Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2(O)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].CCN(S(F)(F)[F:30])CC.[NH4+].[Cl-]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2([F:30])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)c(O)c(F)c2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2cc(F)c(O)c(F)c2)CC1
Reaction time: 0.5 h

Procedure:
In a plastic container, a solution of tert-butyl 4-(3,5-difluoro-4-hydroxyphenyl)-4-hydroxypiperidine-1-carboxylate D1f (0.4 g, 1.2 mmol) in dichloromethane (10 mL) is treated with DAST (0.31 mL, 2.4 mmol) at room temperature. The mixture is stirred for 30 min and treated with sat. aqueous NH4Cl (3 mL). The mixture is extracted with dichloromethane, washed with sat. aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to yield tert-butyl 4-(3,5-difluoro-4-hydroxyphenyl)-4-fluoropiperidine-1-carboxylate D1g as an oil. 1H-NMR (400 MHz, CDCl3) δ=7.01 (d, J=7.2 Hz, 2H), 4.03 (br. s, 2H), 3.19 (br. s, 2H), 1.88 td, J=13.3, 4.8 Hz, 2H), 1.66 (dq, J=14.1, 2.2 Hz, 2H), 1.47 (s, 9H); 19F-NMR (376 MHz, CDCl3) δ=−134.1 (2F), −161.9 (1F). LCMS calcd. for C16H21F3NO3+ ([M+H]+): 332.1, found: 331.8. The product is used without purification.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[B:6]([O:11]C)(OC)[O:7]C.Cl>O1CCCC1>[CH:1]1[C:3]2[CH:4]=[C:2]([C:3]3[CH:4]=[CH:3][C:2]([B:6]([OH:11])[OH:7])=[CH:1][CH:4]=3)[C:1]3[C:1](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:2]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COB(OC)OC
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2cc3ccccc3c3ccccc23)cc1
Temperature: -80 °C
Yield: 74 %

Procedure:
Into a 100 mL three-neck flask, 2.0 g (11 mmol) of PnPBr obtained in the above Step 1 was put, and the air in the flask was replaced with nitrogen. Into the flask, 35 mL of tetrahydrofuran (THF) was added, and then this solution was stirred at −80° C. Into this solution, 8.3 mL (14 mmol) of n-butyllithium (1.6 mol/L hexane solution) was dropped by a syringe. After the dropping, this solution was stirred at the same temperature for 2 hours. After the stirring, 1.3 mL (11 mmol) of trimethyl borate was added to this solution, and the solution was stirred for 18 hours while the temperature of the solution was being increased to room temperature. Into this solution, hydrochloric acid (1.0 mol/L) was added, and then the solution was stirred for one hour. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with saturated saline, and magnesium sulfate was added to the organic layer so that moisture was adsorbed. The mixture was gravity-filtered, and the obtained filtrate was concentrated to give the objective white solid. This solid was recrystallized with ethyl acetate and hexane to give the objective substance as 2.5 g of white powdered solid in a yield of 74%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:12]([NH2:14])=[S:13].[O-]CC.[Na+].[C:19]([CH2:21][C:22](OCC)=[O:23])#[N:20].S(=O)(=O)(O)O>CCO.O>[NH2:20][C:19]1[N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:12](=[S:13])[NH:14][C:22](=[O:23])[CH:21]=1
Reactant: CCOC(=O)CC#N
Reactant: NC(=S)NCc1nc2ccccc2[nH]1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(=O)[nH]c(=S)n1Cc1nc2ccccc2[nH]1
Reaction time: 7 h
Yield: 30.3 %

Procedure:
To a solution of N-(1H-benzimidazol-2-ylmethyl)thiourea (0.85 g, 4.1 mmol, obtained from Example 8(a)) in EtOH (10 mL) was added, dropwise, in portions during 7 h, sodium ethoxide (1M, 16.6 mL, 16.6 mmol) and a solution of ethyl cyanoacetate (1.76 mL, 16.6 mmol) in EtOH (10 mL) while the reaction was stirred at 80° C. After cooling to r.t. water (200 mL) was added followed by 2M sulphuric acid, the mixture was concentrated until precipitation occurred. The formed solid was collected by filtration, washed with water and dried to give the title compound (0.34 g, 30%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(Cl)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(Cl)cc2)n1
Yield: 14 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (8 mg, yield 14%). 1H NMR (CDCl3) δ 8.59 (t, J=1.7 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 8.12 (d, J=6.7 Hz, 1H), 7.99 (d, J=6.6 Hz, 2H), 7.64 (t, J=7.7 Hz, 2H) 7.49 (s, 1H), 7.38 (d, J=4.9 Hz, 1H), 2.03 (s, 2H), 1.40 (s, 6H). MS (ESI) m/z: Calculated for C23H18ClF3N4O3: 490.10. found: 491.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:20]I>C1C=CC=CC=1>[I:20][C:8]1([CH2:16][C:17]([OH:19])=[O:18])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[C:11]2[CH:12]=[CH:13][CH:14]=[C:10]2[O:9]1
Reactant: II
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Solvent: c1ccccc1
Product: O=C(O)CC1(I)OC2=CC=CC2=CC1c1ccccc1

Procedure:
To a solution of 2.08 g. (8.25 mmoles) of 3-phenyl-7-benzofuranacetic acid in 10 ml. of benzene at 60° C. is slowly added small portions of yellow mercuric oxide (1.45 g., 6.7 mmoles) and iodine (2.09 g., 8.25 mmoles). After about two hours the mixture is filtered, then the filtrate is evaporated to dryness to provide 2-iodo-3-phenyl-7-benzofuranacetic acid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.N1CCCCC1>C(O)C>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:20][CH:19]=1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N=Cc1ccc(Cl)cc1
Yield: 55 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in 10 mL of ethanol and 4-chlorobenzaldehyde (644 mg, 1.0 eq.) and piperidine (0.10 eq, 39 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-chlorobenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-chlorobenzaldehyde. Product was allowed to dry under vacuum for 1 hr (850 mg, 55% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[S:31]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]([N:12]2[CH2:13][CH2:14][N:15]([CH2:36][C:33]3[CH:34]=[CH:35][S:31][CH:32]=3)[CH2:16][CH2:17]2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:9][CH:10]=1)[CH3:30]
Reactant: O=Cc1ccsc1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCN(Cc3ccsc3)CC2)cc1
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of compound 1 (500 mg; 0.99 mmol) in methanol (10 ml) was added thiophene 3-carboxaldehyde (104 ul; 1.19 mmol) followed by acetic acid (0.1 ml; 1%) and sodium cyano borohydride (186.6 mg; 2.97 mmol). The reaction mixture was stirred overnight, then sodium hydroxide 2N was added and the mixture extracted with methylene chloride (3×). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN/H2O (TFA as the buffer) gave 258 mg of desired product (TFA salt).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:16](=[O:18])[NH2:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C.[C:19]([O:23][C:24]([NH:26][C@H:27]([C:38]([OH:40])=O)[C@@H:28]([CH3:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][C@H:27]([C:38]([NH:8][C@@H:9]([C:16](=[O:18])[NH2:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:40])[C@@H:28]([CH3:37])[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Product: COC(=O)CC[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)C(N)=O
Yield: 64.7 %

Procedure:
Methyl t-butyloxycarbonyl-D-isoglutaminate (0.65 g, 2.5 mmol) and t-butyloxycarbonyl-O-benzyl-L-threonine (0.77 g, 2.5 mmol) were reacted by the similar procedure to that described in Example 44 (I) to obtain methyl t-butyloxycarbonyl-O-benzyl-L-threonyl-D-isoglutaminate (0.73 g). m.p. 131°-132° C. [α]D22 +7.0° (C 0.5, ethanol). Rf3 =0.39, Rf5 =0.46.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.I[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:27]1[CH:36]=[CH:35][C:34]2[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=2[CH:28]=1>C(O)C>[CH:1]1([NH:4][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=3)=[CH:12][C:11]=2[C:27]2[CH:36]=[CH:35][C:34]3[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=3[CH:28]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCCCNC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 59.4 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 1.7 ml (24.5 mmol) of cyclopropylamine with 670 mg (1.12 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (obtained in Example 1b) in 50 ml of ethanol. 350 mg of ethyl 4′-(3-cyclopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=141° C., yield=59%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=O)[CH:5]2[CH3:13].B.CO.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH2:6][CH:5]2[CH3:13]
Reactant: CC1C(=O)Nc2cc(F)c(F)cc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC1CNc2cc(F)c(F)cc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere 1.6 g (8.7 mmol) 5,6-difluoro-3-methyl-1,3-dihydro-indol-2-one were placed in 50 mL THF. 18 mL (18 mmol) 1 M borane in THF were slowly added dropwise. The reaction mixture was stirred for 2 h at 70° C. After cooling to RT 10 mL methanol and 30 mL semiconc. HCl were successively added dropwise and then the mixture was refluxed for 1 h. After cooling to RT it was extracted with EtOAc. The aqueous phase was made alkaline with 4M NaOH solution and extracted with DCM. The organic phase was dried, filtered and evaporated down.
Reaction SMILES: S(OC)(OC)(=O)=O.[CH3:8][N:9]([CH3:12])[CH:10]=O.[CH2:13]([NH2:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CNC.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:8][N:9]([CH3:12])[CH:10]=[N:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CN(C)C=O
Reactant: CCCCCCCCN
Agent: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: CCCCCCCCN=CN(C)C
Temperature: 50 °C
Yield: 96.6 %

Procedure:
Dimethyl sulfate (34.7 g, 0.27 mole) was placed in a 300 ml 3-necked round bottom flask equipped with a heating mantle, magnetic stirrer, thermometer, addition funnel and calcium chloride drying tube. The reaction was stirred and warmed to 50° C. Heating was discontinued and dimethyl formamide (26 g, 0.36 mole) was added over a 10 minute period. The reaction temperature gradually rose to 85° C. The reaction was stirred an additional hour during which time the temperature fell to 45° C. The reaction was cooled and maintained between 0° and 10° C. while n-octylamine (32.3 g, 0.25 mole) in toluene (50 ml) was added over a period of 15 minutes. After the addition was complete, the addition funnel and drying tube were replaced by a dry ice/acetone condenser and gas inlet tube. The cooling bath was removed and gaseous dimethylamine (6.1 g, 0.14 mole) was added over a period of about 5 minutes. The reaction was stirred at room temperature for 1 hour. The reaction was extracted with sodium hydroxide (12.5 g, 0.31 mole) in water (50 ml), washed with brine (25 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 44.5 g (97 %) of the title compound as a very light yellow liquid. GLC showed 99.6% of volatiles in a single peak.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=2.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=1)=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=2
Reactant: CN1CCC(=O)CC1
Reactant: Cc1cc2cc(NS(C)(=O)=O)ccc2[nH]1
Product: Cc1[nH]c2ccc(NS(C)(=O)=O)cc2c1C1=CCN(C)CC1
Yield: 33.4 %

Procedure:
Beginning with 1.37 gm (6.1 mMol) 2-methyl-5-methanesulfonylamino-1H-indole and 0.98 mL (7.9 mMol) 1-methyl-4-piperidone, 0.65 gm (33.3%) of the title compound were recovered as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27](I)=[C:26]([NH:31][CH3:32])[CH:25]=1.[Cu][C:35]#[N:36].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([C:35]#[N:36])=[C:26]([NH:31][CH3:32])[CH:25]=1
Reactant: CNc1cc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)ccc1I
Reactant: N#C[Cu]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)ccc1C#N
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To 10 mL of DMF were added 0.350 g (0.560 mmol) of N-(2-chloro-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-4-iodo-3-(methylamino)benzamide and 0.200 g (2.25 mmol) of copper (I) cyanide, followed by stirring at 140° C. for 1 hour and 30 minutes. A saturated aqueous sodium thiosulfate solution was poured into the reaction solution to quench the reaction, and the organic layer was collected with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=5:1→3:1) to prepare 0.250 g (yield 86%) of a target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(O)cc2C1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-7-hydroxytetralin (400 mg) was dissolved in N,N-dimethylformamide (8 ml), and cesium carbonate (3.16 g) and ethyl 4-bromobutyrate (650 μl) were added to the solution at room temperature with stirring. After reaction for 1.5 hours, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) gave ethyl (S)-4-[2-(tert-butoxycarbonyl-amino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]butyrate (488 mg) having a melting point of 96-98° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]([OH:26])=O)=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[CH2:52]([NH2:55])[CH2:53][NH2:54]>CN(C)C=O.CO.C(Cl)(Cl)Cl>[NH2:54][CH2:53][CH2:52][NH:55][C:24](=[O:26])[CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:14]([C:9]2[NH:8][C:7]3[N:6]([CH2:28][CH2:29][CH3:30])[C:5](=[O:31])[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]=3[N:10]=2)[CH3:27])=[CH:17][CH:18]=1
Reactant: NCCN
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(NCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(NCC(=O)NCCN)cc3)[nH]c2n(CCC)c1=O
Reaction time: 1 h

Procedure:
Dissolve 2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylamino]acetic acid (754 mg, 1.87 mmol) in dimethylformamide (20 mL) and treat with N-hydroxysuccinimide (215 mg, 1.87 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (751 mg, 3.92 mmol). Stir for 1 hour and add to a stirring solution of ethylenediamine (20 mL of a 10% solution in methanol). Stir for 1 hour and dilute with chloroform (600 mL). Separate the organic phase, wash with 5% sodium carbonate (200 mL), then brine (300 mL). Dry (MgSO4) and evaporate the solvent in vacuo. Purify by radial chromatography to give the title compound.
Reaction SMILES: CS(O)(=O)=O.[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[C:30]1[S:34][C:33]([NH:35][C:36]([O:38][CH3:39])=[O:37])=[N:32][CH:31]=1)[CH:25]([NH:40][C:41](OC(C)(C)C)=[O:42])[C:24]2=[O:48])=[O:21])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[S:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[CH2:54]C(Cl)=O.C(N(CC)CC)C>C(#N)C.C(Cl)Cl.C(=O)(O)[O-].[Na+].O1CCCC1>[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[C:30]1[S:34][C:33]([NH:35][C:36]([O:38][CH3:39])=[O:37])=[N:32][CH:31]=1)[CH:25]([NH:40][C:41](=[O:42])[CH2:54][C:50]1[S:49][CH:53]=[CH:52][CH:51]=1)[C:24]2=[O:48])=[O:21])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Reactant: O=C(Cl)Cc1cccs1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
Methanesulphonic acid (6 cc) is added to a solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-methoxycarbonylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (6.2 g) in acetonitrile (60 cc). After 15 minutes at 20° C., the reaction mixture is diluted with methylene chloride (150 cc) and with a half-saturated sodium bicarbonate solution (200 cc). The aqueous layer is washed with methylene chloride (3×50 cc) and the combined organic phases are washed with distilled water (2×100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. Crude 7-amino-2-benzhydryloxycarbonyl-3-(2-methoxycarbonylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.2 g) is obtained and is redissolved in dry tetrahydrofuran (50 cc). The solution obtained is cooled to 4° C. and treated with a solution of (thien-2-yl)-acetyl chloride (1.23 cc) in dry tetrahydrofuran (10 cc) and then with a solution of triethylamine (1.4 cc) in dry tetrahydrofuran (5 cc), in accordance with the working method described in Example 1. The crude product is chromatographed on a column (height: 32 cm, diameter: 6 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.4 bar (40 kPa) with a 45.55 (by volume) mixture of cyclohexane and ethyl acetate, and 100 cc fractions being collected. Fractions 8 to 21, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 2-Benzhydryloxycarbonyl-3-(2-methoxycarbonylamino-thiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (1.91 g) is obtained in the form of a whitish solid.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1Br.S(=O)(=O)(O)[OH:13]>C(#N)C>[O:13]1[C@@H:3]2[CH2:4][C:5]3[C:10]([C@H:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: BrC1Cc2ccccc2C1Br
Reactant: O=S(=O)(O)O
Solvent: CC#N
Product: c1ccc2c(c1)C[C@H]1O[C@@H]21
Temperature: 40 °C
Reaction time: 5 h
Yield: 25.3 %

Procedure:
Into a 1000 ml four-neck flask, 259.5 g of an acetonitrile solution of 1,2-dibromoindan (corresponding to bromination of 0.559 mol of indene) was introduced. It was then heated to 40° C. To this solution, 86.57 g (0.839 mol) of 97% sulfuric acid was dropwise added at 40°-46° C. in a period of 1.5 hours. The resulting mixture was stirred at the same temperature for 5 hours. According to an HPLC analysis, about 15% of 1,2-dibromoindan was remaining in the mixture. To this mixture, 43.29 g of sulfuric acid was further added. The resulting mixture was stirred at 50°-60° C. for 1.5 hours. According to an HPLC analysis, 1,2-dibromoindan had almost disappeared yielding 11.0% of trans-amide derivative (III: R=CH3) and 25.3% of cis-oxazoline derivative (IV: R=CH3).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([NH:21][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1)(=[O:15])=[O:14])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(C2CCCCC2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccc(C2CCCCC2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
The sulfonyl chloride compound obtained in Example II (338 gm, 1.3M) is suspended in dry dioxane (400 ml) under argon atmosphere in a four-necked round-bottomed flask equipped with a condenser, a thermowatch and a constant pressure addition funnel. Excess t-butylamine (210 gm, 2.78M) is added drop-wise and the temperature of the reaction mixture is allowed to increase to approximately 60°-70° C. When the addition of amine is complete, the reaction mixture is aged at 70° C. for one hour, then cooled to 30° C. and the amine hydrochloride salt is removed by filtration. Concentration of the filtrate yields the crude sulfonamide. Nmr spectra obtained on a Varian EM-360 MHz nmr spectrometer, recorded in ppm downfield from tetramethylsilane, and infrared spectra recorded on a Nicolet MX-1 Fourier Transform infrared spectrometer provides spectral data consistent with the expected structure.