Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][C@@H:3]([CH2:10][OH:11])[O:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][C@H:3]1[O:2][CH2:1][C@@H:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CN2CCC[C@H]2CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1CN2CCC[C@H]2CO1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 80.1 %

Procedure:
(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethanol (1.00 g, 6.37 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (2.4 mL, 17.3 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.93 mL, 12.0 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with saturated sodium bicarbonate solution. The combined aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl methanesulfonate as an orange-brown oil (1.20 g, 5.1 mmol, 80% yield). MS (EI) for C9H17NO4S: 236 (MH+).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][N:5]=1.[BH4-].[Na+].O>CO>[Br:3][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][N:5]=1
Reactant: O=Cc1ccnc(Br)c1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 2-bromo-pyridine-4-carbaldehyde (904 mg, 4.86 mmol) was dissolved in MeOH (10 mL). NaBH4 (236 mg, 5.99 mmol) was added portionwise at 0° C. and the reaction mixture stirred at rt for 1 h. Water (10 mL) was added and the mixture extracted with EA (3×20 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a white solid. TLC: rf (1:1 hept-EA)=0.22. LC-MS-conditions 02: tR=0.63 min; [M+H]+=190.33.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2].[Se](=O)=[O:28]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cc2ccccc2)c2cc(OC)c(OC)cc12
Reactant: O=[Se]=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(C(=O)c2ccccc2)c2cc(OC)c(OC)cc12
Yield: 87.1 %

Procedure:
The above 1-benzyl-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester (77.1 mg, 0.22 mmol) was dissolved in 5 ml of acetic acid. Then selenium dioxide (36.6 mg, 1.50 eq) was added and the mixture was refluxed for 1 hr until no more starting material was left. The mixture was evaporated to dryness and the residue was extracted with ethyl acetate and sodium bicarbonate solution. The organic layer was dried over sodium sulfate and then concentrated. The residue was dissolved in 5 ml of ethyl acetate and the solution was passed through a layer of silica gel. The solution was concentrated go give a pure 1-benzoyl-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester (70 mg, 87%).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[CH2:26][CH3:27].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([C:3]1[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:5][N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:2]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]
Reactant: CCc1c(CN(C)C(=O)OC(C)(C)C)cn(S(=O)(=O)c2ccccc2)c1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1c(CN(C)C(=O)OC(C)(C)C)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Yield: 53.6 %

Procedure:
Using tert-butyl {[5-bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.13 g), phenylboronic acid (462 mg), sodium carbonate (789 mg) and tetrakis(triphenylphosphine)palladium (431 mg), a procedure as in Reference Example 56 was performed to give the title compound as a brown oil (yield 602 mg, 54%).
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](/[CH3:20])\[C:8]#[C:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([OH:18])[CH2:12][C:11]=1[CH3:19])(=[O:3])[CH3:2].C([O:25]O)(C)(C)C.OS([O-])=O.[Na+]>C1(C)C=CC=CC=1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[C:1]([O:4][CH2:5]/[CH:6]=[C:7](/[CH3:20])\[C:8]#[C:9][C:10]12[O:25][C:11]1([CH3:19])[CH2:12][CH:13]([OH:18])[CH2:14][C:15]2([CH3:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CC(=O)OC/C=C(/C)C#CC1=C(C)CC(O)CC1(C)C
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Agent: O=S([O-])O
Solvent: Cc1ccccc1
Product: CC(=O)OC/C=C(/C)C#CC12OC1(C)CC(O)CC2(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 104.9 %

Procedure:
To a solution of Z-4-(5-acetoxy-3-methyl-pent-3-en-1-ynyl)-3,5,5-trimethylcyclohex-3-en-1-ol (42 mg, 0.15 mmol) in toluene (6 mL) was added t-butyl hydroperoxide (3M solution in 2,2,4-trimethylpentane, 0.07 mL, 0.21 mmol) and vanadyl acetylacetonate (3 mg, 0.01 mmol). The reaction mixture, which was reddish orange in color, was stirred under argon at room temperature for 20 min. and then was heated to 70° C. for 30 min. The color of the mixture changed to yellow. After cooling to room temperature, saturated NaHSO3 was added with stirring until there was no peroxide as indicated by peroxide test tapes. The organic and aqueous layers were separated. The aqueous layer was extracted three times with ether. The combined organic layers were washed with H2O, saturated NaHCO3, H2O and dried over anhydrous Na2SO4. Evaporation of solvent gave yellow oil (46 mg) which was purified using the Chromatotron™ sold by Harrison Scientific and with 75% ether+25% hexane as solvent to give compound (4) as a colorless oil (17 mg, 38%), ir: 3620 (weak, sharp, OH), 3500 (weak, broad, OH), 1740 (strong, sharp, C=O) cm-1; 1H nmr d: 5.80 (ddq, J=6.9, 6.9, 1.6 Hz, 1H, =CH), 4.71 (dd, 6.9, 1.0 Hz, 2H, CH2O), 3.83 (m, 1H, CHOH), 2.19 (ddd, J=14.7, 6.8, 1.5 Hz, 1H, CH2), 2.03 (s, 3H, CH3COO), 1.89 (m, 3H, vinyl CH3), 1.81 (dd, J=14.7, 8.9 Hz, 1H, CH2), 1.47 (s, CH3), 1.37 (ddd, J=12.7, 4.0, 1.5 Hz, 1H, CH2), 1.18 (s, 6H, 2CH3); ms (isobutane CI) m/z: 293 (M+1), 331 (M+39); (NH4Cl CI): 310 (M+18), 275 (M-17), 233 (M-59).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[C:7]2[N:8]=[C:9]([CH3:13])[CH:10]=[C:11]([CH3:12])[N:6]2[N:5]=1.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[S:18].[OH-].[K+]>CN(C)C=O>[CH3:15][N:16]([CH3:20])[C:17]([O:3][C:4]1[CH:14]=[C:7]2[N:8]=[C:9]([CH3:13])[CH:10]=[C:11]([CH3:12])[N:6]2[N:5]=1)=[S:18]
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc(C)n2nc(O)cc2n1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)n2nc(OC(=S)N(C)C)cc2n1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
60% oily sodium hydride (3.9 g) is suspended in 100 ml of dimethylformamide, to which 22.8 g of 2-hydroxy-5,7-dimethylpyrazolo[1,5-a]pyrimidine is added under cooling to maintain the reaction solution at 20°-30° C. and then stirred for 30 minutes at the above temperature. To the reaction solution, 22.5 g of dimethylthiocarbamoyl chloride is added during 1.5 hours and then stirred for 2 hours at 70°-80° C. After cooling, 800 ml of 1% aqueous potassium hydroxide solution is added to the reaction solution and stirred for 30 minutes at room temperature. The precipitate as collected by filtration is recrystallized from ethanol to give 18.5 g of 2-(N,N-dimethyl thiocarbamoyloxy)-5,7-dimethylpyrazolo[1,5-a]pyrimidine. mp. 216°-217° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2.S(=O)(=O)(O)O.[CH3:25]O>>[O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([O:16][CH3:25])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2
Reactant: CO
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc2c(c1)C(=O)c1sccc1CO2

Procedure:
A mixture of 0.70 g of 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid (Example 1), 8 ml of concentrated sulfuric acid, and 150 ml of methanol is refluxed for 16 hours. The reaction mixture is concentrated in vacuo, diluted with water and extracted with benzene. The combined benzene extracts are washed with 5% sodium hydroxide and water, dried, filtered and concentrated in vacuo to an oil which solidifies upon standing. The solid is recrystallized from methanol to provide light yellow crystals, mp 80°-81° C. of methyl 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH2:14])[CH2:4][O:3]1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>CCCCC.ClCCl>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:14][C@H:5]1[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:26]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Solvent: ClCCl
Solvent: CCCCC
Product: CC1(C)OC[C@H](NC(=S)Nc2ccc(Cl)cc2Cl)[C@H](c2ccccc2)O1
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To a solution of 130 mg (0.62 mmol) of (4S,5S)-amine 1 in pentane (2.0 mL) was added dropwise a solution of 116 mg (0.62 mmol) of 2,4-dichlorophenyl isothiocyanate in dichloromethane (0.15 mL). After stirring for ˜24 h, a white precipitate was collected, rinsed with pentane, and dried under reduced pressure to yield 172 mg (67%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C@H:14]1[O:18][C:17]([CH3:20])([CH3:19])[N:16]([C:21](=[O:23])[CH3:22])[C@H:15]1[CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)N([O])C(C)(C)CCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@@H:9]1[C@H:14]1[O:18][C:17]([CH3:19])([CH3:20])[N:16]([C:21](=[O:23])[CH3:22])[C@H:15]1[CH2:24][C:25]1[CH:26]=[C:27]([F:32])[CH:28]=[C:29]([F:31])[CH:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(=O)CN2C(=O)OC(C)(C)C)OC1(C)C
Reaction time: 0.08 h
Yield: 100.5 %

Procedure:
Cool to 0° C. a solution of (2R,4R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.01 gr, 0.022 mmol) in dichloromethane (0.5 mL). Add trichloroisocyanuric acid (0.023 g, 0.110 mmol). Stir 5 minutes and then add TEMPO (2,2,6,6-tetramethyl-1-piperidinyl-oxy, free radical, 0.0007 g, 0.0044 mmol). After one hour add dichloromethane to the mixture and wash with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Dry over magnesium sulfate and concentrate under reduced pressure to provide the desired compound (0.010 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1I.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:14]2[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=2[Cl:16])=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: Sc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Clc1ccc(Cl)c(Sc2ccc(Br)cc2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 2,5-dichloroiodobenzene (0.72 g, 2.64 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-(4-bromo-phenylsulfanyl)-2,5-dichloro-benzene (0.7 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)c1
Yield: 46.5 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (95 mg, 47%). MS (ISP) 409.2 [(M+H)+]; mp 241° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[C:4]([C:13]([O:15]CC)=[O:14])[S:5][C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[Br:1][C:2]1[C:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[C:4]([C:13]([OH:15])=[O:14])[S:5][C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(Br)c1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(N2CCOCC2)c(Br)c1Cc1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of ethyl 4-bromo-3-(3,4-dichlorobenzyl)-5-morpholinothiophene-2-carboxylate (109 mg, 0.227 mmol) in THF (1.8 mL) and MeOH (0.37 mL) was added 1.00 M aqueous NaOH (1.82 mL, 1.82 mmol) and the resulting mixture was stirred at 45° C. overnight. The reaction was diluted with water (5 mL) and acidified to pH=3 with 1 N HCl. The mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried, filtered and concentrated in vacuo to give 92 mg (90% yield) of a white solid which was used as is in the next step. LC/MS (AA) ES+ 450, 452, 454. 1H NMR (400 MHz, DMSO-d6) δ: 13.21 (bs, 1H), 7.52 (d, 1H, J=8.0 Hz), 7.39 (d, 1H, 2.0 Hz), 7.09 (dd, 1H, J=8.0, 2.0 Hz), 4.36 (s, 2H), 3.74-3.71 (m, 4H), 3.13-3.11 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:28])[C:21]=4[CH:22]=3)[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(c3ccc(CCCCC(=O)O)cc3)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ccc4c(c3)C(=O)CCCC4)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a solution of 5-[4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]phenyl]pentanoic acid (0.50 g) in THF (10 ml) were added at room temperature oxalyl chloride (0.21 ml) and a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the mixture was concentrated, and the residue was dissolved in dichloromethane (10 ml). To the mixture was added at 0° C. aluminum chloride (0.35 g), and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 5 minutes. The mixture was added to ice/water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give colorless crystals of 3-[1-(4-methylphenylsulfonyl)piperidin-4-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (0.32 g).
Reaction SMILES: C(O)=O.Cl[S:5]([N:8]=C=O)(=[O:7])=[O:6].[Si:11]([O:18][C@@H:19]([CH3:44])[C@@H:20]([NH:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([Cl:42])[C:35]=1[CH3:43])[C:21]1[O:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:24][N:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[2H]C(C(C([2H])([2H])[2H])=O)([2H])[2H]>ClCCl.CN(C)C(=O)C.C(OCC)(=O)C>[S:5](=[O:6])(=[O:7])([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[O:22][C:21]([C@H:20]([NH:33][C:34]3[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([Cl:42])[C:35]=3[CH3:43])[C@@H:19]([O:18][Si:11]([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12])[CH3:44])=[N:25][N:24]=2)=[CH:31][CH:30]=1)[NH2:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(OS(N)(=O)=O)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a 50 mL round bottomed flask, a mixture of formic acid (413 mg, 8.99 mmol) and N,N-dimethyl acetamide (30 mg, 0.09 mmol) was added to a stirred solution of chlorosulfonyl isocyanate (0.77 mL, 8.91 mmol) in dichloromethane (5 mL) at 42° C. The mixture was placed under reflux for 15 min and then cooled to ambient temperature. The resulting mixture was added to a stirred solution of 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (346 mgs, 0.90 mmol) in N,N-dimethyl acetamide (6 mL) at ambient temperature. The mixture was then stirred for 17 h and then poured onto water (15 mL). Ethyl acetate (30 mL) was added to the mixture and the phases were partitioned. The organic phase was washed with water (12 mL) (×2), dried (Na2SO4) and concentrated to furnish a pale yellow oil (385 mg, yield not determined). 1H NMR (Acetone d6, 500 MHz) inter alia δ 8.07 (d, J=9 Hz, 2H), 7.53-7.47 (m, 3H), 6.84 (d, J=9 Hz, 2 H), 5.53 (d, J=9 Hz, 1 H), 5.22-5.17 (m, 1H), 4.77-4.68 (m, 1H), 2.37 (s, 3 H) and 1.46 (d, J=6 Hz, 3 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([OH:17])=[O:16].[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:12])([CH3:13])[CH3:14])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([O:17][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=1)=[O:16]
Reactant: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)O)C2(C)C)cn1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)OCc3cccc(Oc4ccccc4)c3)C2(C)C)cn1
Reaction time: 16 h
Yield: 92.3 %

Procedure:
A mixture of trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]cyclopropane carboxylic acid (500 mg), 3-phenoxybenzylbromide (552 mg), anhydrous potassium carbonate (304 mg) and acetone (10 cm3) was heated at the reflux temperature for 2 hours with stirring after which it was kept at the ambient temperature for 16 hours. After removing the solid precipitate by filtration the filtrate was concentrated by evaporation under reduced pressure. The residual oil was subjected to high performance liquid chromatography (Gilson) using a silica column and, as eluent, a mixture of dichloromethane (100 parts by volume) and ethyl acetate (2 parts by volume). The product, 3-phenoxybenzyl trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)-pyrimidin-5-yl]cyclopropane carboxylate (800 mg) was obtained as an oil and identification was confirmed by n.m.r. and infra red spectroscopy.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:4]=1.[H-].[Na+].[CH3:27][O:28][CH2:29][C:30](OC)=O>O1CCCC1.C(OCC)(=O)C>[CH3:19][C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:4]=[C:3]([C:2]3[N:1]=[C:30]([CH2:29][O:28][CH3:27])[O:24][N:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:22]
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Reactant: COCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1nc(-c2ccnc(N3CCN(C(=O)CCC(C)(C)C)CC3)c2)no1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1-{4-[Amino(hydroxyimino)methyl]pyridin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (62 mg) was dissolved in tetrahydrofuran (2 mL), then oily sodium hydride (13 mg) was added thereto, stirred at 60° C. for 20 minutes, and methyl methoxyacetate (0.028 mL) was added thereto and heated under reflux for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 44.3 mg of the entitled compound as a colorless solid.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH:7]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:8][C:9]1([C:14](=[O:25])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C>FC(F)(F)C(O)=O>[NH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:7]([CH2:8][C:9]1([C:14](=[O:25])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][CH2:13]1)[C:6]([OH:31])=[O:5]
Reactant: CC(C)(C)OC(=O)C(CCCCN)CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1
Solvent: O=C(O)C(F)(F)F
Product: NCCCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)O
Yield: 80.3 %

Procedure:
2-(4-Aminobutyl)-3-{1-[(cis-4-carboxy-cyclohexyl)carbamoyl]cyclopentyl}propanoic acid t-butyl ester (1.0 g, 2.28 mmole) was dissolved in trifluoroacetic acid (8 ml) at 0° C. After 3 days at this temperature the solvent was evaporated and the residue azeotroped with dichloromethane (3×50 ml). The resulting brown oil was purified by passage through ion exchange resin (Bio-Rad AG 50W-X8, 30 ml) eluting with pyridine and water (3:100 by volume), and the appropriate fractions evaporated to give the title product as a colourless foam (700 mg, 80%). Found: C,61.97; H,9.08; N,7.69. C20H34N2O5, 0.1 C5H5N, 0.3 H2O requires C,62.21; H,8.94; N,7.43%.