Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30]([OH:32])=O)=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:72][C@H:73]([CH3:80])[C:74]([NH:76][CH2:77][CH2:78][OH:79])=[O:75]>CN(C=O)C>[OH:79][CH2:78][CH2:77][NH:76][C:74]([C@H:73]([NH:72][C:30]([C:29]1[C:23]2[C:24](=[N:25][CH:26]=[C:21]([C:15]3[C:14]4[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=4)[N:17]([CH3:20])[N:16]=3)[N:22]=2)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[CH:28]=1)=[O:32])[CH3:80])=[O:75]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](N)C(=O)NCCO
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: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
In a round-bottomed flask, (R)-2-amino-N-(2-hydroxy-ethyl)-propionamide trifluoroacetate (crude from Step 2) was dissolved in DMF (2 ml) and N,N-diisopropylethylamine (0.70 ml, 4.0 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (170 mg, 0.39 mmol) was added followed by HATU (161 mg, 0.42 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and diluted with petroleum ether. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-100% EtOAc) and MeOH/EtOAc (gradient 0-10% MeOH) to give 127 mg (59%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(2-hydroxy-ethylcarbamoyl)-ethyl]-amide as an off-white solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([O:14]C2C=CC([N+]([O-])=O)=CC=2)=O)C=CC=CC=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37].C(N(CC)CC)C.CC1C(=O)C2N3[C@@](OC)([C@H](COC(N)=O)C=2C(=O)C=1OC)[C@H]1N[C@H]1C3>CO>[CH2:36]([N:38]([CH2:39][CH3:40])[C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:14])[CH3:37]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNCC
Agent: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(CC)C(=O)SCCN
Yield: 60 %

Procedure:
2-diethylaminocarbonylthioethylamine (formate: 184 mg) was prepared by subjecting N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (500 mg) and diethylamine (316 μl) to the similar reactions to those described in References 2 and 4. The product was dissolved in anhydrous methanol (4 ml). To the solution were added triethylamine (174 μl) and mitomycin A (273 mg: 0.75 molar equivalent). The reaction solution was treated in a similar manner to that described in Example 1 to obtain Compound 4 (130 mg) in the form of grayish blue powders with a yield of 60%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:28]=[CH:27][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)O1.[F:30][C:31]1[CH:47]=[C:46]([N+:48]([O-:50])=[O:49])[CH:45]=[CH:44][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41](I)[S:42][C:35]=12.[F-].[Cs+].C([O-])(O)=O.[Na+]>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.COCCOC.O>[F:30][C:31]1[CH:47]=[C:46]([N+:48]([O-:50])=[O:49])[CH:45]=[CH:44][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:9]3[CH:28]=[CH:27][C:12]([CH2:13][N:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)=[CH:11][CH:10]=3)[S:42][C:35]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cc2)CC1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
Compound 452 (22.36 g, 26.6 mmol), iodide 408 (7.904 g, 19.0 mmol), CsF (8.658 g, 57 mmol), NaHCO3 (4.788 g, 57 mmol) and Pd(PPh3)4 (2.195 g, 1.9 mmol) were combined with a mixture of H2O (25 mL) and DME (100 mL) which was with nitrogen for a half-an-hour and heated to reflux overnight. It was then was cooled to RT, diluted with EtOAc (200 ml), washed with aqueous NaHCO3 (50 mL) and brine (50 mL), and concentrated. The residue was purified by flash column chromatography (eluent pure EtOAc to 5% MeOH/EtOAc) followed by trituration with EtOAc/ether, to produce compound 453 as an off-white solid (5.4 g, 50% yield). LCMS: 565 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12].[Br:13][CH2:14][CH2:15]Br>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Br:13][CH2:14][CH2:15][O:12][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[Cl:3]
Reactant: COc1ccc(O)c(Cl)c1
Reactant: BrCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(OCCBr)c(Cl)c1
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a stirred mixture of 0.5 parts of N,N,N-triethylbenzenemethanaminium chloride, 4 parts to sodium hydroxide and 40 parts of water were added dropwise 16 parts of 2-chloro-4-methoxyphenol and 18.2 parts of 1,2-dibromoethane at 50° C. Upon complete addition, stirring was continued overnight at 50° C. The reaction mixture was poured into water and the product was extracted with a mixture of 2,2'-oxybispropane and dichloromethane. The extract was dried, filtered and evaporated, yielding 14 parts (52.7%) of 1-(2-bromoethoxy)-2-chloro-4-methoxybenzene as a residue (int. 5).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[CH:32]([CH3:37])[C:33]([F:36])([F:35])[F:34])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:38][CH2:39][OH:40])[CH:32]([CH3:37])[C:33]([F:36])([F:35])[F:34])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: CC(N(CCO)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)C(F)(F)F
Reaction time: 4 h
Yield: 88.4 %

Procedure:
To a stirred solution of 5-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(1,1,1-trifluoropropan-2-yl)pyrimidine-4-carboxamide (42) (138 mg, 199 μmol, Eq: 1.00) in tetrahydrofuran (5 ml) was added HCl (1N) (299 μl, 299 μmol, Eq: 1.5) at room temperature and the reaction mixture was stirred for 4 hrs, neutralized with aqueous 1N NaoH solution, extracted with ethyl acetate, dried (MgSO4), concentrated, and chromatographed (silica gel, gradient, 0 to 5% methanol-dichloromethane) to obtain 5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-(1,1,1-trifluoropropan-2-yl)pyrimidine-4-carboxamide (43) (white foam, 102 mg, 176 μmol, 88.5% yield).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[C:23]([C:24]#[N:25])=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[C:24]([C:23]1[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=[CH:21][N:22]=1)#[N:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nccnc3C#N)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2nccnc2C#N)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of [6-(3-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (200 mg, 0.566 mmol) in THF (5 mL) and H2O (2 mL) was added LiOH (0.120 g, 2.83 mmol). The resulting solution was stirred at 0° C. for 2 hrs. The mixture was diluted with H2O and acidified to pH 3 with 1N HCl at 0° C. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The title compound was obtained (150 mg, 82%) as a white solid. 1H NMR (CD3OD) δ8.42 (d, 1H), 8.38 (d, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 5.65 (dd, 1H), 3.20 (dd, 1H), 2.41 (s, 3H), 2.36 (dd, 1H). MS found: (M+H)+: 326.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:10]=1)[CH3:2].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(#N)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]([C:30](=[O:31])[NH:29][C:26]2[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=2)[N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:10]=1)[CH3:2]
Reactant: CCc1ccccc1-c1nc(-c2cccc(OC)c2)n[nH]1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CC#N
Product: CCc1ccccc1-c1nc(-c2cccc(OC)c2)nn1C(=O)Nc1ccc(C)cc1
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 5 g (0.018 mole) of 5-(2-ethylphenyl)-3-(3-methoxyphenyl)-1H-1,2,4-triazole in 50 ml of anhydrous acetonitrile, 2,25 ml (0.018 mole) of 4-methylphenyl isocyanate were added. The resulting mixture was kept in the darkness for 18 hours, then the solid which formed was recovered by filtration and the mother liquors were brought to dryness under vacuum at room temperature. The obtained residue was taken up with 20 ml of diethyl ether, the mixture was filtered and the solid on the filter was collected with the solid deriving from the first filtration. 5.9 Grams (80%) of 5-(2-ethylphenyl)-3-(3-methoxyphenyl)-1-(4-methylphenylcarbamoyl)-1H-1,2,4-triazole were obtained. M.p. 141°-42° C. (from acetonitrile). Δ δ=-0.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([NH2:23])[N:9]=2)=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([NH:23][C:25](=[O:26])[O:27][CH2:28][CH3:29])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2N
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c(C)noc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a round bottomed flask was added 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-amine (218 mg, 0.67 mmol). The flask was purged with nitrogen, MeCN was added (7 mL), and the solution was cooled to 0° C. Ethyl chloroformate (78 μL, 0.81 mmol) and triethylamine (122 μL, 0.88 mmol) were added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction was quenched with a 1:1 mixture of sat. aq. NaHCO3:brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated and purified on a Biotage (isocratic elution 25% EtOAc: 75% Hexanes) to provide the title compound as white solid (120 mg). The enantiomers were separated by chrial SFC using a 3.0×25.0 cm RegisPack column, with 35% cosolvent (1:1 MeOH:i-PrOH), 80 mL/min at 100 bar. Rention time peak 1 (compound 253): 1.48 min, 100% ee. Retention time peak 2 (compound 254): 2.96 min, 98.1% ee.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[S:23]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][O:15][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:3]1)([C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OC(C)(C)C)cc1
Reaction time: 72 h
Yield: 47.1 %

Procedure:
(2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.40 g, 25.84 mmol) and 4-methylbenzene-1-sulfonyl chloride (14.22 g, 74.6 mmol) were combined in pyridine (50 mL) at 0° C. and store in the refrigerator for 3 days. The reaction mixture was concentrated to half the volume under vacuo and some water (˜300 mL) was added slowly. The mixture was stirred 1 h until a white solid formed. The solid was filtered and dried on the pump on high-vacuum over night. The solid was recrystallized from MeOH (˜20 ml) and water (few drops) to afford title compound 204 (6.40 g, 49%). LRMS: (calc) 525.15. (found) 426.4 (MH-Boc)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:31][CH2:32][O:33][CH3:34]>C(OCC)(=O)C>[CH3:34][O:33][CH2:32][CH2:31][O:1][C:2]1[C:11]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCCBr
Reactant: COC(=O)c1cccc(OC(=O)c2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCOc1c(OC(=O)c2ccccc2)cccc1C(=O)OC
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a mixture of methyl 2-hydroxy-3-[(phenylcarbonyl)oxy]benzoate (21.2 g, 78 mmol), potassium carbonate (21.5 g, 156 mmol) and acetonitrile (370 mL) was added 1-bromo-2-(methyloxy)ethane (12.1 mL, 116 mmol). The resulting mixture was heated at reflux 18 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (400 mL), filtered and concentrated. The residue was then diluted with ethyl acetate (200 mL) and washed with 5% sodium hydroxide solution, water and brine (100 mL each), dried over sodium sulfate, filtered, concentrated, and the residue was chromatographed (silica gel, 30-50% ethyl acetate-hexane) to provide methyl 2-{[2-(methyloxy)ethyl]oxy}-3-[(phenylcarbonyl)oxy]benzoate, (22.5 g, 68 mmol, 87% yield). 1H NMR (400 MHz, CDCl3): 8.25-8.23 (d, d, 2H), 7.76-7.74 (d, d, 1H), 7.68-7.64 (d, d, 1H), 7.55-7.51 (d, d, 2H), 7.40-7.38 (d, d, 1H), 7.23-7.19 (d, d, 1H), 4.17-4.15 (m, 2H), 3.92 (s, 3H), 3.58-3.55 (m, 2H), 3.14 (s, 3H).
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2]>Cl.O1CCOCC1>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Reaction time: 2 h
Yield: 102.6 %

Procedure:
tert-Butyl ((1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentyl)carbamate (0.80 g, 1.76 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (10 mL). After being stirred for 2 hours, the solution was evaporated in vacuo to give the desired product (0.64 g, 94%) as an HCl salt. MS calculated for C19H25F3N2O: (M+H)+355; found 355.2.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[N:45]=[C:44]([C:46]([NH:48][CH:49]([CH3:51])[CH3:50])=[O:47])[CH:43]=[CH:42][CH:41]=1>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>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[N:45]=[C:44]([C:46]([NH:48][CH:49]([CH3:51])[CH3:50])=[O:47])[CH:43]=[CH:42][CH:41]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)NC(=O)c1cccc(Br)n1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)NC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Yield: 57.9 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.10 g), 6-bromo-N-isopropyl-2-pyridinecarboxamide (1.13 g) and tetrakis(triphenylphosphine)palladium(0) (0.160 g), the title compound (1.67 g) was obtained as a colorless amorphous powder.
Reaction SMILES: [Br-].[NH2:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13])([CH3:8])[CH3:7].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:58][P-:59]([F:64])([F:63])([F:62])([F:61])[F:60]>CN(C=O)C>[F:58][P-:59]([F:64])([F:63])([F:62])([F:61])[F:60].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=2)=[O:13])([CH3:7])[CH3:8])=[O:32])=[CH:26][CH:25]=1
Reactant: C[N+](C)(CCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[N+](C)(CCCNC(=O)Cc1ccc(Cl)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3-amino-propyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate M) (0.25 g, 0.63 mmol), (4-chloro-phenyl)-acetic acid (0.11 g, 0.64 mmol), N-methylmorpholine (0.25 mL, 2.27 mmol) and HATU (0.24 g, 0.63 mmol) in anhydrous DMF (8 mL) is stirred under a nitrogen atmosphere at RT for 16 h. The reaction mixture is concentrated in vacuo and is purified by column chromatography (basic alumina, 0-4% MeOH in DCM) to afford the title compound. M+ 468. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (1H, t), 8.14 (1H, t), 7.45 (2H, br), 7.32 (2H, d), 7.24 (2H, d), 7.08 (2H, br), 3.57-3.51 (2H, m), 3.43 (2H, s), 3.42-3.25 (4H, m), 3.12-3.03 (2H, m), 3.02 (6H, s), 1.86-1.78 (2H, m).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[C:3](=[O:5])[CH3:4].[Br-:8].[Br-:9].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:8][CH:4]([Br:9])[C:3](=[O:5])[C:2]([OH:7])([CH3:6])[CH3:1]
Reactant: [Br-]
Reactant: CC(=O)C(C)(C)O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(O)C(=O)C(Br)Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 30.8 %

Procedure:
To a stirred solution of 3-methyl-3-hydroxy-2-butanone (40 g, 0.392 mol) in anhydrous dichloromethane (2.2 l) under nitrogen was added solid pyridinium tribromide (250.4 g, 0.784 mol) in portions and the mixture was stirred at room temperature for 14 h. The mixture was then washed with dilute aqueous sodium hydrogensulphite (500 ml), then saturated aqueous NaCl (500 ml), dried (Na2SO4), and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, CH2Cl2) to afford 31.4 g (31%) of the title compound as a colourless oil: 1H NMR (360 MHz, CDCl3) δ 1.54 (6H, s), 2.45 (1H, br s), 6.62 (1H, s).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[O:22])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[CH2:13]([O:12][C:10]([N:8]1[CH2:9][C@@H:5]([SH:4])[CH2:6][C@H:7]1[CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1COCCNC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1COCCNC(N)=O
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (8.20 g) in methanol (82 ml) was added sodium methoxide (28% solution in methanol) (5.7 ml) at -10°-0° C. in a nitrogen stream and the mixture was stirred at the same condition for 1 hour. To the mixture was added glacial acetic acid (1.9 ml) at -10°-0° C. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (100 ml). The solution was washed with water (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (75 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-mercapto-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (6.89 g)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9](Br)=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].N(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1c(C#C[Si](C)(C)C)cc(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
A mixture of 6-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (2.61 g, 6.93 mmol), TMS-acetylene (1.18 mL, 8.32 mmol), Pd(PPh3)2Cl2 (496 mg, 0.693 mmol), CuI (132 mg, 0.693 mmol), and i-Pr2NH (1.95 mL, 13.9 mmol) in THF (11 mL) was stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, diluted with EtOAc, and washed with saturated aqueous NH4Cl and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 1% to 2% EtOAc in hexanes) to afford the desired product (2.15 g, 79%).