Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CC(C)([O-])C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26]C)=[O:25])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Oc2cccc([N+](=O)[O-])c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
A mixture of 3-nitrophenol (3.65 g, 26.2 mmol), potassium tert-butoxide (3.23 g, 28.8 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 min. After stirring, methyl 4-chloropyridine-2-carboxylate (3.00 g, 17.5 mmol) and potassium carbonate (10.9 g, 78.6 mmol) were added, and the mixture was stirred at 120° C. for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (20 mL) and 8N aqueous sodium hydroxide solution (3 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (345 mg, 8.0%) as a white solid. A mixture of 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (339 mg, 1.24 mmol) thus-obtained, diphenylphosphoryl azide (333 μL, 1.55 mmol), triethylamine (215 μL, 1.55 mmol), N,N-dimethylformamide (5 mL) and water (5 mL) was stirred at 100° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (253 mg, 8.8%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C[N:31]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)S(C)(=O)=O.[C:42](OC(N1CCC(NC)CC1)=O)(C)(C)[CH3:43].CS(Cl)(=O)=O>>[NH:31]1[C:36]2[C:37](=[C:42]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][CH:15]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:43]=[CH:40][CH:41]=2)[CH:38]=[N:39]1
Reactant: CN(C1CCNCC1)S(C)(=O)=O
Reactant: CN(C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1)S(C)(=O)=O
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CS(=O)(=O)Cl
Product: CN(C1CCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1)S(C)(=O)=O

Procedure:
Via N-[1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-N-methyl-methanesulfonamide, prepared from N-methyl-N-piperidin-4-yl-methanesulfonamide. The amine, N-methyl-N-piperidin-4-yl-methanesulfonamide, was prepared by treatment of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester with methanesulfonyl chloride, analogous to 128.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6](=[O:8])=[O:7].[CH2:9](Cl)[CH2:10][CH2:11][CH3:12].C(=O)([O-])N>CC#N.C(OCC)C>[C:6](=[O:8])([O:7][CH2:9][CH2:10][CH2:11][CH3:12])[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C=O
Reactant: CCCCCl
Reactant: CCCCO
Agent: NC(=O)[O-]
Solvent: CCOCC
Solvent: CC#N
Product: CCCCOC(=O)OCCCC
Temperature: 85 °C
Yield: 73 %

Procedure:
A 160 cc Parr autoclave was charged with 2.22 g (0.03 mol) butanol, 6.9 g (0.035 mol) N-cyclohexyl-N',N',N",N"-tetramethylguanidine and 30 mL CH3CN. The autoclave was attached to a pressure head and at room temperature with stirring was added 160 psig carbon dioxide. Addition of CO2 resulted in an exothermic reaction with a rise in temperature to ca. 40° C. Into a Fischer-Porter bottle was added 8.33 g (0.09 mol) butyl chloride in 10 mL CH3CN. This mixture was attached to a pressure head and 80 psig carbon dioxide was added above the solution. After 1 h the butyl chloride solution was added all at once under 80 psig CO2 to the pre-formed carbamate anion solution generated in the autoclave. After addition the pressure was raised to 160 psig with carbon dioxide and the reaction mixture was warmed to 85° C. for 16 h. After this time the reaction mixture was allowed to cool to room temperature and then the pressure was released. An aliquot was taken, diluted with diethyl ether, Cl-+HCyTMG filtered off and by G.C. analysis a 73% yield of dibutyl carbonate was calculated. Oil 1H NMR (CDCl3) 4.14(t, J=6.6 Hz, 4H) 1.66 (m, 4H), 1.41 (m, 4H), 0.94 (t, J=7.3 Hz, 6H). 13C{1H} NMR (CDCl3) 155.9, 68.2, 31.2, 19.4, 14.1. IR (film) 1746, 1260; MS (FAB) m/z=175 (MH+).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=O)=[CH:3][CH:2]=1.C(OP([CH2:35][C:36](=[O:40])[N:37]([CH3:39])[CH3:38])(=O)OCC)C.[H-].[Na+]>C1C=CC=CC=1>[CH3:39][N:37]([CH3:38])[C:36](=[O:40])[CH:35]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:4]1[CH:3]=[CH:2][C:1]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][CH:5]=1
Reactant: CCOP(=O)(CC(=O)N(C)C)OCC
Reactant: O=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CN(C)C(=O)C=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
Di-4-biphenylyl ketone (6.68 g.) was added to a mixture of N,N-Di-methylcarbamoylmethyl phosphonic acid diethyl ester (C.A. 65, 615 g. 1966) (4.46 g.), sodium hydride (60%) (0.8 g.) and benzene (400 ml.). The mixture was boiled under reflux for sixty hours. The benzene layer, decanted and evaporated, gave an oil, from which, by column chromatography on silica gel MFC in benzene and elution by ethyl acetate, was isolated N,N-dimethyl3, 3-di(4-biphenylyl) acrylamide, m.p. 121°C after recrystallisation from light petroleum (b.p. 80°-100°C). This, reduced with lithium aluminium hydride in ether/tetrahydrofuran at -30°C, gave 1,1-di(4-biphenylyl) -3 -dimethylaminoprop-1-ene identical with that described in Example 1 .
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH3:6]COCC.[C:11]([C:13](=[CH:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15])#[N:12].C(=O)=O>C1COCC1>[CH3:6][O:15][C:14](=[O:16])[CH:13]([C:11]#[N:12])[CH:17]([CH:18]([CH3:20])[CH3:19])[CH2:1][CH2:2][CH3:3]
Reactant: CC(C)C=C(C#N)C(=O)O
Reactant: CCC[Mg]Cl
Reactant: CCOCC
Agent: O=C=O
Solvent: C1CCOC1
Product: CCCC(C(C)C)C(C#N)C(=O)OC
Reaction time: 4 h

Procedure:
A 2.0 M solution of propyl magnesium chloride in Et2O (9.8 mL, 19.6 mmol) is added to a solution of 2-cyano-4-methyl-2-pentenoic acid (3.0 g, 19.6 mmol) in 50 mL of THF which is cooled in an EPA/dry ice bath to −40° C. under argon. The solution is stirred for 4 hours, and the reaction is quenched by addition of 50 mL of saturated KH2PO4. The THF is evaporated, and the remaining oil is chromatographed under medium pressure over silica gel with 50% CH2Cl2/hexane. Yield=1.9 g (50%) of 2-cyano-3-isopropyl-hexanoic acid methyl ester as an oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1.N1CCCCC1>ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:2]2[C:3](=[O:21])[O:4][C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6][C:7]=2[OH:8])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1
Reactant: CC(C)c1cc(Cl)ccc1S
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)c1cc(Cl)ccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.1 mmol of 4-chloro-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 95-96° C.). 1H NMR (DMSO-d6) δ 1.16 (d, 6 H), 3.23 (m, 1 H), 3.73 (bs, 2 H), 5.60 (d, 1 H), 6.45 (d, 1 H), 7.14 (d, 1 H), 7.32-7.48 (m, 10 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(4-chloro-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4 step 2a and 2b) (13.96 g, 32.96 mmol), trimethylsilylacetylene (5.5 mL, 39.72 mmol) and Et3N (9.2 mL, 67.9 mmol) in dry DMF (33 mL) was stirred for 10 min at 23° C. while being purged with Argon, then PdCl2(PPh3)2 (116 mg, 0.5 mol %), PPh3 (43 mg, 0.5 mol %) and CuI (19 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4 h. The react mixture was then cooled to 23° C., diluted with EtOAc, washed water (twice) and brine, dried over Na2SO4. Removal of the solvent left an orange solid (13.30 g, 102%). MS (ISP) 394.1 [(M+H)+-] and 396.1 [(M+2+H)+]; mp 198° C.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:10]([O:21][C@H:22]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:54](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:17]([CH3:54])[N:18]=[N:19][N:20]=3)[CH2:15][C@@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:10]([O:21][C@H:22]([C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:44])([F:45])[F:43])[CH:33]=1)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc([C@H](COCc2ccccc2)O[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1nnnc1[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](COCc3ccccc3)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-phenylmethoxyethoxy}1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 158; 0.403 g, 0.57 mmol), methyl iodide (0.2427 g, 0.107 ml, 1.71 mmol) and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (10 ml) were heated at 60° C. for 2 hours. The mixture was quenched with water and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 1% methanol/dichloromethane to give the title compounds (isomer A; 60 mg) and (isomer B; 70 mg), together with mixed fractions.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:10])C#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH2:18][NH2:19].S([C:25]1C=CC(C)=CC=1)([O-])(=O)=O>>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:10][C:25]2[NH:19][CH2:18][CH2:17][N:20]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCN
Reactant: CC(C#N)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Product: c1ccc(C(CC2=NCCN2)c2ccccc2)cc1

Procedure:
A mixture of 2.07 g of 2,2-diphenyl propionitrile and 2.78 g of ethylenediamine.tosylate was heated at 200° C. for 3 hours. After cooling, the solution was rendered basic with an alkali hydroxide and extracted with chloroform. The chloroform layer was washed with water and dried. After evaporating chloroform, the resulting residue was recrystallized from a mixture of benzene and hexane to give 1.4 g of 2-(2,2-diphenyl ethyl)-2-imidazoline having a melting point of 98° to 101° C. The hydrochloride thereof had a melting point of 173°-175° C.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:44][CH3:45])[C:32]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:33])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:51])([F:50])[F:52])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:44][CH3:45])[C:32]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:33])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(C(=O)CCCCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
Ethyl 6-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyl]-hexanoate (140 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 6-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyl]-hexanoic acid (137 mg). MS (m/z): 750 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl.[NH2:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[F:28])[CH3:18]>>[CH2:1]([O:8][C:9]([NH:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[F:28])[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(C(=O)O)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1F
Yield: 59 %

Procedure:
Benzyloxycarbonyl chloride (710 mg) was dropwise added to an aqueous solution (10 ml) of (R)-4-(1-aminoethyl)-3-fluorobenzoic acid hydrochloride (610 mg) and-sodium hydroxide (390 mg), and the mixture was stirred at room temperature for 4 hours. After the reaction, conc. hydrochloric acid was added to the reaction mixture to make the same acidic, and the mixture was extracted with chloroform. The mixture was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=40:1) to give 520 mg of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-fluorobenzoic acid.
Reaction SMILES: C[O:2][CH:3]([O:8]C)[C:4](OC)=O.CO.[CH2:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH2:25])(=[O:24])=[O:23])[CH2:13][CH3:14].[OH-].[Na+]>O.O1CCOCC1>[CH2:12]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:24])(=[O:23])[NH:25][CH:4]1[C:3]([OH:8])=[O:2])[CH2:13][CH3:14]
Reactant: CCCNc1ccccc1S(N)(=O)=O
Reactant: COC(=O)C(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CCCN1c2ccccc2S(=O)(=O)NC1C(=O)O
Reaction time: 1.5 h
Yield: 44 %

Procedure:
This compound was prepared according to the method of Close et. al., J. Org. Chem., 1961, 26, 3423-3433, incorporated by reference herein in its entirety. Thus, a solution of methyl dimethoxyacetate (3.6 g, 27.3 mmol) in water (50 l) was refluxed for 2.5 hours. A stillhead was attached and the methanol so generated was allowed to distill off (a total of 10 ml of liquid was collected, of which 5 ml was replenished with water). To the hot solution was added 2-(propylamino)benzenesulfonamide (4.5 g, 21.0 mmol) (prepared according to the procedure of Biressi et. al., Farmeco. Ed. Sci. (It.), 1969, 24, 199-220, incorporated by reference herein in its entirety) and 1,4-dioxane (5 ml, to give a homogeneous solution) and reflux was continued for 1.5 hours. The mixture was adjusted to pH 3 (2N NaOH), extracted with ethyl acetate and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 4.8 g crude product which was recrystallized (ethyl acetate/hexanes) to give 2.5 g (44%) of the title compound as a white solid; NMR (DMSO-d6) δ 0.85 (t, J=7 Hz, 3H), 1.47-1.57 (m, 2H), 2.94-3.04 (m, 1H), 3.38 (br, 1H), 3.40-3.46 (m, 1H), 5.27 (d, J=6 Hz, 1H), 6.70 (t, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H), 7.36 (t, J=7 Hz), 7.43 (d, J=7 Hz, 1H), 8.44 (d, J=7 Hz, 1H), 13.04 (br, 1H); MS: 269 m/z (M-H)- ; Anal. Calc'd for C11H14N2O4S: C, 48.88; H, 5.23; N, 10.37; S, 11.84; Found: C, 49.17; H, 5.21; N, 10.27; S, 11.54.
Reaction SMILES: S(=O)(=O)(O)O.O.[Cl:7][C:8]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([SH:17])=[CH:11][C:9]=1[NH2:10].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)([CH3:28])[CH3:27]>O1CCCC1>[Cl:7][C:8]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([S:17][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])([CH3:28])[CH3:27])=[CH:11][C:9]=1[NH2:10]
Reactant: COc1cc(Cl)c(N)cc1S
Reactant: COc1ccccc1C(C)(C)O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(N)cc1SC(C)(C)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To concentrated sulfuric acid (6 mL) was added water (6 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added a solution of 2-chloro-5-mercapto-4-methoxyaniline (0.5 g) and 2-(2-methoxyphenyl)-2-propanol (0.88 g) in tetrahydrofuran (6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=4/1) to give the title compound (0.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.Br[C:37]1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:37]3[S:38][C:39]4[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=4[N:41]=3)[CH2:14][C@H:13]2[NH:25][CH:26]2[CH2:27][CH2:28]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC2CC2)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC4CC4)C3)sc12
Yield: 25.6 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(cyclopropylamino)piperidine-1-carboxylate obtained in Example (213a) (34.0 mg, 0.083 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (26 mg, 0.091 mmol) and sodium carbonate (87 mg, 0.825 mmol), to obtain 11 mg of the title compound (26%) as a pale yellow oily substance.
Reaction SMILES: [Se-2:1].[Na+].[Na+].Cl[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[C:11]#[N:12].Cl[CH2:14][C:15]#[N:16].C[O-].[Na+]>CN(C=O)C.CO.O>[NH2:12][C:11]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[Se:1][C:14]=1[C:15]#[N:16]
Reactant: N#CCCl
Reactant: [Se-2]
Reactant: N#CC1=C(Cl)CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: N#Cc1[se]c2c(c1N)CCCC2
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 57.2 %

Procedure:
To a suspension of sodium selenide (2.35 g, 18.65 mmol, prepared from 1.5 g of selenium as described above) in DMF (18 mL) was added a solution of 2-chlorocyclohex-1-enecarbonitrile (2.63 g, 18.65 mmol) in DMF (9 mL) at rt for 5 min and stirred the mixture at 60° C. for 45 min. Then chloroacetonitrile (1.18 mL, 18.65 mmol) was added dropwise to the reaction mixture and again stirred at 60° C. for 3 h. Then, a solution of sodium methoxide (1.0 g, 18.65 mmol) in dry methanol (18 mL) was added dropwise and stirring was continued for 2 h at the same temperature. The mixture was allowed to room temperature (rt) and poured into cold water and stirred for 30 min. The precipitated solid was filtered and washed with water to give the product as a dark brown color solid (2.4 g, 57%), mp 86-88° C. 1H NMR (400 MHz, CDCl3): δ 4.39 (2H, br s, —NH2), 2.73-2.74 (2H, m, H-7), 2.28-2.29 (2H, m, H-4), 1.83-1.84 (4H, m, H-5,6).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](=[O:12])([O-])[O-:10].[K+].[K+].[OH2:15]>CN(C)C=O>[CH2:1]([O:10][C:9](=[O:12])[C:5]1[CH:6]=[CH:7][C:2]([C:1]2[CH:6]=[CH:7][C:2]([O:15][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:3][CH:4]=2)=[CH:3][CH:4]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-(41-Hydroxyphenyl)benzoic acid (2.0 g) was dissolved in N,N-dimethylformamide (30 ml). To the solution were added benzyl bromide (3.99 g) and potassium carbonate (3.86 g). The mixture was stirred for 3 hours at 80° C. The reactiontmixture was poured into water (100 ml), which was subjected to extraction with ethyl acetate (150 ml). The organic layer was washed with 5% potassium hydrogensulfate, which was then washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 4-(4′-benzyloxyphenyl)-benzoic acid benzyl ester as a scale-like crystalline product (3.4 g). m.p.: 138-140° C.