Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([C:12]#[N:13])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[NH2:15][OH:16].C(=O)([O-])O.[Na+]>>[OH:16][N:15]=[C:12]([NH2:13])[C:10]1[O:9][C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:11]=1
Reactant: NO
Reactant: COc1cccc2cc(C#N)oc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cccc2cc(C(N)=NO)oc12
Yield: 92.4 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 28 using 7-methoxybenzo(b)furan-2-carbonitrile (3.0 g), hydroxylamine hydrochloride (1.4 g) and sodium hydrogencarbonate (2.1 g), the title compound (3.3 g) was obtained as brown crystals.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:15])=[CH:8][C:7]=1[Cl:25])C.C1COCC1.[OH-].[Na+].Cl>C(O)C>[Cl:25][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:15])[C:10]([Cl:12])=[CH:11][C:6]=1[CH2:5][C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2c[nH]c3ccccc23)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Cl)c(NC(=O)c2c[nH]c3ccccc23)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.3 %

Procedure:
This [2,5-dichloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic acid ethyl ester (5.7 g, 14.57 mmol) was added to THF (50 mL) and ethanol (30 mL), and a 0.25N-aqueous solution of sodium hydroxide (120 mL) was added thereto. The mixture was stirred for 15 hours at room temperature, and then for one hour at 60° C. The reaction mixture was left to cool naturally to room temperature, and then 1N—HCl (32 mL) was added thereto while stirring the reaction mixture under ice cooling. Precipitated crystals were collected by filtration under reduced pressure, washed with water, and then dried, to obtain the title compound (4.25 g, 80%) as a solid.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([CH3:25])([CH3:24])[C:16](=[O:23])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.O>CS(C)=O.O1CCCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([C:16]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:2][O:23]1)([CH3:25])[CH3:24]
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)Cn1cncn1
Reactant: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Reaction time: 6 h
Yield: 73.6 %

Procedure:
15.7 g (71.2 mmol) of trimethylsulphonium iodide are dissolved in 16 g of dimethyl sulphoxide under an atmosphere of nitrogen. 9.4 g (71.2 mmol) of potassium tert.-butylate are added at room temperature, with cooling. The mixture is allowed to stir for 6 hours and then a solution of 20 g (64.1 mmol) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butanone in 30 ml of tetrahydrofuran is added. The reaction mixture is allowed to stir at room temperature for 15 hours and under reflux for 4 hours, then cooled and poured into water. The mixture is extracted with methylene chloride, and the organic phase is dried over sodium sulphate and evaporated in vacuo. 15.4 g (73.7% of theory) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-ylmethyl)oxirane of refractive index nD20 =1.5539 are obtained. ##STR95##
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.Br[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: N#Cc1ccc(Br)nc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C#N)cn3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt and 6-bromonicotinonitrile using procedures analogous to those for Example 14. Analytic LCMS (M+H)+: m/z=427.4.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:20][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)[CH:30]=3)[N:21]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:19])=[O:18]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(Nc5ccccc5S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
To a cooled, stirred suspension of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.961 g, 4.51 mmol) and copper(II)chloride dihydrate (0.20 g, 1.2 mmol) in 12 M of hydrochloric acid (10.0 mL) at 5° C. was added dropwise a solution of sodium nitrite (0.37 g, 5.4 mmol) in water (2 mL). Gentle gas evolution was noted. The mixture was stirred for 30 minutes at 5° C. then at room temperature for 18 hours. The yellow mixture was diluted with water (80 mL) and the resulting precipitate was filtered, rinsed with water and dried in-the-air. 8-Bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was isolated as a pale yellow solid (0.947 g, 90%) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.98 (d, J=6.9 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.22 (t, J=7.0 Hz, 1H). MS=232, 234, 236 (MH)+. 68b) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (234.0 mg, 1.007 mmol) and 2-methanesulfonyl-phenylamine; hydrochloride (220.0 mg, 1.059 mmol) with 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (105.0 mg, 0.1815 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as a pale yellow solid (0.115 g, 35%). MP=180-182° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (s, 1H), 8.18 (d, J=6.7 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.51 (d, J=8.2, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.2 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 3.12 (s, 3H). MS=323, 325 (MH)+. 68c) N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (95.0 mg, 0.294 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (32.0 mg, 0.0585 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a light brown foam (0.077 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (s, 1H), 8.11 (d, J=6.5, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.58-7.51 (m, 2H), 7.43 (s, 1H), 7.30-7.25 (m, 1H), 7.20 (t, J=8.1 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.84-6.78 (m, 2H), 6.57 (d, J=8.1 Hz, 1H), 3.33-3.25 (m, 4H), 3.13 (s, 3H), 2.70-2.57 (m, 4H), 2.39 (s, 3H). MS=478 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)Cl.[NH3:16]>C1(C)C=CC=CC=1.C(O)CCC>[NH2:16][C:6]1[C:7]([CH2:8][CH3:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: CCc1c(Cl)ncnc1Cl
Reactant: N
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCO
Product: CCc1c(N)ncnc1Cl

Procedure:
Formamidine acetate was reacted with diethyl-ethylmalonate in the presence of sodium ethoxide in dry ethanol to yield 5-ethylpyrimidine-4,6-diol, which was converted to 4,6-Dichloro-5-ethylpyrimidine by POCl3 in the presence of TEA in toluene. 4,6-Dichloro-5-ethylpyrimidine was then reacted with aqueous ammonia in n-butanol at 100° C. to afford 4-amino-5-ethyl-6-chloropyrimidine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[N:15]=[C:14]([NH:16][C:17]([NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[S:18])[CH:13]=[CH:12][CH:11]=1>>[Br:9][C:10]1[N:15]=[C:14]([NH:16][C:17]([NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[S:18])[CH:13]=[CH:12][CH:11]=1.[Br:1][C:2]1[N:7]2[N:15]=[C:14]([NH2:16])[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Agent: CCOC(=O)NC(=S)Nc1cccc(Br)n1
Product: Nc1nc2cccc(Br)n2n1

Procedure:
N-(6-Bromo-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 6-bromo-pyridin-2-ylamine (1.0 g, 5.8 mmol) in a manner analogous to Step 2a. The product of the reaction was isolated as a yellow solid. 1H NMR (400 MHz, CDCl3, δ, ppm): 12.03 (br s, 1H), 8.81 (d, J=8.0 Hz, 1H), 8.06 (br s, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H). MS=306 (MH)+. 12b) 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from N-(6-bromo-2-pyridinyl)-N′-carboethoxy-thiourea (1.8 g, 5.9 mmol) in a manner analogous to Step 2b. The product was isolated as an off-white solid (0.71 g, 56%). MP=203-205° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 7.40-7.32 (m, 2H), 7.23-7.20 (m, 1H), 6.26 (br s, 2H). MS=215 (MH)+. 12c) [5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 4-(4-bromo-phenyl)-morpholine (101.0 mg, 0.4172 mmol) in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.018 g, 12%). MP=247-249° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.28-8.24 (m, 2H), 8.15-8.11 (m, 2H), 7.55-7.51 (m, 2H), 7.49-7.44 (m, 2H), 7.04-7.01 (m, 1H), 6.96-6.91 (m, 2H), 6.68 (s, 1H), 3.90-3.85 (m, 4H), 3.15 (s, 3H), 3.14-3.10 (m, 4H). MS=450 (MH)+.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.C([O-])(O)=O.[Na+].[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:20](=[O:22])[CH3:21])[CH:2]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1cccc(-c2ccccc2)c1
Reaction time: 0.75 h
Yield: 128.5 %

Procedure:
C-Biphenyl-3-yl-methylamine (700 mg, 3.8 mmol) was dissolved in 38 mL of CH2Cl2. To this was added 38 mL of satd NaHCO3 (aq) followed by acetyl chloride (1.41 mL 19,8 mmol). The resulting mixture was stirred 45 min. The organic layer was separated, washed with satd NaCl, dried over Na2SO4, filtered and solvent removed under vacuum to yield 1.1 grams of N-biphenyl-3-ylmethyl-acetamide.
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[F:25][C:26]([F:34])([F:33])[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28].C(=O)(O)[O-]>CN(C=O)C.[Cu]I.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.CO>[F:25][C:26]([F:34])([F:33])[C:27]([NH:29][CH2:30][C:31]#[C:32][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)=[O:28]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: C#CCNC(=O)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of 5-iodo-2′-deoxyuridine (1.05 g, 2.96 mmol) and CuI (114 mg, 0.60 mmol) in dry DMF (21 ml) was added triethylamine (0.9 ml). After stirring for 5 min trifluoro-N-prop-2-ynyl-acetamide (1.35 g, 9.0 mmol) and Pd(PPh3)4 (330 mg, 0.29 mmol) were added to the mixture and the reaction was stirred at room temperature in the dark for 16 h. Methanol (MeOH) (40 ml) and bicarbonate dowex added to the reaction mixture and stirred for 45 min. The mixture was filtered and the filtrate washed with MeOH and the solvent was removed under vacuum. The crude mixture was purified by chromatography on silica (ethyl acetate (EtOAc) to EtOAc:MeOH 95:5) to give slightly yellow crystals (794 mg, 71%). 1H NMR (d6 dimethylsulfoxide (DMSO)) δ 2.13-2.17 (m, 2H, H-2′), 3.57-3.65 (m, 2H, H-5′), 3.81-3.84 (m, 1H, H-4′), 4.23-4.27 (m, 3H, H-3′, CH2N), 5.13 (t, J=5.0 Hz, 1H, OH), 5.20 (d, J=4.3 Hz, 1H, OH), 6.13 (t, J=6.7 Hz, 1H, H-1′), 8.23 (s, 1H, H-6), 10.11 (t, J=5.6 Hz, 1H, NH), 11.70 (br s, 1H, NH). Mass (−ve electrospray) calcd for C14H14F3N3O6 377.08, found 376.
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)=[O:7])(C)(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](OC2C=CC=CC=2)=[O:33])[C:24](=[CH:29][CH:30]=1)[C:25](OC)=[O:26]>>[C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([S:16]([N:19]2[C:25](=[O:26])[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:30][CH:29]=3)[NH:31][C:32]2=[O:33])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=1)([OH:5])=[O:7]
Reactant: CC(C)(C)OC(=O)CNc1cccc(S(N)(=O)=O)c1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: O=C(O)CNc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Yield: 9 %

Procedure:
1.62 g (5.65 mmol) of 3-t-butoxycarbonylmethylaminobenzenesulfonamide and 1.73 g (5.65 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 7 to obtain 209 mg (yield 9%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.86 (2H, s), 6.88 (1H, s), 7.12 (1H, s), 7.24 (1H, d), 7.30–7.38 (3H, m), 7.86 (1H, d), 11.61 (1H, br).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5][CH:4]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:3]1.[CH:23]1([N:26]2[C:35]3[C:30](=[CH:31][C:32]([F:37])=[C:33](F)[N:34]=3)[C:29](=[O:38])[C:28]([C:39]([OH:41])=[O:40])=[CH:27]2)[CH2:25][CH2:24]1>>[C:20]([NH:19][CH2:18][CH:4]1[O:3][C:2](=[O:1])[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][N:13]([C:33]4[N:34]=[C:35]5[C:30]([C:29](=[O:38])[C:28]([C:39]([OH:41])=[O:40])=[CH:27][N:26]5[CH:23]5[CH2:25][CH2:24]5)=[CH:31][C:32]=4[F:37])[CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5]1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1cn(C2CC2)c2nc(F)c(F)cc2c1=O
Reactant: CC(=O)NCC1CN(c2ccc3c(c2)CCNCC3)C(=O)O1
Product: CC(=O)NCC1CN(c2ccc3c(c2)CCN(c2nc4c(cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC3)C(=O)O1

Procedure:
The title compound was prepared in a procedure analogous to that used in Example 6, using N-[2-Oxo-3-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-oxazolidin-5-ylmethyl]-acetamide (0.25 g) and 1-Cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (0.23 g). The product was triturated with EtOH to purify. MS (APCI) AP+, 550. NMR (DMSO6)1.1 (m, 2H), 1.22 (m, 2H), 1.74 (s, 3H), 3.04 (m, 4H), 3.3 (m, 6H), 3.70 (m, 2H), 4.0 (m, 2H), 4.65 (m, 1H), 7.13 (d, 1H), 7.26 (dd, 1H), 7.35 (d, 1H), 8.0 (d, 1H), 8.14 (t, 1H), 8.52 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Li]CCCC.[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1Br>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:20]1[C:19]([C:18]([O:17][CH3:16])=[O:29])=[CH:24][C:23]([N+:25]([O-:27])=[O:26])=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COc1cccc(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 1,3-dimethoxybenzene (115.2 ml, 0.88 mol) in anhydrous THF (600 ml) was cooled to 0° C. and treated with n-BuLi (382.4 ml, 0.95 mol, 2.5M solution in hexane) dropwise while maintaining the temperature of the reaction mixture between 0° C. and 5° C. The reaction mixture was allowed to warm to room temperature, stirred for 2 hours and recooled to 0° C. Anhydrous ZnCl2 (141.6 g, 1.04 mol) was added as a solid in portions while maintaining the reaction temperature below 5° C. After adding all the ZnCl2, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours (clear solution). The reaction mixture was recooled to 0° C. and methyl-2-bromo-5-nitrobenzoate (208 g, 0.80 mol) was added as a solid in one portion, followed by the addition of dichloro-bis-(triphenylphosphine)palladium(II) (7 g, 9.90 mmol). Additional THF (200 ml) was added and the reaction mixture was allowed to warm to room temperature. Reaction is exothermic with exotherm starting around 20° C. The reaction mixture was stirred while maintaining the reaction temperature below 45° C. until methyl-2-bromo-5-nitrobenzoate was less than 0.1% peak area detected by HPLC. Solid product started precipitating out typically after 30 minutes. Isopropyl acetate (400 ml) was added and the reaction mixture was stirred for another 30 minutes. The solid was filtered and washed with isopropyl acetate (300 ml), dried at 40° C. under reduced pressure to provide the title compound (203 g, 80%). mp 157° C.; Anal. Calcd. for C16H15NO6: C, 60.57; H, 4.77; N, 4.41; Found C, 60.30; H, 4.76; N, 4.34. 1H NMR [(CD3)2SO] δ3.65 (3H, s); 3.66 (6H, s), 6.73 (1H, s), 6.77 (1H, s), 7.36 (1H, m), 7.59 (1H, d), 8.36 (1H, dd) and 8.52 (1H, d); 13C [(CD3)2SO] δ52.1, 55.6, 63.4, 89.9, 104.2, 115.7, 123.7, 125.3, 130.1, 133.0, 134.4, 141.4, 146.0, 156.2, 165.6. The 13C signal for two methoxy groups at 55.6 are overlapping; IR (KBr): 1740 and 1600 cm−1; MS (APCI) m/z: 318 (M+H)+, m/z 335 (M+NH4)+, 340 (M+Na)+; FAB-HRMS: found, 318.0989, required 318.0978.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[N:21]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[N:21]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Methyl 3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanoate (Example 58; 1.500 g, 3.346 mmol) was dissolved in THF (50 mL) and water (25 mL), followed by the addition of sodium hydroxide (0.2676 g, 6.691 mmol), and the mixture was at ambient temperature for 16 hours. The mixture was concentrated, and partitioned between DCM and saturated aqueous NH4Cl. The layers were separated and the aqueous was extracted with DCM/THF and then 100% THF. The combined organics were dried over Na2SO4, filtered and concentrated to give 3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanoic acid (1.42 g, 98% yield) as white solids. 1H NMR (DMSO-d6) δ 2.58 (t, J=7.6 Hz, 2H), 2.82 (t, J=7.6 Hz, 2H), 5.29 (s, 2H), 6.65 (s, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.41 (t, J=7.2 Hz, 2H), 7.58 (s, 1H), 7.60 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H); Mass Spectrum (apci) 434 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@@H:6]1[CH3:33])=[O:4].CC(O[C:38]1[CH:39]=[C:40]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])[CH:41]=[CH:42][CH:43]=1)C>>[F:20][C:18]([F:19])([F:21])[C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:46]3[C:45](=[O:50])[C:44]([C:40]4[CH:39]=[CH:38][C:43]([O:26][CH:17]([CH3:18])[CH3:14])=[CH:42][CH:41]=4)([CH3:51])[NH:48][C:47]3=[O:49])[C@@H:6]([CH3:33])[CH2:7]2)=[C:12]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([OH:26])[C:22]([F:23])([F:25])[F:24]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@@H](C)C1
Reactant: CC(C)Oc1cccc(C2(C)NC(=O)NC2=O)c1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)[C@@H](C)C1

Procedure:
(S)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-(3-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][C@@H:13]([CH3:17])[CH2:12]2)=[N:7][CH:6]=1)[CH3:2].[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](Cl)=[N:22][N:21]=1.C(N(CC)CC)C>CN1C(=O)CCC1.O>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]([Cl:19])=[N:21][N:22]=3)[C@@H:13]([CH3:17])[CH2:12]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: CCOC(=O)c1ccc(N2CCN[C@@H](C)C2)nc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(c3nnc(Cl)c4ccccc34)[C@@H](C)C2)nc1
Yield: 30.3 %

Procedure:
A solution of 6-((S)-3-methyl-piperazin-1-yl)-nicotinic acid ethyl ester (1.0 g, 4.0 mmol, 1 eq), 1,4-dichlorophthalazine (840 mg, 4.2 mmol, 1.05 eq) and triethyl amine (3.9 g, 2.8 mL, 38 mmol, 9.5 eq) in NMP (8 mL) is heated at 100 C for 26 h. Reaction is diluted with water (15 mL) and extracted with EtOAc (3×25 mL). The combined organic fractions are dried over magnesium sulfate, concentrated and purified by silica gel chromatography (5-50% EtOAc/Heptane) to yield the desired compound (500 mg, 30% yield).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[C:17]([O:35][CH3:36])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:36][O:35][C:17]1[CH:16]=[C:15]([CH:34]=[CH:33][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:14][O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)c1cn(C)nc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (1.93 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyl-1,3-oxazole (3.89 g), potassium carbonate (3.15 g) and N,N-dimethylformamide (30 mL) was stirred overnight at 60° C. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give ethyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylate (5.23 g, yield 97%). The crystals were recrystallized from acetone-hexane. melting point: 134-135° C.