Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH:8]2[CH:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl>[CH:2]([CH:3]1[CH2:9][CH:8]2[CH:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:1]
Reactant: CC(C)(C)OC(=O)N1CC2CC2CC1CO
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC2CC1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (D15) (820 mg, 3.6 mmol) and TEMPO (112.7 mg, 0.72 mmol) in DCM (8 ml), BAlB (1.27 g, 3.96 mmol) was added and the resulting mixture was stirred at RT 4 hrs. The reaction mixture was diluted with DCM (35 ml), washed with Na2S2O3 sat sol (35 ml) and extracted with DCM (2×35 ml). The combined organic extracts were washed with NaHCO3 sat sol (35 ml) and brine (35 ml), dried and evaporated under reduce pressure. The remaining residue was loaded on SPE-Si (25 g) cartridge and eluted with a mixture cHex/EtOAC from 95/05 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D16) (0.62 g).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:25](O)[CH2:26][CH2:27]/[CH:28]=[CH:29]/[CH3:30]>CC(OC)(C)C>[CH2:30]([O:23][C:22](=[O:24])[CH2:21][NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])[CH2:29][CH2:28]/[CH:27]=[CH:26]/[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C/C=C/CCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: COC(C)(C)C
Product: C/C=C/CCCOC(=O)CNC(=O)OC(C)(C)C
Temperature: 40 °C

Procedure:
To a vessel maintained at 40° C. was charged CDI (2.75 g, 0.95 eq) and TBME (9 mL). To this mixture was added with stirring a solution of N-(t-butoxycarbonyl)glycine (3.1 g, 1.0 eq) dissolved in TBME (12 mL) over 30 min. Stirring was continued for an additional 30 min, whereupon trans-4-hexen-1-ol (1.7 g, 0.95 eq) was added over 30 min. The mixture was maintained with stirring at 40° C. for an additional 3.5 h, then cooled to ambient temperature and stirred a further 14 h. The mixture was washed with 1N HCl (2×7.8 mL) then water (1×7.8 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give (E)-hex-4-en-1-yl2-((tert-butoxycarbonyl)amino)acetate as an oil. The oil was dissolved in DCM (12 mL) and 4.0 M HCl in dioxane (2.8 mL) was added drop-wise. The mixture was stirred at ambient temperature for 1.5 h then the mixture was heated to 35° C. and stirred for 3 h. 4.0 M HCl in dioxane (2.8 mL) was added drop-wise. After 6 h at 35° C. a further dose of 4.0 M HCl in dioxane (2.8 mL) was added drop-wise and the mixture was stirred for a further 4 h. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. A portion of the residue (1.0 g) was dissolved in DCM (8 mL) and methyl 2-chloro-2-oxoacetate (0.63 g) was added. Triethylamine (1.0 g) was added drop-wise over 20 min. The mixture was stirred for 1 h before being quenched by 1N HCl (2.5 mL) to form a biphasic mixture. The layers were separated and the organic layer was washed with 1N HCl (1×2.5 mL), water (1×2.5 mL) and concentrated under reduced pressure to provide an oil. Flash column chromatography (SiO2, 10→60% EtOAc/Hex gradient) provided the title compound as an oil as a 95:5 mixture of trans:cis isomers. 1H NMR (300 MHz, CDCl3) δ ppm 7.57 (s, 1H), 5.31-5.55 (m, 2H), 4.17 (t, J=6.69 Hz, 2H), 4.12 (d, J=5.51 Hz, 2H), 3.92 (s, 3H), 1.97-2.10 (m, 2H), 1.67-1.77 (m, 2H), 1.62-1.67 (m, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 168.60, 160.35, 156.28, 129.49, 126.12, 65.34, 53.68, 41.47, 28.62, 28.17, 17.84; HRMS (M+H) m/z, calcd for C11H18NO5, 244.1185; found 244.1187.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])=[O:17])(=[O:13])=[O:12].[N:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][C:22]([N:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH2:36][CH2:35]1)=[O:23])=[O:17])(=[O:13])=[O:12]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(O)CCCNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NCCCC(=O)N1CCN(c2ccncc2)CC1
Yield: 21 %

Procedure:
Using an analogous procedure to that described in Example 18, 4-[2-(2-naphthalenesulphonamido)acetamido]butyric acid was reacted with 1-(4-pyridyl)piperazine to give 2-(2-naphthalenesulphonamido)-N-{3-[4-(4-pyridyl)piperazin-1-ylcarbonyl]propyl}acetamide in 21% yield as a foam;
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:35])[C:5]2[N:10]=[N:9][N:8]([CH:11]3[CH:15]([O:16]C(=O)C4C=CC=CC=4)[CH2:14][CH:13]([CH:25]=[CH:26][P:27]([O:32]CC)([O:29]CC)=[O:28])[O:12]3)[C:6]=2[N:7]=1.[Si](Br)(C)(C)C.[NH4+].[OH-]>CC#N.CO>[NH2:1][C:2]1[N:3]=[C:4]([NH2:35])[C:5]2[N:10]=[N:9][N:8]([CH:11]3[O:12][CH:13]([CH:25]=[CH:26][P:27](=[O:28])([OH:29])[OH:32])[CH2:14][CH:15]3[OH:16])[C:6]=2[N:7]=1
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2nnc3c(N)nc(N)nc32)O1)OCC
Agent: C[Si](C)(C)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: Nc1nc(N)c2nnn(C3OC(C=CP(=O)(O)O)CC3O)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Compound 53.1 (183 mg, 0.36 mmol) was dissolved in 7 mL of anhydrous CH3CN and treated with TMS—Br (240 uL, 1.82 mmol). The solution was stirred at rt for 6 hrs. Added more TMS—Br (100 uL, 0.75 mmol) and stirred at room temperature for 16 hrs. Concentrated the reaction under reduced pressure. The residue was dissolved in methanol and added aqueous NH4OH solution, stirred for another 3 hrs and concentrated under reduced pressure. The residue was subjected to a reverse phase HPLC to give compound 53.2 (110 mg, 81% yield). 1H NMR (D2O, 300 MHz): δ 6.32 (m, 1H), 6.07 (s, 1H), 5.83 (m, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 2.27 (m, 2H). 31P NMR: 11.17 ppm LC/MS: C10H14N7O5P Exact Mass: 343.08. Found: [M−H]− 342.0, [M+H]+ 344.1.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>CN(C)C(=O)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>[CH3:20][N:18]1[CH:19]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[C:33]=4[F:34])=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: OB(O)c1cccc(F)c1F
Reactant: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
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: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(CN2CCN(c3nccnc3-c3cccc(F)c3F)CC2)cn1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
Dissolve 3′-chloro-4-(1-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (160 mg, 0.55 mmol) in N,N-dimethylacetamide (4 mL) and water (2 mL) and purge with nitrogen for 0.5 hr. Add potassium carbonate (180 mg, 1.30 mmol) then 2,3-difluorobenzeneboronic acid (100 mg, 0.66 mmol) and purge with nitrogen for 0.5 hr. Add tetrakis(triphenylphosphine)palladium(0) (0.01 g, 0.0086 mmol) and heat at 110° C. for 3.25 hr. Cool to room temperature and purify (silica gel chromatography, eluting with 0:100 to 30:70 methanol:DCM), followed by reverse phase HPLC to give the title compound (52.69 mg, 26%). MS (ES): m/z=371 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH2:14])[CH3:13])=[CH:7][CH:6]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:31]Br)=[CH:26][C:25]=1[CH2:41][OH:42])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:14][CH2:31][C@@H:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:25]([CH2:41][OH:42])[CH:26]=2)[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH3:13])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C[C@@H](C)N)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)cc1
Yield: 50.5 %

Procedure:
Methyl-{4-[(2R)-2-amino-propyl]phenyl}acetate (Preparation 64) (7.00 g, 33.8 mmol), [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol (Preparation 39) (15.2 g, 33.8 mmol) and diisopropylethylamine (4.36 g, 33.8 mmol) were heated in dimethylsulfoxide (50 ml) at 90° C. under nitrogen for 16 hours. The mixture was cooled and diluted with ethyl acetate (250 ml) and basified with 1M aqueous sodium hydroxide. The aqueous was extracted with ethyl acetate (250 ml) and the combined organics washed with brine (3×200 ml) and dried (magnesium sulfate). The crude material was purified by chromatography (90:10 dichloromethane:methanol) to furnish an orange coloured oil (9.86 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1cc(Cl)ccc1C(=O)O
Reaction time: 20 h
Yield: 54 %

Procedure:
A solution of 2-amino-4-chlorobenzoic acid (10 g, 0.06 mol) in anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) was cooled to 0° C. in a 300 mL 3-necked flask fitted with a magnetic stirring bar and a constant additional funnel. Bromoacetyl bromide was added dropwise over a 2 h period while maintaining the internal temperature between 0°-2° C. After the addition was completed, the ice-water bath was removed, and then the reaction mixture was stirred 20 h. The reaction mixture was cooled in an ice-bath, water (300 mL) was slowly added, and then the white crystalline product which formed was filtered. Recrystallization from EtOAc/hexane gave 9.2 g (54%) of the title compound as a white solid: mp 156.4°-158° C.; 1H NMR (DMSO-d6) δ13.99 (s, 1H, NH), 11.72 (s, 1H, COOH), 8.54 (d, 1H, J=2.0), 8.00 (d, 1H, J=8.8), 7.27 (dd, 1H, J=2.4, J=6.4), 4.28 (s, 2H); 13C NMR (DMSO-d6) δ168.60, 165.54, 141.12, 138.51, 133.88, 123.36, 119.23, 115.58, 30.54; MS (EI, m/z) 293 (M+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I.O>[N:12]1([C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: COC(=O)c1cccc(Br)n1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-n2cccn2)n1
Temperature: 25 °C

Procedure:
A mixture of commercially available methyl 6-bromopicolinate (1.000 g; 4.62 mmol), 1H-pyrazole (315 mg; 4.62 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (135 mg; 0.92 mmol), K2CO3 (1.370 g; 9.72 mmol), and CuI (44 mg; 0.23 mmol) in anh. toluene (15 ml) was heated at reflux for 17 h. After cooling to rt, water was added, and the mixture was extracted with AcOEt. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded methyl 6-(1H-pyrazol-1-yl)picolinate as a colorless solid. LC-MS (conditions A): tR=0.59 min.; [M+H]+: 204.04 g/mol.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9](O[C:12](=[O:13])[CH:2]21)=[O:10].[NH3:14]>O>[CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9](=[O:10])[NH:14][C:12](=[O:13])[CH:2]21
Reactant: O=C1OC(=O)C2C3CCC(CC3)C12
Reactant: N
Solvent: O
Product: O=C1NC(=O)C2C3CCC(CC3)C12

Procedure:
A solution of bicyclo[2.2.2]octane-2,3-dicarboxylic anhydride (3 g; 16.6 mmol) in tetrahydrofurn (9 ml) was dropwise added to a mixture of 29% aqueous ammonia (6 g; 83 mmol) and water (18 ml) while ice-cooling, and the resultant mixture was heated. After removal of the solvent by distillation under an ordinary pressure, acetic anhydride (10 ml) was added thereto, followed by refluxing for 30 minutes. The solvent was removed by distillation under reduced pressure, and the residue was combined with toluene (24 ml) and heated to dissolve. After cooling, the precipitated crystals were collected by filtration to give the objective compound. M.P., 199°-200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9])=[O:5].[F:23][C:24]([F:35])([F:34])[S:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([S:25][C:24]([F:35])([F:23])[F:34])=[CH:27][CH:28]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(SC(F)(F)F)cc2)CC1
Temperature: 60 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
A mixture of 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (16.2 mg, 0.050 mmol), 4-(trifluoromethylthio)benzyl bromide (20.3 mg, 0.075 mmol), piperidinomethyl-polystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.50 mL) was stirred at 60° C. for 15 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with CH3OH (15 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-[4-(trifluoromethylthio)benzyl]piperidine (Compound No.1616) (21.9 mg, 85%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 545.2 (M++H, C23H26ClF3N4O2S).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH2:7]([OH:19])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].C(I)C=C>C1COCC1>[CH2:3]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][OH:19])[CH:2]=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: OCCOCCOCCOCCO
Agent: C=CCI
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCOCCOCCOCCOCCO
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To an anhydrous solution of potassium tert-butoxide (2.3 g, 19.5 mmol) in THF (500 mL), tetraethylene glycol (7.18 g, 37.0 mmol) is added at room temperature. The resulting mixture is stirred for 30 min, and a solution of allyl iodide (3.31 g, 19.7 mmol) in dry THF (60 mL) is added dropwise over 1 h. The reaction mixture is stirred for 30 h and filtered through a silica plug (10 g) using ethyl acetate (800 mL) to elute all product. After evaporation of the solvent in vacuo, the product is purified by column chromatography using a solvent gradient petrol ether/ethyl acetate 10:1 to ethyl acetate 100% yielding a colourless oil (2.41 g, 10.3 mmol, 27%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][OH:10])[CH:2]=1>C(Cl)Cl.O=[Mn]=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH:9]=[O:10])[CH:2]=1
Reactant: OCC#Cc1cccnc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=CC#Cc1cccnc1
Temperature: 25 °C
Yield: 17.4 %

Procedure:
To a solution of 3-(3-pyridinyl)-2-propyn-1-ol (250 mg, 1.88 mmol, obtained as described in J. Org Chem. 1998, 63, 1109-1118) in anhydrous DCM (10 ml) under argon was added MnO2 (3.66 g, 42 mmol) portion wise over 1.5 h. The reaction mixture was stirred at rt for one additional hour. Then the reaction mixture was poured on the top of a column of silica gel and eluted with cHex/EtOAc (2:1 then 1:1) to give 43 mg (17%) of the title compound as a yellow powder. 1H NMR (CDCl3) δ: 9.46 (s, 1H), 8.85 (dd, J=2.1, 0.8 Hz, 1H), 8.71 (dd, J=5.0, 1.7 Hz, 1H), 7.91 (ddd, J=8.0, 2.1, 1.7 Hz, 1H), 7.38 (ddd, J=8.0, 5.0, 0.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[C:13]([N+:19]([O-])=O)[CH:12]=3)=[O:5])[CH3:2].[ClH:22].[H][H]>C(O)C.[Pt](=O)=O>[ClH:22].[ClH:22].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[C:13]([NH2:19])[CH:12]=3)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1cc([N+](=O)[O-])ccc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2c(cn1)[nH]c1cc(N)ccc12

Procedure:
0.1 g of 7-nitro-β-carbolin-3-carboxylic acid ethyl ester is suspended in 30 ml of ethanol and, after the addition of 1 ml of 5 N hydrochloric acid, is hydrogenated at normal pressure over 25 mg of platinum dioxide until the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off and washed well with warm ethanol. The filtrate is treated with active carbon and concentrated until turbidity commences. After cooling, 95 mg of 7-amino-β-carbolin-3-carboxylic acid ethyl ester dihydrochloride of melting point 270° C. (decomposition) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a solution of 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (10 g, 0.031 mol) in CH2Cl2 (100 mL) was added t-butylamine (8.0 mL, 0.076 mol) at 0° C. The reaction mixture was allowed to warm to room temperature, and stirred for 30 min. A white precipitate formed and was filtered, and the filtrate was concentrated in vacuo to afford the title compound as a yellow oil (11 g, 100%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:32])([CH3:31])[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[N:12]=[C:11]2[Sn](CCCC)(CCCC)CCCC)([CH3:4])([CH3:3])[CH3:2].[C:33]([NH:37][C:38]([C:40]1[C:48]2[C:43](=[N:44][CH:45]=[C:46](Br)[N:47]=2)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.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.[Cu]I>[C:33]([NH:37][C:38]([C:40]1[C:48]2[C:43](=[N:44][CH:45]=[C:46]([C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[C:8]([C:7]([CH3:32])([CH3:31])[O:6][SiH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=4)[N:13]([CH3:17])[N:12]=3)[N:47]=2)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Temperature: 90 °C
Yield: 74 %

Procedure:
To a solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-tributylstannanyl-1H-indazole (265 mg, 0.47 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (100 mg, 0.23 mmol) in DMF (2 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and copper(I) iodide (9 mg, 0.047 mmol). The reaction mixture was heated at 90° C. for 1 h then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was absorbed on silica gel and chromatographed with 20% to 50% EtOAc/hexanes to isolate 106 mg (73%) of 2-[5-(tert-butyldimethyl-silanyloxymethyl)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a beige solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([OH:11])/[CH:8]=[CH:9]/[I:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([C:18](Br)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([O:11][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)/[CH:8]=[CH:9]/[I:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(/C=C/I)CC1CCCC1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: I/C=C/C(CC1CCCC1)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 21.4 g. of 4-cyclopentyl-1-iodo-trans-buten-3-ol (Example 34) in 170 ml. of dry pyridine containing 31 g. of triphenylmethyl bromide is heated on the steam bath for 2 hours. The dark mixture is poured into 850 ml. of iced water and the resulting solution is extracted three times with ether. The combind extracts are washed with ice cold 2% hydrochloric acid until the washings are acidic, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Trituration of the residue followed by filtration removes triphenylcarbinol. The mother liquor is taken to dryness and the residual syrup is chromatographed on 400 g. of florisil using hexane gives 32 g. (78%) of syrup which solidifies on standing. Recrystallization from hexane affors white crystals, m.p. 87°-88° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:22](=[O:23])[C:21]4[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and 4-(trifluoromethyl)benzoyl chloride (125 mg, 0.60 mmol; 2.0 eq.) as a white powder (31.2 mg, 28%). HPLC, Rt: 4.02 min. (purity 99.4%). LC/MS, M+(ESI): 373.2, M−(ESI): 373.1.