Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]=2)=[C:7]2[C:3]=1[CH:4](O)[N:5](C(C)(C1C=CC=CC=1)C)[C:6]2=[O:20].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>[N+](C)([O-])=O.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:20]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(-c3nc4ccccc4[nH]3)ccc(Cl)c2C1O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1NCc2c(Cl)ccc(-c3nc4ccccc4[nH]3)c21
Temperature: 25 °C
Reaction time: 23.5 h
Yield: 51.2 %

Procedure:
4-Chloro-3-hydroxy-7-(1H-benzoimidazol-2-yl)-2-(1-methyl-1-phenylethyl)isoindolinone (39.4 mg, 0.0943 mmol) was dissolved in nitromethane (2.8 mL), and the solution was added with trifluoroacetic acid (0.073 mL, 0.94 mmol) and triethylsilane (0.030 mL, 0.19 mmol), followed by stirring at room temperature for 23.5 hours. Then, the mixture was added with trifluoroacetic acid (0.146 mL, 1.89 mmol) and triethylsilane (0.045 mL, 0.28 mmol) and warmed to 70° C., followed by stirring for 7.5 hours. Further, the mixture was added with trifluoroacetic acid (1.00 mL) and triethylsilane (0.15 mL, 0.94 mmol), followed by stirring for 4 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by slurry using chloroform/methanol (9/1) and by preparative thin-layer chromatography (hexane/ethyl acetate=2/1, 1/1) to obtain Compound 174 (13.7 mg, yield 51%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[C@@H:9]1[CH:20]([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:23]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:17]([C:13]2[CH:14]=[C:15]3[CH2:16][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@@H:9]([CH:20]([CH3:21])[CH3:22])[C:10]3=[N:11][CH:12]=2)=[O:19])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:24]
Reactant: CCS(=O)(=O)c1ccc(CN)cc1
Reactant: CC(C)[C@H]1c2ncc(C(=O)O)cc2CN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.5 %

Procedure:
To a solution of (S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylic acid (83.3 mg, 281 μmol) and (4-(ethylsulfonyl)phenyl)methanamine (67.1 mg, 337 μmol) in DMF (2 mL) at rt was added HATU (160 mg, 421 μmol) and diisopropylethylamine (97.8 μL, 561 μmol). The mixture was stirred at rt for 15 h, at which point it was quenched with saturated aqueous ammonium chloride solution (15 mL). EtOAc (25 mL) was added, then the phases were separated. The organic layer was washed with brine (15 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient to 100%) to afford 98.0 mg tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, (15), (77%). LC-MS tR=0.92 min in 1 min chromatography, MS (ESI) m/z 488.5 [M+H]+. 1H NMR (CD3OD, 400 MHz, mixture of rotamers): δ 8.94 (d, J=2.0 Hz, 1H), 8.16 (d, J=12.0 Hz, 1H), 7.89 (dd, J=2.0 Hz, 8.4 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 4.96 (m, 1H), 4.83 (m, 1H), 4.70 (s, 2H), 4.59 (m, 1H), 3.20 (q, J=7.2 Hz, 2H), 2.56-2.42 (m, 1H), 1.48 (s, 9H), 1.20 (t, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 1.5H), 1.02 (d, J=6.8 Hz, 1.5H), 0.80 (d, J=6.8 Hz, 1.5H), 0.74 (d, J=6.8 Hz, 1.5H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:13]([NH2:15])[CH3:14]>>[CH3:14][O:13][NH:15][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CON
Reactant: Nc1nc(Cl)nc2ccccc12
Product: CONc1nc(N)c2ccccc2n1

Procedure:
Prepared as in Example 42 from 2-chloroquinazolin-4-amine (Example 38) and methoxylamine. 1H NMR (400 MHz, DMSO-d6) δ 3.79 (s, 3H), 7.48-7.44 (m, 1H), 7.86-7.80 (m, 2H), 8.27 (d, J=8.0 Hz, 1H), 8.99 (s, 1H), 9.16 (s, 1H), 12.39-12.08 (m, 1H). MS 191 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH2:21](Br)[C:22]#[CH:23]>>[CH2:23]([O:11][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[C:22]#[CH:21]
Reactant: C#CCBr
Reactant: CC(C)=CCCC(C)=CCOc1ccc(C(=O)O)cc1
Product: C#CCOC(=O)c1ccc(OCC=C(C)CCC=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(3,7-dimethyl-2,6-octadienyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(3,7-dimethyl-2,6-octadienyl)oxy]benzoic acid propargyl ester; B.P. 135°-137°C/0.01 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]([F:19])([F:18])[F:17].[CH:21](OC)(OC)OC.FC(F)(F)C(O)=O>CO>[F:18][C:16]([F:19])([F:17])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[C:7]2=[N:6][C:5]([OH:20])=[CH:4][CH:3]=[C:2]2[N:1]=[CH:21]1
Reactant: COC(OC)OC
Reactant: Nc1ccc(O)nc1Nc1ccccc1OC(F)(F)F
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2ncn(-c3ccccc3OC(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
To a solution of 5-amino-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-ol (75.0 mg, 0.26 mmol) dissolved in MeOH was added trimethyl orthoformate (1.0 mL, 9.05 mmol) and catalytical amount of trifluoroacetic acid. The solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (78 mg). LCMS m/z=296.0 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ ppm 6.63 (d, J=8.6 Hz, 1H), 7.66 (m, 3H), 7.81 (d, J=7.6 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.42 (s, 1H), 10.60-11.20 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CO
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1conc1-c1ccc(Cl)c(Cl)c1
Yield: 99 %

Procedure:
A mixture of 3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propionic acid (3.03 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propionate (3.15 g, yield 99%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 87–88° C.
Reaction SMILES: NCC(N)C.[NH2:6][CH2:7][CH:8]([NH2:12])[CH2:9][CH2:10][CH3:11].[C:13]([NH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](O)=O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:9]([CH:8]1[CH2:7][NH:6][C:25]([C:24]2[CH:28]=[CH:29][N:30]=[C:22]([NH:21][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:23]=2)=[N:12]1)[CH2:10][CH3:11]
Reactant: CCCC(N)CN
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: CC(N)CN
Product: CCCC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Yield: 20 %

Procedure:
Following the procedure as described in EXAMPLE 9, making variations as required to replace 1,2-diaminopropane with 1,2-diaminopentane to react with 2-benzamidoisonicotinic acid, N-(4-(4-propyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained in 20% yield: MS (ES+) m/z 309.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[O:18])[S:10]2)=[C:4]([F:19])[C:3]=1[OH:20].[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[O:18])[S:10]2)=[C:4]([F:19])[C:3]=1[O:20][CH2:23][C:22]#[CH:21]
Reactant: C#CCBr
Reactant: O=c1sc(=Nc2ccc(Cl)c(O)c2F)n2n1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1c(Cl)ccc(N=c2sc(=O)n3n2CCCC3)c1F

Procedure:
Into a reaction flask equipped with a Dimroth condenser, 2.2 g (7 mmol) of 9-(4-chloro-2-fluoro-3-hydroxyphenylimino)-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-one, 1.1 g (9 mmol) of propargyl bromide, 1.3 g (9 mmol) of potassium carbonate and 20 ml of acetonitrile, were charged, and refluxed under heating for 3 hours to complete the reaction.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si](C(C)C)(C(C)C)C(C)C)[C:6]2=[CH:5][C:4]=1[CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1.[Si](I)(C)(C)C>C(Cl)Cl>[NH:25]1[CH2:24][CH2:23][CH:22]([C:4]2[C:3](=[O:2])[NH:8][C:7]3[CH:9]=[CH:10][NH:11][C:6]=3[CH:5]=2)[CH2:27][CH2:26]1
Reactant: COc1nc2ccn([Si](C(C)C)(C(C)C)C(C)C)c2cc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=c1[nH]c2cc[nH]c2cc1C1CCNCC1
Temperature: 60 °C
Yield: 85 %

Procedure:
To tert-butyl 4-(5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo [3,2-b]pyridin-6-yl)piperidine-1-carboxylate (130 mg, 0.267 mmol) in CH2Cl2 (3 mL) was added TMS-I (163 μl, 1.20 mmol) at rt. The resulting brown solution was stirred at 60° C. over night. Partial of the solvent was removed on rotary vacuo, the residue was purified on reverse phase PrepHPLC to afford the expected product, 6-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridin-5(4H)-one (49.3 mg, 85%). 1H-NMR (400 MHz, MeOD) δ ppm 1.85 (dd, J=12.84, 3.53 Hz, 2 H) 2.12 (d, J=14.10 Hz, 3 H) 3.06-3.18 (m, 4 H) 3.42-3.52 (m, 3 H) 6.14 (t, J=2.14 Hz, 1 H) 7.20 (dt, J=2.96, 1.42 Hz, 1 H) 7.62 (s, 1 H); Mass spec 218.14 (MH+), Calc for C12H15N3O 217.12.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=1.[O-:19][Mn](=O)(=O)=O.[K+]>O1CCOCC1>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:19])=[O:16])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Yield: 82.2 %

Procedure:
A suspension of the product of step A (0.4 g, 1.6 mmol) and KMnO4 (0.502 g, 3.2 mmol) in dioxane (15 ml) was refluxed for 2 h with stirring. The solution was filtered through silica gel bead and washed with EtOAc (30 ml). The solvent was evaporated to dryness to give the title compound (0.35 g, 81.6%), as white solid. 1H-NMR (CDCl3) 7.30-7.58 (m, 5H); 7.76 (d, 1H, J=8.15 Hz); 8.11 (d, 2H, J=8.03 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[N:17][CH:18]=1.[ClH:29]>C1COCC1.O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1
Reactant: COc1ccc2nccc(-c3ccc(CCNC(=O)OC(C)(C)C)nc3)c2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc2nccc(-c3ccc(CCN)nc3)c2n1
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 1,1-dimethylethyl (2-(5-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-pyridinyl}ethyl)carbamate (4.0 mmole) in dry THF (20 mL) at RT was added 4 M HCl in dioxane (10 mL). After 4 h, the reaction suspension was concentrated in vacuo and dried under high vacuum to give the title compound (100%.) as an off-white solid: LC-MS (ES) m/e 281 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:13])([CH3:12])[CH2:4][NH:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].C(OCC)(OCC)(OCC)C.[C:25]1(C)[C:26](S(O)(=O)=O)=[CH:27]C=[CH:29][CH:30]=1>>[CH3:10][C:7]1([CH3:11])[CH2:6][N:5]2[C:29]([CH2:30][CH2:25][CH2:26][CH3:27])([O:1][CH2:2][C:3]([CH3:13])([CH3:12])[CH2:4]2)[O:9][CH2:8]1
Reactant: CC(C)(CO)CNCC(C)(C)CO
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: CCOC(C)(OCC)OCC
Product: CCCCC12OCC(C)(C)CN1CC(C)(C)CO2
Temperature: 25 °C

Procedure:
3-(3-Hydroxy-2,2-dimethyl-propylamino)-2,2-dimethyl-propan-1-ol (128.0 g, 0.68 mol), triethyl orthoacetate (162.0 g, 1.00 mol) and toluene sulfonic acid (2.0 g) were charged into a oven dried round bottom flask equipped with a stirring bar, distillation head and under nitrogen. The resulting solution was heated until the theoretical amount of methanol was collected. The reaction was cooled to room temperature and triethylamine added to neutralize the acid. Fractional vacuum distillations (twice) afforded the product as a water clear liquid, boiling point 101-103° C. at 0.44 torr. Yield: 156 g (90.5%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([OH:31])[C@H:14]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)(=O)=O)=CC=1.[CH2:32]([NH2:34])[CH3:33]>CO>[F:30][C:26]1[CH:25]=[C:24]([C@H:14]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)[C@H:13]([OH:31])[CH2:12][NH:34][CH2:32][CH3:33])[CH:29]=[CH:28][CH:27]=1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2cccc(F)c2)n2ccc3ccccc32)cc1
Solvent: CO
Product: CCNC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Reaction time: 12 h

Procedure:
(2S,3S)-3-(3-fluorophenyl)-2-hydroxy-3-(1H-indol-1-yl)propyl 4-methylbenzenesulfonate (200 mg, 0.456 mmol) was dissolved in a solution of ethylamine in methanol (2.0 M, 10 mL) and stirred for 12 hours in a sealed reaction vessel. All volatiles were removed under reduced pressure, and the liquid residue was dissolved in dichloromethane (15 mL), washed with a saturated aqueous solution of potassium carbonate, dried (anhydrous sodium sulfate), and concentrated. Purification of the liquid residue by Biotage chromatography (FlasH12i, silica, 0-15% MeOH/dichloromethane/0.5% triethylamine) gave (1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(ethylamino)propan-2-ol, which was used to prepare (1S,2R)-3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol hydrochloride as a white powder in an analogous matter to EXAMPLE 144, step 2. Yield: 99 mg (70%). MS (ES) m/z 313.1 ([M+H]+); HRMS: calcd for C19H21FN2O+H+, 313.1716; found (ESI, [M+H]+), 313.1716.
Reaction SMILES: [CH3:1][N:2]([C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]2)(=[O:12])=[O:11])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[P:38](OCl)([O:43]CC)([O:40]CC)=[O:39].Br[Si](C)(C)C>ClCCl.CO>[P:38]([OH:43])([OH:40])([O:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:13]([S:10]([CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:8][CH2:7]2)(=[O:12])=[O:11])[CH2:14]1)=[O:39]
Reactant: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](O)C2)CC1
Reactant: CCOP(=O)(OCl)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](OP(=O)(O)O)C2)CC1
Reaction time: 8 h

Procedure:
(3R)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]piperidin-3-ol (100 mg, 0.24 mmol) was suspended in dichloromethane (5 mL). Diisopropylethylamine (0.05 mL, 0.3 mmol) was added followed by diethyl chloro phosphate (0.036 mL, 0.24 mmol). The reaction mixture was stirred under nitrogen overnight. Methanol (1 mL) was added to the flask and the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL) and bromotrimethylsilane (2 mL, 14.4 mmol) was added. The reaction mixture was stirred under nitrogen at room temperature for 18 hours and then was concentrated in vacuo. The residue was purified by reverse phase HPLC. (2 mg, 5%). 1H NMR (400 MHz, DMSO-d6) ppm 1.28 (br. s., 1H) 1.50 (br. s., 1H) 1.63-1.72 (m, 2H) 1.86 (d, J=2.56 Hz, 1H) 2.02 (d, J=10.98 Hz, 1H) 2.83 (s, 1H) 2.94 (td, J=14.46, 6.59 Hz, 2H) 3.14 (s, 2H) 3.47 (br. s., 9H) 3.52 (br. s., 11H) 6.51 (br. s., 1H) 7.09 (d, J=2.93 Hz, 1H). LCMS m/z 488.8 (M+H calcd for C19H30N6O6PS requires 487.5). LCMS (C-18 column, gradient elution 5 minute chromatograph, 95:5 to 5:95 water/acetonitrile, retention time 1.23 min).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[S:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:25]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(OC)ccc2OC)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,5-dimethoxybenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (17.0 mg) with purity >80%. LCMS (pos) m/z 387.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([F:16])[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:17])[CH:10]([F:16])[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(c1ccc(Cl)cc1Cl)C(F)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(c1ccc(Cl)cc1Cl)C(F)n1cncn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 2.4 g of 1-(2,4-dichlorophenyl)-2-fluoro-2-(1H-1,2,4-triazol-1-yl)ethanone in 9.5 ml of methanol and 0.5 ml of water is added at 5°-10° C., with stirring, 0.12 g of sodium borohydride, and the resulting mixture is stirred firstly for 1 hour at 0°-5° C. and then for 2 hours at room temperature, in the course of which a clear solution gradually forms. This solution is then poured into ice-water, and the mixture is extracted twice with dichloromethane. The combined extracts are dried over sodium sulfate, filtered, and concentrated by evaporation. The residue is distilled under high vacuum to obtain the above alcohol as a diastereoisomeric mixture; b.p. of the crude product: 150°-160° C./0.07 mbar. Crystallisation from diethyl ether/diisopropyl ether yields the purified diastereoisomeric mixture in the form of beige crystals; melting range 103°-112° C.
Reaction SMILES: [Br:1]Br.[C:3]([Si:7]([CH3:25])([CH3:24])[N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH:16]=[C:11]2[CH:10]=[CH:9]1)([CH3:6])([CH3:5])[CH3:4].N1C=CC=CC=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH:16]=2)[N:8]([Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:25])[CH3:24])[CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3cccc(F)c3)cnc21
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)n1cc(Br)c2cc(-c3cccc(F)c3)cnc21
Yield: 95.8 %

Procedure:
A solution of Br2 (1.12 mL, 21.8 mmol) in CCl4 was added dropwise to a stirred and cooled (0° C.) solution of 8 (7.10 g, 21.8 mmol) and pyridine (2.1 mL, 26.2 mmol) in dry CHCl3 (330 mL). Progress of the reaction was followed by TLC. When the reaction was completed, aqueous NaHCO3—Na2S2O3 solution was added. The organic solution was separated and the aqueous layer was extracted with CH2Cl2 (3×100 mL). Combined organic solutions were dried (MgSO4), concentrated and purified by SGC with hexane:benzene as eluent in gradient (up to 14% benzene) to afford 9 (8.47 g, 91%) as tan solid. 1H NMR (400 MHz, CDCl3) δ 0.65 (s, 6H), 0.97 (s, 9H), 7.02-7.10 (m, 1H), 7.29 (s, 1H), 7.33-7.38 (m, 1H), 7.40-7.47 (m, 2H), 7.97 (d, J=2.2 Hz, 1H), 8.51 (d, J=2.2 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:31][CH:32]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([C:30]4[CH:29]=[CH:28][C:27]([C:26]([F:40])([F:25])[F:39])=[CH:32][N:31]=4)[CH2:34][CH2:35]3)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1)N1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-[5-(trifluoromethyl)pyrid-2-yl]piperazine to give the title compound as a colorless solid. MS: 566.2 ([M+H])
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[N+:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])#[C-:19].CCN(CC)CC>CN(C=O)C.C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:21]([C:20]1[N:18]=[CH:19][O:6][C:4]=1[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:22]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(O)c1c(F)cccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ncoc1-c1c(F)cccc1Cl
Reaction time: 3 h
Yield: 23.5 %

Procedure:
To a solution of 2-chloro-6-fluorobenzoic acid (2.14 g, 12.3 mmol), CH2Cl2 (50 ml), and DMF (2 drops) at room temperature under N2 was added oxalyl chloride (9.2 ml, 18.4 mmol) dropwise. The mixture was stirred for 3 h and the volatiles were removed under reduced pressure to give the crude acid chloride. The crude acid chloride and methyl isocyanoacetate (1.23 g, 12.3 mmol) were dissolved in THF (20 ml) at room temperature under N2 and Et3N (6.8 ml, 49.2 mmol) was added dropwise over a period of 30 minutes. The reaction was allowed to stir for 22 h followed by dilution with Et2O, extraction with H2O, 1N HCl, H2O, brine, dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, hexanes/Et2O gradient) gave 4-methoxycarbonyl-5-(2-chloro-6-fluorophenyl)oxazole (0.74 g, 24%).