Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][C:11]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])=[CH:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][C:11]([C:14]2([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([Cl:25])[CH:27]=3)[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])=[CH:10][NH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CCC(C2C(=O)Nc3cc(Cl)ccc32)=CN1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)=CN1
Temperature: 60 °C

Procedure:
A mixture of 5-[6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-carboxylic acid tert-butyl ester (1.4 g, 4.00 mmol) (from Example 20a supra), 3-chlorobenzyl bromide (0.97 g, 4.67 mmol) (Aldrich), potassium iodide (0.79 g, 4.73 mmol) and potassium carbonate (1.2 g, 8.60 mmol) in acetone (30 mL) was heated at 60° C. for 12 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and washed with water and brine. Aqueous layers were back washed with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-dichloromethane, 1:9, V/V) to give rac-5-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-carboxylic acid tert-butyl ester as a brown solid. (Yield 1.5 g, 79%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6](O)=[O:7])(=[O:3])[CH3:2].S(Cl)([Cl:21])=O>>[C:16]([O:15][CH:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([Cl:21])=[O:7])[CH2:10][O:11][C:12](=[O:14])[CH3:13])(=[O:18])[CH3:17]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)O
Product: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Cl
Reaction time: 48 h

Procedure:
The 2,3,4-triacetoxy-butyric acid (25 g, 0.095 mol) was stirred in thionyl chloride (15.3 mL) at room temperature with a condenser fitted. The reaction was stirred for 48 hours and then the thionyl chloride was removed under reduced pressure to give an oil which was the desire material (26.1 g, 98%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])(O)O>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])[CH:11]=[CH:10]2
Reactant: COc1cc(C(=O)O)ccc1B(O)O
Reactant: Oc1ccc2nc(Cl)ccc2c1
Product: COc1cc(C(=O)O)ccc1-c1ccc2cc(O)ccc2n1

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol and 4-borono-3-methoxybenzoic acid. 1H NMR (CD3OD, 400 MHz): δ 8.81 (d, J=8.4 Hz, 1H), 8.14 (d, J=9.2 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.89 (dd, J=6.8, 1.6 Hz, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.69 (dd, J=9.2, 2.8 Hz, 1H), 7.48 (d, J=2.8 Hz, 1H). MS (ESI): m/z 295.7 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](Cl)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].[OH-:21].[K+]>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:21])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: [OH-]
Reactant: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Br)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a round bottom flask charged with 3-(3-bromo-5-chlorophenoxy)-2-chloro-4-(trifluoromethyl)pyridine (9.1 g, 25.3 mmol) and potassium hydroxide (3.96 g, 70.5 mmol) was added tert-butanol (100 mL). This suspension was placed in an oil bath at 75° C. After 48 hours, the reaction mixture was allowed to cool to room temperature and was quenched with saturated aqueous ammonium chloride (50 mL) and diluted with water (50 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic fractions were washed with water (3×100 mL). The solvent was evaporated under reduced pressure to yield a solid. This was adsorbed onto silica and purified by column chromatography on a pre-packed silica gel Redi Sep 330 gram column, eluting with 0-5% methanol in CH2Cl2 to give the title compound. 1H NMR (DMSO-d6) δ 12.68 (s, 1H), 7.58 (d, J=6.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.20-7.18 (m, 1H), 7.13-7.10 (m, 1H), 6.47 (d, J=6.8 Hz, 1H). FIRMS (M+1)=367.9295.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]2[N:30]=[C:31]([SH:33])[NH:32][C:28]=2[CH:27]=1.C(OC(C)C)(C)C>O.CO.CN(C=O)C>[Si:6]([O:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]2[N:30]=[C:31]([SH:33])[NH:32][C:28]=2[CH:27]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc2nc(S)[nH]c2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CC(C)(C)[Si](OCc1ccc2nc(S)[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Imidazole (24 g) and t-butyldiphenylsilyl chloride (96 g) were added to DMF (300 ml) solution of 5-hydroxymethyl-2-mercaptobenzoimidazole (60 g), and the mixture was stirred at room temperature for 2 hours. Next, this was mixed with MeOH (50 ml) and stirred and then mixed with water and diisopropyl ether and further stirred. The precipitate was collected by filtration and washed with water and diisopropyl ether to obtain 5-(t-butyldiphenylsilyloxymethyl)-2-mercaptobenzoimidazole (107 g). Next, 2-butanone (300 ml) solution of this compound (21 g) and ethyl 2-chloroacetoacetate (11 ml) was heated under reflux for 2 hours. The reaction mixture was concentrated under a reduced pressure, neutralized with saturated NaHCO3 aqueous solution and then extracted with EtOAc and washed with water and saturated brine. After drying with anhydrous MgSO4, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (to be referred to as column chromatography hereinafter) (eluent; n-hexane (to be referred to as Hex hereinafter):EtOAc=3:1-2:1), thereby obtaining ethyl 2-[(5-t-butyldiphenylsilyloxymethylbenzoimidazol-2-yl)thio]acetoacetate (23 g). Next, a DMF (300 ml) solution containing this compound, acetic acid formic acid anhydride (5.5 g) and Py (8.4 ml) was heated and stirred at 75° C. for 2 hours. The reaction mixture was concentrated under a reduced pressure while heating, diluted with EtOAc, washed with saturated NaHCO3 aqueous solution, water and saturated brine and then dried with anhydrous MgSO4, subsequently evaporating the solvent under a reduced pressure. The resulting residue was purified by a column chromatography (eluent; Hex:EtOAc=5:1-4:1) to obtain the title compound (16 g).
Reaction SMILES: [C:1]([OH:4])(=[O:3])C.[OH:5][CH2:6][C:7]1[CH:18]=[CH:17][C:10]([C:11]([NH:13][CH2:14][CH2:15][NH2:16])=[O:12])=[CH:9][CH:8]=1>CO>[C:7]([O:4][C:1]([NH:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][OH:5])=[CH:18][CH:17]=1)=[O:3])([CH3:18])([CH3:8])[CH3:6]
Reactant: CC(=O)O
Reactant: NCCNC(=O)c1ccc(CO)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CO)cc1

Procedure:
p-Hydroxymethylbenzoylaminoethylamine acetate (0.30 g, 1.2 mmol) in methanol was treated with di-t-butyloxycarbonyl dicarbonate (0.38 g, 1.8 mmol). The solvent was evaporated, and the residue was dissolved in ether. The ether solution containing the product was filtered and reduced in volume leaving a white solid, which was removed by filtration and washed with petroleum ether. Yield 0.34 g (99%). Mp 117°-119°.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1.[CH3:13][NH2:14]>CO>[O:11]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:14][CH3:13])=[CH:12][C:8]=2[CH2:9][CH2:10]1
Reactant: CN
Reactant: BrCCc1ccc2c(c1)CCO2
Solvent: CO
Product: CNCCc1ccc2c(c1)CCO2

Procedure:
A solution of 5-(2-bromoethyl)-2,3-dihydrobenzofuran (1.5 g -- see Preparation 20) in 33% methylamine in methanol (40 ml) was heated at 100° C. in a stainless steel pressure vessel for 6 hours then concentrated in vacuo. The residue was partitioned between dichloromethane (50 ml) and 10% aqueous sodium carbonate (50 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2×50 ml). The aqueous layer was concentrated in vacuo to give a solid which was triturated with boiling 2-propanol. The mixture was filtered and the filtrate concentrated in vacuo to give a solid which was purified by column chromatography o silica eluting with dichloromethane containing methanol (0% up to 1%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless solid, yield, 0.31 g, m.p. 153°-155° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH3:12])(=O)=O>C(#N)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:11]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH3:12])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: CC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CC(c1ccc([N+](=O)[O-])cc1)n1ccnc1
Yield: 63.3 %

Procedure:
(a-2) A mixture of 37.5 parts of 1H-imidazole, 61.3 parts of [1-(4-nitrophenyl)ethyl] methanesulfonate and 200 parts of acetonitrile was stirred and refluxed for 2.50 hours. After cooling, the whole was filtered and the filtrate was evaporated. 150 Parts of water were added and the product was extracted three times with 130 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 34.4 parts (63.3%) of 1-[1-(4-nitrophenyl)ethyl]-1H-imidazole as a solid residue (int. 113).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[N+:17]([O-])[CH:16]=[CH:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-:24].[Na+]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([OH:24])=[N:17][CH:16]=[CH:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O=S(=O)(Nc1ccc2c[n+]([O-])ccc2c1)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=S(=O)(Nc1ccc2c(O)nccc2c1)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-(4-Chlorobenzenesulfonylamino)isoquinoline-N-oxide (intermediate in Synthetic Example 83b, 50 mg) was dissolved in acetic acid anhydride (0.75 ml), followed by heating under stirring at 80° C. for 16 hours. Then, the mixture was refluxed under heating for 2 hours. After cooling as it was, an aqueous saturated sodium bicarbonate was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was dissolved in ethanol (2.0 ml) and water (0.5 ml), followed by heating under reflux for 0.5 hours. After evaporating the solvent, the residue was purified by silica gel column, to give the title compound (20 mg) as a pale red solid.
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:19])[C:4]=2[CH:3]=1
Reactant: Ic1cnc2c(c1)NCCN2
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Yield: 61 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (50 mg) was reacted with benzoyl chloride as in General Procedure 2 to give the title compound as a pale yellow solid (61% yield). M.p. 164-166° C., LCMS: m/z=366.00 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.45-3.50 (m, 2H), 3.90 (t, J=4.8 Hz, 2H), 7.37-7.47 (m, 6H), 7.95 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[C:36]([O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH2:43])([CH3:39])([CH3:38])[CH3:37]>C1COCC1.CCOC(C)=O>[C:36]([O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH:45]([CH3:46])[CH3:47])[NH:43][C:17](=[O:19])[C@@H:12]1[CH2:13][CH2:14][C:15](=[O:16])[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: -15 °C

Procedure:
To a solution of N-benzyloxycarbonyl-L-pyroglutamic acid (1.6 g, 6.0 mmols) and N-methylmorpholine (0.66 ml, 6.0 mmols) in anhydrous THF (10 ml), cooled at −15° C. was added dropwise under stirring an equivalent quantity of isobutylchloroformate (0.82 ml, 6.0 mmols). After 10 minutes a solution of L-leucine tertbutylester hydrochloride (1.34 g, 6.0 mmols) and N-methylmorpholinee (0.66 ml, 6.0 mmols) in anhydrous THF (9 ml) was slowly added maintaining the temperature at −15° C. for 2 hours. The reaction mixture was diluted with EtOAc (70 ml) and washed with saturated NaCl solution (20 ml), KHSO4 1M (20+10 ml), saturated NaHCO3 solution (20+10 ml) and saturated NaCl solution (20 ml). The organic phase was dried on Na2SO4 and the solvent was removed at reduced pressure. The crystallization of raw material from EtOAc/n-hexane gave N-benzyloxycarbonyl-L-pyroglutamyl-L-leucine tertbutylester as white crystals: 2.0 g (77%); m.p. 130-1° C.; [a]D22=−70° (1, methanol); IR (CHCl3); 3420, 2958, 1794, 1723, 1514, 1303, 1152 cm−1; 1H-NMR (CDCl3): d 0.8-0.91 [m, 6, CH2CH(CH3)2], 1.20-1.67 [m, 3, CH2CH(CH3)2 and 1.43 (s, 9, OC(CH3)3], 2.00-2.93 (m, 4, CH2CH2 of pGlu), 4.27-4.61 (m, 2, 2 aCH), 5.22 (s, 2, CH2 benzylico), 6.24 (d, 1, NH, J=8 Hz), 7.28 (s, 5, benzylic aromatics). Calculated for C23H32N2O6: C, 63.87; H, 7.46; N, 6.48; Found C, 64.20; H, 7.60; N, 6.48%.
Reaction SMILES: [N:1]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[CH3:15][N:16]([CH:18]=[C:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:17]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cn1ccnc1
Product: CCOC(=O)C(=CN(C)C)n1ccnc1

Procedure:
38.0 g (244.9 mmol) of the compound from Example 3A are stirred in 126 ml (108.1 g, 734.7 mmol) of N,N-dimethylformamide diethyl acetal at a bath temperature of 90° C. for 16 h. After cooling, the mixture is concentrated under reduced pressure, the residue is stirred with diisopropyl ether and the solid is filtered off and finally washed with diisopropyl ether. Yield: 49.0 g (95% of theory)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[CH3:36][N:37]1[C:41]([NH2:42])=[CH:40][CH:39]=[N:38]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[CH3:18][NH:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([C:10]2[C:5]3[C:4]([O:29][CH:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[N:3][C:2]([NH:42][C:41]4[N:37]([CH3:36])[N:38]=[CH:39][CH:40]=4)=[N:7][C:6]=3[N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[CH:9]=2)=[CH:12][CH:13]=1
Reactant: Cn1nccc1N
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4ccnn4C)nc(OC4CCOCC4)c23)cc1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 39.4 %

Procedure:
A mixture of 4-(2-chloro-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 1-methyl-1H-pyrazol-5-amine (1 equiv), and cesium carbonate (3 equiv) in 1,4-dioxane (0.1 M) was degassed with N2 for 10 min. Then (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv), were added to this mixture. The mixture was stirred at 140° C. for 1.5 h. After cooling to room temperature the reaction mixture was purified using flash chromatography (0-100% ethyl acetate in hexane then 0-20% MeOH in DCM) to give the title compound (39.4% yield) as an off white solid. MS (ESI) m/z 578.5 [M+1]+.
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.C[Si](C)(C)[NH:16][C:17]1[C:18]([CH3:25])=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1.[F:28][C:29]([F:36])([F:35])[C:30](OCC)=O>C1CCCCC1>[CH3:24][O:23][C:20]1[CH:19]=[C:18]2[C:17](=[CH:22][CH:21]=1)[NH:16][C:30]([C:29]([F:36])([F:35])[F:28])=[CH:25]2
Reactant: COc1ccc(N[Si](C)(C)C)c(C)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: COc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
Tetramethylethylenediamine (TMEDA) (49 g, 0.42 mole), under nitrogen, is treated with n-butyl lithium (168 mL of 2.57 N in hexanes, 0.42 mole) at 0° C., stirred for 0.5 hour at room temperature, treated dropwise with N-(trimethylsilyl)-4-methoxy-o-toluidine (40.0 g, 0.19 mole), heated at reflux temperature for 4 hours, cooled to -78° C., diluted with dry cyclohexane, treated dropwise with ethyl trifluoroacetate (45 g, 0.23 mole), stirred at -78° C. for 0.5 hour, warmed to room temperature and quenched with saturated NH4Cl solution. The mixture is extracted with diethyl ether. The combined extracts are washed sequentially with saturated NH4Cl and brine, dried over Na2SO4 and concentrated in vacuo to give a brown oil residue. The oil is chromatographed (silica gel/10% ethyl acetate in hexanes) to give the title product as white needles, 5.0 g (12% yield), mp 60° C. (after recrystallization from pentane), identified by IR, 1HNMR, 13CNMR, 19FNMR and mass spectral analyses.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2=CCCc3cncn32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 1.6 g of 5-(p-cyanophenyl)-7,8-dihydroimidazo[1,5-a]pyridine in 50 ml of ethyl acetate is hydrogenated at atmospheric pressure with 0.2 g of 5% palladium on charcoal until the theoretical uptake of hydrogen is complete. The catalyst is filtered, and the solvent evaporated to yield the title compound, m.p. 117°-118°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[OH:11].[CH3:12]I.[H-].[Na+].CO>CS(C)=O.CCOCC.O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[O:11][CH3:12]
Reactant: CI
Reactant: Cc1cc(C)c(C)c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CO
Product: COc1c(C)c(C)cc(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 150 ml of DMSO were dissolved 15.0 g of 2,3,5,6-tetramethylphenol and 28 ml of methyl iodide. Under ice-cooling 6.3 g of 60% sodium hydride in oil was added, and the mixture was stirred at room temperature for 1 hour. The excess sodium hydride was decomposed with MeOH and after addition of water extraction with ether was carried out. The extract was dried over sodium sulfate. Removal of the solvent by distillation leaves crystals which were recrystallized from MeOH.
Reaction SMILES: CC(OC1C=CC=C([N+]([O-])=O)C=1)(C(OCC)=O)C(OCC)=O.CO[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[CH2:35][N:36]1[CH:44]=[C:43]2[C:38]([CH:39]=[C:40]([N+:45]([O-])=O)[CH:41]=[CH:42]2)=[N:37]1)[C:28]([O:30][CH3:31])=[O:29]>>[NH2:45][C:40]1[CH:41]=[CH:42][C:43]2[C:38]([CH:39]=1)=[N:37][N:36]([CH2:35][C:34]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH:44]=2
Reactant: COC(=O)c1ccc(Cn2cc3ccc([N+](=O)[O-])cc3n2)c(OC)c1
Agent: CCOC(=O)C(C)(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Product: COC(=O)c1ccc(Cn2cc3ccc(N)cc3n2)cc1

Procedure:
In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, methyl 3-methoxy-4-[(6-nitroindazol-2-yl)methyl]benzoate was reduced to provide methyl 4-[(6-aminoindazol-2-yl)methyl]benzoate. 1H NMR (CDCl3): δ 7.78 (s, 1H), 7.56-7.53 (m, 2H), 7.43 (d, 1H, J=8.8 Hz), 6.98 (d, 1H, J=8.2 Hz), 6.81 (app s, 1H), 6.58 (dd, 1H, J=1.8 and 8.8 Hz), 5.53 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH:11]=[N:10][C:7]2=[CH:8][CH:9]=1>CCO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[CH2:11][NH:10][C:7]2=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Nc3ccc(Cl)cc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNc1ccc(Cl)cc12
Reaction time: 8 h

Procedure:
NaBH4 (1.29 g, 34.0 mmol) was added to a stirred solution of tert-butyl 5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate (2.57 g, 8.01 mmol) in absolute EtOH (100 mL) portionwise. The reaction was stirred at about room temperature overnight. The reaction was concentrated. The crude residue was taken up in DCM, washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (25-35% EtOAc/Hexane) to yield tert-butyl 5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate. LCMS (APCI+) m/z 223, 225 [M+H-Boc]+; Rt=3.86 min.