Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:62]=[CH:61][C:30]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[CH:35][CH:34]=2)=[O:32])=[CH:29][CH:28]=1)=[N+]=[N-].O>CCOCC.C1COCC1>[NH2:20][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:62]=[CH:61][C:30]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])=[CH:35][CH:34]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCN=[N+]=[N-])cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCN)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
Triphenylphosphine (2.62 g, 10.0 mmol) was added to a solution of tert-butyl 1-((4-(4-(3-azidopropoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate (5.0 g 8.32 mmol) in Ether:THF (1:1, 50 mL) at 0° C. followed by of water (500 mg, 27.8 mmol). The reaction was stirred at r.t. overnight. Upon completion, the reaction was concentrated and purified by silica gel chromatography (EtOAc to EtOAc:MeOH gradient with 1% TEA) to provide 3.24 g (5.63 mmo 68.7% yield) of tert-butyl 1-((4-(4-(3-aminopropoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as yellow oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:34]=2[N:33]=[CH:32]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[CH:38]=[CH:39][C:34]4[N:33]=[CH:32][N:31]([CH3:30])[C:35]=4[CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1cnc2ccc(B(O)O)cc21
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: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4ncn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75 mg, 0.15 mmol), 1-methyl-1H-benzo[d]imidazol-6-ylboronic acid (34 mg, 0.19 mmol), then Pd(PPh3)4 (34 mg, 0.03 mmol). The vial was flushed with argon, diluted with dioxane (1.5 mL) and to this was added 2M aqueous K2CO3 (0.25 mL, 0.50 mmol). The vial was sealed, heated to 100° C. for 2 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-10% MeOH/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C30H31ClN3O3S: 548.2 (M+H+); Found: 548.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.C(Cl)Cl.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][C:16]2[NH:15][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1
Reaction time: 4 h
Yield: 77.1 %

Procedure:
89.2 g 4-chlorophenacyl bromide is dissolved in 170 ml chloroform (or methylene chloride) and the solution is then added dropwise to a solution of 156 g imidazole in 600 ml chloroform (or methylene chloride, as the case may be) while maintaining the reaction mixture at about 0° to 5° C. Thereafter the mixture is continually stirred at this temperature for 4 hours, the solvent is distilled off in a rotation evaporator and the residue is treated with water. After filtering off and drying the precipitate and recrystallizing it in toluene one obtains 65 g p-chlorophenacyl imidazole or 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-1-ethanone in the form of colorless crystals having a melting point of 158° to 160° C.
Reaction SMILES: [OH-].[Na+].Cl.[SH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1.[CH3:12]I>O>[CH3:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:12])[N:10]=1
Reactant: CI
Reactant: Cc1ccnc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nccc(C)n1
Reaction time: 8 h
Yield: 91.5 %

Procedure:
Based on a reported procedure (Ishizumi, K.; Kojima, A.; Antoku, F. Chem Pharm Bull 1991, 39, 2288). Sodium hydroxide (92.5 g, 2.31 mol) was added to a suspension of 2-mercapto-4-methylpyrimidine hydrochloride (150 g, 0.93 mol) in water (1.5 L). Methyl iodide (78.9 ml, 1.39 mol) was rapidly added to the clear solution (solution temp.<20° C.). After overnight stirring, diethyl ether (400 mL), the organic layer was separated and the aqueous layer was extracted with diethyl ether (4×200 ml) all organic layers were combined, washed with 5% aq. NaOH solution (100 ml), brine (200 ml, 2 times), and dried (MgSO4), concentrated in vacuo to afford 119.3 g of crude material (95% pure by NMR) which was used in the next step without purification. 1H NMR (CDCl3, 300 MHz) δ, ppm: 2.46 (s, 3H), 2.56 (s, 3H), 6.82 (d, J=5 Hz, 1H,), 8.37 (d, J=5 Hz 1H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][S:13]([C:16]1[CH:25]=[C:24]([CH2:26][CH2:27][NH:28][C:29]([O:31][CH3:32])=[O:30])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14].[CH3:33][O:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[N:38]=[C:37]([N:43](C2C=CC=CC=2)[C:44](=O)[O-:45])[N:36]=1.Cl>C(#N)C.O.C(OCC)C>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([O:34][CH3:33])[N:36]=[C:37]([NH:43][C:44]([NH:12][S:13]([C:16]2[CH:25]=[C:24]([CH2:26][CH2:27][NH:28][C:29]([O:31][CH3:32])=[O:30])[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])(=[O:14])=[O:15])=[O:45])[N:38]=1
Reactant: COc1cc(OC)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: COC(=O)NCCc1ccc(C(=O)OC)c(S(N)(=O)=O)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)NCCc1ccc(C(=O)OC)c(S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC)n2)c1
Reaction time: 2 h

Procedure:
0.26 ml (1.7 mmol) of DBU was added dropwise to a suspension of 0.54 g (1.7 mmol) of methyl 2-aminosulfonyl-4-[2-(methoxycarbonylamino)ethyl]benzoate and 0.47 g (1.7 mmol) of N-(4,6-dimethoxypyrimidin-2-yl)phenylcarbamate in 15 ml of acetonitrile. After 2 h, the mixture was diluted with water and diethyl ether and acidified with HCl to pH 1-2, and the product precipitated was removed by filtration, washed with water and diethyl ether and dried. Yield: 0.47 g (55.6%) of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonylaminosulfonyl]-4-[2-(methoxycarbonylamino)ethyl]benzoate of m.p.: 165-169° C./decomp.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([C:11]3([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]3)[N:10]=[C:6]2[C:5]([O:17][CH3:18])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[C:32](=[O:36])[O:31][CH2:30]3)O1.B([O-])[O-].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][O:17][C:5]1[C:6]2[N:7]([N:8]=[C:9]([C:11]3([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]3)[N:10]=2)[C:2]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[C:32](=[O:36])[O:31][CH2:30]3)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: COc1ccc(Br)n2nc(C3(C(=O)O)CC3)nc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)O)CC3)nc12
Temperature: 110 °C

Procedure:
1-(5-Bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxylic acid (1.00 g, 3.20 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-isobenzofuran-1-one (preparation of the boronate was described in WO2011/134468) (1.67 g, 6.40 mmol) were dissolved in degassed dioxane (16 mL). Pd2(dba)3 (29 mg, 32 μmol), PCy3 (18 mg, 64 μmol) and K3PO4 (2.38 g, 11.2 mmol) were mixed in degassed water (10 mL). The two solutions were mixed and subsequently heated in a micro wave oven to 110° C. for 10 minutes, cooled to room temperature and diluted with EtOAc (40 mL). The organic phase was extracted with water (25 mL) and an aqueous 0.1 M solution of NaOH (25 mL) and the combined aqueous phases were acidified with conc. HCl to pH 0-1, and extracted with DCM (30 mL×4). Upon evaporation of the combined organic phases the title compound crystallized out (746 mg, 64%). HPLC-Retention time (XE Metode 7 CM): 1.97 minutes. Detected “M+1”-mass: 366.11. Calculated “M+1”-mass: 366.11. 1H NMR (DMSO, 300 MHz): δ=8.25-8.20 (m, 1H), 8.13 (dd, 1H, J=8.2, 1.4 Hz), 8.00 (d, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.2 Hz), 7.24 (d, 1H, J=8.3 Hz), 5.51 (s, 2H), 4.04 (s, 3H), 1.58-1.48 (m, 2H), 1.48-1.39 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:25][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCN
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: CCCCCCCCCCCCNC(=O)c1ccc(C(C)=O)cc1
Yield: 54 %

Procedure:
The same procedure as employed in the preparation of Example 10 (step a) but using 4-acetylbenzoic acid and dodecylamine gave the title compound as a white solid (54%). 1H NMR (CDCl3, 300 MHz) δ 8.00-7.90 (m, 2H), 7.85-7.71 (m, 2H), 6.05 (br s, 1H), 3.41-3.30 (m, 2H), 2.56 (s, 1.5H), 2.54 (s, 1.5H), 1.63-1.73 (m, 2H), 1.72-1.05 (m, 18H), 0.78 (m, 3H). M−(LC/MS(ESI)): 330.4; M+(LC/MS(ESI)): 332.4. HPLC (Condition A), Rt: 5.87 min (HPLC purity: 99.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH2:4][OH:5].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].S(=O)(=O)(O)O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][C:11]([F:14])([F:12])[F:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1cc(SC(F)(F)F)ccc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc(SC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
Triethylbenzylammonium chloride (3.6 g) is added to a solution of 39.9 g of crude 2-chloro-5-(trifluoromethylthio) benzyl alcohol in 400 ml of dichloromethane and the mixture is treated dropwise at 15°-20° C. with a solution of 20.6 g of potassium dichromate in 270 ml of water containing 135 ml of sulfuric acid. The mixture is stirred for 4 hours at room temperature and allowed to stand overnight. The aqueous layer is then separated and the organic layer washed with water and a 5% sodium hydroxide solution, dried with magnesium sulfate and evaporated. The residue is distilled in vacuo. There are obtained 34.1 g of crude 2-chloro-5-(trifluoromethylthio)benzaldehyde boiling at 120°-130° C./2 kPa. According to the 1H-NMR spectrum the product consists of approximately 80% of the named compound and the remainder is the position isomer. In this state the substance is suitable for further processing.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]([OH:11])[CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CC(O)c1ncc(Cl)nc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1ncc(Cl)nc1Cl

Procedure:
5 g of 1-(3,5-dichloro-pyrazin-2-yl)-ethanol obtained in step (i) were dissolved in dry DCM (100 ml) at RT in a reaction vessel containing a magnetic stirring bar and 80.7 ml Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) solution (15% in DCM), and the mixture stirred for 30 min before the reaction was quenched with a saturated aqueous sodium bicarbonate solution (100 ml) and extracted with EtOAc (3×200 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to afford the crude product as a brown oil. Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded 1-(3,5-dichloro-pyrazin-2-yl)-ethanone as a colorless oil after evaporation of the solvents under reduced pressure. Yield: 1.9 g (38%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH2:15]([NH2:18])[CH:16]=C.C=O>C(O)C>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:16]=[CH:15][NH:18]1
Reactant: C=CCN
Reactant: Oc1ccccc1
Agent: C=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 75.5 %

Procedure:
At room temperature, phenol was dissolved in anhydrous ethanol; the pH was adjusted to 8-10; toluene, allyl amine and paraformaldehyde were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:0.8:1.5. After being homogeneously stirred, the mixture was heated and refluxed, reacted for 4 h to vacuum distill off ethanol, toluene, and placed in a cooling unit. Butanone was added to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 75.5%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].[NH4+].[Cl-]>O.C(O)(C)C.[Fe]>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([NH2:9])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: Cc1c(N)cc(F)cc1Br
Temperature: 110 °C

Procedure:
To iron powder (325 mesh, 2.25 g, 40.3 mmol) in 30 ml water and 80 ml isopropanol was added commercially available 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (3.04 g, 13 mmol) in 45 ml isopropanol and NH4Cl (1.46 g, 27.3 mmol). The resulting mixture was heated at 110° C. for 2 h. After evaporation of most of the isopropanol the aq solution was extracted with ethyl acetate three times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:24][CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccccn1
Product: Clc1nccc(-c2cccc(CNCCc3ccccn3)c2)n1

Procedure:
Intermediate 1 was coupled with 2-pyridin-2-yl-ethylamine following procedure B. LC-MS showed the product had the expected M+H+ of 325.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[CH2:19]1)=[O:17].[CH3:38][N:39]=[C:40]=[O:41]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:22][CH:21]([OH:23])[CH:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)[CH2:28][CH2:29]3)[CH2:19]2)=[O:17])=[C:9]([NH:8][C:40]([NH:39][CH3:38])=[O:41])[CH:14]=1
Reactant: CN=C=O
Reactant: Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reaction time: 1 h
Yield: 11 %

Procedure:
A mixture of (3R,4R; 3S,4S)-(2-Amino-4-chloro-phenyl)-{3-[4-(4-chloro-benzyl)-piperazin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-methanone trifluoroacetate (22 mg, 0.05 mmol) was dissolved in DMF and methyl isocyanate (5.8 uL, 0.1 mmol) was added. The reaction mixture was shaken for 1 h and directly used for LC-MS purification to yield 3.4 mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 506.2 (100).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1>C1COCC1.CCCCCC>[OH:24][C:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:22][CH2:23][C:18]2([O:17][CH2:16][CH2:15][O:25]2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(Br)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
A solution of 6-bromonicotinonitrile (2 g, 0.011 mol) in 50 mL of dry THF and 15 mL of dry hexane under argon was cooled to −100° C. in a liquid nitrogen-Et2O bath. n-Butyllithium (7.5 mL, 0.011 mol, 1.6 M solution in hexane) was added rapidly dropwise so that the internal temperature did not exceed −95° C. The orange solution was stirred for an additional 10 min at −100° C. to −95° C. and then treated dropwise over 10 min with a solution of 1,4-cyclohexanedione monoethylene ketal (1.8 g, 0.011 mol) in 55 mL of dry THF, again carefully maintaining the temperature below −95° C. The reaction mixture was stirred for 10 min at −100° C. to −95° C., allowed to warm to 20° C. and poured into ice water (400 mL). The organic layer was separated, and the aqueous layer was extracted twice with Et2O (200 mL). The combined organic extracts were dried over MgSO4 and evaporated to give 2.8 g of white crystalline solid. Trituration with Et2O afforted 1.9 g (67% yield) of white crystals: MS: 261 (M+1)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]=1)=O)C.[BH4-].[Na+]>CO>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:7]=[C:6]([CH2:4][OH:3])[S:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1nc(-c2ccc(Cl)cc2)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 3-(4-chlorophenyl)-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester (0.20 g, 0.74 mmol) in MeOH (10 ml) was added sodium borohydride (0.048 g, 1.26 mmol) portion wise. The resulting reaction mixture was stirred at room temperature for 2 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0° C., quenched it with 2 ml of water and concentrated under vacuum. Added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum to get the product (0.17 g) that was carried forward to the next step without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[C:11]3[CH:18]=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[O:9])[CH2:4][CH2:3]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>C(#N)C.O>[N:13]1[C:12]2[NH:16][CH:17]=[CH:18][C:11]=2[C:10]([C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:25][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=3)[CH2:3][CH2:4]2)=[O:9])=[N:15][CH:14]=1
Reactant: O=C(c1ncnc2[nH]ccc12)C1CCNCC1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ncnc2[nH]ccc12)C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Piperidin-4-yl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone hydrochloride (60.0 mg, 0.224 mmol) in acetonitrile (3 mL) was stirred with 4-(trifluoromethyl)benzyl bromide (70.0 mg, 0.292 mmol) and N,N-diisopropylethylamine (144 μL, 0.784 mmol) at 60° C. for 2 hours and allowed to cool to room temperature. After addition of water and saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a pale yellow solid (65.0 mg, yield 75%).
Reaction SMILES: [CH2:1]([Si:5]([C:18]1([CH2:24][CH:25]([CH3:27])[CH3:26])SCCCS1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[OH2:28]>CC#N.Cl[Hg]Cl>[CH2:1]([Si:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:18](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Si](c1ccccc1)(c1ccccc1)C1(CC(C)C)SCCCS1
Reactant: O
Agent: Cl[Hg]Cl
Solvent: CC#N
Product: C=CCC[Si](C(=O)CC(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 26 (4.64 g 11.2 mmol) in CH3CN (300 mL) was added water (10 mL) and HgCl2 (15.26 g, 56.21 mmol). After stirring overnight at rt, the mixture was concentrated and partitioned between water (100 mL) and hexane (200 mL). The organic layer was isolated and the aqueous layer extracted with hexane (50 mL). The combined organic extracts were washed with saturated aqueous NaCl and dried over Na2SO4. Concentration to dryness in vacuo at rt gave crude ketone 33 as a yellow oil (3.2 g, 88%): Rf=0.80 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=6.4 Hz, 4H), 7.44 (m, 6H), 5.88 (m, 1H), 4.99 (dd, J=17.1, 1.6 Hz, 1H), 4.91 (dd, J=10.2, 1.6 Hz, 1H), 2.50 (d, J=6.6 Hz, 2H), 2.14 (m, 2H), 1.36 (m, 2H), 0.95 (m, 1H), 0.76 (d, J=6.7 Hz, 6H); IR (neat) 3068 (m), 3046(m), 2956(s), 2925 (m), 2864 (m), 1956 (w), 1886 (w), 1826(w), 1641 (s), 1471 (m), 1431 (s), 1113 (s), 1000 (m), 910 (m), 743 (s), 702 (s) cm−1; MS (FAB) m/e (rel. intensity) 323 (MH+, 15), 322 (24), 321 (89), 267, (17), 236 (36), 198 (20), 182 (63), 169 (100), 167 (15), 159 (31); HRMS (FAB) calcd for C23H25OSi: 321.1675 (MH+-2), found: 321.1670.