Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[O:19]1[CH2:24][C:23](=O)[CH2:22][C:21](=[O:26])[CH2:20]1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:22]3[C:21](=[O:26])[CH2:20][O:19][CH2:24][C:23]=3[NH:1][C:2]3[N:3]([CH3:8])[O:4][C:5](=[O:7])[C:6]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=C1COCC(=O)C1
Reactant: Cn1oc(=O)cc1N
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: CCO
Product: Cn1oc(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
The product from Example 45A (0.11 g, 1 mmol), 3-bromo-4-fluoro-benzaldehyde(0.2 g, 1 mmol), and 2H-pyran-3,5(4H,6H)-dione (0.11 g, 1 mmol) in ethyl alcohol (3 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was allowed to cool to ambient temperature and was evaporated under reduced pressure. The residue was chromatographed eluting with 5% ethanol/dichloromethane to provide the title compound as a white solid (0.09 g). 1H NMR (300 MHz, DMSO-d6) δ 3.27 (s, 3H), 4.05 (s, 2H), 4.57 (q, 2H), 4.78 (s, 1H), 7.28 (m, 2H), 7.54 (d, 1H), 10.77 (s, 1H); MS (ESI−) m/z 395 (M−H)−; Anal. Calcd for C16H12BrFN2O4: C, 48.63; H, 3.06; N, 7.09.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[F-].[K+].O>CS(C)=O>[CH3:16][N:15]1[C:11]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]1
Reactant: O=C1CCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(=O)CC1
Yield: 109.8 %

Procedure:
Three identical solutions of piperidin-4-one hydrochloride hydrate (1.84 g, 12.0 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.3 g, 8.0 mmol) and potassium fluoride (1.86 g, 32 mmol) in dry DMSO (20 mL) were heated in a microwave at 100° C. for 12 hr. The mixtures were combined, poured into water (700 mL) and extracted into EtOAc (3×100 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.97 g, 36%). To a solution of this ketone in DMF (40 mL) was added NEt3 (3.05 mL, 21.9 mmol) and chlorotrimethylsilane (1.55 mL, 12.3 mmol). The reaction vessel was sealed and the mixture heated at 90° C. for 16 hr. The mixture was cooled and the product extracted into EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% Et2O/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine as a yellow gum (1.53 g, 59%). This gum was dissolved in MeCN (130 mL) and cooled to 0° C. A solution of SelectFluor® (1.99 g, 5.61 mmol) in 2:1 MeCN:DMF (10 mL) was added dropwise over 20 min and the mixture stirred at between −5° C. and 0° C. for 2 hr. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (40 mL). The product was extracted into EtOAc (50 mL) and DCM (50 mL), and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a pale yellow solid (1.23 g, 99%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.04 (ddd, J=48.3, 8.2, 5.7 Hz, 1H), 3.89 (s, 3H), 3.77-3.64 (m, 2H), 3.64-3.51 (m, 1H), 3.50-3.43 (m, 1H), 2.88-2.72 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1CN([P+](O[N:37]2[N:45]=[N:44][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C1(C)C=CC(S(N2C=CC([C@@H](N)CC)=N2)(=O)=O)=CC=1>CN(C=O)C.O>[NH:45]1[CH:42]=[CH:43][C:38]([C@@H:39]([NH:44][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:19])[CH2:40][CH3:41])=[N:37]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: CC[C@H](N)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc[nH]n1
Reaction time: 0.5 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (185 mg, 0.800 mmol) in DMF was added PyBOP (360 mg, 0.72 mmol) and Et3N (152 mg, 1.50 mmol). After 30 minutes, (S)-1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propylamine (201 mg, 0.720 mmol) was added. After 3 hours, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by reversed-phase HPLC. The major fractions were combined and the solvent was removed in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11](Cl)[C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1.ClC1C=CC(Cl)=CC=1CO>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Agent: OCc1cc(Cl)ccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc(N)nc(N)c1-c1cc(Cl)ccc1Cl

Procedure:
This compound was made in an analogous manner to the compound of Example 6 from 2,5-dichlorobenzylalcohol (Lancaster Synthesis). Mp. 226°-228° C.: TLC (SiO2 : CHCl3 /MeOH, 9:1) Rf=0.24.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][S@@](C(C)(C)C)=O)[CH3:10])=[C:5]([CH3:18])[CH:4]=1>C(OCC)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[C:5]([CH3:18])[CH:4]=1
Reactant: Cc1cc(Br)ccc1[C@H](C)N[S@](=O)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1[C@H](C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrochloric acid (4 mol/L in 1,4-dioxane, 46 mL) was added to a solution of (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-amide (crude from Step 2, 8.85 g, ca. 75% pure) in ethyl acetate (80 mL) at room temperature. The solution was stirred at room temperature for 1 h and then concentrated. The residue was taken up in water and the resulting mixture was washed with diethyl ether. The aqueous phase was basified using aqueous 1 M NaOH solution and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]=[C:25]=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:25]([NH:24][C:18]3[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=3[Cl:16])=[O:26])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Nc2cccc(Cl)c2)ncn1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Product: O=C(Nc1cc(Nc2cccc(Cl)c2)ncn1)Nc1c(Cl)cccc1Cl

Procedure:
The title compound is prepared analogously as described in Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([F:32])[F:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([F:32])[F:31])=[CH:26][CH:25]=2)[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)c1ccc(CBr)cc1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: O=C1NCCC(F)(F)C[C@H]1N(Cc1ccc(C(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 1-bromomethyl-4-difluoromethyl-benzene analogous to Example 1 to afford 4-chloro-N-(4-difluoromethyl-benzyl)-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].CN(C)C=O.[C:21]([C:23]([C:29]#[N:30])=[C:24](C#N)[C:25]#[N:26])#[N:22]>O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:24]([C:25]#[N:26])=[C:23]([C:29]#[N:30])[C:21]#[N:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(C(C#N)=C(C#N)C#N)ccc21
Temperature: 100 °C

Procedure:
About 1 gram (5.24 × 10-3 3 moles) N-ethyl carbazole and 20 milliliters of dimethylformamide are placed in a 50 milliliter one neck flask equipped with a magnetic stirring bar and a nitrogen inlet tube. The flask is purged of air with nitrogen, the contents of the flask agitated and about 0.67 grams (5.24 × 10-3 moles) of tetracyanoethylene introduced into the flask. Upon the admixture of these materials the contents of the flask turns deep blue. This mixture is heated to 100° C for 20 hours, the contents of the flask poured into 60 milliliters of water at room temperature and the redish brown crystals thereby precipitated isolated from the solution by filtration and washed with ethanol. Yield: 1.13 grams brick red crystals m. p. 239°-241° C. Analysis: calculated, carbon 77, hydrogen 4.08, nitrogen 18.92; actual, carbon 77.24, hydrogen 4.07, nitrogen 18.78.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18]>C(N(CC)CC)C>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccccc1CO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CO
Yield: 54.3 %

Procedure:
2.85 g (14 mmol) of 1-chloro-2,6-dinitrobenzene and 1.73 g (14 mmol) of 2-aminobenzyl alcohol were dissolved in 30 ml of triethylamine and heated under reflux for 24 hours. After concentrating, the residue was purified by silica gel column chromatography. Thus 2.2 g of 2-((2,6-dinitrophenyl)amino) benzyl alcohol was obtained. 0.29 g (1 mmol) of this powder was dissolved in 20 ml of dry dimethylformamide. After adding 40 mg (1 mmol) of sodium hydride (in oil, content: 60%), the reaction mixture was stirred at room temperature for 15 minutes and then at 150° C. for 2 hours. After cooling, 200 ml of ethyl acetate was added thereto and the mixture was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography. Thus 0.14 g of the title compound was obtained.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([F:35])([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](OCC4C=CC=CC=4)=O)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:41]([O:46][CH2:47][C@@H:48]1[O:50]C1)(=[O:45])CCC>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([F:35])([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][C@H:47]([CH2:48][OH:50])[O:46][C:41]4=[O:45])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccc(C2(F)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(F)(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
A solution of 4-fluoro-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 2, 2.03 g, contaminated with the elimination side product) in dry tetrahydrofuran (21 mL) at -78° C. under N2 is treated with n-butyllithium (2.80 mL, 1.6 M in hexanes) dropwise over 5 mins. The resulting mixture is stirred at -78° C. for 1.25 hrs and is then treated with (R)-(-)-glycidyl butyrate (0.63 mL) dropwise. The resulting solution is stirred at -78° C. for 1 hr, warmed to ambient temperature and stirred for an additional 20 hrs, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (10 mL), and the layers are separated. The organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 250 g), eluting with methanol/methylene chloride (3/97). Pooling and concentration of those fractions wl.th an Rf =0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent) gives the title compound (contaminated with the elimination side product from the starting material). An analytical sample is prepared by radial chromatography (2000, silica gel rotor, ethyl acetate/hexane (60/40) eluent), NMR (400 MHz, CDCl3) 7.45, 7.34, 7.18, 5.16, 4.74, 4.17, 3.97, 3.72, 3.22, 2.25 and 1.90 δ and HRMS calculated for C23H24F2N2O5 : 446.1653. Found: 446.1660.
Reaction SMILES: [CH3:1][Li].[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH3:21])=[C:12]([C:22]([O:24]CC)=O)[C:11]1=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C1COCC1.[Cu]I>[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH3:21])=[C:12]([C:22](=[O:24])[CH3:1])[C:11]1=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [Li]C
Reactant: CCCCCCCn1c(=O)c(C(=O)OCC)c(OC)c2ccccc21
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCCCCCn1c(=O)c(C(C)=O)c(OC)c2ccccc21
Reaction time: 3 h
Yield: 75 %

Procedure:
A flame-dried 50 ml round bottomed flask was charged with copper (I) iodide (909 rag, 4.78 mmole) and anhydrous THF (20 mL). Methyl lithium (halide-free, 1.4M, 7.2 mL, 10.1 mmole) was added to the white CuI suspension at -78° C. After 0.5 hour the product from step (1) (430 mg. 1.25 mmole) was added drop-wise as a solution in THF (10 mL) to the solution of dimethyllithiocuprate. After 3 hours, the reaction was quenched with saturated ammonium chloride. The product was isolated by acidification of the reaction to pH 5, and extraction (3×) with ethyl acetate. Final purification on Silica-Gel 60 (4:1 hexane:ethyl acetate eluent) gave the title compound in 75% yield. That the expected product was obtained was confirmed by the spectral data: M.S. (E.I.): 315 (M+); NMR (CDCl3): δ8.0 (1H, d), 7.6 (1H, dd), 7.35 (1H, dd), 7.2 (1H, dd), 4.25 (2H, m, CH2N), 3.98 (3H, s, OCH3), 2.65 (3H, s, C(O)CH3), 1.8 (2H, m), 1.35 (8H, m), 0.9 (3H, t, CH3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>ClCCl>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:31](=[O:34])[CH2:32][CH3:33])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC
Reaction time: 15 h

Procedure:
To a solution of 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol), triethylamine (0.20 ml, 14.50 mmol) in dichloromethane (8.0 ml), propionyl chloride (134 mg, 1.45 mmol) was added at room temperature. The mixture was stirred for 15 hours. The solvent was removed under diminished pressure. After evaporation, the mixture was stirred in acetonitrile/methanol (1:2, 9.0 ml) with aqueous ammonia (3.0 ml) for 3 hours. Water (50 ml) was added and the mixture was extracted three times with ethyl acetate (3×50 ml). The combined organic layers were washed with aqueous hydrochloric acid (1N), brine, dried and evaporated to afford a residue purified by HPLC. The title compound was obtained as white powder (19 mg).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br.[Br:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O>>[BrH:15].[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:16]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Product: COC(=O)c1ccc(-c2nc(-c3ccccn3)cs2)cc1
Yield: 80 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 2-bromoacetylpyridine hydrobromide to obtain methyl 4-[4-(2-pyridyl)-2-thiazolyl]benzoate hydrobromide. The product was recrystallized from ethanol. Yield: 80%. Pale yellow prisms. Melting point: 243 to 244° C.
Reaction SMILES: [Cl:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[C:14]=1[CH3:21].[F:22][C:23]([F:36])([F:35])[S:24]([O:27]S(C(F)(F)F)(=O)=O)(=[O:26])=[O:25]>C(OCC)C>[O-:27][S:24]([C:23]([F:36])([F:35])[F:22])(=[O:26])=[O:25].[Cl:1][CH2:2][S+:3]([C:18]1[CH:17]=[C:16]([CH3:19])[C:15]([CH3:20])=[C:14]([CH3:21])[C:13]=1[CH3:12])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C)c(C)c1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(S(=O)CCl)cc1
Solvent: CCOCC
Product: Cc1ccc([S+](CCl)c2cc(C)c(C)c(C)c2C)cc1
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
1-((chloromethyl)sulfinyl)-4-methylbenzene (500 mg, 2.65 mmol) of example 29 was dissolved in dry diethyl ether (5 mL) under an argon atmosphere. 1,2,3,4-Tetramethylbenzene (0.40 mL, 1 eq) was slowly added to the previous solution and then the mixture was cooled to a temperature between 5° C. and 0° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.45 mL, 1 eq) was added maintaining the same temperature. The mixture was stirred until the reaction was complete. The precipitated triflate salt was isolated by filtration and washed with diethyl ether (5 mL) at 0° C. 1.12 g (89.74%) of the desired product was obtained as a white solid. Mp=28-30° C.
Reaction SMILES: [OH-:1].[Na+].ClCl.[Cl:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])C)[S:9][C:10]=1[Cl:11]>O.O1CCOCC1>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]([OH:14])=[O:1])[S:9][C:10]=1[Cl:11]
Reactant: CC(=O)c1cc(Cl)c(Cl)s1
Reactant: [OH-]
Agent: ClCl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)c(Cl)s1
Temperature: 50 °C

Procedure:
Into a solution of sodium hydroxide (19.2 grams, 48.0 mmole) in water (30 ml) and ice (120 g) at −10° C. was bubbled Cl2 gas until 14.4 g was obtained. The solution was warmed to 50° C. and 1-(4,5-Dichloro-thiophen-2-yl)-ethanone (8.5 0 grams, 40.0 mmole) in dioxane (40 ml) was added dropwise as the temperature rose to 80-90° C. This temperature was maintained for 30 minutes. The mixture was poured into 500 ml water. This was extracted with diethyl ether, and the aqueous was treated with NaHSO3, then acidified to pH 1 with concentrated HCl. The resultant precipitate was filtered, and dried to give a white solid. (5.7 g). MW 197.04; 1H NMR (DMSO-d6) d 7.731 (1H, s).
Reaction SMILES: O1CCCC1.[S:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([S:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]([Cl:27])=[CH:17][C:16]=1[F:28])C#N.[F:29][C:30]([Si](C)(C)C)([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.CCCCCC>[F:29][C:30]([F:32])([F:31])[S:6][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([S:21][CH2:22][C:23]([F:26])([F:24])[F:25])[C:18]([Cl:27])=[CH:17][C:16]=1[F:28]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#CSCCCCCOc1cc(SCC(F)(F)F)c(Cl)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)c(SCC(F)(F)F)cc1OCCCCCSC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To 60 ml of tetrahydrofuran were added 3.9 g (10.1 mmol) of 5-thiocyanatopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether and 4.5 g (31.6 mmol) of trifluoromethyltrimethylsilane. Thereto was added 1.0 ml (1.04 mmol) of tetrahydrofuran solution (1 mol/liter) of tetra-n-butylammonium fluoride at 0° C., and reaction was carried out. The mixture was stirred overnight at room temperature. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=20:1), to obtain 2.60 g (yield: 60%) of an intended product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@:4]([NH2:16])([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH:25](O)([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@:4]([NH2:16])([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:5][C:6]([O:8][CH:25]([CH3:27])[CH3:26])=[O:7]
Reactant: CC(C)O
Reactant: COC(=O)[C@@](N)(CC(=O)O)C(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@@](N)(CC(=O)OC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
Commercially available (S)-2-BOC-amino-succinic acid 1-methyl ester (2.4 g, 10 mmol) was dissolved in DCM (30 mL), and triethylamine (2.8 mL, 20 mmol) was added thereto. To the mixture were added isopropanol (660 mg, 11 mmol), EDC (2.5 g, 26 mmol) and HOBt (2.3 g, 30 mmol), and the mixture was stirred for 4 h at room temperature. The reaction was quenched by saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (2.5 g, Yield 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[C@@H:21]([OH:25])[CH2:22][CH2:23][OH:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].N1C=CN=C1.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[C@@H:21]([OH:25])[CH2:22][CH2:23][O:24][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1[C@@H](O)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Yield: 92 %

Procedure:
To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(S)-1,3-dihydroxypropyl]pyrrolidine (16.95 g, 45.2 mmol) in methylene chloride (200 ml) were successively added tert-butylchlorodimethylsilane (6.81 g, 45.2 mmol), 4-N,N-dimethylaminopyridine (0.55 g, 4.5 mmol) and imidazole (3.08 g, 45.2 mmol) in a nitrogen atmosphere under cooling with ice under stirring. The mixture was stirred at room temperature for 1 h. Then, the reaction solution was poured into water (200 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=9:1→4:1) to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(S)-3-tert-butyldimethylsiloxy-1-hydroxypropyl]pyrrolidine (20.36 g, yield: 92.0%).