Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]([C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[S:13])[NH2:11].[CH2:27]([O:34][N:35]1[C:41](=[O:42])[N:40]2[CH2:43][C@H:36]1[CH2:37][CH2:38][C@H:39]2[C:44](O)=[O:45])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:27]([O:34][N:35]1[C:41](=[O:42])[N:40]2[CH2:43][C@H:36]1[CH2:37][CH2:38][C@H:39]2[C:44]([NH:11][NH:10][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[S:13])=[O:45])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)NN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=S)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
DIPEA (1.75 mL, 10.8 mmol) was added to a solution of tert-butyl 4-(hydrazinecarbonothioyl)piperazine-1-carboxylate (0.95 g, 3.6 mmol), (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.0 g, 3.6 mmol) and HATU (1.51 g, 3.98 mmol) in dry DMF (15 mL) and the resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (10 mL), and extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4, then concentrated and purified by silica gel column chromatography (1:50 MeOH/DCM) to afford tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonothioyl)piperazine-1-carboxylate (0.92 g, 49%) as a light yellow solid. ESI-MS (EI+, m/z): 519.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[N+:7]([O-:9])[C:6]([CH3:10])=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Na].[CH:16]1C=CC=CC=1>CO.[Cl-].[Cl-].[Zn+2]>[CH3:16][O:1][CH2:2][C:3]1[CH:8]=[N+:7]([O-:9])[C:6]([CH3:10])=[CH:5][N:4]=1
Reactant: Cc1cnc(CO)c[n+]1[O-]
Reactant: c1ccccc1
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COCc1c[n+]([O-])c(C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 152 %

Procedure:
2-Hydroxymethyl-5-methylpyrazine-4-oxide (3.5 g) was dissolved under stirring in a solution of 8 ml of thionyl chloride in 20 ml of dry benzene containing 0.5 g of ZnCl2, keeping the temperature below 30° C. The reaction mixture was cautiously warmed 3 hours at 60° C., then cooled to room temperature, and filtered. The solvent was evaporated under reduced pressure. The oily residue was dissolved in a solution of sodium methoxide in methyl alcohol, previously prepared dissolving 0.6 of sodium in 30 ml of methyl alcohol. After refluxing 4 hours, the reaction solution was cooled at room temperature, filtered and evaporated to dryness. The residue was taken up with water and repeatedly extracted with ethyl ether. The organic phase was washed with water, dried and the solvent was evaporated to dryness; the residue treated with pentane gave 2-methoxymethyl-5-methylpyrazine-4-oxide (1.5 g), m.p. 69°-72° C.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH2:11](Cl)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][C:4]=2[O:5]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C(=Cc1ccccc1)COc1ccc2c(c1)OCO2

Procedure:
A mixture of sesamol (27.6 g.), cinnamyl chloride (30.4 g.), anhydrous potassium carbonate (50.0 g.), potassium iodide (2.0 g.) in anhydrous acetone (100 ml.) was heated under reflux for 1.5 hrs. The acetone was removed by evaporation, and the residue was treated with excess water and cooled to give an oil, which subsequently solidified. The crude product was collected by filtration and recrystallized from methanol to give MDCB as colorless prisms, m.p. 83° C., yield 15.0 g. (Found: C, 75.4; H, 5.67. Calculated for C16H14O3 : C, 75.6; H, 5.55.) The nuclear magnetic resonance (NMR) spectrum of MDCB at 100 MHz in deuterated chloroform (CDCl3) exhibited absorbances as follows: a doublet (2 protons) at δ 4.59 (coupling constant J = 6.0 Hz), a singlet (2 protons) at δ 5.89 a multiplet (5 protons) at δ 6.22-6.80, and a multiplet (5 protons) at δ 7.18-7.48.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[CH:40]12[N:46]([C:47](=O)[CH2:48]Br)[CH:43]([CH2:44][CH2:45]1)[CH2:42][CH2:41]2>>[CH:40]12[N:46]([CH2:47][CH2:48][O:10][C:8]3[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]4[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=4[CH:14]4[CH2:23][CH2:22][C:21]5[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=5[CH2:15]4)=[CH:35][CH:34]=3)[CH:43]([CH2:44][CH2:45]1)[CH2:42][CH2:41]2
Reactant: O=C(CBr)N1C2CCC1CC2
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCCN3C4CCC3CC4)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 17.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.7 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:23]([O-:25])=[O:24])=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:5][CH2:4]1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][C:37]3([CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:36][CH:35]=2)O1>>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:23]([O-:25])=[O:24])=[C:13]([C:34]3[CH2:39][CH2:38][C:37]4([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]4)[CH2:36][CH:35]=3)[CH:14]=2)[CH2:5][CH2:4]1
Reactant: CC1(C)OB(C2=CCC3(CCCCC3)CC2)OC1(C)C
Reactant: COC1CCN(c2ccc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)c2)CC1
Product: COC1CCN(c2ccc([N+](=O)[O-])c(C3=CCC4(CCCCC4)CC3)c2)CC1
Yield: 111.6 %

Procedure:
Trifluoromethanesulfonic acid 5-(4-methoxypiperidin-1-yl)-2-nitrophenyl ester (2.0 g, 5.43 mmol) prepared in Example (7c) was used as the starting material. 4,4,5,5-Tetramethyl-2-spiro[5.5]undec-2-en-3-yl-[1,3,2]dioxaborolane (1.65 g, 5.97 mmol) prepared in Example (39b) was used instead of 4-t-butylcyclohex-1-enyl-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolane for reaction in a manner similar to Example (7e) and treated in a similar manner, to give 2.331 g of the title compound as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=1
Reactant: COc1ncc(C(F)(F)F)cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ncc(C(F)(F)F)cc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol (14) (0.4 g, 1.93 mmol) dissolved in DCM was added thionyl chloride (0.38 ml, 3.86 mmol). The reaction mixture was stirred for 2 h at RT. The solvent was evaporated under the reduced pressure and the reaction mixture was poured in to water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure to yield 3-(chloromethyl)-2-methoxy-5-(trifluoromethyl)pyridine (15) as a liquid. (Yield 0.3 g, 69.76%)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][C:13]([CH:15]=O)=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:22](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[Si:1]([O:8][CH2:9][C:10]1[O:14][C:13]([C:15]#[N:22])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C=O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)o1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1c) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-2-furaldehyde (9.1 g, 38 mmol) [reference literature: Tetrahedron, vol. 50 (23), 6767 (1994)], hydroxylamine hydrochloride (2.9 g, 42 mmol), triethylamine (11 ml, 76 mmol) and N,N′-dicyclohexylcarbodiimide (8.6 g, 42 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (7.5 g) in a yield of 84% as a colourless oily product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.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.[Cu]I>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH:27]=[C:28]([C:13]2[C:7]3[S:6][C:5]([NH:4][C:3]([O:2][CH3:1])=[O:17])=[N:9][C:8]=3[C:10]([O:15][CH3:16])=[CH:11][CH:12]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc2c(OC)ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2s1
Temperature: 100 °C
Yield: 36.2 %

Procedure:
To a stirred solution of 2.2 g (0.006 Mol) (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 60 ml DMF were added 3.4 g (0.007 Mol) 4-tributylstannanyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, 0.424 g (0.001 Mol) PdCl2(PPh3)2 and 0.12 g (0.001 Mol) CuI. The mixture was heated at 100° C. for 19 h and then concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1:1) afforded 0.91 g (36%) 4-(4-methoxy-2-methoxycarbonylamino-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a light yellow foam. ES-MS m/e (%): 362 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Br)[N:25]=1.C[Si](C)(C)N[Si](C)(C)C.[K]>C1COCC1>[Br:23][C:24]1[N:25]=[C:26]([CH2:30][N:11]2[C:12]3[C:17](=[N:16][CH:15]=[CH:14][CH:13]=3)[C:18](=[O:19])[C:9]([C:7](=[O:8])[C:6]3[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[C:4]([CH3:22])[CH:5]=3)=[CH:10]2)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Reactant: BrCc1cccc(Br)n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3cccnc3c2=O)cc1C
Yield: 16.9 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 2 using 75 mg (0.255 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,5]naphthyridin-4-one, 76.8 mg (0.306 mmol) of 2-bromo-6-bromomethyl-pyridine, 0.61 mL (0.306 mmol, 0.5 M in toluene) of potassium hexamethyldisilazane, and 2.5 mL of THF. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 20 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(4-methoxy-3-methyl-benzoyl)-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C23H18BrN3O3 [M+H]: 464.05 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.0 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].CC(C)N=C=NC(C)C>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:37][CH2:36][N:35]([C:38]4[CH:39]=[CH:40][C:41]([C:44]([F:45])([F:47])[F:46])=[CH:42][CH:43]=4)[CH2:34][CH2:33]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: CNc1cc(N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c(Cl)cc1N
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(Cl)c(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-Chloro-3-isothiocyanatobenzyl)-1-trifluoromethyl-cyclopropane carboxamide (161 mg, 0.48 mmol) was added to the THF solution from step (a) above and the mixture was concentrated. DMF (2 mL) was added to the residue, the mixture was stirred at rt for 1 h and DIC (67 mg, 0.53 mmol) was added. The mixture was stirred at rt overnight, another portion of DIC (17 mg, 0.13 mmol) was added and the mixture was stirred at rt overnight. The mixture was concentrated and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([C:10]3[CH:17]=CC(NC)=C[CH:11]=3)[O:9][C:5]=2[CH:4]=1.BrC1C=[N:23][C:24]([NH:27][CH3:28])=[N:25]C=1>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:17]=3)[O:9][C:5]=2[CH:4]=1
Reactant: CNc1ccc(-c2nc3ccc(OC)cc3o2)cc1
Reactant: CNc1ncc(Br)cn1
Product: CNc1ncc(-c2nc3ccc(OC)cc3o2)cn1

Procedure:
The title compound was synthesised according to the procedure described for 4-(6-methoxy-1,3-benzoxazol-2-yl)-N-methylaniline starting from 5-bromo-N-methylpyrimidin-2-amine. 1H NMR δ ppm 8.84-9.02 (m, 2H) 7.95 (d, 1H) 7.61 (d, 1H) 7.37 (d, 1H) 6.97 (dd, 1 H) 3.83 (s, 3H) 2.89 (d, 3H); ES-MS m/z 257 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13](Cl)(=[O:15])=[O:14])=[CH:5][CH:4]=1.[CH:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][NH:19][CH2:18]2.CCN(C(C)C)C(C)C>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13]([N:19]2[CH2:20][CH:21]3[CH2:24][CH2:25][CH:17]([CH2:23][CH2:22]3)[CH2:18]2)(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: C1CC2CCC1CNC2
Reactant: COc1ccc(S(=O)(=O)Cl)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CC3CCC(CC3)C2)c2ccccc12

Procedure:
The title compound was prepared by reacting 4-methoxy-1-naphthalenesulfonyl chloride (0.25 g) with 3-azabicyclo[3.2.2]nonane (0.12 g) in the presence of DIEA (0.16 g) using a procedure similar to that used in Example 5. Yield: 0.24 g, mp 167.7°-169.5° C. (soften 166.1° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:10]C(=O)[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Na+].C(=O)=O>>[NH2:8][C:5]1[C:4]([OH:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Br)cc1O
Temperature: 25 °C
Yield: 94.2 %

Procedure:
6-Bromo-3H-oxazolo[4,5-b]pyridin-2-one (21.5 g, 100 mmol) was suspended in NaOH solution (2N, 250 mL, 500 mmol). The mixture was refluxed overnight and a clear solution was obtained. After cooling to room temperature, the reaction solution was neutralized to pH ˜7. A lot of CO2 was released and also precipitate was observed. The product was filtered, washed with water, and dried under high vacuum to provide 2-amino-5-bromo-pyridin-3-ol as an off-white solid (17.8 g, 98% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:9])[S:5][C:6]=1[Cl:7].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)OC1>O1CCOCC1.O.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>[Cl:7][C:6]1[S:5][C:4]([C:8]([NH:10][C@@H:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:9])=[CH:3][C:2]=1[C:45]1[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1C(F)(F)F)NC(=O)c1cc(Br)c(Cl)s1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reaction time: 12 h
Yield: 25.9 %

Procedure:
To a solution of 1,1-dimethylethyl {(2S)-2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (750 mg, 1.38 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (762 mg, 5.52 mmol), tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol), and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (373 mg, 1.8 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h where additional tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (373 mg, 1.8 mmol) were added. After 12 h, the solution was poured onto H2O (100 mL) and extracted with DCM. The organics were dried (Na2SO4), concentrated under vacuum, and purified on silica gel (hexanes/EtOAc, 1:1) to give the title compound (194 mg, 26%) as a white solid: LC-MS (ES) m/z=544.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:25]=[CH:24][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:54][C@H:52]([OH:53])[CH2:51][O:50][C:47]3[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=3)=[CH:25][CH:24]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:22])[CH3:23]
Reactant: CC(C)NC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: CC(C)NC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 23.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-isopropyl-1-piperidinecarboxamide formate (0.35 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.364 g, 0.90 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.152 g, 0.214 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=3)=[CH:21][CH:22]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(-c2ccc(N)cc2)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2)nc1C
Yield: 79 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (50 mg, 0.29 mmol), thionyl chloride (3 mL), pyridine (5 mL) and ethyl 2-(4-aminophenyl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (94b) (113 mg, 0.43 mmol), to obtain 96 mg of the title compound as a pale yellow solid (80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][CH:14]([NH:41]C(=O)OCC1C=CC=CC=1)[C:15](=[O:40])[NH:16][CH:17]([C:26](=[O:39])[N:27]([CH2:31][CH:32](OCC)OCC)[CH:28]([CH3:30])[CH3:29])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:11])=[O:10].[CH:52]([OH:54])=[O:53]>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH:17]2[N:16]3[C:15](=[O:40])[CH:14]([NH:41][C:52](=[O:54])[O:53][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][N:12]([S:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])(=[O:11])=[O:10])[CH:32]3[CH2:31][N:27]([CH:28]([CH3:29])[CH3:30])[C:26]2=[O:39])=[CH:24][CH:23]=1
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1)C(C)C)OCC
Reactant: O=CO
Product: CC(C)N1CC2N(C(=O)C(NC(=O)OCc3ccccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reaction time: 5 h

Procedure:
A solution of 218 mg of benzyl (2-(2,4-dichlorobenzenesulfonylamino)-1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate in 3 ml of formic acid is stirred at room temperature for 12 h and then at 55° C. for 5 h. The reaction solution is concentrated under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The desired product is obtained with MW=692.10 (calculated monoisotopic); measured value (M+H)+: 693.05.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12]C=O)[CH2:4][CH2:3]1.[ClH:15]>C(O)C>[ClH:15].[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1
Reactant: O=CNC1CCC(=O)c2ccccc21
Agent: Cl
Solvent: CCO
Product: NC1CCC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 19.6 g of N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)formamide in 214 ml of 95% ethanol and 214 ml of 2N hydrochloric acid is heated at reflux for 3 hours and then stirred at room temperature for 2 days. The solution is filtered and the filtrate concentrated in vacuo to afford a dark residue. The residue is dried using ethanol to remove water in vacuo and this procedure affords 20.2 g of the title compound, melting point 200° C to 216° C (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:44][O:45][C:46](=[O:51])[CH2:47][C:48](Cl)=[O:49]>ClCCl>[CH3:44][O:45][C:46](=[O:51])[CH2:47][C:48]([NH:33][S:30]([C:28]1[CH:27]=[CH:26][C:18]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)=[N:16][C:17]=2[CH:29]=1)(=[O:32])=[O:31])=[O:49]
Reactant: NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reactant: COC(=O)CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Product: COC(=O)CC(=O)NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reaction time: 1 h
Yield: 7 %

Procedure:
A solution of intermediate 69 (0.046 g, 0.1 mmol) in dichloromethane (0.700 mL) was cooled to 0° C. Lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran) (0.10 ml, 0.10 mmol) was added and the mixture was stirred for 1 hr. Methyl-3-chloro-3-oxo-propionate (0.011 ml, 0.10 mmol was added. The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product (0.005 g, 7%). 1H NMR (CDCl3) δ 8.60 (s, 1H), 8.16 (d, 1H, J=8.8 Hz), 7.85 (d, 1H, J=8.8 Hz), 7.64 (d, 2H, J=8.8 Hz), 7.50-7.38 (m, 5H), 7.21 (d, 2H, J=8.8 Hz), 5.18 (s, 2H), 4.49 (m, 1H), 3.70 (s, 3H), 3.35 (s, 2H), 2.30 (br m, 2H), 2.02 (br m, 4H), 1.82 (br m, 1H), 1.35 (br m, 3H); ESI-MS m/e 562.18(M+1); HPLC purity (UV) 99%.