Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.CCN(C(C)C)C(C)C.CN1CCCC1=O>CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: FC(F)(F)c1cncc(Br)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc(C#CC=C2CCN(c3cncc(C(F)(F)F)c3)CC2)n1
Temperature: 160 °C
Yield: 1.3 %

Procedure:
A vial was filled with a mixture of the compound of Example 3 (84.9 mg, 0.4 mmol), 3-bromo-5-(trifluoromethyl)pyridine (93 mg, 0.4 mmol), DIPEA (140 μL, 0.8 mmol), 1 mL of anhydrous N-methylpyrrolidone and sealed. The vial was heated in a microwave oven at 160° C. (200 W) for 2 h. The reaction mixture was then cooled to r.t., diluted with EtOAc, washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. The crude black oily residue was purified by preparative RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient affording 1.8 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([N:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])=[O:12])#N.N1C=CC=CC=1.O.O.[PH2]([O-])=[O:38].[Na+]>C(O)(=O)C.[Ni]>[CH:20]1([N:13]([CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])[C:11](=[O:12])[CH2:10][CH2:9][O:8][CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][CH:28]=[C:3]([CH:1]=[O:38])[CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(C#N)c1)C1CCCCC1)OC
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COC(CN(C(=O)CCOCCc1cccc(C=O)c1)C1CCCCC1)OC
Temperature: 45 °C

Procedure:
To 3-(3-cyanophenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide [Example 10, Step i)] (600 mg) in acetic acid (6 mL), pyridine (9 mL) and water (6 mL) was added sodium hypophosphite monohydrate (1964 mg) and Raney (R) nickel (397 mg). The reaction was heated to 45° C. under nitrogen for 2 h, then cooled to room temperature, filtered and washed with water/ethyl acetate. The filtrate was diluted with ethyl acetate, which was washed with water then dried over brine, filtered and the solvent removed. The residue was azeotroped once with ethanol to afford a light yellow oil (600 mg). MS [M+H-MeOH]+=360 (MultiMode+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:6][NH:7]2.[OH2:22]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:11]([C:12]([NH2:13])=[O:22])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:6][NH:7]2
Reactant: COc1c(C#N)ccc2[nH]nc(/C=C/c3ccccc3)c12
Reactant: O
Agent: O=S(=O)(O)O
Product: COc1c(C(N)=O)ccc2[nH]nc(/C=C/c3ccccc3)c12
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
35 mg of 4-methoxy-3-(E)-styryl-1H-indazole-5-carbonitrile was dissolved in a mixed solvent 2 mL concentrated sulfuric acid/1 mL water, and stirred at 110° C. for 1 hour and 15 minutes. After cooling the reaction mixture on ice, water was slowly poured under ice cooling, and the precipitated crystals were collected by filtration, and washed with water. After drying under reduced pressure, 22 mg of the title compound was obtained as brown crude crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](OCC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.O1CCCC1.CO.[BH4-].[Li+]>O>[CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][CH2:21][OH:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(C)COC)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
To a mixture of ethyl {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (660 mg), tetrahydrofuran (30 mL) and methanol (5 mL) was added lithium borohydride (130 mg) at 0° C. The whole was stirred at room temperature for 5 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:1 to 1:0, volume ratio) to give pale yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (380 mg, 62%) as pale yellow prisms. MS 506 (MH+). mp 138-139° C.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[N:13]1[CH:14]=[C:15]2[N:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=13)[S:18][C:17]([C:25]([OH:27])=O)=[CH:16]2.ON1C(=O)CCC1=O.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:42](=[O:55])[CH2:41]1.C(N(CC)CC)C.N12CCCNC1CCCC=C2>C(#N)C>[C:49]1([CH2:48][CH2:47][CH2:46][N:43]2[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][CH2:37][NH:36][C:25]([C:17]3[S:18][C:19]4[N:24]5[C:15](=[CH:14][N:13]=[C:23]5[CH:22]=[CH:21][CH:20]=4)[CH:16]=3)=[O:27])[CH2:41][C:42]2=[O:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NCCCN1CCN(CCCc2ccccc2)C(=O)C1
Agent: C1=CN2CCCNC2CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCN(CCCc2ccccc2)C(=O)C1)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.58 g, 8.24 mmol) was added to a stirred suspension of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (900 mg, 4.12 mmol) and N-hydroxysuccinimide (948 mg, 8.24 mmol) in acetonotrile (10 ml) at room temperature and the mixture was stirred at room temperature for 2 hours. A solution of 4-(3-aminopropan-1-yl)-1-(3-phenylpropan-1-yl)-2-oxopiperazine (1.38 g, 5.01 mmol), triethylamine (459 mg, 4.54 mmol) and 1,8-diazabicyclo[5.4.0]undecene (1.25 g, 8.24 mmol) in acetonitrile (20 ml) was added to the mixture. After stirring at room temperature for 1 day, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (60 g) with Ethyl acetate-Methanol (5:1) to give N-[3-[1-(3-phenylpropan-1-yl)-2-oxopiperazin-4-yl]propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide as a purple amorphous powder (978 mg, 50%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=3[OH:12])=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2c(O)cccc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(O)cccc2c1O
Temperature: 180 °C
Yield: 49.5 %

Procedure:
A mixture of 2-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature. Diphenyl ether (50 mL) is added and the mixture is heated to 240° C. for 90 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to room temperature and the resulting solid is collected and washed with hexanes. The crude solid is recrystallized from acetone to yield 0.650 g of ethyl 4,8-dihydroxyquinoline-3-carboxylate. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature and diluted with CH2Cl2. The resulting solid is collected and chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to afford 0.349 g of the desired product as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]([OH:15])[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]([OH:15])[C:9]2[CH2:10][CH2:11][O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2ccoc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)c2c(c1)OCC2
Reaction time: 48 h
Yield: 94 %

Procedure:
Pd on carbon (100 mg) was added to a solution of 4-hydroxy-benzofuran-6-carboxylic acid ethyl ester (8a) (333 mg, 1.61 mmol) in acetic acid. The mixture was stirred under H2 (50 psi) for 48 hr. The mixture was filtered through Celite and concentrated. The residue was taken into saturated aqueous NaHCO3 and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 15% EtOAc in hexanes to give a pale yellow solid (315 mg, 94% yield). 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=1.26 Hz, 1 H) 7.05 (s, 1 H) 4.65 (t, J=8.72 Hz, 2 H) 4.35 (q, J=7.07 Hz, 2 H) 3.21 (t, J=8.72 Hz, 2 H) 1.38 (t, J=7.07 Hz, 3 H); LCMS for C11H12O4 m/z 209.10 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)[CH3:2].[CH:14]1C=CC=C[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].C=C>ClCCl.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[CH2:10][C:11](=[O:13])[CH2:15][CH2:14]2)[CH3:2]
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: c1ccccc1
Agent: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc2c(c1)CCC(=O)C2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 5.0 g of p-ethoxyphenyl acetic acid, 7.0 g of phosphoric pentachloride and 10 ml of anhydrous benzene was heated at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure and the residue obtained was dissolved in 20 ml of anhydrous dichloromethane. This solution was added dropwise to a mixture, cooled to -50° C., of 7.3 g of anhydrous aluminum chloride and 80 ml of anhydrous dichloromethane. Then, ethylene gas was fed into the solution for 20 minutes. Subsequently, the solution was stirred at room temperature (about 25° C.) for 4 hours. Into the reaction solution cooled with ice was added dropwise 30 ml of water. The dichloromethane layer was removed and washed with an 8% hydrochloric acid aqueous solution, water, a saturated sodium bicarbonate aqueous solution and water in this order. Then the dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 6-ethoxy-2-tetralone as a pale-yellow oily product. The crude product, 6-ethoxy-2-tetralone obtained as described above, was catalytically reduced in the presence of hydrogen in a mixture of 0.4 g of platinum oxide and 40 ml of a 20% ethylamine-ethanol solution. After take up of hydrogen had been completed, the platinum oxide catalyst was filtered from the reaction solution and the filtrate was concentrated under reduced pressure. Then the residue was extracted with chloroform and the chloroform layer as washed with a 2 N-NaOH aqueous solution and water in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Adding an ethanolic solution of hydrogen chloride having a concentration of about 18% to the residue, the solution was concentrated under reduced pressure to cause crystals to form. The crystals were recrystallized from a mixed solution of ethanol and diethyl ether to obtain 1.4 g of N-ethyl-6-ethoxy-1,2,3,4-tetrahydro-2 -naphthylamine hydrochloride as colorless needles having a melting point of 207°-209° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=3)[C:4]=2[O:3]1.[CH3:21][O:22][N:23]([CH3:27])[C:24](Cl)=[O:25]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:24]([N:23]([O:22][CH3:21])[CH3:27])=[O:25])=[CH:15][N:14]=3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(COc3ccc(N)cn3)c2O1
Reactant: CON(C)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)Nc1ccc(OCc2cccc3c2OC(C)(C)C3)nc1
Yield: 83.2 %

Procedure:
2.0 g of 2-(2,3-dihydro-2,2-dimethyl-7-benzofuranylmethyloxy)-5-aminopyridine was dissolved into 5 ml of pyridine, and 1.1 g of N-methoxy-N-methylcarbamoyl chloride was slowly added dropwise thereto under cooling with ice. After 2-hours' continuous stirring, pyridine was distilled off under a reduced pressure, and the residual oily matter was dissolved into 30 ml of toluene. After the mixture was subsequently washed with water, diluted hydrochloric acid and saturated sodium chloride aqueous solution, toluene was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/1) as a developer to obtain 2.2 g of 1-[2-(2,3-dihydro-2,2-dimethyl-7-benzofuranylmethyloxy)-5-pyridyl]-3-methoxy-3-methylurea.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH2:8][CH2:9][NH2:10])[N:7]=1)[CH3:2].O.[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=O>O1CCCC1>[CH2:1]([C:3]1[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[CH:14][CH:13]=2)[C:5]2[CH:33]([C:32]([O:36][CH2:37][CH3:38])=[O:35])[NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc(CCN)cn1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 2-ethyl-4-(2-aminoethyl)-1-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methylimidazole (5.30 g) in tetrahydrofuran (40 ml) is added ethyl glyoxylate hydrate (1.67 g). The reaction mixture is stirred overnight at room temperature and then refluxed for two hours. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.90 g) as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:5][CH:4]=1.Br.[OH-].[Na+]>C(O)(=O)C>[OH:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC2CCCN2C)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCCC1Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Boil 6.2 g of 2-(4-methoxybenzyl)-1-methylpyrrolidine under reflux for 24 hours in a mixture of 30 ml of acetic acid and 30 ml of 48% strength hydrobromic acid. Add a further 20 ml of acetic acid and 20 ml of hydrobromic acid to the refluxed mixture and continue boiling for a further 24 hours. Pour the mixture onto 400 ml of ice water before adjusting its pH to 10 with 6 N sodium hydroxide solution and then extracting it 4 times with, in each case, 50 ml of diethyl ether. Dry the combined ether extracts over sodium sulfate and distil off the solvent. Recrystallize the resulting residue from 25 ml of ethanol to obtain a yield (65% of theory) of the title compound (m.p. 161° to 162°).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=[C:16]3[S:20][C:19]([NH:21][CH:22]4[CH2:24][CH:23]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:18][C:17]3=[O:31])[N:13]=2)[N:8]=[CH:7][C:6]=1C#N)([CH3:3])[CH3:2].C(O[Na])(C)=O.C(OC1C=CN=C2C=1N=C(C=O)C=C2)(C)C>CC(O)=O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][N:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH:15]=[C:16]1[S:20][C:19]([NH:21][CH:22]3[CH2:24][CH:23]3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:18][C:17]1=[O:31])[CH:11]=[CH:10]2)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc12
Agent: CC(=O)O[Na]
Agent: CC(C)Oc1ccnc2ccc(C=O)nc12
Solvent: CC(=O)O
Product: CC(C)Oc1ccnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc12
Temperature: 100 °C
Yield: 73.7 %

Procedure:
To a mixture of 2-(trans)-phenylcyclopylamino-thiazol-4-one (76.0 mg, 0.32 mmol) (see Example 3) AcONa (160 mg, 1.95 mmol), and 8-isopropoxy-[1,5]naphthyridine-2-carbaldehyde (77.8 mg, 0.36 mmol) (prepared as described below) in a sealed tube was added AcOH (0.4 mL). The reaction mixture was heated to 100° C. (oil bath) for 4 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, acetone and ether to give 5-(8-isopropoxy-[1,5]naphthyridin-2-ylmethylene)-2-(2-phenyl-cyclopropylamino)-thiazol-4-one as a yellowish solid (101.5 mg, 73.7%). HR-ES (+) m/e calcd for C24H22N4O2S (M+H)+ 431.1536. found 431.1537.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([NH:6][C:7](OC1C=CC([N+]([O-])=O)=CC=1)=[O:8])[CH3:5].Cl.[C:22]1([C@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([NH:6][C:7]([N:30]1[CH2:31][CH2:32][C@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29]1)=[O:8])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc([C@H]2CCNC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)N1CC[C@H](c2ccccc2)C1

Procedure:
Combine 2-methyl-2-(4-nitro-phenoxycarbonylamino)-propionic acid methyl ester (500 mg, 1.77 mmol) and (R)-3-phenyl-pyrrolidine hydrochloride (325 mg, 1.77 mmol) in 1,4-dioxane (5 mL). Add TEA (494 uL, 3.54 mmol) and heat to 130° C. for 5 min by microwave irradiation. Dilute the reaction mixture with DCM (100 mL) and extract with 1 N NaOH (30 mL) followed by 1 N HCl (30 mL). Dry the organic layer over MgSO4 and concentrate. Purify the concentrate by silica gel chromatography (40-60% EtOAc/HEP) to afford the title compound: 1H NMR (400 MHz, DICHLOROMETHANE-d2) 1.51 (d, J=1.77 Hz, 6H) 1.98-2.14 (m, 1H) 2.22-2.38 (m, 1H) 3.31 (t, J=9.28 Hz, 1H) 3.35-3.48 (m, 2H) 3.53-3.65 (m, 1H) 3.70 (s, 3H) 3.80 (dd, J=9.41, 7.52 Hz, 1H) 7.15-7.40 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:35][C:32]1[S:33][CH:34]=[C:30]([CH2:29][O:1][C:2]2[CH:26]=[CH:25][C:5]([CH2:6][N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8]3)=[CH:4][CH:3]=2)[N:31]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(C)n3)cc2)cc1-c1ccccc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 81.1 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (349 mg), 4-chloromethyl-2-methylthiazole hydrochloride (276 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (5 ml) was stirred at 90° C. for 6 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[4-(2-methyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (373 mg, yield: 81%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30]([O:32][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(OC(C)(C)C)[NH2:44]>B(F)(F)F.CCOCC.C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30]2[O:32][CH:33]=[C:34]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[N:44]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2CC(=O)OCC(=O)c2ccc(F)cc2)c(-c2ccc(F)cc2)s1
Reactant: CC(C)(C)OC(N)=O
Agent: FB(F)F
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2Cc2nc(-c3ccc(F)cc3)co2)c(-c2ccc(F)cc2)s1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
(RS)-4-{1-[5(4-Fluorophenyl)-2-methylthiazol4-yl]-methanoyl}-3-[2-(4-fluoro-phenyl)-2-oxo-ethoxycarbonylmethyl]-piperazine-1-carboxylic acid tert-butyl ester, description 111 (0.385 g), tert-butyl carbamate (0.376 g) and boron trifluoride etherate (4 drops) were dissolved in xylene (5 ml) and heated to 140° C., under argon and with stirring for 48 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was dried (MgSO4), evaporated and the residue chromatographed over silica gel. Elution with a gradient of 25 to 100% ethyl acetate in hexane provided the title compound as a pale yellow oil (0.130 g), mass spectrum (API+) 581 [MH+], C30H30F2N4O4S requires 580.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:10].C(Cl)(Cl)Cl.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Cu+2].N1C=CC=CC=1>[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([O:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: Oc1cccc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCc1ccc(Oc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 102.2 %

Procedure:
A suspension of 3-bromophenol (2.3 g, 13.3 mmol), 4-ethylphenyl boronic acid (1.0 g, 6.67 mmol), molecular sieve 4 A (14.7 g), Cu(OAc)2 (1.21 g, 6.67 mmol) and chloroform (25 mL) was stirred at room temperature for three minutes and added with triethylamine (3.6 mL) and pyridine (2.7 mL). The insolubles were filtered off with celite after the mixture was stirred for 15 hours. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain 1.89 g of a colorless oily title compound.