Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(CC2C(=O)OC(C)(C)OC2=O)=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl.[S:40]1[C:44]([CH2:45][CH:46]2[C:51](=[O:52])[O:50]C(C)(C)[O:48][C:47]2=[O:55])=[CH:43][C:42]2[CH:56]=[CH:57][CH:58]=[CH:59][C:41]1=2>>[S:40]1[C:44]([CH2:45][CH:46]([C:51]([OH:52])=[O:50])[C:47]([OH:55])=[O:48])=[CH:43][C:42]2[CH:56]=[CH:57][CH:58]=[CH:59][C:41]1=2
Reactant: CC1(C)OC(=O)C(Cc2cc3ccccc3s2)C(=O)O1
Agent: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: O=C(O)C(Cc1cc2ccccc2s1)C(=O)O

Procedure:
The title compound was prepared by substituting 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a) with 5-(benzo[b]thiophen-2-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 10: step a) then following the procedure described for the preparation of 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b).
Reaction SMILES: [N:1]1([CH2:7][C:8]23[CH2:16][CH:12]4[CH2:13][CH:14]([CH2:15]2)[C:10]([NH:17]C(=O)OC(C)(C)C)([CH2:11]4)[CH2:9]3)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[ClH:25]>CCOC(C)=O>[ClH:25].[N:1]1([CH2:7][C:8]23[CH2:16][CH:12]4[CH2:13][CH:14]([CH2:15]2)[C:10]([NH2:17])([CH2:11]4)[CH2:9]3)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(CN1CCSCC1)(C3)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: NC12CC3CC1CC(CN1CCSCC1)(C3)C2
Reaction time: 2 h
Yield: 88 %

Procedure:
To a stirred solution of the compound (0.22 g, 0.63 mmol) obtained in step I, in EtOAc (2.0 mL) cooled to ice bath temperature was added a solution of dry HCl in EtOAc (3 N, 4 mL). The reaction mixture was stirred at same temperature for 2 h and the solvent was removed under reduced pressure to obtain a crude product, which was triturated several times with diethyl ether to obtain 1-(thiomorpholin-4-ylmethyl) tricyclo[3.3.1.03,7]nonan-3-amine hydrochloride salt (180 mg) in 88% yield.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2(C)CC2)=CC=1.[Li]CCCC.CN(C=O)C>>[CH3:13][C:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: CC1(c2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC1(c2ccc(C=O)cc2)CC1
Yield: 80 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 1-bromo-4-(1-methylcyclopropyl)-benzene (2.10 g, 9.95 mmol), nBuLi (9.33 ml, 1.6M solution in hexane, 14.92 mmol) and DMF (3.87 ml, 49.74 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-(1-methylcyclopropyl)-benzaldehyde (1.28 g, 80%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): 9.96 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 1.46 (s, 1H), 0.98-0.93 (m, 2H), 0.90-0.84 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]3[C@H:33]([C:34]([F:37])([F:36])[F:35])[CH2:32][C:31](=[O:38])[NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)(=O)=O.CN(C)C=O.[NH:44]1[CH2:47][CH2:46][CH2:45]1>C(OCC)(=O)C>[N:44]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]2[CH:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]4[C@H:33]([C:34]([F:36])([F:35])[F:37])[CH2:32][C:31](=[O:38])[NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:22][CH2:23]2)[CH2:47][CH2:46][CH2:45]1
Reactant: CS(=O)(=O)OCCn1cc(CC(F)(F)F)nc1C1CCN(c2ncnc3c2[C@H](C(F)(F)F)CC(=O)N3)CC1
Reactant: C1CNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C[C@@H](C(F)(F)F)c2c(ncnc2N2CCC(c3nc(CC(F)(F)F)cn3CCN3CCC3)CC2)N1
Temperature: 50 °C

Procedure:
Combine (R)-2-(2-(1-(7-oxo-5-trifluoromethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-1-yl)ethyl methanesulfonate (1.04 g, 1.82 mmol), dimethylformamide (9.3 mL), and azetidine (1.11 mL, 9.0 eq) under nitrogen. Heat the reaction mixture at 50° C. overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash the organic layer with water. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with 10% methanol/dichloromethane to 10% 2 M ammonia in methanol/dichloromethane, to give the title compound, (R)-4-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one, as a white solid (0.49 g, 51%). MS (ES) m/z=532 [M]+.
Reaction SMILES: F[C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[N:14]2[CH3:17])=[CH:9][CH:8]=1)=[O:5].CN1CCCCC1=O.[NH2:35][C@@H:36]([CH3:39])[CH2:37][OH:38]>>[OH:38][CH2:37][C@@H:36]([NH:35][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[N:14]2[CH3:17])=[CH:9][CH:8]=1)=[O:5])[CH3:39]
Reactant: C[C@H](N)CO
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3F)cc21
Agent: CN1CCCCC1=O
Product: C[C@@H](CO)Nc1cc(C(F)(F)F)ccc1C(=O)Nc1ccc2c(c1)N(C)C(=O)CC2
Temperature: 180 °C
Reaction time: 0.67 h
Yield: 65.4 %

Procedure:
2-Fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide (250 mg), N-methylpiperidone (0.5 mL) and (2S)-2-aminopropan-1-ol (800 mg) were mixed, followed by stirring at 180° C. for 40 minutes under microwave irradiation. After spontaneous cooling and subsequent purification by silica gel column chromatography (chloroform:methanol, 99:1 to 95:5), 2-{[(1S)-2-hydroxy-1-methylethyl]amino}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide (188 mg) was obtained as a solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].OC1C2N=NNC=2C=CC=1.[C:17]([NH:24][C@@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.C(N(CC)CC)C>[C:17]([NH:24][C@@H:25]([C:30]([NH:2][CH2:3][C:4]([NH2:6])=[O:5])=[O:32])[CH2:26][CH:27]([CH3:28])[CH3:29])([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: NCC(N)=O
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(N)=O
Reaction time: 48 h

Procedure:
1.55 g (0.014 mole) of glycinamide hydrochloride is dissolved in 50 ml of DMF by warming to 50°. The solution is cooled to 25° and 2 ml of triethylamine is added, followed by 1.89 g of hydroxybenztriazole, 3.5 g (0.014 mol) of BOC-D-leucine H2O and lastly, 2.9 g (0.014 mol) of dicyclohexylcarbodiimide. The mixture is stirred two days at 25° and then evaporated in vacuo to an oil. The oil is dissolved in 200 ml EtOAC, 50 ml CHCl3. The organic solution is washed with water, 20% citric acid solution, water, 10% Na2CO3 solution. The EtOAc solution is dried over MgSO4 and the solvent removed in vacuo to a glass, 3.7 g (93%).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4](=[O:27])[CH:5]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][C:19]=2[F:26])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]1(=[O:59])[NH:53][C:52](=[O:54])[C:51]2=[CH:55][CH:56]=[CH:57][CH:58]=[C:50]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:54]=[C:52]1[C:51]2[C:50](=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:49](=[O:59])[N:53]1[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:14][CH2:13][N:12]([CH:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:4]([N:3]([CH2:28][CH3:29])[CH2:1][CH3:2])=[O:27])[CH2:17][CH2:16]2)=[C:19]([F:26])[CH:20]=1
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(CO)cc2F)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(CN3C(=O)c4ccccc4C3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.4 %

Procedure:
A solution of N,N-diethyl-2-[4-(2-fluoro-4-hydroxymethyl-phenyl)-piperazin-1-yl]-2-phenyl-acetamide (0.14 g, 0.362 mmol) in THF (3 mL) was added triphenylphosphine (96.5 mg), phthalimide (76.9 mg), and diethyl azodicarboxylate (50 μL), and the mixture stirred at rt. After 16 h, the solvent was removed and the residue purified on SiO2EtOAc/hexanes) to provide 115.5 mg of the title compound. MS (ESI): mass calcd. for C31H33FN4O3, 528.62. m/z found, 529.6 [M+H]+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH2:13]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCCCCCC1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCCCC1

Procedure:
The title compound is prepared from 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol and cyclooctane following a procedure to that of Example 5.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]([OH:12])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.Cl.Cl.[CH3:47][C:48]1([CH3:55])[CH2:52][CH2:51][CH2:50][CH:49]1[NH:53][NH2:54]>CC(N(C)C)=O.O>[CH3:47][C:48]1([CH3:55])[CH2:52][CH2:51][CH2:50][CH:49]1[NH:53][NH:54][C:10](=[O:12])[C:3]1[C:2]([I:1])=[CH:7][CH:6]=[N:5][C:4]=1[O:8][CH3:9]
Reactant: CC1(C)CCCC1NN
Reactant: COc1nccc(I)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1nccc(I)c1C(=O)NNC1CCCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a mixture of 4-iodo-2-methoxy-3-pyridinecarboxylic acid (2.8 g) and triethylamine (4.5 g) in DMA (40 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (5.7 g) under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, and (2,2-dimethylcyclopentyl)hydrazine trihydrochloride (2.8 g) was added thereto under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and added to water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (3.0 g).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH3:25])[NH:6][C:7](=[O:24])[C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH3:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[C:5]([CH3:25])[N:6]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.5 %

Procedure:
A mixture of 4′-[(4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.99 g), phenylboronic acid (0.73 g), molecular sieves 4 A (0.49 g), triethylamine (2.1 mL), pyridine (1.0 mL), copper(II) acetate (1.09 g) and methylene chloride (20 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.42 g, 34%).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH:6]1([C:9]2[C:10](=[O:20])[N:11]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[CH:12]=[CH:13][C:14]=2O)[CH2:8][CH2:7]1>CN(C=O)C>[Br:3][C:14]1[CH:13]=[CH:12][N:11]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:10](=[O:20])[C:9]=1[CH:6]1[CH2:8][CH2:7]1
Reactant: O=c1c(C2CC2)c(O)ccn1CC1CC1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: O=c1c(C2CC2)c(Br)ccn1CC1CC1
Temperature: 110 °C

Procedure:
Phosphorus oxybromide (2.4 g, 8.28 mmol) was added to a solution of intermediate D35 (0.85 g, 4.14 mmol) in DMF (60 ml), and the mixture was heated at 110° C. for 1 hour. After cooling in an ice bath, the solution was partitioned between water and EtOAc. The mixture was extracted with EtOAc (3×200 ml), the combined organic fractions were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D36 (0.99 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]=1[NH2:5].S(=O)(=O)(O)O.[OH2:18].[OH-].[Na+]>C(OC(=O)CCCC)(=O)CCCC>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]=1[NH:5][C:6](=[O:18])[CH2:4][CH2:3][CH2:9][CH3:8]
Reactant: O
Reactant: COc1cccc([N+](=O)[O-])c1N
Agent: CCCCC(=O)OC(=O)CCCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCC(=O)Nc1c(OC)cccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 36 %

Procedure:
To a mixture of 2-methoxy-6-nitroaniline (5.9 g) in valeric anhydride (14 g) was added a catalytic amount of conc. sulfuric acid, which was stirred for 1.5 hour at 130°-140° C. To the reaction mixture was added water, which was made basic with 6N NaOH. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off. The residue was purified by column chromatography on silica gel. Crude crystals thus obtained were recrystallized from ethyl acetate-hexane to give colorless crystals (3.2 g, 36%), m.p. 113°-114° C.
Reaction SMILES: [CH3:1][Mg]I.[CH3:4][O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([C:9]3=[O:16])[CH2:7]1)[CH2:13]2>CCOCC.C1COCC1>[CH3:4][O:5][C:6]12[CH2:7][CH:8]3[CH2:14][CH:12]([CH2:11][CH:10]([C:9]3([CH3:1])[OH:16])[CH2:15]1)[CH2:13]2
Reactant: COC12CC3CC(C1)C(=O)C(C3)C2
Reactant: C[Mg]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC12CC3CC(C1)C(C)(O)C(C3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Freshly prepared methyl magnesium iodide in ether (1M, 32 mL), was added through a canula to 5-methoxyadamantan-2-one (3.0 g, 16 mmol) in THF (32 mL) at 0° C. After stirring the mixture at 0° C. for 0.5 h, the reaction mixture was quenched by adding saturated aq. NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain 5-methoxy-2-methyladamantan-2-ol as 1:1 anomeric mixture (3.0 g yield, 96%). m/z (M+23), 219; 1H NMR (CDCl3) 300 MHz δ 3.24 (s, 1½H), 3.23 ((s, 1½H), 2.68-2.62 (m, 1H), 2.40-1.55 (m, 10H), 1.53-1.35 (m, 2H), 1.38 (s, 3H).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])([OH:3])=O.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:1]([C@@H:4]2[CH2:8][C@H:7]([S:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH2:6][N:5]2[CH3:19])=[O:3])[CH2:25][CH2:24]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Reactant: OCCN1CCNCC1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C)C2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
800 mg of N,N'-carbonyldiimidazole were added to a suspension of 1.13 g of (2S,4S)-2-carboxy-4-(4-methoxybenzylthio)-1-methylpyrrolidine in 20 ml of dry acetonitrile, and the resulting mixture was stirred at 40° C. for 30 minutes. At the end of this time, the reaction mixture was ice-cooled, and 600 mg of N-hydroxyethylpiperazine were added to the mixture. The temperature was allowed to rise to room temperature over a period of 30 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by reversed phase column chromatography using LiChroprep RP-8 (trade mark) as the stationary phase and 70% v/v aqueous methanol as the eluent, to give 1160 mg of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][O:13][C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[C:11]([CH2:12][O:13][C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)=[C:10]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(COc2ccnn2C)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nccc1OCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl

Procedure:
6.95 g (19 mmol) of methyl 2-chloro-[(1-methylpyrazol-5-yl)oxymethyl]-4-methylsulfonylbenzoate in a mixture of 30 ml of tetrahydrofurane and 30 ml of water are treated at room temperature with 0.93 g of lithium hydroxide for 12 h. The reaction mixture is adjusted to pH4 with 10% strength hydrochloric acid and extracted with methylene chloride. The organic phase is dried and freed from the solvent. Yield: 4.3 g; m.p. 197° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].[O:11]1CC[CH2:13][CH2:12]1>C(O)C>[ClH:10].[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=N)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of 4-fluorobenzonitrile (50 g) in tetrahydrofuran (300 mL) and ethanol (60.5 mL) at 0° C. was saturated with anhydrous hydrogen chloride gas and the resulting solution was allowed to stand overnight. The solvent was evaporated and the resulting solid was collected and washed with ether to provide ethyl 4-fluorobenzimidate hydrochloride as a white solid (20 g); NMR: 8.27 (m,2), 7.51 (m,2), 4.63 (q,2), 1.47 (t,3).
Reaction SMILES: [NH:1]([C:43](OC(C)(C)C)=[O:44])[C@H:2]([C:12]([N:14]1[CH2:42][CH2:41][CH2:40][C@@H:15]1[C:16]([NH:18][C@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:50]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[C@H:51](C(O)=O)[CH2:52][C:53](=[O:55])[NH2:54].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>Cl.CCOC(C)=O>[NH:50]([C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])[C@H:51]([C:43]([NH:1][C@H:2]([C:12]([N:14]1[CH2:42][CH2:41][CH2:40][C@@H:15]1[C:16]([NH:18][C@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:44])[CH2:52][C:53](=[O:55])[NH2:54]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: N=C(NCCC[C@H](NC(=O)[C@H]1CCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 3.0 g of Boc-Ser(Bzl)-D-Pro-Arg(NO2)-OBzl, 10 ml of 4N HCl-AcOEt, 1.2 g of Z-Asn-OH, 0.9 g of HOBt and 0.95 g of DCC in the same manner as in Example 7-(3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CO.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of methyl 4-(4-fluorophenylcarbamoyl)benzoate (2.98 g, 10.9 mmol) in THF (35 mL) was added MeOH (8 mL) and a solution of LiOH (1.79 g, 43.6 mmol) in H2O (8 mL). The reaction was stirred at room temperature for 2 h. The reaction was quenched upon the addition of 1N HCl (50 mL) and extracted with EtOAc (2×60 mL). The organic extracts were dried over MgSO4, and concentrated under vacuum to afford 4-(4-fluorophenylcarbamoyl)benzoic acid (2.43 g, 86%) as a white solid. 1H-nmr (400 MHz, d6-DMSO) δ 10.49 (s, 1H), 8.11-8.02 (m, 4H), 7.87-7.77 (m, 2H), 7.25-7.16 (m, 2H); MS (ESI) m/z 259.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4](O)([C:21]([F:24])([F:23])[F:22])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:20].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH3:20])[C:21]([F:23])([F:24])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C(C)C)cc2)c1=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=C1C(=O)N(c2ccc(C(C)C)cc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 2,5-dihydro-α-hydroxy-1-(4-isopropylphenyl)-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Brc1ccc(CN2CCCCC2)cc1
Reaction time: 27 h

Procedure:
A solution of 4-bromobenzaldehyde (5 g), piperidine (2.9 mL), and acetic acid (1.5 mL) in DCE (65 mL) was treated with sodium triacetoxyborohydride (6.9 g). After 27 h, the resulting mixture was treated with saturated aqueous sodium bicarbonate (50 mL), and extracted with DCM (2×50 mL). The combined organic phases were dried (magnesium sulfate) and evaporated. Kugelrohr distillation of the residue (160° C., 5 mm Hg) gave the title compound as a pale yellow oil (5.9 g).
Reaction SMILES: [C:1]([O:4][CH:5]=[C:6]([CH2:9][CH3:10])[CH2:7][CH3:8])(=[O:3])[CH3:2].ClS([N:15]=[C:16]=[O:17])(=O)=O.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOCC.CCCCCC>[C:1]([O:4][CH:5]1[NH:15][C:16](=[O:17])[C:6]1([CH2:9][CH3:10])[CH2:7][CH3:8])(=[O:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCC(=COC(C)=O)CC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC1(CC)C(=O)NC1OC(C)=O
Reaction time: 8 h
Yield: 35.9 %

Procedure:
A solution of the material prepared in Step A (169 gm, 1.19 mol) in CH2Cl2 (300 ml) was cooled in an ice-ethanol bath under N2 and chlorosulfonyl isocyanate (200 gm, 1.41 mol) was added via an addition funnel. The solution was allowed to rise to room temperature and stirred overnight. The reaction mixture was then diluted with Et2O and added to ice-cold NaHCO3 solution containing Na2SO3, keeping the solution below 5° C. during the addition. After the evolution of gas had ceased, the layers were separated and the aqueous layer was extracted with Et2O. The combined ether extracts were washed with H2O, brine and then dried over Na2SO4 before being evaporated to dryness. This gave a dark oil which was diluted with hexane (100 ml) and cooled in the freezer for 2 days. The low melting white solid which formed was filtered off and washed with cold hexane to give 79.2 gm of the title compound.