Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]Br)=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.[I-:29].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][I:29])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(-n2nc(CBr)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc(-n2nc(CI)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
According to Scheme 7 Step 6: A mixture of N-(3-(4-(4-chlorobenzyl)-6-(bromomethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (200 mg, 0.43 mmol) and sodium iodide (97 mg, 0.65 mmol) in acetone (10 mL) was stirred overnight at room temperature. The mixture was diluted with water (100 mL) and the aqueous layer was extracted twice with 100 mL of DCM. The organic layer were combined and successively dried over MgSO4, filtered and concentrated under reduced pressure to afford N-(3-(4-(4-chlorobenzyl)-6-(iodomethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 14(A) (220 mg) as a white solid. The tittle product was used in the next reaction without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (7.94 g, 39.45 mmol) in CH2Cl2 (100 mL), cooled to 0° C., was slowly added NEt3 (5.54 mL, 39.45 mmol) followed by methane sulfonyl chloride (3.06 mL, 39.45 mmol) and DMAP (48 mg, 0.39 mmol). The mixture was stirred at room temperature overnight. To the mixture was added water (30 mL). Extraction with CH2Cl2 (3×30 mL) followed by drying (Na2SO4) and removal of the solvent in vacuo afforded 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester as a white solid (11.00 g, >99% yield). 1H NMR (CDCl3, 400 MHz) δ 4.89 (m, 1H), 3.69 (m, 2H), 3.31 (m, 2H), 3.04 (s, 3H), 1.95 (m, 2H), 1.83 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[C:18]([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[CH2:18])=[CH:10][CH:9]=2)[CH:16]=1
Reactant: O=Cc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 0.17 h

Procedure:
To a solution of Ph3PCH3I (0.97 g) in toluene (5 mL), KN(TMS)2 (0.5M in toluene, 4.8 mL) was added dropwise at room temperature. After 10 min, the solution of 4-(5-bromo-2-chlorobenzyl)benzaldehyde (intermediate AL) (0.62 g) in toluene (2 mL) was added dropwise. After 2 h, aqueous NaHCO3 was added to quench the reaction, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography to obtain pure intermediate AM (0.5 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=O)OC(C)(C)C.C([O-])(=O)C.[Na+].COC1[CH2:27][CH2:26][CH:25](OC)O1.O1CCOCC1.[ClH:36]>C(O)(=O)C>[ClH:36].[N:8]1([C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH2:1])[CH:9]=[CH:27][CH:26]=[CH:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: N[C@@H]1CCCC[C@H]1n1cccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
tert-Butyl N-[(1R,2R)-2-aminocyclohexyl]carbamate (1.06 g, 4.93 mmol), sodium acetate (1.70 g, 20.7 mmol) and 2,5-dimethoxytetrahydrofuran (764 μL, 5.91 mmol) were combined in acetic acid (10.6 mL). The reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was then evaporated to dryness and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The layers were separated, and the organic layer was washed twice with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness to yield a brown solid. This solid was then dissolved in HCl in dioxane (10.3 mL of 4.0 M, 41.1 mmol) and was allowed to stand for 3 hours. The solvent was then removed to yield trans-2-(1H-pyrrol-1-yl)cyclohexanamine hydrogen chloride (989 mg, 99%) as a brown solid. ESI-MS m/z calc. 164.1, found 165.2 (M+1)+; Retention time: 0.27 minutes (4 min run).
Reaction SMILES: [N+:1]([C:4]1[CH:36]=[CH:35][C:7]([CH2:8][C@@H:9]2[NH:13][C:12](=[O:14])[N:11]([N:15]([C:31](=[O:33])[CH3:32])[C@H:16]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH2:17][C:18](=[O:20])[OH:19])[C:10]2=[O:34])=[CH:6][CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C@@H:9]2[NH:13][C:12](=[O:14])[N:11]([N:15]([C:31](=[O:33])[CH3:32])[C@H:16]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH2:17][C:18](=[O:19])[OH:20])[C:10]2=[O:34])=[CH:35][CH:36]=1
Reactant: CC(=O)N([C@@H](CC(=O)O)C(=O)N[C@H](C(=O)O)C(C)C)N1C(=O)N[C@@H](Cc2ccc([N+](=O)[O-])cc2)C1=O
Solvent: CO
Product: CC(=O)N([C@@H](CC(=O)O)C(=O)N[C@H](C(=O)O)C(C)C)N1C(=O)N[C@@H](Cc2ccc(N)cc2)C1=O
Reaction time: 3 h

Procedure:
220 mg (0.43 mmol) of (5-(S)-(4-nitrobenzyl)-2,4-dioxoimidazolidin-3-yl)-acetyl-L-aspartyl-L-valine are dissolved in 50 ml of methanol. After addition of 10 mg of 10% strength Pd-on-charcoal, the mixture is hydrogenated at room temperature for 3 hours, the catalyst is filtered off, the filtrate is concentrated and the product is freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:17])[C:11]#[C:12][C:13](O)([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(NCC)C.C([OH:25])C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:17][C:13]([CH3:14])([CH3:15])[C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCO
Reactant: COc1ccc(C(=O)C#CC(C)(C)O)cc1Cl
Solvent: CCNCC
Product: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1Cl
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 1-(3-chloro-4-methoxyphenyl)-4-hydroxy-4-methylpent-2-yn-1-one (0.7 g, 2.75 mmol) in ethanol (5 mL), a solution of diethyl amine (0.20 g, 2.75 mmol) in EtOH (7 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 30 min. The ethanol was removed, and the reaction mixture diluted with EtOAc (10 mL). The combined organic layers were then washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(3-chloro-4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.7 g, 100%) as a semi solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:48])[NH:12][C@@H:13]([C:23]([N:25]1[CH2:30][CH2:29][N:28]2[C:31](=[O:40])[N:32]([CH2:35][C:36]([F:39])([F:38])[F:37])[C:33](=[O:34])[C@:27]2([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH2:26]1)=[O:24])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:10])[CH3:9])(C)(C)C.[ClH:50]>CCO>[ClH:50].[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@@H:13]([C:23]([N:25]1[CH2:30][CH2:29][N:28]2[C:31](=[O:40])[N:32]([CH2:35][C:36]([F:37])([F:38])[F:39])[C:33](=[O:34])[C@:27]2([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH2:26]1)=[O:24])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:48]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)[C@]2(Cc2ccccn2)C1
Agent: Cl
Solvent: CCO
Product: CC(C)(N)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)[C@]2(Cc2ccccn2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 199, Step D (73 mg) in EtOH (5 mL, 0° C.) was added conc. HCl (0.5 mL). The solution was stirred at 0° C. for 1 h and concentrated down to deliver 68 mg of Example 199, Step E: +APcl MS (M+1)+ 589; 1H NMR=400 MHz (CD3OD) δ: 8.36 (d, 1H), 4.86 (br m, 3H), 1.44 (s, 3H), 1.42 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([NH:22][C:23](=[O:25])[CH3:24])[CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH:14]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:28][C:29]([OH:47])([CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[N:34]1)[CH3:30]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:14]=[C:9]([N:6]3[C:5]4[CH:26]=[CH:27][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:32][CH2:31][C:29]([OH:47])([CH3:28])[CH3:30])[CH:37]=5)=[CH:3][C:4]=4[N:8]=[CH:7]3)[CH:10]=[C:11]([NH:22][C:23](=[O:25])[CH3:24])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(O)CCn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(Br)ccc32)c1
Product: CC(=O)Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(-c4cnn(CCC(C)(C)O)c4)ccc32)c1
Yield: 22.2 %

Procedure:
The compound was prepared from N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-4′-fluoro-[1,1′-biphenyl]-3-yl)acetamide (0.07 g, 0.164 mmol) using the procedure of Example 200(c) and 2-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-ol (0.092 g, 0.329 mmol, 2.0 eq.) to give the title product in 22.2% yield (0.018 g). 1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.68 (s, 1H), 8.25 (s, 1H), 7.99 (d, 2H), 7.93 (s, 1H), 7.83 (s, 1H), 7.69 (m, 2H), 7.65 (m, 1H), 7.61 (m, 2H), 7.36 (t, 2H), 4.48 (s, 1H); 4.26 (m, 2H); 2.12 (s, 3H); 1.91 (m, 2H); 1.15 (s, 6H); LC-MS (ESI): Calculated mass: 497.56 Observed mass: 497.9 [M+H]+ (rt: 0.9 min).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:24])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[C:25](O)(=[O:27])[CH3:26]>>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@H:3]([CH3:24])[CH2:2][NH:1][C:25](=[O:27])[CH3:26])[N:10]=[CH:9][N:8]=2)=[CH:17][C:18]=1[CH3:23]
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN)c23)ccc1O
Reactant: CC(=O)O
Product: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Yield: 90 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 4-({5-[(1R)-2-amino-1-methylethoxy]quinazolin-4-yl}amino)-2-methylphenol (obtained as described in Example 82, preparation of starting materials) to give N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide as a ginger solid in 90% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.76 (s, 3H), 2.17 (s, 3H), 3.41 (dt, 1H), 3.62 (dt, 1H), 4.96 (m, 1H), 6.85 (d, 1H), 7.31 (d, 1H), 7.36 (m, 2H), 7.49 (d, 1H), 7.96 (t, 1H), 8.24 (t, 1H), 8.77 (s, 1H), 9.57 (s, 1H), 10.77 (s, 1H); Mass spectrum MH+ 367.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11](=[O:29])[C@@H:12]([NH:14][C:15](=[O:28])[C@@H:16]([NH:20]C(OC(C)(C)C)=O)[CH:17]([CH3:19])[CH3:18])[CH3:13])[NH:6]1)=[O:4].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11](=[O:29])[C@@H:12]([NH:14][C:15](=[O:28])[C@@H:16]([NH2:20])[CH:17]([CH3:18])[CH3:19])[CH3:13])[NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid methyl ester (150 mg, 0.36 mmol) in dichloromethane (5 mL) was stirred at 0° C. under nitrogen. Trimethylsilyl trifluoromethanesulfonate (160 mg, 0.13 mL, 0.72 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hour. N,N-Diisopropylethylamine (186 mg, 0.25 mL, 1.44 mmol) was added and the solvent was evaporated to afford (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid methyl ester (0.36 mmol) as a white solid which was used without further purification. A solution of 75f (134 mg, 0.33 mmol) in acetonitrile was stirred at 0° C. under nitrogen. A solution of (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid methyl ester (0.36 mmol) and N,N-diisopropylethylamine (129 mg, 0.17 mL, 1.0 mmol) in acetonitrile (5 mL) was added followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (175 mg, 0.46 mmol) and the reaction mixture was stirred at 0° C. for 10 min and then at RT for 1 hour. The solvent was evaporated and the residue was apportioned between ethyl acetate and water. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using iso-hexane/ethyl acetate 1:5 to ethyl acetate to afford the title compound (165 mg, 72%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[NH2:21]>>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)[CH:22]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 71.7 %

Procedure:
The title compound was prepared as described in Example 1d by starting from ethyl 4-chloro-6-methyl-2-(methyl thio)pyrimidine-5-carboxylate (1.2 g, 4.86 mmol) and 3,5-bis(trifluoromethyl)aniline (777 uL, 4.86 mmol) and continuing until the reaction yielded the brown solids, title compound ethyl 4-(3,5-bis(trifluoromethyl)phenylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (1.53 g, 70.2%). MS m/z: 440.1 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:26])=[O:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:8][C:7]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:26])=[O:25])=[CH:22][CH:23]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: CS(=O)c1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2cc(-c3ccc(S(C)=O)cc3)nn(CC3CC3)c2=O)CC1
Yield: 60.6 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 60.6%).
Reaction SMILES: CC(OC([NH:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=O)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(C)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(C)ccc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-methyl-2-pyridinecarboxylate D34 (1.3 g) was dissolved in DCM (80 ml) and the mixture stirred at 0° C. A solution of TFA (5 ml, 64.9 mmol) in DCM (10 ml) was dropped into the cold mixture over 3 minutes. The resulting solution was left under stirring at 0° C. for 30 minutes, then the mixture was left still at room temperature overnight. TFA (4 ml, 51.9 mmol) dissolved in DCM (10 ml) was added over 3 minutes and the mixture stirred again at room temperature for 5 hours. The solution was loaded onto an SCX-25 g column, the column was eluted and after evaporation under reduced pressure of the solvent it was obtained the title compound D35 (770 mg) was obtained as a white solid. UPLC (Basic GEN_QC): rt=0.44 minutes, peak observed: 167 (M+1). C8H10N2O2 requires 166. 1H NMR (400 MHz, CDCl3) δ ppm 7.14 (d, 1 H), 7.01 (d, 1 H), 3.99 (s, 3 H), 2.52 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:23]=2[CH3:32])[C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12]C)=[O:11])=[C:4]2[N:3]=1>[Li+].[OH-].C1COCC1>[CH3:1][C:2]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[C:23]=2[CH3:32])[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C)nc3c(C(=O)O)cc(N4CCOCC4)nc32)cccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A mixture of methyl 2-methyl-3-(2-methyl-3-(trifluoromethyl)benzyl)-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (310 mg, 0.69 mmol) in 2N LiOH (15 mL) and THF (15 mL) was stirred at 50° C. for 8 h. It was cooled to room temperature and the precipitate was collected by filtration. It was then poured into water (50 mL) and the suspension was acidified with formic acid to pH=1. It was filtered and the solid was purified by chromatography on silica gel eluted with MeOH/DCM=1/5 to afford the desired product as a gray solid (184 mg, 61%); LC/MS: MS (ES+) m/e 435 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.54 (s, 3H), 2.79 (s, 3H), 3.51 (s, 4H), 3.67 (s, 4H), 5.67 (s, 2H), 7.20 (d, J=10.2 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.69 (d, J=10.2 Hz, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:9]([OH:11])[CH3:10]>C1C=CC=CC=1>[CH2:9]([O:11][C:1](=[NH:2])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:10]
Reactant: CCO
Reactant: CCOC(=O)CC#N
Solvent: c1ccccc1
Product: CCOC(=N)CC(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.6 %

Procedure:
Ethyl cyanoacetate (8 mL, 75 mmol) in anhydrous benzene (100 mL) was combined under nitrogen with anhydrous ethanol (6 mL, 105 mmol). The mixture was cooled to 10° C. (ice/acetone) and bubbled 20 minutes with dry hydrogen chloride gas. The mixture was slowly warmed to room temperature, sealed and stirred for approximately 18 hours. The mixture was diluted with diethyl ether (400 mL) and let stand for 5 hours at room temperature to give a crystalline solid. The solid was isolated by filtration, washed several times with anhydrous diethyl ether and dried to provide ethyl 3-ethoxy-3-iminopropionate (13.2 g, 90% yield) as a colorless, crystalline solid; 1H-NMR (300 Mhz, CDCL3): 7.84 (d, 1H, J=10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, J=5.7 Hz), 2.73 (t, 2H, J=6.5 Hz), 1.89 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH3:20])[C:14]=3[CH:21]=2)=[N:7][CH:8]=1.Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].O1CCCC1.CCN(C(C)C)C(C)C>CO.ClCCl>[CH3:39][O:38][C:36](=[O:37])[CH2:35][N:18]1[CH2:19][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:6]3[N:5]=[C:4]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH:29][S:30]([CH3:33])(=[O:31])=[O:32])[C:3]([Cl:2])=[CH:8][N:7]=3)=[CH:21][C:14]=2[N:15]([CH3:20])[CH2:16][CH2:17]1
Reactant: COC(=O)CBr
Reactant: CN1CCNCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4NS(C)(=O)=O)n3)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1CCN(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4NS(C)(=O)=O)n3)ccc2C1
Yield: 41.6 %

Procedure:
To 40 ml sure-seal reaction vial, N-{2-[5-Chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide hydrochloride (53 mg, 0.11 mmole), methyl bromoacetate (0.010 ml, 0.11 mmole), tetrahydrofuran (5 ml), and Hunig's base (0.2 ml, 1.2 mmoles) were added. The reaction was then heated to 7{tilde over (0)} C for 5 hours. The solvent was then removed under vacuum. The product (25 mg, 41% yield) was isolated via column chromatography with dichloromethane and methanol as eluant. NMR 1H-(CDCl3)-δ-8.04 (s, 1H), 7.74 (d, 1H, J=7.33 Hz), 0 7.61 (s, 1H), 7.46 (d, 1H, J=7.08 Hz), 7.02-7.35 (m, 3H), 7.07 (s, 1H), 6.92 (d, 1H, J=8.34 Hz), 6.86 9d, 1H, J=8.08 Hz), 6.82 (s, 1H), 3.83 (s, 2H), 3.75 (s, 3H), 3.30 (s, 2H), 3.02 (bd, 2H, J=4.65 Hz), 2.96 (bd, 2H, J=5.31 Hz), 2.91 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:9]=1[C:10]([NH:12][C@@H:13]([CH2:18][CH2:19][S:20][CH3:21])[C:14]([O:16]C)=[O:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([C:8]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:9]=1[C:10]([NH:12][C@@H:13]([CH2:18][CH2:19][S:20][CH3:21])[C:14]([OH:16])=[O:15])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1cc([N+](=O)[O-])ccc1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)c1cc([N+](=O)[O-])ccc1Cc1ccccc1)C(=O)O

Procedure:
A solution of methyl (2S)-2-(2-benzyl-5-nitro-benzoylamino)-4-methylsulfanyl-butyrate compound 34(d) (25.24 g, 62.78 mmol) in methanol (500 mL) was treated with 2N aqueous sodium hydroxide solution (35 mL, 70 mmol). The resulting solution was then evaporated to dryness and the solids partitioned between ethyl ether (200 mL) and water (500 mL). The aqueous material was then acidified to pH2 with 2N HCl and extracted with ethyl acetate (2×250 mL). The combined organics were washed with water(2×100 mL), brine(100 mL), filtered through phase separating paper and evaporated to give (2S)-2-(2-benzyl-5-nitro-benzoylamino)-4-methylsulfanyl-butyric acid (compound 36(a)) as a white solid, 23.57 g(96.8%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[F:30][C:31]([F:36])([F:35])[C@H:32]1[CH2:34][O:33]1.C(N(CC)CC)C>C(O)C.CO>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:34][C@@H:32]([OH:33])[C:31]([F:36])([F:35])[F:30])[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: FC(F)(F)[C@H]1CO1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C[C@@H](O)C(F)(F)F)C1
Temperature: 120 °C
Yield: 28.2 %

Procedure:
A mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (20 mg, 0.044 mmol, chiral intermediate from peak 1 of Example 1, Step 7), (2R)-2-(trifluoromethyl)oxirane (9.4 μL, 0.11 mmol), and triethylamine (18 μL, 0.13 mmol) in ethanol (0.3 mL) was heated in a microwave at 120° C. for 25 min. The mixture was diluted with MeOH and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.2 mg (28%) of the desired product. The product was isolated as a single enantiomer. LCMS calculated for C22H27ClF3N6O2(M+H)+: m/z=499.2; Found: 499.1.