Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.[OH-].[Na+]>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:8]2[C:9]3[CH:10]=[C:2]([F:1])[CH:3]=[C:4]([NH2:11])[C:5]=3[CH:6]=[CH:7]2)=[CH:15][CH:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1cc(F)cc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(F)cc2c1ccn2Cc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 6-fluoro-1H-indol-4-amine (5 g, 0.033 mol), 4-chlorobenzyl chloride (5.55 g, 0.035 mol) and sodium hydroxide (1.32 g, 0.033 mol) was heated at 60° C. for 3 h. The solvent was evaporated and the residue was dissolved in EA (150 mL) and water (70 mL). The aqueous layer was extracted with EA and washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE:EA=8:1) to afford the title compound. LC/MS m/z=275.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([CH2:15][CH:16]1[CH2:19][CH:18]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])[CH2:17]1)=O>CC(O)=O>[CH3:25][O:24][N:22]([CH3:23])[C:20]([CH:18]1[CH2:19][CH:16]([CH2:15][C:13]2[NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N:12]=2)[CH2:17]1)=[O:21]
Reactant: CON(C)C(=O)C1CC(CC(=O)Nc2cc(C(F)(F)F)ccc2N)C1
Solvent: CC(=O)O
Product: CON(C)C(=O)C1CC(Cc2nc3cc(C(F)(F)F)ccc3[nH]2)C1
Temperature: 125 °C
Reaction time: 2.5 h
Yield: 96 %

Procedure:
A solution of the 3-({[2-amino-5-(trifluoromethyl)phenyl]carbamoyl}methyl)-N-methoxy-N-methylcyclobutane-1-carboxamide (0.82 g, 2.29 mmol) in AcOH (10 ml) was heated to reflux (˜125° C.) whilst stirring for 2.5 h. The reaction was monitored by LC MS. The reaction mixture was allowed to cool to RT and then evaporated in vacuo. The residue was dissolved in DCM (30 ml) and washed with sat. NaHCO3 (50 ml), dried over Na2SO4, filtered and evaporated. The crude was purified by silica gel column chromatography, eluting with MeOH:DCM (2:98-5:95) to give a yellow-brown oil (0.75 g, 94%); MS (ESI+) for C16H18F3N3O2 m/z 342.10[M+H]+; HPLC purity 97% (ret. time, 1.40 min); 1H NMR (500 MHz, MeOD) δH ppm 1.96-2.17 (2 H, m), 2.27-2.55 (2 H, m), 2.66-2.92 (1 H, m), 2.97-3.15 (2 H, m), 3.15-3.22 (3 H, m), 3.32-3.62 (1 H, m), 3.63-3.73 (3 H, m), 7.37-7.53 (1 H, m), 7.53-8.00 (2 H, m).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]4[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[O:26][N:25]=4)[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:27]1[O:26][N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][N:10]4[CH2:11][CH:8]([C:6]([OH:7])=[O:5])[CH2:9]4)=[CH:14][CH:15]=3)[N:23]=2)[C:28]=1[C:29]([F:31])([F:30])[F:32]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl-1-(4-(5-(5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (previous reaction) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was treated with triethylamine and re-concentrated. The product mixture was purified by flash silica gel chromatography using a mixture of methanol, dichloromethane, and ammonium hydroxide (10:90:0-10:90:1-15:85:1-20:80:1) to give 1-(4-(5-(5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (0.007 g, 0.015 mmol) as an off-white solid. The product had an HPLC retention time=2.33 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=472.0. 1H NMR (500 MHz, methanol-d3) δ ppm 3.50 (quin, J=8.25 Hz, 1H), 4.21-4.29 (m, 4H), 4.46 (s, 2H), 7.66-7.71 (m, 3H), 8.02-8.05 (m, 1H), 8.08-8.13 (m, 1H), 8.28 (d, J=8.25 Hz, 2H), and 8.83-8.85 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[CH2:4][CH2:3]1.CC1(C)C2C(=CC(/C=C/C3C=CC(C([O-])=O)=CC=3)=CC=2)N(C2C=CC(C)=CC=2)CC1.[Li+].[OH-]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:32])[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)N(c2ccc(C)cc2)CCC3(C)C)cc1
Agent: Cc1ccc(N2CCC(C)(C)c3ccc(/C=C/c4ccc(C(=O)[O-])cc4)cc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCC(C)(C)c3ccc(/C=C/c4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.033 g (0.08 mmol) of ethyl (E)-4-(2-(4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl)quinolin-7-yl)ethenyl)benzoate (Compound 13) in 4.0 mL of tetrahydrofuran and 1.0 mL of methanol was added 1.0 mL (0.6 mmol) of 0.6M aqueous LiOH. The resulting solution was stirred at room temperature for 48 hours. The mixture was concentrated in vacuo, water was added, and the mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo, followed by recrystallization in acetonitrile to give the title compound as a solid. PNMR (300 MHz, DMSO) d 1.30 (6 H, s), 1.77 (2 H, t, J=6.0 Hz), 2.30 (3 H, s), 3.54 (2 H, t, J=6.0 Hz), 6.69 (1 H, s), 6.95-7.28 (8 H, m), 7.46 (2 H, d, J=8.4 Hz), 7.96 (2 H, d, J=8.4 Hz).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)c(F)cc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C)c(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a11) and commercially available (2-chloromethoxy-ethyl)trimethyl-silane the title compound is obtained as yellow solid.
Reaction SMILES: CCOCC.[F:6][C:7]([F:23])([F:22])[CH:8]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:9][C:10](OCC)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:23][C:7]([F:6])([F:22])[CH:8]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:9][CH2:10][OH:11]
Reactant: CCOC(=O)CC(OC1CCCCO1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OCCC(OC1CCCCO1)C(F)(F)F
Yield: 110.6 %

Procedure:
Fifty milliliters of an ether solution of 30.1 g of ethyl 4,4,4-trifluoro-3-tetrahydropyranyloxybutyrate (1) were added dropwise to an ether suspension of 4.2 g of lithium aluminum hydride over a period of 1.5 hours. The mixture was further refluxed for 30 minutes, and a mixed solution of 8 g of water and 50 ml of tetrahydrofuran was added dropwise under ice cooling. The solid was separated by filtration and extracted with ether. After drying, the ether was evaporated to obtain 28.1 g of 4,4,4-trifluoro-3-tetrahydropyranyloxybutyl alcohol (2) in a purity of 65%. Since the compound (2) was relatively unstable to heat and acid, said compound was only dried in pyridine with a molecular sieve 4A and used in the subsequent step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:35]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36]1>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:39]([CH:35]3[CH2:38][CH2:37][CH2:36]3)(=[O:41])=[O:40])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Reactant: O=S(=O)(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)C3CCC3)cc2C1Cc1ccccc1
Reaction time: 8 h
Yield: 92.2 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. Cyclobutanesulfonyl chloride (0.253 g, 1.637 mmol) was added. The solid immediately dissolved. The mixture was stirred overnight, then it was diluted with DCM and washed with brine (1×50 mL). The organic phase was collected, dried on MgSO4 and the volatiles were evaporated under reduced pressure, yielding the product as a pale yellow solid (731.7 mg, 1.51 mmol, 92%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3]>>[OH:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[NH:5][C:3](=[O:4])[CH2:2]2
Reactant: COc1ccc(NC(=O)CCl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Cc2cc(O)ccc2N1
Temperature: 240 °C

Procedure:
2-chloro-N-(4-methoxyphenyl)-acetamide (10 g) and Anhydrous aluminum trichloride (17 g) was heated to 120° C. for 15 minutes and then heated to 240° C. for 1 hour. The reaction was cooled to room temperature and quenched with ice water and Concentrate hydrochloride acid, and extracted with ethyl acetate (5×). Organic layers combined and dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was flash chromatography (silica, ethyl acetate) to give product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])C=O)([CH3:4])([CH3:3])[CH3:2].[O:18]=[C:19]1[NH:23][N:22]=[C:21]([CH2:24][C:25](O)=O)[NH:20]1.N1CCCCC1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:2][C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[CH:24][C:21]2[NH:20][C:19](=[O:18])[NH:23][N:22]=2)[CH:10]=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:12]=1[OH:13])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C(O)Cc1n[nH]c(=O)[nH]1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=Cc2n[nH]c(=O)[nH]2)cc(C(C)(C)C)c1O
Yield: 40 %

Procedure:
A solution of 3,5-di-t-butyl-4-hydroxybenzaldehyde (3.5 g, 15 mmol), 2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) acetic acid (N. W. Jacobsen, B. L. McCarthy, and S. Smith, Aust. J. Chem., 32 161-5 (1979](2.15 g, 15 mmol), and piperidine (1.3 g, 15 mmol) in pyridine (15 ml) and toluene (45 ml) is heated at reflux (with removal of water) for 40 hours. The reaction mixture is cooled, filtered, and evaporated. The residue is partitioned between ethyl acetate (100 ml) and 1N HCl (400 ml). The organic layer is washed two additional times with 1N HCl (400 ml) and then is dried (MgSO4) and evaporated. The residue crystallized upon addition of hot dichloromethane. Recrystallization from isopropyl ether/ethyl acetate gives 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (2.49 g, 40%), mp 280°-284° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].C=O.[Ca:8].[C:9]([O-:12])(=[O:11])[CH3:10].[CH:13]([O-:15])=[O:14].[C:16]([O-:20])(=[O:19])[CH2:17][CH3:18]>C(O)=O.C(O)(=O)C>[C:1]([O-:5])(=[O:4])[CH3:2].[Ca+2:8].[C:9]([O-:12])(=[O:11])[CH3:10].[CH:13]([O-:15])=[O:14].[Ca+2:8].[CH:16]([O-:20])=[O:19].[C:16]([O-:20])(=[O:19])[CH2:17][CH3:18].[Ca+2:8].[C:1]([O-:5])(=[O:4])[CH2:2][CH3:3]
Reactant: [Ca]
Reactant: CCC(=O)O
Agent: C=O
Agent: CC(=O)[O-]
Agent: CCC(=O)[O-]
Solvent: O=CO
Solvent: CC(=O)O
Product: [Ca+2]

Procedure:
Calcium salts, such as calcium acetate, calcium formate or calcium proprionate, are obtained from aqueous liquors derived from the pyrolysis of lignocellulosic biomass containing cellulose, hemicelluloses or starch. The above biomass is subjected to rapid pyrolysis to obtain a crude product containing an aqueous phase and an organic phase. The product obtained, preferably as the aqueous phase, is then distilled to produce a distillate containing at least one acid selected from acetic acid, formic acid and propionic acid as well as their esters and formaldehyde. An alkaline source of calcium is added to this distillate to adjust the pH to an alkaline level sufficient to hydrolyze the esters, cause at least partial oxidation of the formaldehyde and prevent volatilization of acetate, formate or propionate ions as acetic acid, formic acid or propionic acid respectively. This pH adjusted alkaline liquid is then subjected to a further distillation to remove water and volatile organic components and produce at least one of calcium acetate, calcium formate and calcium propionate as solid residue.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:1]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[NH:8][C:7]=12
Reactant: Cc1ccnc(N)c1N
Reactant: CCCCCC(=O)O
Product: CCCCCc1nc2nccc(C)c2[nH]1

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and hexanoic acid (0.25 ml, 2 mmols) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (9:1) to give the pure product (0.28 g, 69%) as a tan colored solid. 1H NMR (300 MHz, CDCl3): 8.17 (d, 1H, J=5 Hz), 7.05 (d, 1H, J=5 Hz), 3.03 (t, 2H, J=7.8 Hz), 2.70 (s, 3H), 1.32-2.1 (m, 6H), 0.92 (t, 3H, J=7.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=2I)=[O:19])[CH2:14][CH2:13]1.[CH3:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=2[N:34]2[CH:33]=[C:32]([CH3:31])[CH:36]=[N:35]2)=[O:19])[CH2:14][CH2:13]1
Reactant: Cc1cn[nH]c1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3F)CC2)c1
Product: Cc1cnn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3F)CC2)c1
Yield: 30 %

Procedure:
The title compound was prepared according to the procedure described for example 294 from [4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-iodo-5-methanesulfonyl-phenyl)-methanone (compound CN) and 4-Methyl-1H-pyrazole (30% yield, light brown solid, MS (m/e): 511.2 (M+H, 100%)
Reaction SMILES: C([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([F:30])[CH:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5][CH:4]=1)C.[CH2:31](C1OC(CCN)=NC=1)[CH3:32].C(C1N=C(CCN)OC=1)C.Cl.C(C1OC(CCN)=NC=1)C.NCC(O)CC.NC(CC)CO>>[CH2:31]([C:4]1[N:5]=[C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([F:30])[CH:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])[O:7][CH:3]=1)[CH3:32]
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)o1
Reactant: CCc1cnc(CCN)o1
Agent: CCC(N)CO
Agent: CCC(O)CN
Agent: CCc1coc(CCN)n1
Product: CCc1coc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)n1

Procedure:
The title compound is prepared by the same procedure as 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 178) by replacing 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) with the hydrochloride salt of 2-(4-ethyl-oxazol-2-yl)-ethylamine. This is prepared by the same procedure as 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) by replacing 1-amino-2-butanol (step 1) with 2-amino-1-butanol.
Reaction SMILES: [Na].COS([O-])(=O)=O.[CH:8]([N+:11]1[CH2:15][CH2:14][CH2:13][C:12]=1N(C)C)([CH3:10])[CH3:9].[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21]>C(O)C>[CH:8]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[CH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21])([CH3:10])[CH3:9]
Reactant: CC(C)[N+]1=C(N(C)C)CCC1
Reactant: COc1cccc(C(C)=O)c1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: COc1cccc(C(=O)C=C2CCCN2C(C)C)c1
Reaction time: 4 h

Procedure:
A solution of 7.6 g of sodium in 100 ml of ethanol is added dropwise(*) at 90° within 2 hours to a mixture of 88 g of 1-isopropyl-2-dimethylamino-1-pyrrolinium methyl sulfate and 42 g of 3-methoxyacetophenone. Stirring is continued for a further 4 hours at this temperature; the solvent is distilled off in a vacuum; and the residue is distributed in 250 ml of dichloromethane and 250 ml of water. The organic phase is collected, dried over sodium sulfate and concentrated. The oil remaining behind is freed from excess 3-methoxyacetophenone by heating under a high vacuum. Yield: 42.8 g (59% of theory) of the title compound as brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1.[H-].[Na+]>CN(C)C=O>[C:13]([C:8]1[CH:9]=[C:10]([CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:7])[O:12][C:18]1[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1[N+](=O)[O-]
Yield: 6.4 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2,6-di-t-butylhydroquinone (4.44 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (8.60 g), sodium hydride (55 wt. %, 2.18 g) and anhydrous N,N-dimethylformamide (50 ml) and the reaction mixture was purified to give the title compound (0.60 g).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.O1CCCC1.Cl>O.CO>[CH3:3][C:4]1[S:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][OH:22])=[CH:23][CH:24]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
Sodium borohydride (0.38 g) was added to a mixture of 4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzaldehyde (6.00 g), tetrahydrofuran (30 ml) and methanol (20 ml) under ice-cooling, which was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with dilute hydrochloric acid and water to give a precipitate, which was collected by filtration and air-dried to obtain crystals of 4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl alcohol (5.68 g, yield 94%). This was recrystallized from ethyl acetate-hexane to obtain colorless prisms. Melting point: 94–95° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:23][C:24]#[CH:25])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=O)(C)(C)C.[Cl-]>C(O)C.C(OCC)C>[NH2:8][C:9]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:23][C:24]#[CH:25])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)OC(C)(C)C)cccn12
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCO
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3N)cccn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a solution of 8-(2-t-butoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (1.04 g) in ethanol (15.5 ml) was added dropwise 25% ethanolichydrogen chloride (8.4 ml) with ice-cooling. After being stirred for 3 hours at ambient temperature, the mixture was diluted with diethyl ether. The resulting precipitates were collected by filtration, treated with a saturated aqueous solution of sodium hydrogen carbonate and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with diethyl ether to give 8-(2-amino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.58 g).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:4]2[C:3]3[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=3[S:1][CH:5]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)#[N:20]
Reactant: O=C(O)c1csc2c1CCCC2
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Product: N#Cc1cc(NC(=O)c2csc3c2CCCC3)ccc1N1CCC(O)CC1
Yield: 52.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (1.2 g) and 5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (1.3 g), the title compound (1.2 g) was obtained. melting point: 172-173° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:9][C:12]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]=2[Cl:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-amino-5-chlorophenol (11.0 g), 2-chloro-1-fluoro-4-nitrobenzene (1.5 g) and potassium carbonate (2.8 g) in dry DMF (20 ml) was stirred room temperature for 1 h then heated at 60° C. for 2 h. The mixture was partitioned between water/ethyl acetate, the organics separated, washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% ethylacetate/isohexane, yield 1.96 g.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14](=[O:17])([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:1]([N:8]2[CH2:13][CH2:14][O:17][CH2:10][CH2:9]2)=[O:2])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 195 %

Procedure:
Amine preparation: a mixture of 4-morpholinocarbonyl chloride (0.38 ml), 1-BOC-piperazine (552 mg) and potassium carbonate (439 mg) in MeCN (7 mL) was stirred at room temperature for 3 h. The reaction mixture was then diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(morpholine-4-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (865 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.