Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10]([C:20](O)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=C=O)=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10]([C:20]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:26][CH:27]=3)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To 0.70 g (0.0022 mol) of the product obtained in Step B, dissolved in 10 mL toluene, was added 0.625 g (0.0030 mol) α,α,α-trifluoro-p-tolylisocyanate and 0.30 g (0.0029 mol) triethylamine. The reaction mixture was heated at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The crude product was triturated with ether to afford 0.50 g of a white solid, mp 183°-184° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[CH:11][C:10]=2[CH3:18])[CH:6]=[CH:7][CH:8]=1)=O.[ClH:19].[CH3:20][C:21]1([CH3:29])[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.CO>[ClH:19].[CH3:20][C:21]1([CH3:29])[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][CH2:1][C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[CH:11][C:10]=3[CH3:18])[CH:6]=[CH:7][CH:8]=2)[CH2:23][CH2:22]1
Reactant: CC1(C)CCC(CN)CC1
Reactant: Cc1cc(C(N)=O)ccc1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1cc(C(N)=O)ccc1-c1cccc(CNCC2CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3′-formyl-2-methyl-4-biphenylcarboxamide (0.15 g, 0.63 mmol; Ex. IX-23), 4,4-dimethylcyclohexylmethylamine hydrochloride (0.28 g, 1.6 mmol; Ex III-1) and acetic acid (4 drops) in methanol was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (0.34 g, 1.6 mmol) was added in one portion and the mixture was stirred at room temperature for 72 hr. Water (10 mL) was added and the mixture was stirred at room temperature for 2 hr. The mixture was concentrated in vacuo to remove the methanol and the residue was taken up in a mixture of ethyl acetate and 5% Na2CO3 (aq). The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, silica gel was added and the mixture was concentrated in vacuo.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:36][CH3:37])([CH:9]([S:34][CH3:35])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].I([O-])(=O)(=O)=[O:39].[Na+]>CO.O>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:36]([C:7]([CH2:5][CH3:6])([CH:9]([S:34]([CH3:35])=[O:39])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:37]
Reactant: CCC(C)(CC)C(SC)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C)(CC)C(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)S(C)=O
Temperature: 5 °C
Reaction time: 5 h
Yield: 108.1 %

Procedure:
A solution of diethyl 3-methylthio-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.53 g, prepared as described in Example 39) in methanol (7 ml) was added slowly to a stirred solution of sodium periodate (0.23 g) in water (3 ml) cooled to 5° C. After ten minutes, the cooling bath was removed and stirring continued for a further five hours. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate, and evaporated under reduced pressure to give diethyl 3-methanesulphinyl-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.59 g, white gum) as a 2:1 mixture of diastereoisomers. NMR (CDCl3): δ1.3(6H,m), 1.7-1.9(2H,m), 2.4(3H,2xs), 2.5-2.7(2H,m), 4.05(5H,m), 7.1-7.3(15H,m), 8.0(1H,2xs).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[C:11]([Cl:18])[N:10]=2)[CH2:5][CH2:4]1.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27](NC1CCN(C2C=C(C3N=CON=3)C=C(Cl)N=2)CC1)=[O:28]>>[C:15]([C:13]1[CH:12]=[C:11]([Cl:18])[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([NH:2][C:27]([C:21]3[NH:22][C:23]([CH3:26])=[C:24]([Cl:25])[C:20]=3[Cl:19])=[O:28])[CH2:4][CH2:5]2)[CH:14]=1)(=[O:17])[CH3:16]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(-c4ncon4)cc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: CC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Product: CC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1

Procedure:
The title compound was synthesized by an analogous method to Example 18 starting from 1-[2-(4-aminopiperidin-1-yl)-6-chloropyridin-4-yl]ethanone hydrochloride salt (Intermediate 197) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3).
Reaction SMILES: [OH:1]O.O.S(=O)(=O)(O)O.[CH3:9][C:10]([OH:16])([CH3:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>ClCCl>[CH3:9][C:10]([O:16][OH:1])([CH3:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: OO
Reactant: CC(C)(C)C(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(C)(C)OO
Reaction time: 2 h
Yield: 91.7 %

Procedure:
A 300-ml four-necked flask equipped with a stirrer, thermometer and dropping funnel was charged with 73.7 g of a 50% hydrogen peroxide aqueous solution. Stirring was started, the flask was kept at a temperature below 20° C. by water cooling, and 51.7 g of 98% conc. sulfuric acid was added dropwise to form a mixed acid. While the flask was cooled at a temperature of 0° to 5° C. with an ice bath, with stirring, 40 ml of a dichloromethane solution containing 42.9 g of 1,1,2,2-tetramethylpropyl alcohol which was previously synthesized according to Journal of the American Chemical Society/89:7/Mar. 29, 1967, was slowly added dropwise. At the end of addition, stirring was continued for a further 2 hours. The reaction solution was washed with pure water until the organic layer became neutral. The organic layer was dried over anhydrous sodium sulfate and distilled of the solvent, yielding 47.4 g of 1,1,2,2-tetramethylpropylhydroperoxide having structural formula (2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[I-].[Na+].C([O-])([O-])=O.[K+].[K+]>CCOCC.CC(C)=O>[N:20]1([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#CC1(c2ccc(O)cc2)CCCCC1
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Yield: 50.8 %

Procedure:
1-(4-Hydroxyphenyl)cyclohexanecarbonitrile (1.70 g, 8.45 mmol), 1-(3-chloro-propyl)-pyrrolidine (1.87 g, 12.67 mmol), acetone (50 mL), sodium iodide (0.444 g, 2.96 mmol) and K2CO3 (5.45 g, 39.44 mmol) were heated to 50° C. overnight. The solvent was evaporated and the crude product was taken into DCM, washed with 0.5N NaOH, extracted with 0.5N HCl solution and washed with DCM. The aqueous layer was basified with 0.5N NaOH and extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, washed with DCM and concentrated in vacuo to give a yellowish solid. The solid was slurried in ether, filtered, washed with ether to give the title compound as a white solid (1.34 g, 51%). 1H NMR (400 MHz, CDCl3) δ7.30 (d, 2H), 6.83 (d, 2H), 3.95 (t, 2H), 2.54 (t, 2H), 2.44 (m, 4H), 2.06 (m, 2H), 1.92 (m, 2H), 1.84-1.58 (m, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(O)CCCCc1cccc(Br)c1
Solvent: Clc1ccccc1
Product: O=C1CCCCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To a solution of 5-(3-Bromo-phenyl)-pentanoic acid (6 g, 23 mmol) in chlorobenzene (300 mL) was added PPA (18 g) and the mixture was heated to reflux for 8 h. The mixture was cooled to rt and filtered. The filtrate was concentrated under reduced pressure then purified by silica gel chromatography using a solvent system of 10:1 petroleum ether/EtOAc to give 2-bromo-6,7,8,9-tetrahydro-benzocyclohepten-5-one (2.4 g, 42.9%). MS ESI calcd for C11H11BrO [M+H]+ 239, found 239.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:19]2([OH:22])[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: O=C1CCOCC1
Product: OC1(c2cccc(OCc3ccccc3)c2)CCOCC1
Yield: 77 %

Procedure:
Using the Grignard reaction procedure described in the portion of Example 1 which is concerned with the preparation of starting materials, 3-benzyloxybromobenzene was reacted with tetrahydropyran-4-one to give 4-(3-benzyloxyphenyl)-4-hydroxytetrahydropyran in 77% yield, m.p. 84°-86° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([N:23]2[CH2:30][CH2:29][CH2:28][C@H:24]2[C:25]([NH2:27])=[O:26])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (WO 2003101442, 38.2 g, 0.125 mol), L-prolinamide (14.3 g, 0.125 mol,) N-methyl morpholine (34.4 mL, 0.313 mol,) and HOBt (18.65 g, 0.138 mol) were dissolved in DMF (400 mL) with stirring. EDC (26.46 g, 0.138 mol) was added portionwise and the solution was stirred at room temperature for 3 hours. The majority of the DMF was removed in vacuo and the residue was diluted with ethyl acetate (1 L.) This solution was washed with cold 0.5M HCl solution (200 mL), twice with water (200 mL), saturated aqueous NaHCO3 solution, brine, and then dried over MgSO4. After filtering and evaporating, the crude material was dissolved in hot ethyl acetate (˜150 mL) with stirring. While keeping the solution hot, hexanes (˜150 mL) was added until the solution was cloudy. Cooling slowly to room temperature while stirring gave a thick slurry. The solid was filtered off and washed with 1:1 ethyl acetate:hexanes, followed by a wash with hexanes. After drying, the product 1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-L-prolinamide was obtained as a white solid (34.4 g, 69% yield). LC/MS m/z 402 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCBr)cc1
Reaction time: 5 h
Yield: 14.4 %

Procedure:
3-(4-Methoxyphenyl)-1-propanol (5.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (8.86 g) and N-bromosuccinimide (5.94 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=100:1-3:1) to give the object product (990 mg) as a colorless oil.
Reaction SMILES: C[Zn]C.[CH:4]([Mg]Br)=[CH2:5].[F:8][C:9]1[CH:10]=[C:11]([CH:20]=[C:21]([CH2:23][F:24])[CH:22]=1)/[CH:12]=[N:13]/[S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15]>C1COCC1>[F:8][C:9]1[CH:10]=[C:11]([C@H:12]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH:4]=[CH2:5])[CH:20]=[C:21]([CH2:23][F:24])[CH:22]=1
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cc(F)cc(CF)c1
Agent: C[Zn]C
Solvent: C1CCOC1
Product: C=C[C@@H](N[S@](=O)C(C)(C)C)c1cc(F)cc(CF)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Dimethyl Zinc (2M in Toluene) (0.434 mL, 0.868 mmol) and vinylmagnesium bromide (1M in THF) (4.51 mL, 4.51 mmol) was mixed at room temperature for 20 min under argon before cooling down to −78° C., then (R,E)-N-(3-fluoro-5-(fluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (0.900 g, 3.47 mmol) in dry THF (11.57 mL) as added dropwise, maintain the internal temperature between −74° C. to −72° C., after addition the reaction mixture was stirred at −78° C. for 1 h, the reaction was quenched by sat.NH4Cl, THF was removed in vacuo, then extracted by EtOAc. The organic was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (0-30% EtOAc/heptaneatane) to yield product 660 mg, LCMS (m/z): 288.0 (MH+), 0.83 min. 1H NMR (400 MHz, CDCl3) δ ppm 7.14 (s, 1H), 7.03 (d, J=9.0 Hz, 1H), 7.07 (d, J=9.4 Hz, 1H), 5.90 (ddd, J=7.4, 10.1, 17.3 Hz, 1H), 5.45-5.35 (m, 2H), 5.35-5.25 (m, 2H), 5.01-4.94 (m, 1H), 3.45 (br. s., 1H), 1.30-1.22 (m, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH:19][C:20]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:21]=2[C:22]([O:24]C)=[O:23])[CH2:13]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH:19][C:20]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:21]=2[C:22]([OH:24])=[O:23])[CH2:13]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1NC1Cc2ccc(Nc3ccc(Cl)c(Cl)c3)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NC1Cc2ccc(Nc3ccc(Cl)c(Cl)c3)cc2C1
Yield: 18 %

Procedure:
By following the procedure of Example 4, methyl 2-[5-(3,4-dichlorophenylamino)-indan-2-ylamino]-5-nitro-benzoate was reacted with sodium hydroxide in THF/MeOH to give 2-[5-(3,4-dichlorophenylamino)-indan-2-ylamino]-5-nitro-benzoic acid (0.017 g, 18% yield). MS (APCI) m/z 457.9 (M++1).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:7]1)(=O)=O.[C:36]([O-:39])(=[S:38])[CH3:37].[K+]>CN(C)C=O>[C:36]([S:38][CH:6]1[CH2:9][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:7]1)(=[O:39])[CH3:37]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Temperature: 80 °C
Reaction time: 9 h
Yield: 54.2 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (540 mg, 1.06 mmol) (obtained as described in Reference Example 77(3)) in dimethylformamide (27 ml) was added potassium thioacetate (726 mg, 6.36 mmol) at room temperature, and the mixture was stirred in an oil bath (80° C.) for 9 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:6)→ethyl acetate as the eluant to afford 3-acetylthio-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (281 mg, yield 54%) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O)cc2)=CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound I) 50.0 mg (0.095 mmol) in 1.0 ml of THF at room temperature was added 73.2 mg (0.29 ml, 0.29 mmol) of tetrabutylamonium fluoride (1 M solution in THF). After stirring overnight, the solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (4:1, Hexanes:EtOAc) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.98 (2H, d, J=8.2 Hz), 7.52 (2H, d, J=8.3 Hz), 7.41-7.20 (5H, m), 6.88 (2H, d, J=8.4 Hz), 5.96 (1H, t, J=4.5 Hz), 4.37 (2H, q, J=7.1 Hz), 2.34 (2H, d, J=4.5 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:20][C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
In 150 ml of chloroform were dissolved 26.5 g of Boc-Phe-OH and 22.9 g of H-Phe-OEt.HCl, to which 18.4 ml of WSC was added under cooling at 0° C. This was then subjected to stirring for 2 hours at -10° C., then 15 hours at room temperature. The reaction solution was concentrated in vacuo and the residue was dissolved in 20 ml of ethyl acetate, washed successively with 1 N HCl, water, 5% aqueous NaHCO3 solution and water, dried over Na2SO4 then again concentrated in vacuo. The thus obtained residue was added to n-hexane and the resultant amorphous precipitate was collected, and was recrystallized from n-hexane, which gave 37 g (yield=84%) of the title product. m.p. 106.5°-107.5° C. [α]D25 -9.7° (C 1.3, DMF). Analysis--Calculated for C25H32O5N2 : C, 68.16; H, 7.32; N, 6.36. Found: C, 67.85; H, 7.32; N, 6.49.
Reaction SMILES: C([NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[NH:15][C:14]=12)C1C=CC=CC=1.C([O-])=O.[NH4+]>[C].[Pd].CO>[NH2:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[NH:15][C:14]=12
Reactant: COC(=O)c1cc2ccnc(NCc3ccccc3)c2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cc2ccnc(N)c2[nH]1
Yield: 74.5 %

Procedure:
A mixture of methyl 7-(benzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (3.2 g), ammonium formate (7.2 g), 10% palladium-carbon (50% containing water, 3.2 g) and methanol (120 mL) was heated under reflux for 4 hr. Ammonium formate (6.0 g) was further added to the reaction solution, and the mixture was heated under reflux for 16 hr. The insoluble material was filtered off by passing the reaction solution through celite without cooling. The filtrate was concentrated and the obtained crystals were washed with methanol to give the title compound (1.62 g, yield 75%) as pale-yellow prism crystals. melting point not less than 300° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:34]1([CH2:37]Br)[CH2:36][CH2:35]1>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:37][CH:34]3[CH2:36][CH2:35]3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2CC1CC1)N1CCN(C2CCC2)CC1
Yield: 80 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (80%).
Reaction SMILES: [CH2:1]1[NH:5][CH:4]([C:6]([OH:8])=[O:7])[CH:3]=[CH:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>C([O-])(O)=O.[Na+]>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:5]2[CH2:1][CH:2]=[CH:3][CH:4]2[C:6]([OH:8])=[O:7])=[O:18])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(O)C1C=CCN1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)C1C=CCN1C(=O)Nc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
0.250 g (2.21 mmol) 3,4-dehydro-DL-proline are dissolved in 15 ml of 5% NaHCO3 solution, combined with 0.678 ml (4.42 mmol) 4-chlorophenylisocyanate and stirred for 16 h at 80° C. Then the mixture is cooled, filtered and the residue is washed with water. The filtrate is adjusted to pH 1 with semi-concentrated HCl, extracted 2× with ethyl acetate, dried on sodium sulphate and concentrated i. vac.