Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
2-Chloro-5-nitropyridine (5.0 g, 31.5 mmol) and tetrakis(triphenylphosphine)palladium (0.35 g, 0.3 mmol) were added to 1,2-dimethoxyethan (50 ml), then degassed and purged with nitrogen three times under reduced pressure. Under nitrogen atmosphere the mixture was stirred at room temperature for 20 minutes, 4-methylphenylboronic acid (4.29 g, 31.5 mmol) and 2M aqueous sodium carbonate (31.5 ml) were poured in, and the temperature was raised to 80° C. After the reaction at 80° C. for 3 hours, the mixture was cooled to room temperature and extracted with addition of ethyl acetate and water. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The products were purified by column chromatography to give the title compound (5.4 g, 80.0% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:68][CH3:69])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:45]=[CH:46][CH:47]=2)[C:16]([N:18]([CH3:44])[CH2:19][CH2:20][N:21]([CH2:40][CH2:41][O:42][CH3:43])[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:17])=[O:12])=[C:6]([C:48]2[CH:53]=[CH:52][C:51]([C:54](=[O:67])[NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=3)=[CH:50][N:49]=2)[CH:5]=1)[CH3:2].Cl>>[CH2:68]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:45]=[CH:46][CH:47]=2)[C:16]([N:18]([CH3:44])[CH2:19][CH2:20][N:21]([CH2:40][CH2:41][O:42][CH3:43])[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:17])=[O:12])=[C:6]([C:48]2[CH:53]=[CH:52][C:51]([C:54](=[O:67])[NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:64])([F:66])[F:65])[CH:58]=3)=[CH:50][N:49]=2)[CH:5]=1)[CH3:69]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN(CCOC)CCOCCOCCOCCC(=O)OC(C)(C)C)c2)c(-c2ccc(C(=O)NCc3cccc(C(F)(F)F)c3)cn2)c1
Agent: Cl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN(CCOC)CCOCCOCCOCCC(=O)O)c2)c(-c2ccc(C(=O)NCc3cccc(C(F)(F)F)c3)cn2)c1

Procedure:
tert-Butyl 3-[2-[2-[2-[2-[[3-[[4-(diethylamino)-2-[5-[[3-(trifluoromethyl)phenyl]methylcarbamoyl]-2-pyridyl]phenyl]carbamoyl]benzoyl]-methyl-amino]ethyl-(2-methoxyethyl)amino]ethoxy]ethoxy]ethoxy]propanoate (0.101 g, 0.105 mmol) Example 336 and hydrochloric acid (4N in dioxane, 3 mL) were stirred for 4 hours at room temperature and then evaporated to give the carboxylic acid, 3-[2-[2-[2-[2-[[3-[[4-(diethylamino)-2-[5-[[3-(trifluoromethyl)phenyl]methylcarbamoyl]-2-pyridyl]phenyl]carbamoyl]benzoyl]-methyl-amino]ethyl-(2-methoxyethyl)amino]ethoxy]ethoxy]ethoxy]propanoic acid, as a white solid. DIEA (0.091 mL, 0.525 mmol) was added to a mixture of the acid, tert-butylamine (7.65 mg, 0.105 mmol) and HATU (48 mg, 0.126 mmol) in DMF (1 mL) and the reaction stirred for 2 hours at room temperature. The reaction was diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (10% methanol/20% ethyl acetate/dichloromethane) to give product as an orange foam (30 mg, 30%); MS (ES, m/z): 966 [M+H]+; NMR (400 MHz, DMSO-d6, ppm): δ 11.8 (m, 1H); 9.53 (m, 1H); 8.85 (d, J=5.2 Hz, 1H); 8.23 (m, 1H); 8.06 (m, 1H); 7.91 (m, 1H); 7.86 (s, 1H); 7.81 (m, 1H); 7.70 (m, 1H); 7.54-7.66 (m, 5H); 7.37 (m, 1H); 7.06 (d, J=2.8 Hz, 1H); 6.86 (dd, J=2.8 and 9.2 Hz, 1H); 4.61 (d, J=6.0 Hz, 2H); 3.36-3.56 (m, 15H); 3.22 (m, 3H); 3.14 (m, 1H); 3.06 (m, 2H); 3.01 (m, 2H); 2.92 (m, 2H); 2.72 (m, 2H); 2.60 (m, 1H); 2.40 (m, 2H); 2.23 (m, 2H); 1.21 (s, 9H); 1.12 (t, J=6.8 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[O:20][CH3:21]>CS(C)=O.O>[CH3:21][O:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCCCN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
3-(Dimethylamino)propan-1-ol (1 g, 10.6 mmol) was dissolved in dimethylsulfoxide (20 ml) and sodium hydride (0.42 g, 10.5 mmol) was added. After stirring at room temperature for 15 min, 1-chloro-2-methoxy-4-nitrobenzene (1 g, 5.3 mmol) in dimethylsulfoxide (10 ml) was added and the reaction mixture stirred 4 h at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase dried over magnesium sulphate and filtered. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (0% to 85%, ethyl acetate-methanol) to obtain 480 mg (34% yield) of the title compound as an oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH:21](/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1)=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccc(C=O)cc21
Temperature: 100 °C
Yield: 66.8 %

Procedure:
A solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.249 mmol), styrene (37 uL, 0.324 mmol), diisopropylethylamine (87 uL, 0.324 mmol) and DMF (2.5 mL) was purged with Ar gas for 20 min at which time Pd(OAc)2 (2.8 mg, 0.0125 mmol) and P(o-tol)3 (11 mg, 0.0374 mmol) were added and the reaction heated to 100° C. for 20 hours. The reaction was cooled to room temperature and partitioned between EtOAc and NH4Cl. The aqueous layer was extracted 3× with EtOAc and the combined organics washed with water (2×) and brine (2×). The organic layer was dried over MgSO4 and the EtOAc removed in vacuo. The residue was purified by column chromatography (silica gel, 5:1 hexanes/EtOAc) to give the title compound (63 mg, 67%) which was used without further purification. MS ESI 379.2 [M+H]+, calcd for [C22H26N2O2Si+H]+ 379.18.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][C@H:10]([N:17]([C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH3:25])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CC(C)(C)CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-5-hydroxy-4,4-dimethylpentan-2-yl(methyl)carbamate (1.23 g, 3.27 mmol) in THF (20 mL) were added pyridine (0.79 mL) and acetyl chloride (0.386 g, 4.91 mmol). The reaction mixture was stirred at RT overnight and filtered. The filtrate was concentrated to give (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butyldimethylsilyloxy)-2,2-dimethylpentyl acetate (1.36 g, crude), which was used without further purification. LRMS (M-Boc+H+) m/z 318.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[K]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COC(=O)c1cc(I)ccc1O
Reactant: CCOC(=O)CBr
Agent: [K]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(I)cc1C(=O)OC
Yield: 96.1 %

Procedure:
Reflux a mixture of 2-hydroxy-5-iodo-benzoic acid methyl ester (TCI; 5.5 g, 20 mmol) and ethyl bromoacetate (Aldrich; 6.7 g, 40 mmol) in acetone (60 mL) in the presence of potassium (5.5 g, 40 mmol) for 3 h. Filter out the solid and evaporate acetone to give a white residue. Dissolve the residue in ethyl acetate and wash with brine. Evaporate the solvent in vacuum to give final product as a white solid (7 g, 96%). MS (electrospray, m/z) 365 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.1 (d, J=2.0 Hz, 1H), 7.70 (dd, J=8.8, 2.8 Hz, 1H), 6.6 (d, J=8.8 Hz, 1H), 4.68 (s, 2H), 4.3 (q, J=6.8 Hz, 2H), 3.9 (s, 1H), 1.3 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11](=[O:16])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>O1CCOCC1>[O:16]=[C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:3]=[C:2]([NH:1][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:13]=2[NH:12]1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reaction time: 16 h
Yield: 92 %

Procedure:
Prepared from 2-amino-6(5H)-phenanthridinone 3 and succinic anhydride. To a solution of 2-amino-6(5H)-phenanthridinone (150 mg, 0.71 mmol) in dioxane (30 mL) was added a solution of succinic anhydride (87 mg, 1.1 mmol) in dioxane (5 mL) over 5 minutes. The mixture was stirred for 16 hours and a yellowish precipitation was formed. Purification of the precipitation by crystallization in dioxane gave a light white solid (92% yield), mp 224-228° C. 1H-NMR (400 MHz DMSO-d6), 11.7 (s, 1H), 10.1 (s, 1H), 8.67 (s, 1H), 8.33 (d, J=7.8 Hz, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.87 (t, J=7.0 Hz, 1H), 7.66 (t, J=7.44 Hz, 1H), 7.60 (t, J=8.7 Hz, 1H),7.30 (d, J=8.7 Hz, 1H), 2.60 ((d, J=5.4 Hz, 2H), 2.56 (d, J=5.4 Hz, 2H). Anal. (C17H24N2O4 .0.1 H2O), C H N.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:13]=[C:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]1[CH2:24][C:25](O)=[O:26]>>[Cl:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:25](=[O:26])[CH2:24][N:15]2[C:16]3[C:21](=[N:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][CH2:23][C:14]2=[O:13])[S:5][CH:6]=1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: Nc1scc(Cl)c1-c1nnc[nH]1
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Cl)c1-c1nc[nH]n1

Procedure:
The titled compound was synthesized from 4-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid via protocol A. LCMS method [4], retention time=1.035; MS(ESI) 389.1 (MH+, 35Cl).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@@H:33]([NH2:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@@H:33]([NH:36][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Product: COc1ccc(F)cc1C(=O)c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc1N
Yield: 87.8 %

Procedure:
The same procedure was used as described in Example 9 starting from (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (400 mg, 1.18 mmol, Example 48) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (233 mg,1.25 mmol, Astatech), to give (R)-3-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (447 mg). MS (M+H)+, 432.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][CH3:15])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([OH:30])=O)[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([N:14]([C:10]4[CH:11]=[C:12]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]5)[CH3:15])=[O:30])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: CNc1ccc2[nH]c(C(C)(C)C)cc2c1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)C1(c2ccc3c(c2)OCO3)CC1)c1ccc2[nH]c(C(C)(C)C)cc2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-tert-Butyl-N-methyl-1H-indol-5-amine (20.2 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 μL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 80° C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)-N-methylcyclopropanecarboxamide. ESI-MS m/z calc. 390.2, found 391.3 (M+1)+. Retention time of 3.41 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[CH2:21]([N:23]([CH2:29][CH3:30])[C:24](=[O:28])/[CH:25]=[CH:26]/[CH3:27])[CH3:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:21]([N:23]([CH2:29][CH3:30])[C:24](=[O:28])/[CH:25]=[C:26](/[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1)\[CH3:27])[CH3:22]
Reactant: C/C=C/C(=O)N(CC)CC
Reactant: OCCc1cc(Br)ccc1OCc1c(F)cccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OCc2c(F)cccc2F)c(CCO)c1

Procedure:
A solution of 2-[5-bromo-2-[2,6-difluorobenzyloxy)phenyl]-1-ethanol (14.07 g, 41.02 mmol) and N,N-diethylcrotonamide (8.68 g, 61.53 mmol) in 60 mL triethylamine in a thick-walled pyrex tube is degassed wish nitrogen for 15 minutes. Pd(OAc)2 (0.46 g, 2.05 mmol) and tri-o-tolylphosphine (1.25 g, 4.10 mmol) are placed into the tube, which is then sealed, and the mixture is heated to 100° for 5 hours. The mixture is diluted with EtOAc (400 mL), and white precipitate is filtered out. The filtrate is then washed with 1 N HCl (2×400 mL), H20 (1×100 mL) and brine (1×100 ni), dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 3:1 EtOAc/hexane) gives (E)-3-[4-(2,6-difluorobenzyloxy)-3-(2-hydroxyethyl)-phenyl]-2-butenoic acid diethy amide.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH2:20][C@H:21]([CH2:26][OH:27])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:20][C@H:21]([CH2:26][OH:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:16])=[CH:18][CH:19]=3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CC(C)C[C@H](N)CO
Product: CC(C)C[C@@H](CO)NC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoic acid (which was obtained in Example 150) (0.53 g, 2 mmol) and (S)-leucinol (0.30 g, 2.5 mmol) according to the procedure shown for Example 154 to give 0.53 g of a white solid; m.p. 90–91° C.; MS (ES) m/z: 363.3 (MH+); HRMS (ES) Calcd. for C20H31N2O4 (MH+): 363.2278. Found: 363.2275.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[C:24]([CH3:30])=[N:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[CH3:29][C:27]1[C:26]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)=[N:25][C:24]([CH3:30])=[CH:23][N:28]=1
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: Cc1cnc(C)c(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 3-chloro-2,5-dimethyl-pyrazine. MS (ESI) mass calcd. for C23H24N4OS, 404.54; m/z found, 405.2 [M+H]+.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:30])=[O:22])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CC(C)C)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-leucine methyl ester hydrochloride using the procedure described in Method 3. the title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32]C(=O)C2C=CC=CC=2)[CH2:28][O:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[C@H:29]([CH2:31][OH:32])[CH2:28][O:27][C:26]4=[O:25])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3F)CC2)c(C)c1
Yield: 21.2 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.2 g) described in Preparation Example 65 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (849 mg), the title compound (278 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](OC)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.[NH2:13][NH2:14].O>CO>[Cl:1][C:2]1[C:3]([NH:13][NH2:14])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c(OC)n1
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1ncc(Cl)c(NN)n1
Reaction time: 8 h

Procedure:
A solution containing 0.35 g (2.0 mmol) of 5-chloro-2,4-dimethoxypyrimidine and 0.35 g (7.0 mmol) of hydrazine hydrate in 2.9 g of methanol was heated at reflux with stirring for 8 hours. The mixture was then cooled causing a precipitate to form. Water was added until the precipitation appeared to be complete and the precipitate was then recovered by vacuum filtration and allowed to air dry overnight to obtain 0.23 g (66 percent of theory) of the title compound as a white solid. The product melted at 172°-173° C. after changing crystalline form from needles to cube-like shapes in a phenomenon that appeared to involve sublimation.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])C.[N:31]1(C(Cl)=O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:3])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: O=C(Cl)N1CCOCC1
Product: CCO[C@H]1CN(C(=O)N2CCOCC2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 4-morpholinecarbonyl chloride and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.34, 7.28, 5.23, 4.69, 4.10, 3.90, 3.80–3.68, 3.58–3.28, 2.70, 2.49, 1.33–1.26, 1.16; IR (liq.) 2970 (s), 2934 (s), 2874 (s), 2353 (w), 1996 (w), 1956 (w), 1642 (s), 1567 (s), 1552 (s), 1500 (s), 1469 (s), 1414 (s,b), 1397 (s), 1118 (s), 1102 (s), cm−1 HRMS (FAB) calcd for C25H33Cl2N5O3+H 522.2039, found 522.2038.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([CH2:45][CH2:46][OH:47])[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:41]([C:39]1[CH:40]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:37]([CH2:45][CH2:46][OH:47])[N:38]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of Intermediate 96c (160 mg, 0.41 mmol), Intermediate 110b (142 mg, 0.41 mmol) and DIPEA (142 μL, 0.82 mmol) in dioxane (5 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-8% MeOH in DCM followed by MDAP (Method 7) purification, to afford the title compound (86 mg, 32%) as a glassy white solid. LCMS (Method 5): Rt 4.32 min, m/z 601 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6.2 Hz), 0.58 (3H, d, J=6.2 Hz), 1.17 (9H, s), 1.35-1.55 (3H, m), 1.63-1.69 (2H, m), 1.73-1.79 (1H, m), 1.82-2.00 (2H, m), 2.00-2.13 (2H, m), 3.09-3.19 (2H, m), 3.62 (2H, br s), 3.90 (2H, t, J=5.9 Hz), 4.82 (1H, td, J=8.6, 5.7 Hz), 4.92-4.98 (1H, br s), 5.50 (1H, t, J=4.2 Hz), 6.02 (1H, s), 7.04 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=9.8, 2.3 Hz), 7.20-7.25 (1H, m), 7.30-7.36 (3H, m), 7.62 (1H, dd, J=9.7, 0.6 Hz), 7.86 (1H, d, J=2.1 Hz), 8.14 (1H, s).