Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][C:3](=[O:7])[C:2]1=[O:8].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(#N)C.[C:24]1([C:30](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([C:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:1]2[CH2:6][CH2:5][NH:4][C:3](=[O:7])[C:2]2=[O:8])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1NCCNC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O
Solvent: CC#N
Product: O=C1NCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A mixture of 2,3-piperazinedione (11.4 g, 100 mmol), bistrimethylsilylacetamide (55.7 g, 270 mmol) and 150 ml of acetonitrile was heated under reflux for one hour. Within 30 minutes, triphenylmethylchloride (22.2 g, 80 mmol) was added dropwise and the mixture was again refluxed for two hours. After stirring overnight at room temperature, 21.6 ml of water was added to the clear solution. The resulting precipitate (3.13 g) was filtered off and the filtrate concentrated in vacuo. The residue was triturated with water and dried to yield 25.5 g of crude title compound which was recrystallized from ethanol. Yield of pure product: 12.19 g, melting point 230°-235° C.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](NCCN3CCCC3)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([N:31](CC)CC)C.C(Cl)(=O)C>C(#N)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:31]
Reactant: CCN(CC)CC
Reactant: Cc1[nH]c2ccc(NCCN3CCCC3)cc2c1C(=O)OCc1ccccc1
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Nc1cc2ccccc2[nH]1
Yield: 33 %

Procedure:
To a stirred solution of the 2-methyl-5-(2-pyrrolidine-1-yl-ethylamino)-1H-indole-3-carboxylic acid benzyl ester (147 mg, 0.39 mmol, 1.0 eq) and triethylamine (47.6 mg, 0.47 mmol, 1.2 eq) in acetonitrile in an ice-water bath was added dropwise a solution of acetyl chloride in acetonitrile. After the ice-water bath was removed, the reaction mixture was heated to reflux for overnight. After the mixture was concentrated, the residue was purified by preparative HPLC (reverse-phase, 10-100 CH3CN:H2O, 0.1% TFA) to yield the desire indole amine in 33.0% yield. Elemental Analysis: C25H29N3O3.2HCl.0.3H2O Calcd: C: 60.31; H: 6.40; N: 8.44. Found: C: 60.63; H: 6.40; N: 8.04. ESI-MS: m/z 420.78 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][N:6]1[CH:10]=[C:9]([CH2:11][NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[N:8]=[N:7]1)([CH3:4])[CH3:3].C(Cl)Cl.CCN(CC)CC.[C:34](Cl)(=[O:36])[CH3:35]>CCOC(C)=O>[C:34]([N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1)[CH2:11][C:9]1[N:8]=[N:7][N:6]([CH2:5][Si:2]([CH3:3])([CH3:1])[CH3:4])[CH:10]=1)(=[O:36])[CH3:35]
Reactant: COC(=O)c1ccc(CNCc2cn(C[Si](C)(C)C)nn2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN(Cc2cn(C[Si](C)(C)C)nn2)C(C)=O)cc1
Reaction time: 0.08 h

Procedure:
A solution of methyl 4-{[({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate (133 mg, 400 mmol), DCM (1.33 mL) and Et3N (167 uL, 1.2 mmol) were treated with acetyl chloride (42.7 uL, 0.600 mmol) and stirred for 5 min. The reaction was diluted with EtOAc and washed with 2M aq. HCl, water, brine, dried (MgSO4) and concentrated to afford the requisite compound as a clear, colorless residue. MS: cal'd 375 (MH+), exp 375 (MH+).
Reaction SMILES: [NH2:1][C@:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[C:3](OCC)=[O:4].[BH4-].[Na+]>CCO>[NH2:1][C@:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH2:3][OH:4]
Reactant: CCOC(=O)[C@@](C)(N)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@](N)(CO)c1ccccc1
Yield: 109.2 %

Procedure:
The product of Example 445C (1.28 g, 6.6 mmol, prepared in) was reacted with sodium borohydride (1.25 g, 33 mmol) in 75% aqueous EtOH (32 mL) at reflux for 1 hour. The reaction was concentrated, diluted with water (20 mL) and extracted with ethyl acetate (3×75 mL). The organic layer was washed with 10% NaHCO3 solution (2×10 mL), dried over MgSO4, and concentrated to give the title compound as colorless viscous oil (1.09 g., 100%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.[NH2:25][C@@H:26]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH:40]1([CH2:39][C@H:26]([NH:25][C:7]([C:5]2[S:6][C:2]([CH3:1])=[C:3]([C:10]3[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=3)[CH:4]=2)=[O:9])[CH2:27][N:28]2[C:29](=[O:38])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]2=[O:37])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1sc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (138 mg, 0.62 mmol), N,N-diisopropylethylamine (0.541 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (285 mg, 0.581 mmol, 94% yield) as a white foam: LCMS (ES) m/e 491, 493 (M, M+2)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][CH2:12]O)=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: OCCCc1csc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1csc2ccccc12
Yield: 84.6 %

Procedure:
Compound 80-3 (1.46 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (2.19 g) and N-bromosuccinimide (1.49 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.64 g) as a pale-yellow oil.
Reaction SMILES: FC1C=CC([CH:8]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:17]=2)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=CC=1.[OH-].[Na+]>CO>[F:32][C:29]1[CH:30]=[CH:31][C:26]([N:15]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH:17]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(NC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(N(CCn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1

Procedure:
Methyl 4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethylamino]-2-(4-fluorophenyl)benzoate (4.36 g; 10 mmol) in methanol (100 ml) was treated with 2N aqueous sodium hydroxide solution (20 ml; 40 mmol) at reflux for 24 hours. After evaporation of the methanol, the residue was taken up in water, the pH adjusted to 4.5 with HCl 2N. The resulting precipitate was filtered, washed with water and pentane to give 4-[-(4-fluorophenyl)-2-(imidazol-1-yl)ethylamino]-2-(4-fluorophenyl)benzoic acid as a solid (4 g; 95%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([Br:19])=[CH:14][N:13]=2)=[CH:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C.O1CCCC1>[Br:19][C:15]1[CH:16]=[C:17]([CH3:18])[C:12]([C:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH:8]=2)=[N:13][CH:14]=1
Reactant: CCOC(=O)C1CC=C(c2ncc(Br)cc2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Br)cnc1C1=CCC(C(=O)O)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of [4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]carboxylic acid ethyl ester (8.57 g) in ethanol (26 ml) and tetrahydrofuran (26 ml) was added 2N aqueous solution of sodium hydroxide (52 ml) at room temperature, and stirred at 70° C. for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, and extracted with diethyl ether. To the obtained aqueous layer was added 1 N hydrochloric acid aqueous solution under ice-cooling, and the precipitated solid was collected by filtration to give [4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]carboxylic acid (5.37 g) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH3:20].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:20][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][CH:11]=2)[N:6]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO

Procedure:
g (3.39 mmol) of the above synthesized 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester in 7 ml of abs. THF was cooled down to 0° C. and reacted with 7.06 ml of DIBAL-H-solution (1.2 M in toluene, 2.5 eq.) for 1 h. Careful quenching with ice/NH4Cl, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/AcOEt=7/3) to deliver finally 0.875 g of the title compound as off-white solid, mp. 76–78° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=O)[N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=[S:27])[N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1c(-c2ccccc2)nc(=O)c2sccc21
Solvent: Cc1ccccc1
Product: Cn1c(-c2ccccc2)nc(=S)c2sccc21
Reaction time: 3 h

Procedure:
2.10 g (8.67 mmol) 1-Methyl-2-phenyl-1H-thieno(3,2-d)pyrimidine-4-one and 3.51 g (8.67 mmol) Lawesson's reagent (C14H14O2P2S4, Fluka) were dissolved in 40 ml toluene. The reaction mixture was boiled for 3 h. After evaporation the residue was further purified by column chromatography with silica, eluent dichloromethane/acetone 95/5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: -5 °C

Procedure:
3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester is dissolved in dry pyridine (20 ml) and cooled to −5° C. Methanesulphonyl chloride is added over a period of 10 minutes keeping the temperature between −5° C. and 0° C. after which the yellow solution is allowed to warm up to room temperature over a period of 30 minutes. Water (20 ml) is added and the mixture is then extracted using DCM (2×30 ml), the organic washings being combined and washed with 2N potassium hydrogen sulphate solution (2×30 ml). The organic phase is dried (using MgSO4), filtered and evaporated to give the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=4)[CH:16]=3)[NH:11][C:10](=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=3)=[O:26])[CH:16]=2)[N:11]=1
Reactant: O=C(c1ccc(I)cc1)c1ccc2[nH]c(=O)nc(-c3cccc(Cl)c3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(c1ccc(I)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of intermediate (38) (0.0103 mol) in phosphoryl chloride (20 ml) was stirred and refluxed for 1 hour. The mixture was cooled to room temperature and evaporated till dryness. The residue was taken up in DCM. This solution was poured out into ice/NH4OH and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (5.3 g) was crystallized from 2-propanone/DIPE. The precipitate was filtered off and dried, yielding 4.25 g (82%) of [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-iodophenyl)-methanone, mp. 153° C. (intermediate 39).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=C[C:44]4[O:45]COC=4C=3)C2=O)CC1>>[CH:13]1([CH2:12][CH2:11][N:6]2[C:7]3[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=3)[C:4]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[O:21][CH2:22][O:23][C:19]=4[CH:18]=3)([CH2:44][OH:45])[C:5]2=[O:16])[CH2:14][CH2:15]1
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1CCC1CC1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 1E, making variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (53%): Rf=0.28 (EtOAc/Hexanes, 1/1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH:10]=1)[OH:9])([CH3:3])[CH3:2].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[ClH:26]>C(O)(=O)C>[ClH:26].[CH2:12]([N:19]1[CH2:20][CH:21]=[C:22]([C:7]2[C:8]([OH:9])=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[OH:11])[CH2:23][CH2:24]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)c1cc(O)cc(O)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)c1cc(O)c(C2=CCN(Cc3ccccc3)CC2)c(O)c1

Procedure:
5-Isopropyl resorcinol (20.2 g), N-benzyl-4-piperidone (24.6 g) and 45 ml acetic acid was treated with HCl gas as described in Example VI to give 39.15 g product, m.p. 286°-288°.
Reaction SMILES: C(O[CH:5]1[O:30][C@H:29]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[ClH:40]>CCOCC>[C:26]([O:25][C@H:24]1[C@@H:29]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:30][C@H:5]([Cl:40])[C@H:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:15]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:28])[CH3:27]
Reactant: Cl
Reactant: CC(=O)OC1O[C@H](COCc2ccccc2)[C@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CCOCC
Product: CC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H](Cl)O[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1,4-di-O-acetyl-2,3,6-tri-O-benzyl-D-galactopyranose (4.64 g, 8.67 mmol) in ether (10 ml) is treated with ethereal hydrogen chloride (0.2 g/ml, 25 ml). The mixture is stirred at room temperature during 48 h. The solvents are evaporated under reduced pressure so as to afford an oil. Flash chromatography on silica gel and elution with a graded mixture of carbon tetrachloride and ethyl acetate will afford 4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl chloride as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14]([O:17]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>O1CCCC1>[CH3:12][O:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:14](=[O:17])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(N)c1C(=O)O
Solvent: C1CCOC1
Product: COc1cccc2[nH]c(=O)oc(=O)c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 283.3 %

Procedure:
To a stirred warm (50° C.) solution of 2-amino-6-methoxybenzoic acid (2.70 g, 16.2 mM) in tetrahydrofuran (25 mL) under a nitrogen atmosphere was added bis(trichloromethyl)carbonate (1.60 g, 5.38 mM), whereupon a tan precipitate formed. The reaction mixture was maintained at 50° C. for 30 min, cooled, rewarmed to 50° C. for 30 min, filtered cool and dried to provide the title compound (2.95 g, 94.6%) as an off-white solid; MS(CI): 194 (M+H).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]\[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([OH:34])[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1>>[Si:7]([O:6][CH2:5]/[CH:4]=[CH:3]\[CH2:2][O:34][C:27]1[C:28]([O:32][CH3:33])=[CH:29][CH:30]=[C:31]2[C:26]=1[O:25][C:24](=[O:35])[CH:23]=[C:22]2[NH:21][C:20]1[C:19]([Cl:36])=[CH:18][N:17]=[CH:16][C:15]=1[Cl:14])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CC(C)(C)[Si](C)(C)OC/C=C\CBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC/C=C\CO[Si](C)(C)C(C)(C)C

Procedure:
(Z)-8-(4-(tert-Butyldimethylsilyloxy)but-2-enyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one was prepared from (Z)-(4-bromobut-2-enyloxy)(tert-butyl)dimethylsilane and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. MS (ESI): 537.0.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.C[Si]([C:24]#[CH:25])(C)C.N1CCCCC1>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.[Cl-].[NH4+]>[C:24]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1)#[CH:25]
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNCC1
Product: C#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.2 g of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 156 μl of trimethylsilylacetylene, 20 mg of dichlorobis(triphenylphosphine)palladium and 2 ml of piperidine are charged to a 20 ml microwave tube. The mixture is heated for 15 minutes in the microwave device adjusted to 130° C. After cooling, the mixture is poured into 50 ml of a saturated aqueous ammonium chloride solution. Extraction is carried out twice with 70 ml of ethyl ether. The combined organic phases are separated by settling, dried and concentrated to dryness under reduced pressure. The residue is taken up in 4 ml of a 1M solution of tetrabutylammonium fluoride in THF and stirred at 25° C. for 16 hours. After evaporating the reaction medium to dryness, the residue is chromatographed on silica, elution being carried out with a mixture of cyclohexane and ethyl acetate (gradient from 0 to 35%), to give 30 mg of 6-ethynyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a beige solid.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(C(C)C)C(C)C)C>CS(C)=O.C(OCC)(=O)C>[C:1]([NH:5][C:6]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h

Procedure:
The N-tert-butyl-3-(chloromethyl)benzamide was placed under an argon atmosphere and treated with a solution of tert-butyl 1-piperazine-carboxylate (2.96 g, 15.9 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.53 mL, 31.7 mmol) in dimethyl sulfoxide (15 mL) at room temperature. The reaction mixture was stirred overnight, diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride (×5). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum to give a crude oil. This oil was purified by iterative rounds of silica chromatography (20-70% ethyl acetate in n-hexanes, followed by 0-6% methanol in dichloromethane) to give the intermediate tert-butyl 4-(3-(tert-butylcarbamoyl)benzyl)piperazine-1-carboxylate (5.04 g).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][CH:8]1[CH2:12][O:11][S@@:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(OCC)(=[O:22])C>O.C(#N)C.[Ru](Cl)(Cl)Cl>[CH3:7][C@@H:8]1[CH2:12][O:11][S:10](=[O:22])(=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CC1CO[S@@](=O)N1c1ccccn1
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1COS(=O)(=O)N1c1ccccn1

Procedure:
A solution of sodium periodate (21 g, 0.10 moles) in water (150 ml) was added slowly to a solution of (R)-4-methyl-3-pyridin-2-yl-[1,2,3]oxathiazolidine-2-oxide (15.4 g, 0.78 moles) and ruthenium(III)chloride (20 mg) in acetonitrile (1540 ml) whilst the temperature was kept below 5° C. A heavy precipitate developed. The mixture was poured into a mixture of ethyl acetate (500 ml) and water (500 ml) and then shaken. The organic phase was retained and the aqueous phase was extracted with further ethyl acetate (2×500 ml). The organic phases were combined, backwashed with water (500 ml), dried (MgSO4) and then evaporated in vacuo to give (R)-4-methyl-3-(2-pyridyl)-[1,2,3]oxathiazolidine-2,2-dioxide (15.5 g) as a yellow oil which solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([CH3:35])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31](O)=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:17][CH:18]([CH3:35])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2CC(C)C)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2CC(C)C)c1

Procedure:
0.58 g of compound 9 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.10 g of ethyl 4-(2-aminophenoxy)butyrate and 0.64 g of 3-[1-(2-methylpropyl)indol-5-yl]isocrotonic acid obtained according to a similar manner to procedures described in the Reference Examples 1-4.