Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:30])[CH:7]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[N:8]([C:10](=[O:21])[CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])[CH3:9])C.C(O)C.[H][H]>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:7]2[N:8]([CH3:9])[C:10](=[O:21])[CH:11]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]2=[O:30])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)N(C)C(=O)Cc1c(C)cc(C)cc1C
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(C)c(C2C(=O)C(Cc3ccc(Cl)cc3)N(C)C2=O)c(C)c1
Yield: 68.3 %

Procedure:
To a boiling solution of 120 ml of absolute toluene and 7.5 g (0.25 mol) of sodium hydride there are added dropwise 79.9 g (0.199 mol) of 2-(4-chlorobenzyl)-N-(2,4,6-trimethylphenylacetyl)-sarcosine ethyl ester in 200 ml of absolute toluene, and the batch is refluxed while being monitored by thin-layer chromatography. When the reaction is complete, ethanol is added dropwise, while cooling in an ice-bath, until no more hydrogen escapes. After the mixture has been evaporated under reduced pressure, the residue is taken up in water and the mixture is acidified with concentrated hydrochloric acid at 0° C. to 20° C. The precipitate is filtered off with suction and recrystallised from chloroform/n-hexane. 48.4 g (68.4% of Theory) of 5-(4-chlorobenzyl)-1-methyl-3-(2,4,6-trimethylphenyl)-pyrrolidine-2,4-dione of melting point >230° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29]OS(C)(=O)=O)[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C.[NH4+].[Cl-]>[N:35]([CH2:29][CH2:28][O:27][CH:24]1[CH2:23][CH:12]2[CH2:13][O:14][C:15]3[C:20]([C:11]2([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:26][CH2:25]1)=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
A solution of methanesulfonic acid 2-[10a-(4-chloro-benzene sulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yloxy]-ethyl ester (180 mg, 0.355 mmol) in DMF (5 mL) was treated with NaN3 (46 mg, 0.707 mmol) and the reaction mixture was heated to 80° C. After 16 h, the reaction mixture was cooled to ambient temperature and diluted with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with H2O, saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to afford the title compound (153 mg, 95%): 1H NMR (CDCl3 400 MHz) δ 7.63 (d, J=8.1 Hz, 2H), 7.49 (d, J=7.3 Hz, 2H), 7.07 (m, 1H), 6.42 (m, 1H), 5.25 (dd, J=2.9, 11.7 Hz, 1H), 4.12 (d, J=11.7 Hz), 3.60 (m, 2H), 3.36 (m, 2H), 3.02 (m, 1H), 2.37 (m, 2H), 1.94 (m, 2H), 1.56 (m, 2H), 1.16 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:21][CH2:20][CH2:19][Br:18])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 2.1, 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-ol and 1,3-dibromopropane were converted to yield 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole as yellow oil, MS: 425 (M, 2Br).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.CS(O[CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)=[C:26]([F:36])[CH:25]=2)[CH2:19]1)(=O)=O>C1COCC1>[O:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)=[C:26]([F:36])[CH:25]=2)[CH2:19]1
Reactant: Nc1ncco1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1O[C@@H](CNc2ncco2)CN1c1ccc(C2=CCOCC2)c(F)c1
Yield: 3.5 %

Procedure:
To a stirred partial solution of 2-aminooxazole(169 mg, 2.0 mmol) in dry THF (10 ml), cooled to −78° C., under argon, was added slowly n-BuLi(1.33M, 1.5 ml, 2.0 mmol), followed after 1 h by 5(R)-methylsulfonyloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one (see Example 41; 371 mg, 1.0 mol) suspended in dry THF(20 ml). The reaction was allowed to come to room temperature and then refluxed for 24 h. The reaction was quenched with ammonium chloride solution(10%w/v, 30 ml), extracting the mixture with chloroform (3×50 ml). The extracts were dried (magnesium sulfate), concentrated by rotary evaporation chromatographed by MPLC (Merck 9385 silica, 3-10% gradient methanol/dichloromethane eluent) and the pure fractions combined, concentrated and triturated with diethyl ether to. give the title compound (25 mg, 4.6%). NMR (300 Mz, DMSO-d6), δ/ppm: 2.31 (m, 2H), 3.35 (m, 2H, obscured), 3.64 (dd, 1H), 3.84 (t, 2H), 3.90 (m, 1H), 4.15 (m, 1H), 4.24 (m, 2H), 4.46 (m, 1H), 5.97 (m, 1H), 6.90 (m, 1H), 7.19 (m, 2H, partially obscured), 7.37 (dd, 1H), 7.44 (dd, 1H). MS: ES+ (M+H)=360.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=O)([CH3:17])([CH3:16])[CH3:15].O>COCCOC>[C:14]([O:18][C:19](=[O:28])[NH:20][CH:21]([CH2:5][C:6]#[N:7])[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCCCCC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=CCCCC(CC#N)NC(=O)OC(C)(C)C
Temperature: 20 °C

Procedure:
Sodium hydride (50% suspension in oil, 1.2 g, 0.025 mol) is placed in 100 ml of dry 1.2-dimethoxyethane. The slurry is cooled to 20° C. and diethylcyanomethyl phosphonate (4.43 g, 0.025 mol) is added dropwise with stirring. After the addition, the solution is stirred at room temperature for 1 hour until gas evolution has ceased. To the yellow solution, maintained below 25° C., is added dropwise t-butyl(5-formylpentyl)carbamate (5.38 g, 0.025 mol). The solution is stirred at room temperature for 1 hour and refluxed for 0.5 hour. A large excess of water is added and the product t-butyl-(7-cyanohepten-6-yl)carbamate (3.63 g, 61%) is extracted with ether.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@@H:12]1[CH2:18][CH2:19][S:20][CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:24](=[N:37][C:38]1[CH:45]=[C:44]([CH2:46]Br)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:46][C:44]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([N:37]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:45]=2)[C:13](=[O:17])[C@@H:12]1[CH2:18][CH2:19][S:20][CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1N=C(c1ccccc1)c1ccccc1
Reactant: CSCC[C@H]1C(=O)NCCN1C(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC[C@H]1C(=O)N(Cc2ccc(C#N)c(N=C(c3ccccc3)c3ccccc3)c2)CCN1C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
To a solution of 4-benzyloxycarbonyl-3-(S)-(2-methylsulfanyl-ethyl)-piperazin-2-one (1.15 g, 3.74 mmol) in 10 ml of DMF is added at 0° C. sodium hydride (164 mg at 60% in oil, 4.12 mmol). The solution is stirred 10 minutes then 2-(benzhydrylidene-amino)-4-bromomethyl-benzonitrile (2.6 g at 52%, 3.74 mmol) in 25 ml of DMF is added dropwise. The resulting mixture is stirred for 20 hours at room temperature, diluted with ethyle acetate, washed with water, with a saturated aqueous NaHCO3 solution, brine. The solution is dried over MgSO4, concentrated. The resulting crude product is purified by column chromatography on silica gel eluting with 2% MeOH:CH2Cl2. The title compound (1.8 g, 80% yield) is obtained as a viscous oil.
Reaction SMILES: C(O[C:9]1[CH:14]=C[C:12]([C:15]2[CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.Cl.[NH2:29]N>C(O)C>[N:29]1[CH:14]=[CH:9][CH:10]=[CH:11][C:12]=1[C:15]1[CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:18](=[O:21])[NH:19][N:20]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]c1=O
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccn2)n[nH]c1=O

Procedure:
Working as in example 19 for the preparation of ethyl 6-[4-(benzyloxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate, but starting with 31.1 g of diethyl hydroxy(pyridin-2-oxoethyl)malonate, 11.55 g of hydrazine dihydrochloride and 700 cm3 of ethanol, and after purification by chromatography on silica gel (particle size 40-63 μm, under an argon pressure of 150 kPa), eluting with dichloromethane, followed by recrystallization from ethanol, 6.9 g of ethyl 6-pyridin-2-yl-3-oxo-2,3-dihydropyridazine-4-carboxylate were obtained in the form of a yellow solid melting at 182° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O>[Cl:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: C1COCCN1
Solvent: O
Product: O=[N+]([O-])c1cnc(N2CCOCC2)c(Cl)c1
Temperature: 120 °C

Procedure:
2,3-Dichloro-5-nitropyridine (Synthesis, 1990, 6, 499-501) (20 g, 104 mmol) was added portionwise to morpholine (40 mL) at 0° C. and heated at 120° C. for 1 h. The reaction was cooled to room temperature, water (100 mL) added and the reaction extracted with DCM (3×150 mL). The organics were dried (MgSO4), filtered, and the solvent removed under reduced pressure to give the product as a yellow solid, which was triturated with isohexane and allowed to dry under vacuum at 60° C. 1H NMR δ 8.98 (1H, d), 8.47 (1H, d), 3.74-3.69 (4H, m), 3.67-3.62 (4H, m); MS m/e MH+ 244.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].F[B-](F)(F)F.[CH3:17][O+](C)C>>[CH3:17][O:3][C:2]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: O=C1CCc2ccccc2N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=Nc2ccccc2CC1

Procedure:
A sample of 3,4-dihydrocarbostyril (Apin Chemicals Ltd., 736 mg, 5.0 mmol) was reacted with trimethyloxonium tetrafluoroborate (924 mg, 6.2 mmol) by the method of EXAMPLE 26 to yield, after chromatography, 130 mg (16%) of the title material.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30]([OH:32])=O)[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([S:72]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)(=[O:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([S:72]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)(=[O:73])=[O:74])[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([C@@H:20]1[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[C@H:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: COc1cc(S(=O)(=O)N2CCOCC2)ccc1N
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(S(=O)(=O)N2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Yield: 16 %

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.37 g, 1.6 mmol), then reacted with 2-methoxy-4-(morpholinosulfonyl)aniline (Matrix) (0.16 g, 0.59 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [2-methoxy-4-(morpholine-4-sulfonyl)-phenyl]-amide as a white solid (Yield 0.06 g, 17%).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[O:12]([CH2:19][CH2:20][CH2:21]Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31]>C(O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH2:21][CH2:20][CH2:19][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCCCOc1ccccc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CCN(CCCOc2ccccc2)CC1

Procedure:
A mixture of ethyl isonipecotate (35.5 g 0.226 mole) 3-phenoxy-1-bromopropane (51.6 g, 0.24 mole) and sodium carbonate (25.4 g, 0.24 mole) in 500 ml of absolute ethanol was heated at reflux for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solution was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give a liquid. The liquid was dissolved in absolute ethanol, and a solution of oxalic acid (~0.23 mole) in absolute ethanol was added. The product 73.43 g (87.7%) precipitated as a white, crystalline solid, m.p. 180°-181° C.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]([C:10]1[S:14][C:13]([NH:15][C:16](=[O:33])[CH:17]([NH:21][C:22](=[O:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:18][CH2:19][CH3:20])=[N:12][N:11]=1)([CH3:9])[CH2:6][CH:7]=C.N#N>C(Cl)Cl>[CH3:4][C:5]([C:10]1[S:14][C:13]([NH:15][C:16](=[O:33])[CH:17]([NH:21][C:22](=[O:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:18][CH2:19][CH3:20])=[N:12][N:11]=1)([CH3:9])[CH2:6][CH:7]=[O:1]
Reactant: C=CCC(C)(C)c1nnc(NC(=O)C(CCC)NC(=O)Cc2cc(F)cc(F)c2)s1
Reactant: O=[O+][O-]
Agent: N#N
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CC=O)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stream of ozone was generated and passed through a solution of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide (631 mg, 1.445 mmol) in 40 ml of methylene chloride until the mixture turned to blue solution or until the disappearance of starting material at −78° C. The mixture was stirred at −78° C. for 10 min, then the excess ozone was replaced with N2 at −78° C. The mixture was quenched with excess of dimethylsulfide and stirred at r.t. overnight. The mixture was concentrated to dryness, purified by Shimadzu HPLC to give the title compound as a yellow solid, RT=2.3 min, M+1=439.5.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21]COC)=[CH:17][CH:16]=3)[CH:9]3[CH2:25][C:26](=[O:28])[CH2:27][CH:8]3[C:7]=2[CH:6]=1>C1COCC1.Cl.CCOC(C)=O>[OH:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][C@@H:10]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[C@H:9]3[CH2:25][C:26](=[O:28])[CH2:27][C@H:8]3[C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(=O)CC32)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Yield: 102.6 %

Procedure:
Stir a solution of cyclopentanone 23 (384 mg, 1.0 mmol) in 10 mL of THF and 8 mL of 3 M HCl overnight. Dilute the solution with EtOAc. Separate the aqueous solution and extract 2× with EtOAc. The combined organic solutions were washed with saturated aqueous sodium bicarbonate, brine, dried over Na2SO4, filtered, and concentrated to afford 304 mg of cyclopentanone 24. The material was purified by preparative chiral chromatography (Chiralpak AD, 65/35 heptane/ethanol).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[NH2:22][C:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2>>[C:23]12([NH:22][C:16](=[O:18])[CH:15]([C:7]3[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=3)[CH3:21])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: NC12CC3CC(CC(C3)C1)C2
Product: CC(C(=O)NC12CC3CC(CC(C3)C1)C2)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and 1-aminoadamantane were used to obtain N-Adamantyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17]S(C)(=O)=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:41])([F:40])[C:24]1[CH:25]=[C:26]([CH2:34][S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:41][C:23]([F:22])([F:40])[C:24]1[CH:25]=[C:26]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:34][S:35]([N:38]([CH2:17][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1)[CH3:39])(=[O:36])=[O:37]
Reactant: CNS(=O)(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(CS(C)(=O)=O)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(CN(C)S(=O)(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 12 h

Procedure:
5.00 g (14.4 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-[(methylsulphonyl)methyl]-1H-pyrazole-5-carboxylate were dissolved in 50 ml of acetonitrile, and 4.64 g (14.4 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-N-methylmethanesulphonamide were added a little at a time at room temperature. Then 2.40 g (17.35 mmol) of potassium carbonate were added to the reaction solution, and the mixture was stirred at 50° C. for 12 hours. After cooling to room temperature, the reaction solution was freed from the solvent under reduced pressure. 250 ml of water were added to the residue, and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by chromatography. (logP: 3.83; MH+: 571; 1H-NMR (400 MHz, DMSO, δ, ppm): 2.79 (s, 3H), 3.74 (s, 3H), 4.43 (s, 2H), 4.80 (s, 2H), 7.06 (s, 1H), 7.70 (dd, 1H), 8.12 (s, 2H), 8.15 (s, 1H), 8.26 (d, 1H), 8.57 (d, 1H).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:5]=1[CH:6]=[O:7]>CO>[F:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(F)c(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Sodium borohydride (15.0 g, 0.397 mol) was added portionwise to a 0° C. solution of 2-fluoro-5-nitrobenzaldehyde (82.4 g, 0.487 mol) in anhydrous methanol (1 L). The reaction mixture was stirred at 0° C. for 0.5 hours and was quenched by adding 1N hydrochloric acid solution (500 mL), which resulted in a pH range of between 4 and 5. The product, which precipitated out when methanol was removed, was collected by filtration. To obtain additional product, the filtrate was extracted with ether (4×500 mL). The ether layer was washed with brine and dried to give crude material which was combined with the other material and recrystallized from ethyl acetate in petroleum ether to give 1-fluoro-2-hydroxymethyl-4-nitrobenzene (69.4 g, 0.406 mol, 83%, mp 50°-53° C.). This material was dissolved in ethyl acetate (1 L) and treated with stannous chloride dihydrate (451 g, 1.99 mol) at reflux temperature for 24 hours. The reaction mixture was poured into ice water (1.5 L), basified using 2.5N sodium hydroxide solution to pH 9, and extracted with ethyl acetate (4×1 L), which was washed with brine and dried. Removal of ethyl acetate gave 3-hydroxymethyl-4-fluoroaniline (34.2 g, 60%, mp 80°-84° C.; Tani et al., Chem. Pharm. Bull. 30, 3530, 1982: mp 95°-98° C.).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].[CH3:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]([SH:10])[CH2:13][C@H:8]1[C:9]([N:19]1[CH2:20][CH2:21][CH:16]([CH3:15])[CH2:17][CH2:18]1)=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Reactant: CC1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N1CCC(C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one (38.5 mg) in tetrahydrofuran (1 ml) was added 4-methylpiperidine (19.7 mg). The mixture was stirred for 4 hours at room temperature. After the reaction was over, 1N-hydrochloric acid (0.036 ml) was added thereto, and the mixture was diluted with ethyl acetate (2 ml) and dried above magnesium sulfate. Distillation of the solvent, followed by purifying the residue by silica gel chromatography, gave oily 1-[(2S,4S) -1-allyloxycarbonyl-4-mercapto-2-pyrrolidinecarbonyl]-4-methylpiperidine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.[NH:14]([CH2:18][CH2:19]O)[CH2:15][CH2:16]O>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[C:5]([B:9]2[O:10][CH2:19][CH2:18][NH:14][CH2:15][CH2:16][O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCCNCCO
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(B2OCCNCCO2)c1
Yield: 79 %

Procedure:
The title compound (79%, crystals) was prepared from 3-trifluoromethylphenylboronic acid and diethanolamin.