Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19]Br)=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:44]([NH2:49])[CH2:45][CH2:46][CH:47]=[CH2:48].[CH:50](N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19][NH:49][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH2:50])=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOc1ccc(C(CC(=O)N=C(Cc2cc(Cl)c(NC(=O)CBr)c(Cl)c2)NC(=O)OC(C)(C)C)=NOCC)cc1
Reactant: C=CCCCN
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: C=CCCCCNCC(=O)Nc1c(Cl)cc(CC(=NC(=O)CC(=NOCC)c2ccc(OCC=C)cc2)NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl-1-(3-(4-(allyloxy)phenyl)-3-(ethoxyimino)-propanoylimino)-2-(4-(2-bromoacetamido)-3,5-dichlorophenyl)ethylcarbamate (60 mg) in dichloromethane (0.30 mL) at room temperature was added pent-4-en-1-amine hydrochloride (47 mg) and diisopropylethylamine (76 μL), and the resulting solution was stirred at room temperature for 4 h. The solvents were removed in vacuo to give the title compound as a white solid, which was used in Step B without purification. retention time: 2.10 min (method A). MS (ESI) (M+H)+ 717.83.
Reaction SMILES: [OH:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.I[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1>>[O:17]([C:18]1[CH:19]=[CH:20][C:21]([O:1][C@@H:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:22][CH:23]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Ic1ccc(Oc2ccccc2)cc1
Product: c1ccc(Oc2ccc(O[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
3-(R)-Hydroxy-quinuclidine (the product of Reference Example 1, 152 mg, 1.2 mmol), was coupled with 1-iodo-4-phenoxy-benzene (178 mg, 0.6 mmol) according to the procedure of Example 3A. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as oil (25 mg, yield, 14%). 1H NMR (MeOH-d4, 300 MHz) δ 1.45–1.58 (m, 1H), 1.64–1.85 (m, 2H), 2.00–2.15 (m, 1H), 2.20–2.30 (m, 1H), 2.70–3.10 (m, 5H), 3.34–3.40 (m, 1H), 4.52 (m, 1H), 6.83–6.98 (m, 6H), 7.03 (tt, J=7.5, 1.0 Hz, 1H), 7.30 (t, J=7.5 Hz, 2H) ppm. MS (DC m/z 296 (M+H)+.
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]([CH:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)=[N:12][C:11]=1[C:23]([O:25]C)=O)(=O)C1C=CC=CC=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35].[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>C(Cl)(Cl)Cl.CN1C(=O)CCC1>[C:34]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:10]([OH:9])=[C:11]([C:23]([NH:44][CH2:43][C:42]2[CH:45]=[CH:46][C:39]([F:38])=[CH:40][CH:41]=2)=[O:25])[N:12]=1)(=[O:36])[CH3:35]
Reactant: COC(=O)c1nc(C2CCCN2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C
Temperature: 25 °C

Procedure:
To a stirred solution of the product of Step 1 (1.0 eq.) in CHCl3, triethylamine (3.0 eq.) was added followed by the addition of acetyl chloride (1.5 eq.). The reaction was stirred at room temperature until the starting material was consumed as determined by MS analysis. The reaction mixture was concentrated and the crude product was used directly in the subsequent step without further purification. A solution of the crude product from above (1.0 eq.) in NMP was treated with 4-fluorobenzylamine (2.0 eq.). The solution was stirred at reflux until the reactants were consumed as determined by MS analysis. The title compound was obtained by RP-HPLC purification (C18, eluting with water and acetonitrile containing 0.1% trifluoroacetic acid) as a 4:1 mixture of rotamers by NMR.
Reaction SMILES: C(#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9]N1C(=O)C2=CC=CC=C2C1=O>C1CCCCC1>[C:2]1(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:2]1([OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: N#Cc1ccccc1
Solvent: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1
Yield: 5.2 %
Yield: 0.6 %

Procedure:
To 20 ml of benzonitrile were added 10 mmol of cyclohexane, 1 mmol of N-hydroxyphthalimide and 0.05 mmol of cobalt acetate Co(OAc)2 and the resultant mixture was stirred under an oxygen atmosphere at a temperature of 75° C. for 16 hours. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, cyclohexane was converted into cyclohexanone (yield 5.2%), cyclohexanol (yield 0.6%) with a conversion of 6.3%. Adipic acid was not detected.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.C[Mg+].[Br-].[CH3:19]COCC>Cl[Ni]Cl.C1COCC1>[CH3:19][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: CCOCC
Agent: Cl[Ni]Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc2ncc(C)nc2cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound is prepared using an adaptation of the published method of Tamao, et al. Tetrahedron, 1982, 38, 3347-3354. To a THF solution under argon is added 2-Chloro-6,7-dimethoxyquinoxaline (5 g, 26 mmol) and NiCl2 (dppp) (0.14 g, 0.26 mmol). The reaction mixture is cooled to 0° C., and a 3 M solution of MeMgBr in Et2O (13 mL, 39 mmol) is added portionwise. The reaction mixture is allowed to warm to room temperature, stirred for 1 hours then refluxed for 1.5 hours. The mixture is cooled, quenched with 10% HCl, stirred 10 minutes, then made basic with 5% NaOH. CH2Cl2 and H2O are added to the reaction, and the mixture stirred overnight. Additional CH2Cl, H2O, and NaCl are then added and the mixture is filtered. The resulting solution is poured into a separatory funnel, and the aqueous layers are washed 3× with CH2Cl2. The organic layers are combined, washed with brine, dried (MgSO4), concentrated onto silica gel, and chromatographed (50%-80% EtOAc/hexanes) to provide a orange solid (49% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=O)=[CH:14][CH:13]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:12]1[CH:13]=[CH:14][C:15]([N:18]([OH:20])[C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[O:30])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N(O)c1ccc(-n2cnc3c(Cl)ncnc32)cc1

Procedure:
The title compound can be synthesized from 6-chloropurine, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 45.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[OH:10].C(N(C(C)C)CC)(C)C.[CH3:20][O:21][CH2:22]Cl.O>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH2:20][O:21][CH3:22]
Reactant: N#Cc1ccc(F)c(O)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCOc1cc(C#N)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 4-fluoro-3-hydroxybenzonitrile (25.0 g, 182 mmol), diisopropylethylamine (47.7 mL, 273 mmol) in dichloromethane (530 mL) was added chloromethyl methyl ether (16.6 mL, 219 mmol) dropwise at 0° C., and the mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-fluoro-3-methoxymethoxybenzonitrile (33.0 g, quant.), which was used for the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[N:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[C:37]([Cl:42])[CH:38]=5)[CH:33]=4)(=[O:31])=[O:30])[CH2:25][CH2:24]3)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:42][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([S:29]([N:26]1[CH2:25][CH2:24][N:23]([C:21]([C:18]3[N:19]=[N:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]4)=[CH:16][CH:17]=3)=[O:22])[CH2:28][CH2:27]1)(=[O:30])=[O:31])[CH:41]=[CH:40]2
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)nn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(N2CCCNCC2)nn1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 1-[6-(4-t-butoxycarbonylhexahydro-1,4-diazepin-1-yl)pyridazin-3-ylcarbonyl]-4-(6-chloronaphthalen-2-ylsulfonyl)piperazine (0.320 g, 0.52 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred overnight at room temperature, and the solvent removed by evaporation. The residue was purified using a SCX column to afford the title product (0.230 g, 86%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([C:22]#[N:23])=[N:8][C:9]([S:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[CH:10][CH:11]=1.O.O.Cl[Sn]Cl>O.Cl>[F:21][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[CH:17]=1)[CH2:13][S:12][C:9]1[N:8]=[C:7]2[C:22]([NH2:1])=[N:23][NH:5][C:6]2=[CH:11][CH:10]=1
Reactant: O=N[O-]
Reactant: N#Cc1nc(SCc2cc(F)cc(F)c2)ccc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2ccc(SCc3cc(F)cc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution cooled to 0° C. of NaNO2 in 3 ml of water is added drop by drop to a solution at 0° C. of 3-amino-6-(3,5-difluorobenzylthio)picolinonitrile (1.587 mmol, 0.44 g) in 15 ml of 6 N HCl solution. After 15 minutes, a solution cooled to 0° C. of SnCl2.2H2O diluted in 4 ml of 12 N HCl is added drop by drop. The reaction medium is then stirred at 25° C. for 1 hour. The solution is extracted with ethyl acetate and then washed using saturated NaHCO3 solution and then saturated NaCl solution. The organic phase is collected, dried on magnesium sulfate and then concentrated under reduced pressure. The residue is purified by silica gel chromatography (AcOEt/heptane) to yield, after concentration of the organic phases, 0.07 g (15%) of black crystals.
Reaction SMILES: C(O[C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)C.[CH2:11]([Mg]Br)[CH3:12]>C(OCC)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH2:11]1[C:4]2([CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5]2)[CH2:12]1
Reactant: CC[Mg]Br
Reactant: CCOC1=CC(=O)CCC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: CCOCC
Product: O=C1CCCC2(CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Ethoxycyclohex-2-enone (25 g) was dissolved in diethyl ether (500 mL), and tetraisopropoxytitanium (55 mL) was added, followed by the addition of ethyl magnesium bromide (3.0M in diethyl ether, 180 mL) over 30 minutes. The reaction was stirred at room temperature for another two hours, and quenched by the careful addition of water (250 mL). The mixture was filtered through diatomaceous earth, and rinsed with diethyl ether. The filtrate was transferred to a separatory funnel, the aqueous layer was drawn off, and p-toluenesulfonic acid monohydrate (2 g) was added to the organic layer, which was stirred at room temperature for two days. The reaction mixture was washed with saturated aqueous NaHCO3 and brine, then dried over Na2SO4. The mixture was filtered, and concentrated and chromatography on silica gel using 93/7 hexanes/ethyl acetate provided the title compound.
Reaction SMILES: [CH:1]1C=CC2N(O)N=NC=2[CH:6]=1.CCN(CC)CC.[C:18]([O:22][C:23]([NH:25][CH:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:27]([OH:31])[C:28]([OH:30])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(N)CC1.C(Cl)CCl>C(Cl)Cl>[C:18]([O:22][C:23]([NH:25][CH:26]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:27]([OH:31])[C:28]([O:30][CH2:1][CH3:6])=[O:29])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)O
Reactant: On1nnc2ccccc21
Agent: NC1CC1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
74.2 Tert-butyl 4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-ylcarbamate EDC (8.3 g, 43.3 mmol), HOBT (6.6 g, 43.1 mmol) and Et3N (7 ml, 50.2 mmol) were added to a mixture of 3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutanoic acid (10.6 g, 35.9 mmol) and cyclopropylamine (3.3 ml, 47.6 mmol) in DCM (300 mL) at 5° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. After cooling to 5° C. more cyclopropylamine (2 ml, 28.5 mmol), EDC (5 g, 26.1 mmol), HOBT (4 g, 26.1 mmol) and Et3N (3.5 ml, 25.1 mmol) were added, the mixture was allowed to warm to room temperature and the stirring was continued overnight. DCM (300 mL) was added, followed by washing with 0.5 M aqueous HCl solution, brine and drying with MgSO4. The crude product was recrystallized from methyl-tert-butylether, the crystals obtained were washed with n-pentane and dried providing the title compound (10.2 g, 85%).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH2:8]=[O:9].[OH-].[Na+]>>[OH:9][CH2:8][C:2]1[C:1]([NH:5][C:4](=[O:6])[CH:3]=1)=[O:7]
Reactant: C=O
Reactant: O=C1C=CC(=O)N1
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=C(CO)C(=O)N1

Procedure:
A mixture of 24 parts of maleimide (manufactured by Aldrich), 21 parts of an aqueous 35 wt % formaldehyde solution (manufactured by Wako Pure Chemical Industries), and 0.7 part of an aqueous 5 wt % sodium hydroxide solution is allow to react at 40° C. for 2 hours, to give white crystalline hydroxymethyl maleimide. The crystals are filtered under reduced pressure and dried under reduced pressure at room temperature. The crude crystalline hydroxymethyl maleimide is recrystallized in ethyl acetate, to give 22 parts of hydroxymethyl maleimide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=O)[CH3:11])[C:7](=O)[CH3:8])[CH3:2].C(O)(=O)C.O.[NH2:19][NH2:20]>CO>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:10]([CH3:11])=[N:19][NH:20][C:7]=1[CH3:8])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)n[nH]c1C
Yield: 89 %

Procedure:
18.6 grams 3,3-diacetyl-propionic acid-ethyl ester, 9.0 grams glacial acetic acid and 150 milliliters methanol were mixed, and 5.3 grams hydrazine hydrate were added dropwise to this mixture within 30 minutes. The reaction mixture was then heated to the boiling temperature under reflux for 3 hours. The reaction mixture was then evaporated and distilled in vacuo. The fraction obtained at 142°-150° C.).05 Torr consisted of an oil which later crystallized. 16.2 grams 3,5-dimethyl-1H-pyrazol-4-acetic acid-ethyl ester were obtained, representing a yield of 80%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:31])=[CH:26][CH:25]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1)C(=O)OC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (1.0 g), 3-oxo-2-[4-(pyrrolidine-1-carbonyl)benzyl]pentanoic acid methyl ester (1.9 g), polyphosphoric acid (6.0 g) and dioxane (20 mL) was heated at 120° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, ethyl acetate and methanol (9:1:0 to 0:9:1 by volume) to afford title compound, 0.079 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.NCCCN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C1CCCC(=O)O1
Agent: NCCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CCCC(=O)O)CC1
Reaction time: 2 h

Procedure:
The compound (1.46 g) obtained in the above (1) is dissolved in dichloromethane (20 ml), and thereto are added glutaric anhydride (0.86 g) and triethylamine (1.14 ml), and the mixture is stirred for two hours. To the mixture is added dropwise N-(3-aminopropyl)morpholine (0.3 ml), and the mixture is further stirred for 30 minutes. The mixture is evaporated under reduced pressure to remove the solvent, and thereto is added 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (1.54 g).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.FC(F)(F)C(O)=O.[Cl:32][C:33]1[CH:34]=[C:35]([S:39]([N:42]2[CH2:58][CH2:57][C:45]3([N:49]=[C:48]([CH:50]4[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]4)[NH:47][C:46]3=[O:56])[CH2:44][CH2:43]2)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>C(Cl)Cl>[C:13]([NH:17][C:2]([N:52]1[CH2:53][CH2:54][CH2:55][CH:50]([C:48]2[NH:47][C:46](=[O:56])[C:45]3([CH2:57][CH2:58][N:42]([S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=4)(=[O:41])=[O:40])[CH2:43][CH2:44]3)[N:49]=2)[CH2:51]1)=[O:4])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1NC(C2CCCNC2)=NC12CCN(S(=O)(=O)c1cccc(Cl)c1)CC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)N1CCCC(C2=NC3(CCN(S(=O)(=O)c4cccc(Cl)c4)CC3)C(=O)N2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
A solution of triphosgene (345 mg, 1.16 mmol) in CH2Cl2 (7 ml) was added to a solution of tert-butylamine (331 μl, 3.14 mmol) and triethylamine (876 μl, 6.29 mmol) in CH2Cl2 (10 ml) at −78° C. The mixture was stirred at room temperature for 10 minutes, followed by addition of a solution of 8-(3-chloro-benzenesulfonyl)-2-piperidin-3-yl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one trifluoroacetate (165 mg, 0.314 mmol) and triethylamine (876 μl, 6.29 mmol) in CH2Cl2 (2 ml). Further, the reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-[8-(3-Chloro-benzenesulfonyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-en-2-yl]-piperidine-1-carboxylic acid tert-butylamide as a colorless oil (40 mg, yield 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 23.5 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (599 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.72 ml) and 1-methyl-2-chloropyridinium iodide (946.8 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (306.3 mg).
Reaction SMILES: [OH:1][C@H:2]([C:13]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH2:41][CH2:42][OH:43])[C:20]=1[NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:44](Cl)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:1][C@H:2]([C:13](=[O:14])[NH:15][C:16]1[CH:17]=[N:18][N:19]([CH2:41][CH2:42][O:43][C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:20]=1[NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a stirred solution of tert-butyl ((3S)-3-hydroxy-4-{[1-(2-hydroxyethyl)-5-(tritylamino)-1H-pyrazol-4-yl]amino}-4-oxobutyl)carbamate (2.5 g) in N,N-dimethylformamide (25 ml) were added trityl chloride (1.25 g), triethylamine (1.78 ml) and 4-dimethylaminopyridine (52.1 mg), and the mixture was stirred for 1 hour. The reaction mixture was warmed up to 60° C. and stirred at the same temperature for 2 days. Water was added to the mixture, and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave an oil, which was purified by column chromatography on silica gel (methylene chloride:ethyl acetate=5:1) to give tert-butyl [(3S)-3-hydroxy-4-oxo-4-({5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazol-4-yl}amino)butyl]carbamate (1.5 g).