Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C@@H:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([CH3:29])[CH:21]=2)[C:13]=1[F:31])[CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Zn]>[C:1]([O:5][C:6](=[O:32])[NH:7][C@@H:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:29])[CH:21]=2)[C:13]=1[F:31])[CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C(=O)c2c(Cl)ccc([C@H](NC(=O)OC(C)(C)C)C3CC3)c2F)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)c2c(Cl)ccc([C@H](NC(=O)OC(C)(C)C)C3CC3)c2F)ccc1N
Reaction time: 0.75 h
Yield: 100 %

Procedure:
Step 2 To a solution of {(R)-[4-Chloro-2-fluoro-3-(3-methyl-4-nitro-benzoyl)-phenyl]-cyclopropyl-methyl}-carbamic acid tert-butyl ester (608 mg, 1.31 mmol) from step 1 in acetic acid (15 mL) was added zinc dust (859 mg, 13.1 mmol, 10 eq.) and the reaction stirred for 45 minutes. The reaction mixture was filtered and then the filtrate concentrated. The residue was partitioned between EtOAc (30 mL) and sat. aq. sodium bicarbonate (20 mL). The organic phase then washed with water (20 mL) and brine (10 mL) before it was dried (MgSO4), filtered and then concentrated to give {(R)-[3-(4-amino-3-methyl-benzoyl)-4-chloro-2-fluoro-phenyl]-cyclopropyl-methyl}-carbamic acid tert-butyl ester (570 mg, 1.31 mmol, 100%) as a yellow gum. [M−H]− 431
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[N:33](COCC[Si](C)(C)C)[CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:16][C@H:17]([CH:19]3[CH2:21][CH2:20]3)[CH3:18])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].C(N)CN>FC(F)(F)C(O)=O.C(Cl)Cl.CO>[C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:16][C@H:17]([CH:19]3[CH2:21][CH2:20]3)[CH3:18])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C1CC1
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
5-{3-(Cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]pyrazine-2-carboxamide (0.23 g) was dissolved in a solution of trifluoroacetic acid (2 mL) and methylene chloride (2 mL). The mixture was stirred at room temperature for 2 h, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-5%) to afford an intermediate which was dissolved in methanol (3.0 mL). To the solution was added ethylenediamine (1.0 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-5%) to afford the desired product (0.13 g). LCMS (M+H)+: m/z=468.5. 1H NMR (500 MHz, DMSO-d6): δ 12.13 (s, 1H), 8.96 (s, 1H), 8.65 (d, J=1.3 Hz, 1H), 8.44 (s, 1H), 8.30 (d, J=5.5 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 7.67-7.61 (m, 1H), 7.52 (d, J=5.5 Hz, 1H), 7.09-7.04 (m, 1H), 4.82 (d, J=9.7 Hz, 2H), 4.56 (d, J=9.7 Hz, 2H), 3.77 (s, 2H), 3.50-3.28 (m, 1H), 1.22 (d, J=6.7 Hz, 3H), 1.15-0.98 (m, 1H), 0.49-0.39 (m, 1H), 0.39-0.30 (m, 1H), 0.29-0.22 (m, 1H), 0.22-0.15 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]1([C:7]2[C:2]([C:22]3[CH:23]=[CH:24][C:19]([CH:17]=[O:18])=[CH:20][CH:21]=3)=[N:3][C:4]3[N:5]([N:14]=[CH:15][N:16]=3)[CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Clc1nc2ncnn2cc1-c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(-c2nc3ncnn3cc2-c2ccccc2)cc1
Temperature: 90 °C

Procedure:
To a mixture of 130 mg 5-chloro-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine and 93 mg 4-formylphenylboronic acid in 5 mL 1,2-dimethoxyethane was added 1.2 mL of a 10% w/w sodium carbonate solution and 65 mg tetrakis (triphenylphosphine) palladium(0) and the resulting mixture was heated to 90° C. under an inert gas atmosphere for 18 h. The work up was performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers were dried over sodium sulphate, evaporated and the residue suspended in methanol. The crystalline product was isolated by filtration yielding the desired product. The filtrate was evaporated to dryness, dissolved in ethyl acetate and additional product precipitated by the addition of petrolether.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]2[N:16]=[CH:17][CH:18]=[C:14]2[N:13]=[C:12]([CH3:19])[C:11]=1[CH2:20][CH2:21][Cl:22]>C(Cl)(Cl)Cl>[Cl:1][C:18]1[CH:17]=[N:16][N:15]2[C:10]([Cl:9])=[C:11]([CH2:20][CH2:21][Cl:22])[C:12]([CH3:19])=[N:13][C:14]=12
Reactant: Cc1nc2ccnn2c(Cl)c1CCCl
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(Cl)cnn2c(Cl)c1CCCl
Reaction time: 1 h
Yield: 59 %

Procedure:
1.60 g (12 mmoles) of N-chlorosuccinimide were added to a solution of 2.30 g (10 mmoles) of 7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1.5-a]pyrimidine (prepared as described in Example 3) in 10 ml of chloroform, and the resulting mixture was heated under reflux, with stirring, for one hour. At the end of this time, the reaction mixture was washed with a 2N aqueous solution of potassium hydroxide and then with water, after, which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through alumina (eluted with chloroform) and recrystallized from diisopropyl ether to afford 1.56 g (yield 59%) of the title compound as light yellow needles, melting at 115°-117° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CC(O)=O>[Br:14][C:11]1[S:10][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(Cc2cccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1ccc(Cc2ccc(Br)s2)cc1
Yield: 98.1 %

Procedure:
The above thiophene (9.61 g, 50.0 mmol) was brominated using N-bromosuccinimide (8.90 g, 50.0 mmol) in CHCl3 and CH3COOH (1:1) to provide 13.3 g (98%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:16]1[CH:21]=[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:19]([F:35])=[CH:18][C:17]=1[N+:36]([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+].Cl>CN(C)C=O>[F:35][C:19]1[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]([O:1][C:2]2[C:3]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:17]([N+:36]([O-:38])=[O:37])[CH:18]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: CCOC(=O)COc1ncccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a mixture of 10.45 g of 3-hydroxy-2-(ethoxycarbonyl)methoxypyridine, 16.92 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 100 ml of N,N-dimethylformamide was added 7.32 g of potassium carbonate, and the mixture was stirred for 2 hours at 70° C. The solution was cooled to room temperature, poured into a mixture of ice water, sodium chloride and hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 17.28 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(ethoxycarbonyl)methoxypyridine [present compound 9-46].
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:34])[CH2:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:16][CH2:15]1>C1COCC1>[C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:34])[CH2:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:16][CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Solvent: C1CCOC1
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(=O)Nc2cccc3ccccc23)CC1
Temperature: 25 °C

Procedure:
2.6 g (17.7 mmol) 1-naphthyl isocyanate are dissolved in 15 ml abs. THF and cooled to 0° C. under moisture exclusion. 5.1 g (17.7 mmol) N-(4-piperidine-4-yl-butyl)-3-(pyridine-3-yl)-propionamide are dissolved in 35 ml abs. THF and added dropwise under ice cooling. The mixture is stirred without further cooling at RT overnight. Subsequently, the solution is drawn off under vacuum to a large extent and the residue is chromatographically purified over silica gel with CHCl3/CH3OH (90/10) and further purified by flash-chromatography with CHCl3/CH3OH (95/5 to 90/10). After drawing off the solvent, crystallization occurs from isopropanol/diisopropanol. Colorless crystals with a MP of 143-144° C. were recovered; yield 0.77 g (9%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]([CH:29]([NH2:36])[CH2:30][C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)=[O:28])[CH2:23][CH2:22]1)=[O:20])[CH3:17].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl.CO.C(N(CC)CC)C>[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]([CH:29]([NH:36][C:1]([C:4]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:30][C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)=[O:28])[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: COc1cc(C(=O)O)nc2ccccc12
Reactant: CCOC(=O)N1CCN(C(=O)C(N)Cc2c[nH]cn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Reaction time: 8 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCI (1.65 g, 1.2 eq. ), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%–6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCl (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%–6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10–3.30 (m, 2), 3.20–3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55–7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 370.3 %

Procedure:
3,5-Dichlorophenol (500 mg, 3.07 mmol) was dissolved in dimethylacetamide (8.0 mL), and 4-fluorobenzaldehyde (0.390 mL, 0.368 mmol) and cesium carbonate (1.50 g, 3.69 mmol) were sequentially added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 150° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, water was added thereto, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 85:15 (v/v)), whereby the objective title compound was obtained as a white solid (364 mg, yield: 44%).
Reaction SMILES: C[C@@H]([C@@H]1[C@@]2(C)CC[C@@]34C[C@]53C[CH2:24][C@H:25]([O:29][C:30](/[CH:32]=[CH:33]/[C:34]3[CH:35]=[CH:36][C:37]([OH:42])=[C:38]([O:40][CH3:41])[CH:39]=3)=[O:31])C(C)(C)[C@@H]5CC[C@H]4[C@]2(C)CC1)CCC=C(C)C.C(OC(=O)C)(=[O:47])C>N1C=CC=CC=1>[C:30]([O:29][C:25](=[O:47])[CH3:24])(=[O:31])/[CH:32]=[CH:33]/[C:34]1[CH:35]=[CH:36][C:37]([OH:42])=[C:38]([O:40][CH3:41])[CH:39]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(/C=C/C(=O)O[C@H]2CC[C@]34C[C@]35CC[C@]3(C)[C@@H]([C@H](C)CCC=C(C)C)CC[C@@]3(C)[C@@H]5CC[C@H]4C2(C)C)ccc1O
Solvent: c1ccncc1
Product: COc1cc(/C=C/C(=O)OC(C)=O)ccc1O

Procedure:
Commercial available γ-oryzanol (100 g, 24-methylenecycloartanol content 45%) was acetylated with acetic anhydride in pyridine. This acetylated γ-oryzanol was recrystallized repeatedly from chloroform-ethyl acetate-ethanol (4:3:2, V/V), giving acetyl ferulate (18 g) of 24-methylenecycloartanol content 95%. This acetyl ferulate was completely saponified in the solution of 2N NaOH-ethanol, then the obtained alcohol was converted into the benzoate. This benzoate was recrystallized repeatedly, and completely saponified to give 24-methylenecycloartanol (5 g). A portion (2 g, 0.0045 mole) thereof wa converted into 24-methylenecycloartanol-4-acetoxy-3-methoxycinnamate according to following the procedure of Example 65. This ester was then deacetylated according to following the procedure of Example 100-2, giving 24-methylenecycloartanol-4-hydroxy-3-methoxycinnamate (2.58 g), in a 90% yield. m.p. 166°-167° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:22][CH2:21][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:21][CH2:22]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CCC(O)CC2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CCC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 391C (23.66 g) in dichloromethane (350 mL) was added Dess-Martin Periodinane (33.1 g). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (600 mL) and washed with 2N aqueous NaOH, water, and brine. After drying over Na2SO4, the mixture was filtered and concentrated to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]([NH2:4])[CH3:3].[OH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[O:7].[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[N:22][C:23](Cl)=[C:24]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=4[F:44])[CH2:31][CH2:30]3)[N:25]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[N:22][C:23]([NH:4][CH:2]([CH3:3])[CH3:1])=[C:24]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=4[F:44])[CH2:31][CH2:30]3)[N:25]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:6]([OH:7])([C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: CC(C)N
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3Cl)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of propan-2-amine (71 μL, 0.827 mmol), 6-benzyl-3-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine TFA salt (123.4 mg, 0.207 mmol), sodium tert-butoxide (39.7 mg, 0.413 mmol), BINAP (19.3 mg, 0.031 mmol) and Pd2(dba)3 (9.5 mg, 10.33 μmol) in toluene (690 μL) was heated at 100° C. for 16 h. The mixture was then purified by HPLC Method A to give the title compound as a TFA salt (54.7 mg, 42.7%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.22 (d, J=6.6 Hz, 6H), 1.87-2.13 (m, 4H), 2.94-3.10 (m, 4H), 3.35-3.53 (m, 3H), 3.75 (s, 3H), 3.79-3.88 (m, 1H), 4.07-4.27 (m, 3H), 4.31-4.39 (m, 1H), 4.52 (br s, 2H), 6.66 (ddd, J=8.9, 3.0, 1.5 Hz, 1H), 6.73 (dd, J=12.9, 3.0 Hz, 1H), 7.03-7.10 (m, 1H), 7.51-7.60 (m, 5H); ESI-MS m/z [M+H]+ 506.4.
Reaction SMILES: C1(C[CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19](C4CCCCC4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=C(C4C=CC=CC=4)C=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])CCCCC1.CC[C@@H]([C@H](NC(OCC1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:64]2[C:59]1=CC=CC=2)=O)C=O)C>>[CH:15]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([NH:12][CH:8]([CH:22]([CH3:20])[CH2:31][CH3:30])[C:9]([OH:11])=[O:10])=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:64]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:59]=[N:25]3)[CH2:45][CH2:44][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: CC[C@H](C)[C@@H](C=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: CCC(C)C(NC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1)C(=O)O
Yield: 54 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Ile Wang resin (250 mg, 0.4 mmol/g), producing 23 mg of the title compound (54% yield). MS: 560.26 (M−H+) HPLC Procedure A, retention time=14.34 min.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH2:13]2)[C:8]([C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:28]3=[N:29][CH:30]=2)=[CH:7][N:6]=1)(=O)=O.[OH-].[NH4+:43]>O1CCOCC1>[CH3:24][CH:22]([CH3:23])[CH2:21][S:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([NH:11][C:9]2[C:8]([C:25]3[N:26]=[C:27]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:28]4=[N:29][CH:30]=3)=[CH:7][N:6]=[C:5]([NH2:43])[N:10]=2)[CH2:13]1)(=[O:20])=[O:19]
Reactant: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(S(C)(=O)=O)ncc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(N)ncc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
In a 10 mL sealed tube {2-methanesulfonyl-5-[5-(2-trimethysilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-amine (38 mg, 609 μmol) and ammonium hydroxide (450 mg, 0.5 ml, 12.8 mmol) were combined with 1,4-dioxane (2 ml) to give a light yellow solution. The reaction mixture was heated to 90° C. and stirred for 6 h. It was concentrated and diluted with water, extracted with ethyl acetate (2×20 ml). The organic layers were dried (MgSO4) and concentrated to give N*4*-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidine-2,4-diamine as a yellow foaming solid. MS (ES+): 561.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1)[NH2:22]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:23]=[CH:24][C:25]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Product: COc1cc2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2cc1OC

Procedure:
In the manner of Example 141 reaction of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile with 3-chloro-4-(1-methyl-2-imidazolylthio)aniline (WO-9615118) gave the title compound as a white solid, mp 302-307° C.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][C:3](=O)[CH2:2]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCOCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCC(CC2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: C1CN2CCC(CC2)N1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g, 113 mmol) in absolute dioxane (130 ml), LiAlH4 (4.9 g, 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperatre. To this reaction mixture, water (5 ml in 10 ml of dioxane) was added, by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using a Kugelrohr apparatus at 90° C. (0.1 mbar) to yield 1,4-diazabicyclo[3.2.2]nonane (11.1 g, 78%) as colourless hygroscopic material.