Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14](/[CH:16]=[CH:17]/[C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][C:14](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(C(C)(C)C)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccc(/C=C/C(=O)O)s2)cc1
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of methyl (E)-3-[5-(4-tert-butyl-phenyl)-thiophen-2-yl]acrylate (190 mg) of THF/ethanol (15/15 ml) was added at room temperature 2N sodium hydroxide solution (2.0 ml), and the mixture was stirred 18 hours. To the mixture was added 1N hydrochloric acid (5 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the precipitated crystals were collected by filtration, which were washed with hexane to give yellow crystals of (E)-3-[5-(4-tert-butylphenyl)thiophen-2-yl]acrylic acid (149.7 mg). This compound was used for the following reaction, without subjecting further purification.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:18])([CH2:8][CH2:9][C:10]([O:13][C:14](=[O:17])[CH2:15]Cl)([CH3:12])[CH3:11])[CH3:7])=[O:4].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[CH2:20]([NH:19][CH2:2][C:3]([O:5][C:6]([CH3:18])([CH2:8][CH2:9][C:10]([O:13][C:14](=[O:17])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:12])[CH3:11])[CH3:7])=[O:4])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(CCC(C)(C)OC(=O)CCl)OC(=O)CCl
Reactant: CCCCCCN
Solvent: ClCCl
Product: CCCCCCNCC(=O)OC(C)(C)CCC(C)(C)OC(=O)CNCCCCCC

Procedure:
The cleavable diol is made by the following manner. Compound (61) is reacted with 5 equivalents of 1-aminohexane (65) in methylene chloride. Wash with brine and dry to yield 2,5-dimethylhexane-2,5-diyl bis(2-(hexylamino)acetate) (66).
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[C@H:5]([O:8][CH3:9])[CH2:4][C@H:3]1[CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.CO>C1COCC1>[CH3:9][O:8][CH:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: CO[C@@H]1C[C@@H](COc2cccnc2)N(C)C1=O
Solvent: CO
Solvent: C1CCOC1
Product: COC1C[C@@H](COc2cccnc2)N(C)C1

Procedure:
To the compound from step 47a above, dissolved in 4 mL of THF, was added 3.39 mL of BH3 and the mixture was heated at reflux for 2 hours. Methanol was added to the reaction mixture and evaporated The residue was dissolved in anhydrous ethanol. Cesium fluoride was added, and the resultant solution was stirred under reflux for 16 hr. Evaporation of the solvent provided a white solid which was purified on a silica gel column. MS (DCI/NH3) m/e: 223 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.34 (m, 1H), 8.23 (t, J=3 Hz, 1H), 7.22 (m, 1H), 3.93-4.10 (m, 3H), 3.44-3.54 (m, 1H), 3.32 (s, 3H), 3.03-2.87 (m, 1H), 2.51 (s, 3H), 2.44-2.33 (m, 1H), 2.11-1.92 (m, 2H).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@@H:7]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([CH2:15][CH2:16][O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH2:10]1)(=[O:5])[CH3:4].[OH-:37].[Na+].OO>C(O)C.O.C1COCC1>[C:3]([O:6][C@@H:7]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:11]([OH:37])[CH2:10]1)(=[O:5])[CH3:4]
Reactant: CC(=O)O[C@H](CN1CC=C(CCOC(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Reactant: [OH-]
Agent: OO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)O[C@H](CN1CCC(CCOC(c2ccccc2)c2ccccc2)C(O)C1)c1ccccc1

Procedure:
With reference to FIG. 8, General procedure II was used. The quantities of the chemicals in order of addition are as follows: NaBH4 (0.0191 g, 0.505 mmol), THF (10 ml), BF3-ether complex (0.066 ml, 0.536 mmol), (S)-2-(4-(2-(benzhydryloxy)ethyl)-5,6-dihydropyridin-1(2H)-yl)-1-phenylethyl acetate 7b (0.115 g, 0.252 mmol), water (0.3 ml), ethanol (0.5 ml), 3N NaOH (0.2 ml) and 30% H2O2 (0.2 ml, 1.26 mmol).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([C:12]#[C:13][CH2:14][NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)(=[O:18])=[O:17])=O)=[CH:4][C:3]=2[O:2]1.[BrH:26]>C(O)(=O)C>[Br:26][C:13]1[CH:12]=[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[N:15]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)(=[O:18])=[O:17])[CH:14]=1
Reactant: Br
Reactant: O=C(C#CCNS(=O)(=O)c1cccc(Cl)c1)c1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: O=S(=O)(c1cccc(Cl)c1)n1cc(Br)cc1-c1ccc2c(c1)OCO2

Procedure:
The title compound is prepared from 3-(m-chlorobenzenesulfonylamino)-1-propinyl 3,4-methylenedioxyphenyl ketone and HBr in acetic acid following the procedure of Example 3b. 1H-NMR (300 MHz, CDCl3): 7.6-7.5 (m, 1H); 7.54 (d, J=2.0 Hz, 1H); 7.4-7.3 (m, 3H); 6.8-6.7 (m, 1H); 6.7-6.6 (m, 2H); 6.16 (d, J=2.0 Hz, 1H); 6.05 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([C:21]3[CH2:28][C:24]4([CH2:27][CH2:26][CH2:25]4)[O:23][N:22]=3)[CH:20]=2)[C:11]([O:13]C(C)(C)C)=[O:12])=[N:6][CH:7]=1.Cl>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([C:21]3[CH2:28][C:24]4([CH2:25][CH2:26][CH2:27]4)[O:23][N:22]=3)[CH:20]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C3=NOC4(CCC4)C3)c2)nc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)cc(C3=NOC4(CCC4)C3)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
To a solution of tert-butyl 3-(5-methylpyridin-2-yl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)benzoate (1.27 g, 3.36 mmol) in dichloromethane (8 mL) was added hydrogen chloride (4.0 M in dioxane; 5.05 mL, 20.1 mmol). The reaction mixture was stirred at ambient temperature. After 18 h, the mixture was concentrated. Dichloromethane was added and the suspension was filtered. The solid cake was washed with dihchloromethane and dried under reduced pressure gave the title compound (1.09 g). MS 323.2 (M+1).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=CC=[C:12]([C:13]3[CH:18]=CC=CC=3OC)[N:6]2[N:5]=1)=O.CS([C:24]1[N:29]=[CH:28][C:27]2=[CH:30][CH:31]=[C:32]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[N:26]2[N:25]=1)=O>>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:32]2[N:26]3[C:27]([CH:28]=[N:29][C:24]([N:5]4[C:18]5[CH:13]=[CH:12][N:6]=[CH:7][C:8]=5[N:9]=[CH:4]4)=[N:25]3)=[CH:30][CH:31]=2)[CH:34]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Product: c1cncc(-c2ccc3cnc(-n4cnc5cnccc54)nn23)c1

Procedure:
The compound was made in an analogous fashion to Example 322 replacing 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine to afford 60.57 mg of 1-(7-Pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-1H-imidazo[4,5-c]pyridine as a lyophilized powder. (M+H)=314.6. 1H NMR (400 MHz, DMSO, d6) δ 9.43 (s, 1H), 9.36 (s, 1H), 9.29 (s, 1H), 8.69 (m, 2H), 8.50 (m, 2H), 8.23 (m, 1H), 7.65 (m, 2H), 7.38 (d, 1H, J=4.84 Hz).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH:11]1[N:16]2[N:17]=[CH:18][N:19]=[C:15]2[NH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:12]1>CO.O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C@H:11]1[N:16]2[N:17]=[CH:18][N:19]=[C:15]2[NH:14][C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:12]1
Reactant: Fc1cccc(Cl)c1C1C=C(c2ccc(Cl)cc2)Nc2ncnn21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Fc1cccc(Cl)c1[C@@H]1C[C@H](c2ccc(Cl)cc2)Nc2ncnn21
Temperature: 25 °C
Yield: 89 %

Procedure:
Sodium borohydride (10 mmol) was added to a suspension of 7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (1 mmol) in methanol (5 mL). The reaction mixture was refluxed for 30 min, then cooled to room temperature, diluted with water (50 mL) and stirred sufficiently. The resulting mixture was filtered and washed with water to give the crude product, which was further purified by recrystallization from a mixture of EtOAc and Hexanes to provide the product as a white solid. Yield: 89%. m.p. 227-228° C. Rf=0.16 (EtOAc/Hexanes 33.3:66.7). MS: MH+=363. 1H NMR (500 MHz, DMSO-d6): δ 7.54-7.15 (m, 8H, CHar), 5.98-5.94 (m, 1H, CH), 4.82-4.78 (m, 1H, CH), 2.47-2.13 (m, 2H, CH2). HPLC: 99.8% (Method A, tR=3.67 min).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:6]([O:8][CH3:9])=[O:7])C.[Br:14][C:15]1[CH:20]=C[N:18]=[C:17](N)[CH:16]=1>CC(O)=O.O>[Br:14][C:15]1[CH:16]=[CH:17][N:18]=[C:1]([NH:2][CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:6]([O:8][CH3:9])=[O:7])[CH:20]=1
Reactant: Nc1cc(Br)ccn1
Reactant: COC(=O)C(=CN(C)C)C(=O)OC
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(=CNc1cc(Br)ccn1)C(=O)OC
Yield: 52.7 %

Procedure:
A solution of dimethyl 2-((dimethylamino)methylene)malonate (11.5 g, 65 mmol, 2.2 equiv) and 4-bromopyridin-2-amine (5 g, 28.9 mmol, 1 equiv) in AcOH (40 mL) was stirred at room temperature for 24 h. Then the reaction mixture was diluted with water, filtered, the filter cake was dried to give 4.8 g of the desired product. MS (ESI): 315, 317 (MH+).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:7][C:6](=[O:17])[N:5]([CH2:4][C@H:3]([CH3:18])[CH2:2][N:26]3[CH2:27][CH2:28][CH:23]([O:22][CH2:19][CH2:20][CH3:21])[CH2:24][CH2:25]3)[C:10]=2[CH:11]=1
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCOC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(OC)cc32)CC1
Yield: 56.9 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.556 g, 1.5 mmol) and 4-propyloxypiperidine (0.20 g, 1.4 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF42) (0.30 g, 53%). 1H NMR (CDCl3) δ 6.89 (d, J=8.8 Hz, 1H), 6.85 (d, 2.8 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.53 (q, J=14.6 Hz, 2H), 3.93 (d, J=6.6 Hz, 2H), 3.77 (s, 3H), 3.38 (t, J=6.8 Hz, 2H), 3.29-3.22 (m, 1H), 2.80-2.77 (t, 6.4 Hz, 1H), 2.65-2.61 (t, J=6.0 Hz, 1H), 2.29-2.00 (m, 5H), 1.88-1.84 (m, 2H), 1.65-1.53 (m, 4H), 0.94-0.87 (m, 6H); 13C NMR (CDCl3) δ 165.4, 155.5, 139.8, 129.8, 117.2, 107.1, 103.3, 75.1, 69.7, 68.0, 63.7, 56.0, 52.5, 51.9, 45.4, 31.6, 31.5, 29.2, 23.5, 16.9, 10.8; HPLC-MS (ammonium acetate) [M+H]+=377.3.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C-:23]#[N:24].[Na+]>CS(C)=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([CH2:2][C:23]#[N:24])[N:12]=2)=[CH:16][CH:17]=1
Reactant: [C-]#N
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(N(C)c2nc(CC#N)nc3ccccc23)cc1
Temperature: 120 °C

Procedure:
A mixture of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.14 mmol) and NaCN (21 mg, 0.43 mmol) in DMSO was heated by microwave for 10 min at 120° C. The reaction was quenched with H2O, diluted with EtOAc and the layers separated. The aqueous phase was extracted with EtOAc (2×5 mL), washed with brine, filtered over Na2SO4 and concentrated. Purification by gradient MPLC (SiO2, EtOAc/hexanes, 0-50%) gave the desired compound. 1H NMR (CDCl3) δ 7.74 (d, 1H), 7.56 (m, 1H), 7.13 (d, 2H), 7.02 (m, 1H), 6.94 (m, 3H), 4.04 (s, 2H), 3.85 (s, 3H), 3.62 (s, 3H); LC-MS (ESI+; 305 ([M+H]+)) and (ESI−; 303 ([M−H]−)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][C:11]=2[O:19][CH3:20])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][C:11]=1[O:19][CH3:20]
Reactant: COc1cc(C(N)=O)ccc1C(O)c1ccc(Cl)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(N)=O)ccc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 122.3 %

Procedure:
To a solution of 4-((3,4-dichlorophenyl)(hydroxy)methyl)-3-methoxybenzamide (Preparation 156, 142 mg, 0.435 mmol) in DCM (5 mL) was added TFA (0.065 mL, 0.870 mmol) followed by triethylsilane (0.083 mL, 0.522 mmol) and the reaction stirred at room temperature for 72 hours. Further TFA (0.065 mL, 0.870 mmol) and triethylsilane (0.083 mL, 0.522 mmol) were added and the reaction stirred for a further 24 hours. The reaction was partitioned between saturated aq. NH4Cl (20 mL), and EtOAc (20 mL). The layers were separated and the aqueous was extracted with EtOAc (2×20 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and the solvent removed in vacuo to give a white solid (165 mg, 100%). The material was used as crude in the next reaction without further purification.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[CH:10]=[O:11].Cl[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].O>C(OCC)C>[CH3:15][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([O:6][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:14]=1)[CH:10]=[O:11]
Reactant: Cc1cc(O)cc(C=O)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C=O)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
After adding 1.11 g of imidazole to a solution of 2.02 g of 3-hydroxy-5-methylbenzaldehyde [CAS No. 60549-26-0] in 20 ml of DIVEF, the reaction mixture was cooled to 0° C. Next, 3.56 ml of chlorotriisopropylsilane was added and the mixture was stirred at room temperature for 19 hours and 10 minutes. Water was added to the reaction mixture, and extraction was performed twice with diethyl ether. The organic layer was washed twice with water and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-diethyl ether) to give the title compound (3.86 g) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH:11]([S:15]([OH:18])(=[O:17])=[O:16])[C:12]([OH:14])=[O:13].C(N=C=NCCCN(C)C)C.O[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37]>CC(N(C)C)=O>[O:37]=[C:32]1[CH2:33][CH2:34][C:35](=[O:36])[N:31]1[O:13][C:12](=[O:14])[CH:11]([S:15]([OH:18])(=[O:16])=[O:17])[CH2:10][CH2:9][S:8][S:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)C(CCSSc1ccccn1)S(=O)(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CC(=O)N(C)C
Product: O=C(ON1C(=O)CCC1=O)C(CCSSc1ccccn1)S(=O)(=O)O
Yield: 80.2 %

Procedure:
A mixture of 4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid (245 mg, 0.792 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (345 mg, 2.222 mmol) and 1-hydroxypyrrolidine-2,5-dione (120 mg, 1.043 mmol) were stirred in 8 ml of DMA overnight. The resulting solution was evaporated and the residue was purified on a silica column using MeOH/CH2Cl2 (1:10 to 1:5) containing 0.5% acetic acid as eluting solvent to afford 1-(2,5-dioxopyrrolidin-1-yloxy)-1-oxo-4-(pyridin-2-yldisulfanyl)butane-2-sulfonic acid (258 mg, 0.635 mmol, 80% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.IC.[C:31](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:31])[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CCc1ccc(N(C)Cc2cccc(-c3c(C)cccc3C)c2)cc1
Yield: 47.9 %

Procedure:
To a solution of methyl 3-(4-{[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.598 g, 1.60 mmol) and iodomethane (0.498 mL, 8.00 mmol) in acetone (10 mL) was added potassium carbonate (0.332 g, 2.40 mmol), and the mixture was heated under reflux under a nitrogen atmosphere for 6 hr. After cooling, the reaction mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-25% ethyl acetate/hexane) to give the title compound (0.297 g, yield 48%) as a yellow oil.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([O:5][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)OCc1ccccc1

Procedure:
Boc-DL-Pip-OH (2.29 g, 10 mmol) and benzyl bromide (1.79 ml, 15 mmol) were reacted in DMF (20 ml) in the presence of triethylamine (2.1 ml, 15 mmol) to obtain Boc-DL-Pip-OBzl as an oily product. This product was reacted with 2 N HCl/dioxane (5 eq.) for 3 hours to obtain H-DL-Pip-OBzl-HCl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Br:22])[CH:16]=1.[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Br:22])[CH:16]=1)[CH3:28]
Reactant: COC(=O)CCCc1ccccc1NC(=O)c1ccc(Cl)c(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
To 4-[2-(3-bromo-4-chloro-benzoylamino)-phenyl]-butyric acid methyl ester (1.04 g, 2.54 mmol) in DMF (10 mL) at 0-5° C., was added NaH (152 mg, 3.81 mmol, 60% in mineral oil) in two portions. The mixture was stirred for 15 min at 0° C. and 15 min at rt. After addition of iodomethane (316 μl, 5.08 mmol), the mixture was stirred at room temperature for 12 hrs and was partitioned between ethyl acetate and citric acid. The separated organic layer was then washed with brine and dried over Na2SO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (4/1) up to hexane/ethyl acetate (3/2) yielded 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid methyl ester (1.0 g). MS [M+H]+: 426.0; tR=2.46 min. (method 1)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH:12]([NH2:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1CCCCC1>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:11]
Reactant: CCOC(=O)CCCCCBr
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: C1CCCCC1
Product: CCOC(=O)CCCCCNC(c1ccccc1)c1ccccc1
Yield: 69.2 %

Procedure:
22.3 g of ethyl 6-bromocaproate, 55 g of benzhydrylamine and 30 ml of cyclohexane are stirred at room temperature for 20 days. Preparation analogously to Example 19 yields 22.5 g (69% of theory) of ethyl-6-benzhydrylaminocaproate [B.P. 162° to 167° (0.02 mm Hg)].
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:30].[K+]>[Cu].O>[I:30][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [I-]
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Agent: [Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c(I)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To .05 moles of ethyl 3-amino-4-cyclohexylphenylglyoxylate dissolved in a mixture of 50 g. of ice water and .06 moles of concentrated sulfuric acid at 0° C is added a solution of 0.05 moles of 95% sodium nitrite in 8 ml. of water. Stirring is continued for 1/2 hour and then 1.5 ml. of concentrated sulfuric acid is added. This solution is poured into an ice cold solution of .06 moles of potassium iodide in 10 ml. of water. To this is added 0.075 g. copper bronze with stirring and the solution is warmed slowly on a water bath to about 80° C for 2 hours. After cooling to room temperature the reaction mixture is extracted thrice with 15 ml. portions of chloroform. This is then washed with dilute thiosulfate solution, water, dried over sodium sulfate and evaporated in vacuo. The residue is crystallized to obtain 3-iodo-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: [NH:1]1[CH2:9][C@@H:7]([OH:8])[CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:10](ON1C(=O)CCC1=O)([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11].O1CCOCC1.Cl>C(=O)([O-])O.[Na+]>[N:1]1([C:10]([O:12][CH2:13][CH:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:11])[CH2:9][C@@H:7]([OH:8])[CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@H]1C[C@H](O)CN1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1C[C@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
262 mg (2.0 mmol) of D-Hyp-OH was dissolved in 5 ml of a saturated aqueous solution of sodium hydrogencarbonate under stirring and a mixture of 742 mg (2.2 mmol) of Fmoc-OSu and 10 ml of 1,4-dioxane was added dropwise under cooling with ice; thereafter, and the mixture was stirred at room temperature for 3 days. In the meantime, a saturated aqueous solution of sodium hydrogencarbonate was added as appropriate to keep the pH of the reaction mixture at 8-9. After being rendered acidic with hydrochloric acid under cooling with ice, the reaction mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluting solvents were chloroform and acetic acid supplemented chloroform:methanol=10:1); to remove the acetic acid used in eluting, the fractions were once concentrated under reduced pressure and dissolved again in ethyl acetate; thereafter, the solution was washed with water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give a colorless powder in the amount of 660 mg (93%).