Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.[CH3:8][CH:9]([CH3:13])[C@H:10]([NH2:12])[CH3:11]>CO.[Pd].O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:12][C@@H:10]([CH:9]([CH3:13])[CH3:8])[CH3:11]
Reactant: CC(C)[C@@H](C)N
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(CN[C@H](C)C(C)C)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethoxyacetaldehyde (60% in water, 8.7 mL) was added to (R)-3-methylbutan-2-amine (5.0 g) in methanol (25 mL) and the mixture stirred at ambient temperature overnight. A slurry of palladium on carbon (5%, 1.2 g) in water (10 mL) was added and the mixture was hydrogenated at 5 bar pressure with stirring for 3 hours. The mixture was filtered through Celite and the filter pad washed with methanol (3×100 mL). The combined filtrate and washings were concentrated to a volume of ˜10 mL and then toluene (200 mL) was added. The mixture was concentrated, more toluene (200 mL) was added and the mixture was concentrated once more to give the titled compound as a yellow oil. Yield 8.0 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][NH:7]1.Br[CH2:27][C:28](Br)=[O:29].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][N:7]1[CH2:27][C:28]([NH:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: COc1ccc(OC)c(CC2NCCc3c(OC)ccc(OC)c32)c1
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1
Product: COc1ccc(OC)c(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NCc2ccccc2)c1

Procedure:
prepared by reaction of 1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Br:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[Br:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][CH:5]=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1Br
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccccc1Br
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To acetic anhydride (74.2 g, 727 mmol) was added formic acid (32.9 mL, 872 mmol) under a nitrogen atmosphere while stirring at room temperature, followed by stirring at 70° C. for 3 hours. The reaction mixture was allowed to cool down to room temperature, and tetrahydrofuran (50 mL) was added. To the solution was added a solution of 2-bromoaniline (50.0 g, 291 mmol) in tetrahydrofuran (50 mL) at room temperature, followed by stirring at the same temperature for 1 hour, and concentration was carried out. To the resultant crude crystals was added ethanol (200 mL), followed by heating and stirring at 60° C. After the crystals dissolved, the mixture was allowed to cool down to room temperature, then water (400 mL) was added, followed by stirring for 3 hours. The precipitated crystals were collected by filtration to give 48.8 g of the title compound as white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C1(C)C=CC=CC=1.O>[CH2:19]([S:21]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:23])=[O:22])[CH3:20]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccccc1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)Oc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
8.00 g (53.3 mol) of 2-tert-butylphenol and 5.93 g (58.6 mol) of triethylamine were dissolved in 80 mL of toluene followed by dropping in 7.53 g (58.6 mol) of ethanesulfonyl chloride over the course of 10 minutes at 10° C. followed by stirring for 10 minutes at 25° C. and confirming the 2-tert-butylphenol to no longer be present by gas chromatography. The reaction liquid was placed in water and following separation of the organic layer, was washed three times with water, once with saturated aqueous NaHCO3 solution and once with saturated brine followed by drying with MgSO4, concentrating and purifying the resulting residue by vacuum distillation to obtain 11.93 g (yield: 92%) of 2-tert-butylphenyl ethanesulfonate.
Reaction SMILES: Br[CH:2]([CH:18](Br)[CH2:19][CH3:20])[CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.O>C(O)(=O)C.[Zn]>[CH:3](/[C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)=[CH:2]\[CH2:18][CH2:19][CH3:20].[CH:3](/[C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)=[CH:2]/[CH2:18][CH2:19][CH3:20]
Reactant: CCC(Br)C(Br)C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Product: CCC/C=C\[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.98 g of p-[trans-4-(2,3-dibromopentyl)cyclohexyl]benzonitrile (erythro/threo 66.6:32.8) in 30 ml of glacial acetic acid was treated at room temperature with 2.0 g of zinc powder while gassing with argon and the suspension was stirred at room temperature for 1 hour. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of petroleum ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the yellowish residue (1.16 g) on silver nitrate-coated silica gel with hexane/diethyl ether (vol. 90:10) gave 586 mg (48%) of p-[trans-4-(2E-pentenyl)cyclohexyl]benzonitrile and 171 mg (14%) of p-[trans-4-(2Z-pentenyl)cyclohexyl]benzonitrile as colourless oils. The 2E-isomer has a melting point of 9.6° C. and 16.1° C. (2 modifications) and a virtual clearing point of -67° C.; the 2Z-isomer has a melting point of -7.7° C. and a virtual clearing point of -54° C.
Reaction SMILES: CCO[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].Cl.[Cl:14][CH2:15][C:16]([NH2:18])=[NH:17].C(N(CC)CC)C>CO>[Cl:14][CH2:15][C:16]1[NH:18][C:4](=[O:5])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:17]=1
Reactant: N=C(N)CCl
Reactant: CCOC(=O)C1CCCCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1[nH]c(CCl)nc2c1CCCC2
Temperature: 25 °C
Reaction time: 60 h
Yield: 12.9 %

Procedure:
To a solution of ethyl 2-cyclohexanone-carboxylate (5.5 g, 32 mmol) in methanol was added chloroacetamidine hydrochloride (4.2 g, 32 mmol) and triethylamine (14 mL, 97 mmol). The mixture was stirred at ambient temperature for 60 h. It was then concentrated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide product (0.82 g, 13% yield). 1H NMR (400 MHz, CD3OD) δ 4.40 (s, 2H), 2.61 (t, J=6.3 Hz, 2H), 2.45 (t, J=6.3 Hz, 2H), 1.68-1.87 (m, 4H). MS m/z 199.2 (M+1), retention time=0.94 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19]([Cl:28])=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][Si:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][O:39][CH2:40]Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:43])([CH3:42])[CH3:35])[C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19]([Cl:28])=[N:18][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)[nH]c2c1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
A mixture of 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.298 g, 0.00075 mol) and potassium carbonate (0.311 g, 0.0023 mol), were taken in DMF (2 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (0.4 ml, 0.0023 mol) was added drop wise at 0° C. and the mixture was stirred at 20° C. for 4 hours. The mixture was cooled to 10° C. and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate (2×10 ml). The organic layer was washed with saturated brine solution (2×15 ml) and dried over Na2SO4. Solvent was removed and the residue was further purified by column chromatography to obtain pure 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.278 g, 70%) as off white solid.
Reaction SMILES: [NH2:1]CC1C=CC(CCC(O)=O)=CC=1.[CH3:14][C:15]([CH3:32])([CH3:31])[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]C(N)=O)=[CH:22][CH:21]=1)=[O:17].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>>[CH3:14][C:15]([CH3:32])([CH3:31])[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:1])=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)(C)C(=O)NCc1ccc(CCC(N)=O)cc1
Reactant: NCc1ccc(CCC(=O)O)cc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(CCN)cc1

Procedure:
4-Cyanocinnamic is catalytically hydrogenated to form 4-(aminomethyl)-benzenepropanoic acid, the amino function is then protected by a tert.butoxycarbonyl group and the carboxylic acid function is converted into the primary carboxamide; the resulting 4-[[(2,2-dimethyl-1-oxopropyl)amino]methyl]benzenepropanamide when reacted with I,I-bis-(trifluoroacetoxy)iodobenzene, yields 4-[[(2,2-dimethyl-1-oxopropyl)amino]methyl]benzeneethanamine (see also: A. S. Radhakrishna, M. E. Parham, R. M. Riggs and G. M. Loudon, J. Org. Chem. 44: 1746-1747 (1979) and K. Seraminathan and N. Venkatasubramanian, J. Chem. Soc. Perkim Trans. II 1975, 1161), which may be converted into the corresponding urea in the usual way, e.g. by treating the hydrochloride with sodium cyanate; cleaving the tert.butoxycarbonyl group with suitable acids, e.g. trifluoroacetic acid, finally yields the desired 4-[2-(aminocarbonylamino)ethyl]phenylmethanamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.3 %

Procedure:
2-Benzyloxyaniline (S1) (16.4 g), 4-dimethylamino-pyridine (11.0 g), and N-tertiarybutoxycarbonylglycine (14.4 g) were dissolved in dichloromethane. To the resulting solution, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16.3 g) was added and stirred for 12 hours at room temperature. The reaction mixture was washed -successively with 1N HCl, saturated aqueous sodium hydrogencarbonate solution and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, obtaining 11.5 g of the compound S2 as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]([O:21][C:22](=[O:26])[CH2:23][CH2:24][NH2:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:26])[CH2:23][CH2:24][NH:25][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: NCCC(=O)OCc1ccccc1
Product: O=C(Cc1cccc([N+](=O)[O-])c1)NCCC(=O)OCc1ccccc1

Procedure:
coupling m-nitrophenylacetic acid and β-alanine benzyl ester to give N-[(m-nitrophenyl)acetyl]-β-alanine benzyl ester, MS: 236 (6, M--C6H5 --CH2O),
Reaction SMILES: [CH3:1][C:2]1[C:3](I)=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[N+:13]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18])([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.[Cu]>[N+:13]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:3]1[C:2]([CH3:1])=[C:10]([CH3:11])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])([O-:15])=[O:14]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(C(=O)O)c(I)c1C
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)O)c(Nc2ccccc2[N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
10 g of 3,4-dimethyl-2-iodobenzoic acid, 6 g of 2-nitroaniline, 250 mg of powdery copper and 25 g of potassium carbonate were added to N,N-dimethylformamide and heated under reflux while stirring for 2 hr. Then the reaction mixture was cooled to room temperature and diluted with water. After adjusting the pH value thereof to pH 4 with conc. hydrochloric acid, it was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 2.5 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O.[F:25][C:26]1[CH:27]=[C:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:29]=[CH:30][C:31]=1[OH:32]>C(OCC)(=O)C>[F:25][C:26]1[CH:27]=[C:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:29]=[CH:30][C:31]=1[O:32][C:2]1[CH:7]=[N:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Reactant: CS(=O)(=O)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(S(C)(=O)=O)nc2)c(F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4.00 g of 5-chloro-2-methanesulfonyl-pyridine and 8.80 g of cesium carbonate were added to an N-methylpyrrolidinone (50 ml) solution of 4.74 g of tert-butyl (3-fluoro-4-hydroxy-phenyl)-carbamate obtained in (step 1), and the reaction liquid was stirred at 100° C. for 2 hours. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.Cl[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32])=O.O.CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2>C1(C)C=CC=CC=1.CCOC(C)=O>[N+:31]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=1[C:19]1[S:17][C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[C:5]([C:8]1([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]1)[N:4]=2)[C:25]([O:27][CH3:28])=[O:26])([O-:33])=[O:32]
Reactant: COC(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A slurry of 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (1.00 g, 4.13 mmol) and methyl 4-(chlorocarbonyl)-3-nitrobenzoate (1.11 g, 4.54 mmol) in 10 mL toluene was heated under nitrogen with a water cooled reflux condenser was heated in a 120° C. oil bath. After bubbling had subsided, ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (0.479 g, 2.06 mmol) was added through the condenser and heating continued for 30 min. The slurry was treated with 5 mL toluene to and heating continued overnight to give a dark brown solution. The reaction mixture was cooled to ambient temperature, then diluted with EtOAc, washed with water, sat'd aq. Bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. Purification by silica gel chromatography, 40 g, 0-30% EA/hexanes gave methyl 3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoate as a light brown solid. MS (ESI) m/z: Calculated: 431.1; Observed: 432.0 (M++1).
Reaction SMILES: CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:35][CH:34]([OH:36])[CH2:33]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.I[C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1>>[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH:34]([O:36][C:38]4[CH:39]=[CH:40][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:42][CH:43]=4)[CH2:35]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc(OC(F)(F)F)cc2)C1

Procedure:
In a similar fashion (Route 21, GP J) except for replacing phenanthroline with 3,4,7,8-tetramethylphenanthroline, 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (50 mg, 0.19 mmol) and 1-iodo-4-(trifluoromethoxy)benzene (86 mg, 0.3 mmol) gave the title compound as colourless oil after purification by preparative HPLC (44 mg, 52%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tetrahydrofuran. N,N-dimethylamine (7.7 mL, 15.5 mmol, 2M in tetrahydrofuran) and and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) were added, and the reaction was allowed to stir at ambient temperature for 2 hours. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil which deposited needles that were a mixture of the title compound and 4-chloromethyl N,N-dimethylbenzenesulfonamide. The resulting needles were collected. and dried (2.3 g, 44%). ES-MS m/z 534 (M+H) and 578 (M+H)
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].Br[CH:14]1[CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCC1
Reactant: O=C(O)c1cccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1SC1CCC1
Reaction time: 0.5 h

Procedure:
2-Mercapto-nicotinic acid (0.1 g, 0.64 mmol) was dissolved in DMF (2 mL), and the solution was cooled to 0˜5° C. NaH (0.13 g, 3.2 mmol) was added slowly thereto, and the mixture was stirred at 0˜5° C. for 30 minutes. Bromo-cyclobutane (0.12 mL, 1.28 mmol) was added thereto, and the mixture was stirred at 55˜65° C. for 3 hours, and then stirred at room temperature for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure. The residue was diluted with water, and then 3N HCl was used to adjust the pH of the solution to 2˜3. The solution was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:14]([CH3:15])=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=[C:11]([Br:19])[C:10]=1F)([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:14]([CH3:15])=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=[C:11]([Br:19])[C:10]=1[N:22]1[CH:26]=[CH:25][CH:24]=[N:23]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(F)c1CNC(=O)OC(C)(C)C
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c([N+](=O)[O-])cc(Br)c(-n2cccn2)c1CNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of the compound (233 mg) obtained in Example 7c, pyrazole (53 mg), sodium carbonate (82 mg) and dimethylformamide (6 ml) was stirred at 100° C. for 2 hours. Water was added to the reaction mixture and extraction with ethyl acetate was conducted. The organic layer was washed with brine, dried with anhydrous magnesium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:3) to give the titled compound (yield, 62%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7].[I-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.[Na]>C(#N)C>[ClH:1].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[C:15]4[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8][C:6]3=[O:7])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COc1cccc2c1CCC(=O)N2CCCCl
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Product: COc1cccc2c1CCC(=O)N2CCCN1CCN(c2cccc(Cl)c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.2 %

Procedure:
A solution composed of 1-(3-chloropropyl)-5-methoxy-3,4-dihydrocarbostyril (39.1 g, 0.15 mole), sodium iodide (33.5 g, 0.23 mole) and acetonitrile (200 ml) was heated under reflux for 1 hour and then cooled to room temperature. To this solution was further added 1-(3-chlorophenyl)piperazine (39.3 g, 0.2 mole) and sodium corbonate (21 g, 0,2 mole). The mixture was further stirred for 4 hours and then filtered while it was hot. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, made acidic with hydrochloric acid and then recrystallized from ethanol to give 31.2 g of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydrocarbostyril hydrochloride as colorless flakes.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][C@@H:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]1[OH:34].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:24][C@@H:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@@H:26]2[OH:34])=[O:19])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: N[C@@H]1Cc2ccccc2[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)N[C@@H]1Cc2ccccc2[C@@H]1O
Reaction time: 17 h
Yield: 73 %

Procedure:
A suspension of 2,2,2-trichloroethyl 5-tert-butyl-3-(hydroxymethyl)-2-methoxyphenylcarbamate (1.50 g, 3.90 mmol), (1S,2R)-2-amino-2,3-dihydro-1H-indene-1-ol.L-tartaric acid salt (1.28 g, 4.29 mmol) and N,N-diisopropylethylamine (2.37 mL, 13.6 mmol) in acetonitrile (19.5 mL) was heated to reflux. After 17 hours, the mixture was allowed to cool and the reaction solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/50-0/100) to obtain 1.09 g of the captioned compound (73% yield).