9 g, 10 mmol), 4-aminophenylacetic acid (1.5 g, 10 mmol), anhydrous sodium carbonate (3.2 g, 26 mmol), activated copper metal powder (0.25 g, 4 mmol) and 1-butanol (50 ml). The flask was fitted with a magnetic stirrer bar, water condenser, silica gel guard tube and heated under reflux for 48 hours. TLC (RPC18, Water, 20: methanol, 80) showed the formation of a slower moving component at Rf 0.55. The solvent was removed under reduced pressure with final drying under high vacuum. The residue was dissolved in 50 ml water and heated to boiling, then charcoal was added and the mixture filtered through celite, washing through with a further 25 ml of hot water. This solution was cooled to 10° C. in an ice bath and then acidified to pH≈2 with concentrated aqueous HCl. The oil that separated was extracted into chloroform, the solution dried with anhydrous magnesium sulphate, filtered and the solvent removed by rotary evaporation to leave a sticky solid. Recrystallization from water/acetic acid gave the title compound (1.07 g, 35%). δH (300 MHz, DMSO-d6) 3.54 (2H, s), 7.15-7.27 (5H, m), 7.39 (1H, dd) 7.81 (1H, d), 9.54 (1H, broad s) and 12.0-13.5 (2H, broad). Mass spectrum: (ES−) 304 (M−H). λmax (EtOH)=292, 364 nm.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:24][CH2:23]2.C(O)(C(F)(F)F)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:58]([Cl:60])[Cl:59]>>[NH3:1].[CH2:58]([Cl:60])[Cl:59].[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:15][C:14]3[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:13]=3)[CH2:31][CH2:30]1)[CH2:24][CH2:23]2
Reactant: Brc1ccc2c(c1)CCN2C1CCNCC1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2c(c1)CCN2C1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (93 mg) and 5-bromo-1-piperidin-4-yl-2,3-dihydro-1H-indole*2 TFA (191 mg) in DCM (2 mL) was treated with sodium triacetoxyborohydride (150 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (79 mg). 1H NMR (400 MHz, CDCl3): 7.20 (d, J=8.6 Hz, 2H), 7.11–7.07 (m, 2H), 6.84 (d, J=8.6 Hz, 2H), 6.23 (d, J=9.1 Hz, 1H), 4.00 (t, J=6.1 Hz, 2H), 3.46 (s, 2H), 3.37 (7, J=8.3 Hz, 2H), 3.28 (m, 1H), 2.97 (m, 2H), 2.90 (t, J=8.3 Hz, 2H), 2.54 (m, 2H), 2.47 (br, 4H), 2.06–1.97 (m, 4H), 1.75–1.60 (m, 8H), 1.50–1.43 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:19])[CH3:18].C(=O)(O)[O-].[Na+]>CCO.C1COCC1>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17](=[O:19])[CH3:18])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(=O)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 80 °C
Reaction time: 14 h
Yield: 46.6 %

Procedure:
A mixture of 5-bromo-2,4-dichloropyrimidine (1.25 g, 5.5 mmol) and 1-(2-aminophenyl)ethanone (675 mg, 5.0 mmol) with sodium bicarbonate (1.26 g, 15.0 mmol) in 4:1 EtOH/THF (7.5 mL) was stirred at 80° C. for 14 hours. The reaction was cooled to room temperature and the resulting mixture was filtered, washing the solid with cold EtOH. The collected solid was stirred in hot water, filtered, and the resulting solid washed with cold EtOH. The solid was then dried under vacuum to give 1-{2-[(5-bromo-2-chloropyrimidin-4-yl)amino]phenyl}ethanone (761 mg, 47%) as a yellow solid. 1H NMR (DMSO-d6): δ 11.91 (s, 1H), 8.60-8.64 (m, 2H), 8.15 (d, 1 H), 7.74 (t, 1 H), 7.31 (t, 1 H), 2.72 (s, 3 H). MS m/z 326 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]([NH2:11])[CH2:4][CH2:3]1.Cl.[O:13]([C:15]#[N:16])[K]>O>[O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]([NH:11][C:15]([NH2:16])=[O:13])[CH2:4][CH2:3]1
Reactant: NC1CCC(=O)c2ccsc21
Reactant: N#CO[K]
Agent: Cl
Solvent: O
Product: NC(=O)NC1CCC(=O)c2ccsc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 0.17 g. sample of dl-4,5,6,7-tetrahydro-4-oxobenzo[b]thiophen-7-amine is stirred in 10 ml. of water, acidified with 3N HCl to pH 3-4, and 0.3 g. of KOCN is added. The mixture is stirred at room temperature for 16 hours, and the title compound is collected by filtration, washed with water and dried. It melts at 238°-242° C. and recrystallization from methanol gives analytical sample of the title compound, m.p. 240°-241° C.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([O:12]CC)=O)[CH:8]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[CH2:21]([NH:24][C:10](=[O:12])[CH:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH3:23]
Reactant: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Reactant: CCCN
Product: CCCCCCC(C(=O)NCCC)n1cnc([N+](=O)[O-])c1

Procedure:
Ethyl 2-(4-nitro-1H-imidazole-1-yl)octanoate (17 moles, 5.0 g) was reacted with propylamine as in Example 1 to yield 2.5 g of N-propyl-2-(4-nitro-1H-imidazol-1-yl)octanoamide. (MS).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1.C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[C:22]1[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[N:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Cl)c1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)c1cncc(Cl)n1

Procedure:
A solution of (3-chloro-benzyl)-carbamic acid tert-butyl ester (458 mg, 1.9 mmol) in DMF (20 mL) was treated with 60% NaH in mineral oil (152 mg, 3.79 mmol). The resulting mixture was stirred at room, temperature until the gas evolution ceased and 2,6-dichloro-pyrazine (282 mg, 1.89 mmol) was added. The reaction mixture was stirred at 80° C. until the LC/MS indicated the reaction was complete. The reaction mixture was cooled and poured into Ethyl Acetate and washed with H2O and brine. The organic layers were combined, dried (Na2SO4), and concentrated to yield the title compound I-4e (199 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]1([CH3:14])[CH3:13].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:15]([O:1][CH2:2][CH2:3][N:4]1[C:5]([CH3:14])([CH3:13])[CH2:6][CH:7]([OH:12])[CH2:8][C:9]1([CH3:10])[CH3:11])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(O)CC(C)(C)N1CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCCN1C(C)(C)CC(O)CC1(C)C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Into a 250 ml flask equipped with a magnetic stirbar, thermometer, addition funnel and nitrogen atmosphere was placed 1-(2-hydroxyethyl)-2,2,6,6-tetramethyl-4-piperidinol (10.0 g, 0.499 mole) and 75 ml of methylene chloride. The resulting slurry was cooled to -20° C. and the addition funnel was charged with acetic anhydride (5.1 g, 0.496 mole) and 15 ml of methylene chloride. The anhydride was added dropwise to the diol slurry with no apparent reaction. The mixture was warmed to 15° C. at which temperature the solids began to dissolve. The mixture was stirred at ambient temperature for 2 hours. The mixture was poured into 80 ml of 10% sodium carbonate (aqueous) and stirred for 15 minutes at ambient temperature. The mixture was transferred to a separatory funnel and extracted with 100 ml of methyl t-butyl ether. The ether solution was dried with anhydrous magnesium sulfate and the solvent removed using aspirator and high vacuum systems. The product was a white solid melting at 56°-58° C. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:23]([C:25]2([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]2)=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:43][CH2:44][CH2:45][N:46]1[CH2:52][CH:51]([OH:53])[C:48]2([CH2:50][CH2:49]2)[CH2:47]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:53][CH:51]1[C:48]2([CH2:50][CH2:49]2)[CH2:47][N:46]([CH2:45][CH2:44][CH2:43][O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([N:22]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[C:23]([C:25]5([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]5)=[O:24])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][C:16]=2[O:19][CH3:20])[CH2:52]1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1O
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (240 mg, 0.475 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (236 mg, 0.95 mmol) and Cs2CO3 (463 mg, 1.425 mmol). The reaction was then stirred at rt for 2 days. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as a white solid (250 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][CH2:8][C:9](=O)[CH2:10][C:11](OCC)=[O:12].[OH-].[Na+]>>[Cl:7][CH2:8][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][N:6]2[C:11](=[O:12])[CH:10]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1nccs1
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(CCl)nc2sccn12
Temperature: 110 °C
Yield: 25.9 %

Procedure:
A solution of 2-aminothiazole (5.0 g, 49.993 mmol) in polyphosphoric acid (40.0 g) was treated with ethyl chloroacetoacetate (11.176 g, 67.866 mmol) and heated at 110° C. for 5.0 h. The reaction mixture was cooled to room temperature and adjusted to pH 7 with 10% aq. NaOH. The solid formed was filtered and purified by column chromatography using ethyl acetate in dichloromethane as solvent to afford 2.6 g of the desired compound as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 4.59 (s, 2H), 6.41 (s, 1H), 7.56 (d, J=4.8 Hz, 1H), 8.03 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 200.42 (M+H)+.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([O:25]COC)[CH3:24])=[CH:19][N:18]=2)=[CH:10][CH:9]=1)[C:3]([O:5]C)=O.[NH2:29][C:30](N)=[S:31].C([O-])(=[O:35])C.[Na+].Cl>C(O)C>[OH:25][CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][O:14][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH:2]3[S:31][C:30](=[O:35])[NH:29][C:3]3=[O:5])=[CH:13][CH:12]=2)=[N:18][CH:19]=1)[CH3:24]
Reactant: NC(N)=S
Reactant: COCOC(C)c1ccc(CCOc2ccc(CC(Br)C(=O)OC)cc2)nc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Yield: 66.6 %

Procedure:
A mixture of methyl 2-bromo-3-[4-[2-[5-(1-methoxymethoxyethyl)-2-pyridyl]ethoxy]phenyl]propionate (27.0 g), thiourea (4.6 g), sodium acetate (4.9 g) and ethanol (250 ml) was heated under reflux for 4 hours. To the reaction mixture was added 2N hydrochloric acid (250 ml). The mixture was further heated under reflux for 20 hours and concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue thus obtained was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (40:1, v/v) gave 5-[4-[2-[5-(1-hydroxyethyl)-2-pyridyl]ethoxy]benzyl]-2,4-thiazolidinedione (14.8 g, yield: 66%). This crude compound was recrystallized from ethanol to obtain colorless prisms, m.p. 155°-156° C.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1.CC(N(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][CH2:44][OH:45]>O>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]([CH2:42][CH2:43][CH2:44][OH:45])[C:20]4=[O:28])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: OCCCBr
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2CCC3CCc4cccc2c43)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1n(CCCO)c2ccccc2n1C1CCN(C2CCC3CCc4cccc2c43)CC1
Temperature: 85 °C

Procedure:
To 1-[1-(1,2,2a,3,4,5-hexahydroacenaphthylen-5-yl)piperidin-4-yl]-1,3-dihydro-2H -benzimidazol-2-one (500 mg), dimethylacetamide (3 ml) and potassium carbonate (370 mg) was added 3-bromopropanol (0.242 ml), and the mixture was stirred with heating at 85° C. for 2 hr. The reaction mixture was cooled to room temperature, water was added, and the precipitate was collected by filtration to give 1-[1-(1,2,2a,3,4,5-hexahydroacenaphthylen-5-yl)piperidin-4-yl]-3-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[Cl:12][CH2:13][C:14](Cl)=[O:15].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:14](=[O:15])[CH2:13][Cl:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(Cl)CCl
Reactant: Brc1ccc2c(c1)CCCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CCl)N1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-bromo-1,2,3,4-tetrahydroquinoline (2.09 g, 9.85 mmol) in 55 mL toluene was treated with 2-chloroacetyl chloride (0.863 mL, 10.84 mmol) dropwise over 10 minutes. The resulting suspension was stirred at room temperature for 1.5 hour then heated at 95° C. for 30 minutes. After cooling to room temperature, the yellow solution was diluted with 20 mL ethyl acetate and treated with 25 mL of a saturated aqueous sodium bicarbonate solution. The mixture was poured into a separatory funnel and extracted. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using 30% ethyl acetate:70% hexanes as eluant. A white solid was obtained after drying under reduced pressure (Yield: 2.4 g, 84%). 1H-NMR (CDCl3) δ 7.35-7.33 (m, 3H), 4.19 (s, 2H), 3.80 (t, J=6.3 Hz, 2H), 2.74 (t, J=6.6 Hz, 2H), 2.04-1.98 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12]Cl.[Na+].[CH2:15]([C:27]1C=CC=CC=1S([O-])(=O)=O)[CH2:16]CCCCCCCCCC>O>[CH2:11]1[CH2:12][N:1]2[C:2]3[C:3]([CH2:16][CH2:15][CH2:27]2)=[C:4]([OH:8])[CH:5]=[CH:6][C:7]=3[CH2:10]1
Reactant: Nc1cccc(O)c1
Reactant: CCCCCCCCCCCCc1ccccc1S(=O)(=O)[O-]
Reactant: ClCCCBr
Agent: [Na+]
Solvent: O
Product: Oc1ccc2c3c1CCCN3CCC2
Yield: 14.8 %

Procedure:
According to a procedure similar to that of Embodiment 1, a mixture of m-aminophenol (116 mg, 1 mmol), 1-bromo-3-chloropropane (0.48 g, 0.3 ml, 3 mmol), dodecylbenzenesulfonic acid sodium salt (349 mg, 1 mmol) and a buffer solution prepared by dissolving 1.50 g (4 mmol) of Na2HPO4 12H2O and 0.60 g (4 mmol) of NaH2PO42H2O in water (10 ml) was heated and refluxed for 12 hours. After silica gel column chromatography, 8-hydroxyjulolidine (28 mg) was obtained in 15% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][O:16][CH:17]([CH3:19])[CH3:18].[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([OH:30])=[CH:24][C:23]=2[O:22]1>CC(C)=O>[CH:17]([O:16][CH2:15][CH2:14][C:13]([CH3:20])=[CH:12][CH2:11][CH2:10][O:30][C:25]1[CH:26]=[CH:27][C:28]2[O:29][CH2:21][O:22][C:23]=2[CH:24]=1)([CH3:19])[CH3:18]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(=CCCBr)CCOC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=CCCOc1ccc2c(c1)OCO2)CCOC(C)C

Procedure:
2.35 g (0.017 mol) of potassium carbonate and 50 mg of potassium iodide are added to a solution of 4.0 g (0.017 mol) of 1-bromo-6-isopropoxy-4-methyl-3-hexene and 2.35 g (0.017 mol) of 3,4-methylendioxy-phenol in 120 cc of acetone. The suspension is boiled under reflux during the course of 20 hours, is then filtered and liberated from acetone in a vacuum. The residue is taken up in ether, washed with water and saturated salt solution, dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate 9 : 1. Thus the cis/trans isomeric mixture of the 5-(6-isopropoxy-4-methylmethyl- 3-hexenyloxy)-1,3-benzodioxol is obtained as colourless oil. nD20 = 1.5111.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)=[O:31])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)N1CCC(O)CC1

Procedure:
5-[5-(2,3-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) was coupled with piperidin-4-ol (22 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) to give the titled compound.