Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]1([CH2:7][C:8]([N:13]=[C:12]=[S:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N=C=S
Reaction time: 2 h

Procedure:
2-Phenylacetyl chloride (0.180 ml) was dissolved in acetonitrile (20 ml) under a nitrogen atmosphere, and then potassium thiocyanate (197 mg) was added thereto at 50° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was concentrated under a reduced pressure to give a residue, to which ethyl acetate (20 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml) were then added, followed by stirring for 30 min. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to provide 2-phenylacetyl isothiocyanate, which was used to prepare a solution in toluene (5 ml)-ethanol (5 ml). To the solution was added 4-(4-amino-2-fluorophenoxy)-2-[(4-hydroxypiperidin-1-yl)carbonylamino]pyridine (168 mg), followed by stirring overnight. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (20 ml) was added to suspend. The resultant solid was filtered off and dried under aeration to provide the titled compound (106 mg, 42%) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Br:8])[CH:3]=1.C([O-])(=O)C.[Na+].[I:14]Cl>C(O)(=O)C.C(OCC)(=O)C.ClCCl>[Br:8][C:4]1[CH:3]=[C:2]([NH2:1])[C:7]([I:14])=[CH:6][N:5]=1
Reactant: Nc1ccnc(Br)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1cc(Br)ncc1I
Temperature: 75 °C
Yield: 51.3 %

Procedure:
4-Amino-2-bromopyridine (22.8 g, 131.8 mmole) and sodium acetate (20.8 g 254 mmole) were stirred in acetic acid (82 mL) and a solution of iodine monochloride (1M in acetic acid, 134 mL, 134 mmole) was added. The mixture was stirred and heated at 75° C. for 3 hours. Most of the acetic acid was evaporated and the residue was partitioned between water (500 mL) and ethyl acetate (550 mL). The aqueous was again extracted with ethyl acetate (300 mL) The combined extracts were washed twice with 10% sodium carbonate solution (600, 300 mL), with 10% sodium thiosulfate solution (200 mL), with water and with brine, then dried and evaporated. This gave 40.3 g of a crude product mix. This was combined with the crude product from a reaction on 7.5 g of 4-amino-2-bromopyridine for purification. A large silica column (9 cm internal diameter with 28 cm bed of silica) was prepared in 5% ethyl acetate in dichloromethane. The crude material was applied in the same solvent. The column was eluted with 5% ethyl acetate in dichloromethane, with 10% ethyl acetate in dichloromethane and with 20% ethyl acetate in dichloromethane to give the desired isomer 5 (20.2 g, 38%): 1H-NMR (CDCl3, 500 MHz): δ 4.74 (br s, 2H, NH2), 6.80 (s, 1H), 8.34 (s, 1H); and subsequently with 1:1 ethyl acetate:dichloromethane to give 6 undesired isomer: 2-bromo-3-iodopyridin-4-amine 6 (19.3 g, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13](=[O:15])[CH3:14])[NH2:12])=[C:7]([N+:16]([O-])=O)[CH:6]=1)=[O:4].[H][H]>[Pd].COC(O)C>[NH2:16][C:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[CH:9][C:8]=1[N:11]([C:13](=[O:15])[CH3:14])[NH2:12]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(N(N)C(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: COC(C)O
Product: COC(=O)c1ccc(N(N)C(C)=O)c(N)c1
Yield: 85.6 %

Procedure:
2.5 g of 10% palladium-on-carbon catalyst were added to a solution of 25.3 g of 4-methoxycarbonyl-2-nitro-N-acetylphenylhydrazine in 380 ml of methoxyethanol and the mixture was hydrogenated in a shaking equipment until the hydrogen uptake ceased. After filtering off the catalyst, the filtrate was evaporated under reduced pressure and the residue was mixed with 100 ml of water. The separated crystals were filtered by suction, washed with water and dried at 80° C. Thus, 19.1 g (85.6%) of 2-amino-4-methoxycarbonyl-N-acetylphenylhydrazine were obtained as a beige crystalline solid, m.p.: 175°-178° C. After recrystallization from methanol, the m.p. was raised to 180°-182° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[N:18]=[C:17](Cl)[C:16]2[C:11](=[CH:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>C(O)C>[NH2:8][C:9]1[N:18]=[C:17]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:16]2[C:11](=[CH:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:15]=2)[N:10]=1
Reactant: COC(=O)c1ccc2c(Cl)nc(N)nc2c1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Temperature: 110 °C
Yield: 63.1 %

Procedure:
1-Methyl-piperazine (210 uL, 1.9 mmol) was added to a mixture of methyl 2-amino-4-chloroquinazoline-7-carboxylate (300 mg, 1 mmol) in ethanol (3 mL) and triethylamine (350 μL, 2.5 mmol). The mixture was heated in an oil bath at 110° C. for 1 h. The reaction mixture was concentrated to remove the ethanol and was partitioned between water and EtOAc. The organic phase was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered, and concentrated to give the crude product, (190 mg, 50%) as an off white amorphous solid. 1H NMR (300 MHz, DMSO) δ 2.23 (s, 3H), 3.56 (m, 4H), 3.86 (s, 3H), 3.90 (m, 4H), 6.53 (b, 2H), 7.50 (d, 1H), 7.80 (m, 2H); Analytic LCMS (M+H)+: m/z=302.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:18]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]([CH3:27])=[N:21][CH:20]=4)[C:16]([F:28])=[CH:15][N:14]=3)=[CH:8][CH:7]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:28][C:16]1[C:17]([C:19]2[N:23]([CH:24]([CH3:25])[CH3:26])[C:22]([CH3:27])=[N:21][CH:20]=2)=[N:18][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([N:4]3[CH2:3][CH:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:5]3)=[CH:11][CH:10]=2)=[N:14][CH:15]=1
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(N)C4)cc3)ncc2F)n1C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC(NS(C)(=O)=O)C4)cc3)ncc2F)n1C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of N-[4-(3-aminoazetidin-1-yl)phenyl]-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 140; 110 mg, 0.29 mM) and triethylamine (44 μl, 0.317 mM) in dry DCM (4.0 ml), methanesulphonyl chloride (25 μl, 0.317 mM) was added. The reaction was stirred at room temperature under nitrogen for 24 hours. The reaction was filtered and the filtered solid washed with DCM. This solid which was pure product was retained. The filtrate was taken and more DCM added. The solution was washed in turn with water (twice), saturated sodium chloride and then dried with anhydrous sodium sulphate, filtered and evaporated. The product so obtained was combined with the 1st batch of product and both were triturated with ether, filtered, washed with ether and dried to give the title compound as a yellow solid. NMR 1.4 (d, 6H), 2.6 (s, 3H), 2.9 (s, 3H), 3.55 (t, 2H), 4.13 (t, 2H), 4.25 (m, 1H), 5.37 (m, 1H), 6.4 (d, 2H), 7.33 (d, 2H), 7.58 (d, 1H), 7.75 (d, 1H), 8.5 (d, 1H), 9.22 (s, 1H); m/z 460.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:20])=[CH:16][C:15]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:14]2)[CH:8]=1)C.[Li+].[OH-]>CO>[C:29]([C:15]1[CH:16]=[C:17]([NH:18][C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[O:20])[N:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:33])=[O:3])[CH:12]=[CH:11][CH:10]=2)[N:14]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(F)cc2)n(-c2cccc(CCC(=O)O)c2)n1
Yield: 87.2 %

Procedure:
A solution of Example 145 (45 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH=4, extracted with ethyl acetate (3×20 mL), the combined organic extracts were washed with brine, dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[3-(4-fluoro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionic acid, (37 mg, 90%). 1H NMR (CD3OD): 7.63-7.62 (m, 2H), 7.56 (s, 1H), 7.53-7.48 (m, 1H), 7.41-7.38 (m, 2H), 7.04 (t, J=8.8 Hz, 2H), 5.49 (s, 1H), 3.07 (t, J=7.6 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 415 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ncc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ncc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
0.66 g of 5-(4-chlorophenyl)-4-(3,5-dichloro-2-pyridyl)-6-methyl-2H-py ridazin-3-one and 6 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.67 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.47 g of 3-chloro-5-(4-chlorophenyl)-4-(3,5-dichloro-2-pyridyl)-6-met hylpyridazine (hereinafter, described as compound (11) of the present invention.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=3)[C:39]([O:41]C)=[O:40])[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.O.CO>[C:1]([O:5][C:6]([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=3)[C:39]([OH:41])=[O:40])[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc(-c2ccc3c(c2)CC[C@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(-c3cccc(C(=O)O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
The product from Example 85 (3.0 g, 4.8 mmol) was diluted with 10 mL each of tetrahydrofuran, water, and methanol; 15 mL of 1 N sodium hydroxide (14.4 mmol) was added; and allowed solution to stir overnight at room temperature. The solution was concentrated, water added, and neutralized with 1 N phosphoric acid. The aqueous layer was extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purified by Biotage in gradient 10-30% ethyl acetate/hexanes, then flushed column with ethyl acetate to 5% methanol/ethyl acetate. Yielded 2.3 g (78%) of product. MH+=619.6
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1.[H][H].C(OCC)(=O)C.CCCCCC>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Yield: 76.7 %

Procedure:
To a stirred solution of (4-benzyloxy-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (18.5 g, 57.0 mmol) in methanol (200 mL) was added 10% palladium on carbon (2.78 g). The resulting mixture was vigorously stirred under a balloon of hydrogen overnight. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to obtain a crude product. Silica gel chromatography (10% ethyl acetate-hexane) afforded (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (10.24 g, 76%) as a white solid. MS cald. for C13H12FO3 [(M+H)+]: 235, obsd. 235.2.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:5]([NH:8][CH:9]=O)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>COCCOC.O.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>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[CH:9]=[N:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc(CNc2nc(Br)cnc2NC=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(Cn2cnc3ncc(-c4ccc(F)cc4)nc32)cc1
Yield: 30.5 %

Procedure:
A mixture of N-[5-bromo-3-(4-methoxy-benzylamino)-pyrazin-2-yl]-formamide (160 mg, 0.47 mmol), 4-fluoro-phenyl boronic acid (200 mg, 1.44 mmol), Pd(PPh3)2Cl2 (2 mg, 0.0028 mmol), and NaHCO3 (118 mg, 1.41 mmol) in DME (1 mL) and water (0.2 mL) was put in a microwave reaction tube and reacted in a microwave reactor at 110° C. for 7 minutes. The reaction mixture was partitioned in ethyl acetate and water, and the organic layer was evaporated. The residue was purified on a C-18 reversed phase preparative HPLC eluting with Methanol/Acetontrile containing 0.1% trifluoroacetic acid to provide 6-(4-fluoro-phenyl)-1-(4-methoxy-benzyl)-1H-imidazo[4,5-b]pyrazine as a white solid (48 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([N:11]([C:19]3[CH:20]=[N:21][C:22]([N:26]([CH3:28])[CH3:27])=[CH:23][C:24]=3[CH3:25])C(=O)OC(C)(C)C)[N:7]([CH2:29][CH:30]=C)[C:6]=2[C:5]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:4][CH:3]=1.B.[O:38]1CCC[CH2:39]1.O.O.O.O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:19]3[CH:20]=[N:21][C:22]([N:26]([CH3:28])[CH3:27])=[CH:23][C:24]=3[CH3:25])[N:7]([CH2:29][CH2:30][CH2:39][OH:38])[C:6]=2[C:5]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=CCn1c(N(C(=O)OC(C)(C)C)c2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: B
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CCCO)c12
Reaction time: 2 h
Yield: 29.5 %

Procedure:
To a solution of tert-butyl [4-chloro-7-(1-ethylpropyl)-1-prop-2-en-1-yl-1H-benzimidazol-2-yl][6-(dimethylamino)-4-methylpyridin-3-yl]carbamate (450 mg, 0.88 mmol) in tetrahydrofuran (8.8 mL) was added borane-tetrahydrofuran complex (1.18 M in tetrahydrofuran, 7.46 mL, 8.8 mmol) at room temperature. After stirring for 2 hr, the mixture was poured into a suspension of sodium peroxyborate tetrahydrate (2.03 g, 13.2 mmol) in water (10 mL). The mixture was stirred for 14 hr at room temperature. The mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in methanol (5 mL) followed by addition of 6 N hydrochloric acid (5 mL). After stirring for 14 hr at room temperature, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound (110 mg, 0.26 mmol, 29%) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:3][NH:4][CH:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1([NH:39][C:40]([Cl:42])=[O:41])CCCCCC1.C(N(CC)C(C)C)(C)C.[ClH:52].[CH:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(OCC)C>[ClH:42].[ClH:52].[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:5]([NH:4][CH2:3][CH:2]([NH:1][C:40]([N:39]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)=[O:41])[CH2:28][CH:29]([CH3:31])[CH3:30])[C:6](=[O:7])[NH:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:19][CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)CC(N)CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reactant: c1ccccc1
Reactant: O=C(Cl)NN1CCCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)N1CCCCCC1
Temperature: 25 °C

Procedure:
A solution of 746 mg (1.6 mmol) 2-(2-amino-4-methyl-pentylamino)-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide, 0.408 mL (3.1 mmol) hexahydroazepinyl carbamoyl chloride, 20 mg (0.16 mmol) 4-dimethylaminopyridine (Aldrich, Milwaukee, Wis.), 0.818 mL (4.7 mmol) N,N-diisopropylethylamine (Aldrich, Milwaukee, Wis.), in 10 mL of benzene was heated under reflux for 16 hours, cooled to 25° C. and filtered, and the solids washed with benzene. The filtrate was concentrated under reduced pressure, and the residue thus obtained was dissolved in 100 mL ethyl acetate, and washed with 100 mL each saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to give a pale amber oil that was purified by column chromatography on silica gel with 1:1 ethyl acetate:chloroform as eluant. The clear, colorless oil obtained was dissolved in 10 mL diethyl ether, and treated with diethyl ether that had been saturated with hydrogen chloride gas. The precipitate that formed was collected by filtration, and the solids washed with ethyl acetate and dried. The title compound was obtained as 440 mg off-white solid (77%); mp 51-57° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[N:23]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:30])=[O:29])[CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1
Reactant: COCc1nccc(N2CCNCC2)n1
Reactant: O=S(=O)(Cl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1nccc(N2CCN(S(=O)(=O)N3CCCC3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-methoxymethyl-4-piperazin-1-yl-pyrimidine (prepared according to the method of Preparation One, 2.08 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in tetrahydrofuran (20 mL) was added N-pyrrolidinesulfonyl chloride (1.69 g, 10 mmol) at 0° C. and stirred for 3 h at ambient temperature. The mixture was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to an oil which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound of Example 121, Step A as a clear oil, 3.24 g (93%). 1H NMR (CDCl3, 300 MHz) δ 1.81-1.85 (m, 4H), 3.12-3.18 (m, 8H), 3.59 (s, 3H), 3.81 (m, 4H), 4.43 (s, 2H), 6.71 (d, 1H), 8.18 (d, 1H); MS (TS) 342 (MH+).
Reaction SMILES: [C:1]([NH:9][CH:10]([CH3:22])[C:11]([N:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:24](F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:16]([CH2:15][NH:13][C:11]1[O:12][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[CH3:22])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:24]=1
Reactant: CC(NC(=O)c1ccccc1)C(=O)N(C)Cc1ccccc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccccc2)oc1NCCc1ccccc1
Yield: 82.8 %

Procedure:
2-Benzamido-N-benzyl-N-methylpropanamide (80.0 g., 0.0269 mol.), was dissolved in dry chloroform (40 ml.) and trifluoroacetic anhydride (17.0 g., 0.0809 mol.) was added dropwise with stirring under nitrogen. The mixture was stirred for 4 hours, then sufficient anhydrous sodium carbonate was added portionwise to neutralise the acid formed. The solid was filtered off and washed with dry chloroform (2 × 10 ml.). The combined filtrates were evaporated under reduced pressure to give a brown oil, which was extracted with warm pentane. The pentane solution was evaporated to give a yellow oil 6.20 g. (82.5%). IR and NMR confirm the structure.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])/[C:14](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30]COC)[CH:25]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.O1CCOCC1.O>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])/[C:14](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[C:15](/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)\[CH2:16][CH3:17])=[CH:8][CH:7]=1
Reactant: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1cccc(OCOC)c1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1cccc(O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of 4a (50 mg, 0.105 mmol) in MeOH (2 ml) was added 4N HCl in 1,4-dioxane (0.26 ml) under ice cooling, and the mixture was stirred at room temperature for 3 h. A solution of NaHCO3 in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residual was crystallized with AcOEt to give 5a (73%). 5a: colorless powder; 1H-NMR (CD3OD) δ 0.97 (3H, t, J=7.5 Hz), 2.36 (6H, s), 2.66 (2H, q, J=7.5 Hz), 2.79 (2H, t, J=5.4 Hz), 4.10 (2H, t, J=5.4 Hz), 6.52 (1H, dd, J=1.0, 8.1 Hz), 6.57 (1H, m), 6.64 (1H, m), 6.90 (1H, t, J=7.8 Hz), 6.94 (2H, d, J=9.1 Hz), 7.13-7.23 (5H, m), 7.53 (2H, d, J=9.1 Hz). HRMS calcd for C27H31N2O3 [M+H]+: 431.2335. Found: 431.2336.