Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH3:23][N:24]([CH2:26]N(C)C)[CH3:25].C(Cl)(=O)C.C(=O)(O)[O-].[Na+].[Cl-].[Na+].[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>CN(C)C=O.C(O)C>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:23][N:24]([CH3:26])[CH3:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: CN(C)CN(C)C
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 0 °C
Yield: 79.9 %

Procedure:
A stirred solution of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (3.09 g., 0.01 mole) in dry dimethylformamide (50 ml.) was cooled in an ice bath, under nitrogen, and treated successively with N,N,N',N'-tetramethyldiaminomethane (1.229 g., 0.012 mole) and dropwise with acetyl chloride (0.923 ml., 0.013 mole). The cloudy mixture was kept in the ice bath for 1 hour and 55 minutes and poured into a mixture of ice and saturated sodium bicarbonate. The solution was saturated with sodium chloride and extracted five times with chloroform. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo using xylene and toluene to help remove residual dimethylformamide. A solution of the resulting oil in absolute ethanol was acidified to a pH 3.5-4with a solution of p-toluenesulfonic acid (1 equivalent) in absolute ethanol. The remaining salt was crystallized to give 8-chloro-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine p-toluenesulfonate in three crops: 3.69 g. of melting point 196°-197° C., 0.612 g. of melting point 197°-198° C. and 0.022 g. of melting point 198.5°-199° C. The total yield was 79.9%. Ethanol crystallization of this material usually results in a product which contains residual ethanol or water. To remove the solvent, the first two crops (4.3 g.) were combined, recrystallized once from 95%-100% ethanol, redissolved in 95% ethanol and added slowly to boiling toluene at such a rate that the temperature of the distilling azeotrope remained between 85°-95° C. The level of the boiling mixture was maintained constant by the addition of fresh toluene. After the addition the temperature of the distillate was allowed to rise to 108° C. The mixture was cooled and the finely divided 8-chloro-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine was collected by filtration to give 3.747 g. of melting point 199°-199.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([CH3:27])[C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([CH3:27])[C:19]([NH:32][CH2:30][CH3:31])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: CCN
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Product: CCNC(=CC(=O)OCC)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
In the same manner, ethyl 4-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-oxopentanoate and ethylamine are reacted together to give ethyl 4-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-ethylamino-2-pentenoate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19](S(C3C=CC([N+]([O-])=O)=CC=3[N+]([O-])=O)(=O)=O)[C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[CH:13]=2)=[CH:4][N:3]=1.C(N)CC>C(Cl)Cl.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[CH:13]=2)=[CH:4][N:3]=1
Reactant: CNC(=O)c1cc(-c2cccc(CN([C@H]3CCc4ccccc43)S(=O)(=O)c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])c2)cnc1N
Solvent: CCCN
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc(-c2cccc(CN[C@H]3CCc4ccccc43)c2)cnc1N

Procedure:
2-Amino-5-(3-{[[(2,4-dinitrophenyl)sulfonyl][(1S)-2,3-dihydro-1H-inden-1-yl]amino}methyl}phenyl]-N-methylpyridine-3-carboxamide was treated with excess n-propylamine (4 eq) in CH2Cl2 (150 mL). The mixture was diluted with additional ethyl acetate (200 mL). The mixture was subsequently washed with aqueous saturated sodium carbonate (3×30 mL) and brine (3×30 mL). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by preparative HPLC (acetonitrile/water) gave desired product (5.8 g). The compound was converted to the hydrochloride salt using 4 M solution HCl in dioxane: 1H NMR (400 MHz; DMSO-d6): 9.9 (br s, NH); 9.02 (s, 1H); 8.9 (s, 1H); 8.6 (s, 1H); 8.35 (br s, NH); 8.2 (s, 1H); 7.8 (d, 2H); 7.75 (m, 2H); 7.37 (m, 2H1); 7.29 (m, 1H); 4.85 (m, 1H); 4.25 (m, 2H); 3.4 (m, 1H); 2.9 (m, 1H); 2.80 (d, 3H); 2.43 (m, 1H); 2.4 (m, 1H); MS (EI) for C23H24N4O HCl: 374 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[CH:15][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.CC1C(N)=CON=1.[CH:32]1C=C[C:35]2[N:40]([OH:41])N=[N:38][C:36]=2[CH:37]=1.C(Cl)CCl>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[CH:15][C:11]=2[C:12]([NH:38][C:36]2[CH:35]=[N:40][O:41][C:37]=2[CH3:32])=[O:13])=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)O)c2)cn1
Reactant: On1nnc2ccccc21
Agent: Cc1nocc1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oncc1NC(=O)c1cc(-c2cnn(C)c2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-{[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1H-pyrazol-4-yl)benzoic acid (may be prepared as described in Description 121; 80 mg, 0.25 mmol), 3-methylisoxazol-4-amine (49.5 mg, 0.37 mmol), HOBT (56.3 mg, 0.37 mmol) and EDC (70.5 mg, 0.37 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 16 hours. Water (50 ml) was added. A white precipitate was filtered, washed with ethyl acetate, and dried in vacuo to yield the title compound as a white solid. 54 mg,
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].C([O-])=[O:28].[K+]>CO>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:28])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: O=C[O-]
Agent: [K+]
Solvent: CO
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Yield: 75.2 %

Procedure:
A mixture of 5.0 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 5.0 g of potassium formate is refluxed in 100 ml of methanol for 4 hours. The solvent is distilled off under reduced pressure and water is added to the residue. The mixture is extracted with 150 ml of ethyl acetate, and the ethyl acetate layer is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the resulting crystalline precipitate is recrystallized from diethyl ether-n-hexane (1:2) to give 3.2 g of the above-identified compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].Cl>CN(C=O)C>[CH3:32][O:31][C:29](=[O:30])[CH2:28][N:13]1[C:14](=[O:15])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:24])[C:9]2[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=2[C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]1=2
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 63 %

Procedure:
((S)-6-Oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-carbamic acid tert-butyl ester (284 mg, 0.88 mmol) were diluted in DMF (5 ml) and treated with sodium hydride (60 mg of 60% suspension in mineral oil, 1.5 mmol). After stirring for 30 minutes, methyl bromoacetate (0.14 ml, 1.5 mmol) were added and the solution stirred for another 6 h. The pH is adjusted to 1.5 with 2N hydrogen chloride and extracted with ethyl acetate (10 ml). After back-extraction of the aqueous phases with ethyl acetate, the combined organic phases were washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated to dryness. After chromatography (silica, eluent cyclohexane/ethyl acetate 88/12), the product was obtained as off-white viscous oil (63%); MS: m/e=397(M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([Cl:23])[CH:11]=1.O1C2C=CC=CC=2N=[C:25]1C1C=CC(CC#N)=C(Cl)C=1.BrCCCCCBr>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:21]#[N:22])[CH2:25][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([Cl:23])[CH:11]=1
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1Cl
Reactant: N#CC1(c2ccc(-c3nc4ccccc4o3)cc2Cl)CCCC1
Agent: BrCCCCCBr
Product: N#CC1(c2ccc(-c3nc4ccccc4o3)cc2Cl)CCCCC1

Procedure:
Utilizing the general procedure outlined for 1-[4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]cyclopentanecarbonitrile, [4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]acetonitrile (400 mg, 1.5 mmol) and 1,5-dibromopentane (250 μL, 1.8 mmol) reacted to afford the desired 1-[4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]cyclohexanecarbonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, 1H), 8.06 (d, 1H), 7.68–7.73 (m, 1H), 7.51–7.55 (m, 2H), 7.28–7.35 (m, 2H), 2.49 (d, 2H), 1.73–2.00 (m, 8H). MS (ESI) 337 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[S:4]/[C:3]/1=[N:20]\[CH3:21].C([Li])CCC.[Cl-].[NH4+].[C:29](=O)(O)[O-:30].[Na+]>C1COCC1.C(OCC)(=O)C.CN(C=O)C.CCCCCC>[CH:29]([C:6]1[N:2]([CH3:1])/[C:3](=[N:20]/[CH3:21])/[S:4][C:5]=1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]1)=[O:30]
Reactant: O=C([O-])O
Reactant: C/N=c1\sc(C2CCN(C(=O)OC(C)(C)C)CC2)cn1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/N=c1\sc(C2CCN(C(=O)OC(C)(C)C)CC2)c(C=O)n1C

Procedure:
To a solution of tert-butyl 4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate (5.0 g) obtained in Example 46a) in THF (75 mL) was added n-butyllithium (24 mL, a 1.6 M hexane solution) at −78° C. The reaction solution was mixed for 15 minutes, and then DMF (5 mL) was added thereto, and the mixture was further mixed for 30 minutes. To the reaction solution was added a saturated aqueous ammonium chloride solution, and then poured into a mixed solution of ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was collected by separation, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (3.45 g) as a yellow solid.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH:9]([CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)[C:10]([NH:12][C@H:13]([C:18]([NH:20][CH3:21])=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([CH2:8][CH:9]([CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26]1)[C:10]([NH:12][C@H:13]([C:18]([NH:20][CH3:21])=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])([OH:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)C(CC(=O)OC(C)(C)C)CC1CCC1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)C(CC(=O)O)CC1CCC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.3 %

Procedure:
A solution of 1.37 g of N2[2(RS)[tert-butoxycarbonylmethyl]-3-cyclobutylpropionyl]-N1,3-dimethyl-L-valinamide as a 1:1 mixture of diastereoisomers in 20 ml of trifluoroacetic acid was stirred at room temperature for 2.5 hours. The solvent was removed by evaporation to leave an oil which was partitioned between diethyl ether and 5% sodium hydrogen carbonate solution. The aqueous phase was acidified with hydrochloric acid and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulphate and then evaporated to give 1.2 g of N2-[2(RS)[carboxymethyl]-3-cyclobutylpropionyl]-N1,3-dimethyl-L-valinamide as a 1:1 mixture of diastereoisomers in the form of a white foam.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[O:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH2:26])[CH2:21][CH2:20]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([NH:26][CH2:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC1CCOCC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: C(#Cc1cnc(NCC2CCOCC2)nc1)c1ccccc1

Procedure:
The title compound, white solid, MS: m/e=294.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and (tetrahydro-2H-pyran-4-yl)methanamine.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][O:25]CC3C=CC=CC=3)[CH:16]=2)=[C:7]([NH:33][C:34]([NH:36][C:37]2[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][C:40]([NH:46]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:39][C:38]=2[CH:66]([CH3:68])[CH3:67])=[O:35])[C:6]1=[O:69])[CH2:2][CH2:3][CH3:4].Cl.N>CC(C)=O.CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:16]=2)=[C:7]([NH:33][C:34]([NH:36][C:37]2[C:38]([CH:66]([CH3:68])[CH3:67])=[CH:39][C:40]([NH2:46])=[CH:41][C:42]=2[CH:43]([CH3:45])[CH3:44])=[O:35])[C:6]1=[O:69])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2C(C)C)c(-c2cccc(OCCCOCc3ccccc3)c2)c2cccnc21
Agent: Cl
Agent: N
Solvent: CO
Solvent: CC(C)=O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(N)cc2C(C)C)c(-c2cccc(OCCCO)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.8 %

Procedure:
To a solution of N-[1-butyl-4-[3-[3-(benzyloxy)propoxy]phenyl]-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2,6-diisopropyl-4-tritylaminophenyl]urea (1.60 g, 1.74 mmol) in a mixture of acetone (20 ml) and methanol (20 ml) is added conc. hydrochloric acid (1 ml, 12 mmol) under ice-cooling, and the mixture is stirred at room temperature for 14 hours. The reaction solution is made basic by adding thereto aqueous ammonia under ice-cooling, and extracted with ethyl acetate. The organic layer is washed twice with aqueous sodium hydrogen carbonate solution, and the solvent is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound (1.07 g, 1.58 mmol).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:24][N:25]([CH3:29])[C:26]([S:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])=[O:27]
Reactant: Cc1c(NC(=O)C(CS)Cc2ccccc2)cccc1C(=O)O
Reactant: CN(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(NC(=O)C(CSC(=O)N(C)C)Cc2ccccc2)cccc1C(=O)O
Yield: 28.7 %

Procedure:
3-[(2-Mercaptomethyl-3-phenylpropionyl)amino-2-methylbenzoic acid (compound of Example 7) (0.66 g) is dissolved in pyridine (2 ml), and thereto is added dimethylaminocarbonyl chloride (0.26 g) with stirring under ice cooling, and the mixture is stirred under ice cooling for 2 hours and further at room temperature for 2 hours. To the reaction mixture is added ethyl acetate (50 ml) and the mixture is washed with saturated aqueous citric acid solution and water, dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and the precipitates are separated by filtration to give the title compound (0.23 g). m.p.: 84°-87° C. (amorphous) IR (KBr; cm-1): 1710, 1690, 1650
Reaction SMILES: [CH:1]1([NH:4][CH:5]([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9](/[CH:15]=[CH:16]/[CH2:17][NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([C:36](O)=[O:37])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH:1]1([N:4]([CH:5]([C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[CH2:17][NH:18][C:19]([O:20][CH3:21])=[O:22])[N:10]=[C:11]([O:13][CH3:14])[CH:12]=2)[CH3:6])[C:36]([C@@H:32]2[O:33][CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31]2)=[O:37])[CH2:3][CH2:2]1
Reactant: COC(=O)NC/C=C/c1cc(C(C)NC2CC2)cc(OC)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Product: COC(=O)NC/C=C/c1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cc(OC)n1

Procedure:
Methyl ((2E)-3-{4-[1-(cyclopropylamino)ethyl]-6-methoxypyridin-2-yl}prop-2-en-1-yl)carbamate and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid were treated in the similar manner to Example 162 to give tert-butyl (2R)-2-({cyclopropyl[1-(2-methoxy-6-{(1E)-3-[(methoxycarbonyl)amino]prop-1-en-1-yl}pyridin-4-yl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(298-3)] as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@H:3](OS(C(F)(F)F)(=O)=O)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.Cl.[NH2:31][C@@H:32]([CH2:36][S:37]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)(=[O:39])=[O:38])[C:33]([OH:35])=[O:34]>C(Cl)Cl.CCOCC>[N:40]1([S:37]([CH2:36][C@H:32]([NH:31][C@@H:3]([C:4]2[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=2)[C:2]([F:1])([F:19])[F:20])[C:33]([OH:35])=[O:34])(=[O:39])=[O:38])[CH2:41][CH2:42][O:43][CH2:44][CH2:45]1
Reactant: O=S(=O)(O[C@H](c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Reactant: N[C@@H](CS(=O)(=O)N1CCOCC1)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)[C@H](CS(=O)(=O)N1CCOCC1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
To a solution of trifluoromethanesulfonic acid-2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethyl ester (0.511 g, 88% pure, 1.38 mmol) in CH2Cl2 (5 mL) at rt was added DIPEA (Aldrich, 0.74 mL, 4.24 mmol) followed by the solid HCl salt of 2(R)-amino-3-(morpholin-4-sulfonyl)-propionic acid (0.292 g, 1.06 mmol) in small portions over 2 min. The initially homogeneous orange-brown solution became heterogeneous within minutes and was allowed to stir overnight at rt. The reaction mixture was then diluted with Et2O and quenched with 1M NaOH. The pH 14 aqueous layer was separated, washed with Et2O and acidified to pH 2 with 12M HCl. The aqueous layer was then extracted with Et2O. The combined Et2O extractions of the acidic solution were washed with brine and dried over anhydrous Na2SO4. Following concentration in vacuo, 0.034 g (7.7%) of 3-(morpholin-4-sulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethylamino]propionic acid was obtained as a colorless film.
Reaction SMILES: CN(C)C=O.[NH:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)(O)[O-].[Na+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:18]([O:25][C:26]([N:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CNCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCCNCC1
Yield: 65.5 %

Procedure:
To 230 ml of dimethylformamide were added 25 g of homopiperazine and 5.4 g of sodium bicarbonate and then 25 ml of water followed by dropwise addition of 10 g of benzyloxycarbonyl chloride with stirring under ice cooling, and the mixture was stirred at a room temperature overnight. After evaporating off dimethylformamide under a reduced pressure, the reaction mixture was extracted three times with 100 ml of chloroform, and the extract was dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (9:1), to obtain 9 g of the title compound as a light yellow liquor liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][CH2:10]O)[CH:7]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][CH2:10][Cl:16])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cl)cc1CCCO
Product: COc1ccc(Cl)cc1CCCCl

Procedure:
58.2 g of 3-(5-chloro-2-methoxyphenyl)propan-1-ol and 50 ml of thionyl chloride are stirred at 50° for 8 hours; the excess thionyl chloride is distilled off in vacuo and the residue is distilled under a high vacuum. 50.9 g of 3-(5-chloro-2-methoxyphenyl)propyl chloride of b.p. 87° to 95° under 0.005 mm Hg are obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[C:21]([O:25][C:26](=[O:45])[C:27]([CH2:29][N:30]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH2:28])([CH3:24])([CH3:23])[CH3:22].Cl>O1CCCC1>[C:21]([O:25][C:26](=[O:45])[CH:27]([CH2:29][N:30]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: C=C(CN(Cc1ccccc1)Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)C1CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CN(Cc1ccccc1)Cc1ccccc1)CC1(C(=O)O)CCCC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a stirred solution of diisopropylamine (14.98 g, 20.75 ml, 148 mmole) in dry tetrahydrofuran (250 ml) cooled to -30° C. under nitrogen, was added dropwise, n-butyl lithium (59.3 ml of a 2.5M solution, 148 mmole), keeping the temperature below -20° C. The reaction was stirred at -20° C. for 1 hour, then cooled to -30° C. and cyclopentanecarboxylic acid (8.05 g, 7.65 ml, 70.6 mmole) added dropwise in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at 0° C. for two hours, during which time a white precipitate formed. The solution was then cooled to -70° C., and a solution of 2-(dibenzylaminomethyl)-propenoic acid t-butyl ester (23.8 g, 70.6 mmol) in dry tetrahydrofuran (35 ml) was added dropwise. The reaction was left overnight (below -40° C.), and then poured into iced hydrochloric acid (4.2 eq, final pH=2) and the product extracted into diethyl ether. The ether layer was washed with hydrochloric acid, water (2x), dried (Na2SO4) and evaporated to yield the crude product (40 g). This was chromatographed over silica gel (500 g) eluting with dichloromethane containing methanol (0 to 5%) to yield, on evaporation of the pure fractions, 3-(1-carboxycyclopentyl)-2-(dibenzylaminomethyl)propanoic acid t-butyl ester as an oil (18.3 g, 57%). Found: C,74.38; H,8.41; N,2.91. C28H37NO4 requires C,74.47; H,8.26; N,3.10%.