Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1.CN1CCCC1=O.[OH-].[Na+]>ClCCl>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][C:12]([NH:11][C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=2)=[CH:13][CH:14]=1)[CH3:20]
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (21.3 g; 79.5 mmol), ethyl 4-aminobenzoate (13.1 g; 79.5 mmol), and 1-methyl-2-pyrrolidinone (10 mL) was heated at 130 degrees for 1 hr. The mixture was cooled to room temperature, diluted with dichloromethane and filtered to give a dull brown solid. This was slurried with 0.5N NaOH, filtered, washed with water and diethyl ether to give 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acid ethyl ester (1) as a light brown solid (21.3 g)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]2[O:14][C:15](=[O:24])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:10]2[CH2:9]1.[NH2:25][C:26]1[C:27]([C:45](O)=[O:46])=[N:28][C:29]([C:32]2[CH:37]=[C:36]([C:38](=[O:43])[NH:39][CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:34][C:33]=2[F:44])=[CH:30][CH:31]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH2:25][C:26]1[C:27]([C:45]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]3[O:14][C:15](=[O:24])[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@@H:10]3[CH2:9]2)=[O:46])=[N:28][C:29]([C:32]2[CH:37]=[C:36]([C:38](=[O:43])[NH:39][CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:34][C:33]=2[F:44])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3N)C[C@H]21
Reactant: CC(C)NC(=O)c1ccc(F)c(-c2ccc(N)c(C(=O)O)n2)c1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)NC(=O)c1ccc(F)c(-c2ccc(N)c(C(=O)Nc3cnccc3N3CC[C@@H]4OC(=O)N(C(=O)OC(C)(C)C)[C@@H]4C3)n2)c1
Reaction time: 15 h

Procedure:
To a solution of (3aR,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate (1.0 equiv.) in DMF (0.3 M) was added 3-amino-6-(2-fluoro-5-(isopropylcarbamoyl)phenyl)picolinic acid (1.2 equiv.), EDC (1.2 equiv.) and HOAt (1.2 equiv.). The solution was stirred for 15 h. To the mixture was added water and the precipitate was filtered. To the filtrate was added EtOAc, and the organic solution was extracted (3 times), dried with Na2SO4, and concentrated to give an orange syrup. The crude was triturated with EtOAc and hexanes mixture and the precipitate was filtered off to give (3aR,7aS)-tert-butyl 5-(3-(3-amino-6-(2-fluoro-5-(isopropylcarbamoyl)phenyl)picolinamido)pyridin-4-yl)-2-oxohexahydro-oxazolo[4,5-c]pyridine-3(2H)-carboxylate. LCMS (m/z): 634.3.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(OCC)(=O)C.O>CO>[OH:3][CH:1]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(C)O)nn1
Temperature: -70 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of methyl 6-acetylpyridazine-3-carboxylate (0.8 g, 4.4 mmol) in methanol (30 mL) was added sodium borohydride (340 mg, 8.8 mmol) at −70° C. under nitrogen gas protected. The mixture solution was stirred for 3 hours at −70° C., then poured into ethyl acetate (50 mL) and water (50 mL). Separated organic layer was dried over sodium sulfate and concentrated to dry. The residue was purified by column chromatography (silica-gel, petroleum/ethyl acetate=5:) to give methyl 6-(1-hydroxyethyl)pyridazine-3-carboxylate as a white solid (200 mg, 25%). 1H NMR (300 MHz, CDCl3): δ 8.22 (d, J=9 Hz, 1H), 7.93 (d, J=9 Hz, 1H), 5.07 (m, 1H), 3.96 (s, 3H), 1.46 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]([NH:18][NH:19][CH3:20])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].N[C@H:28]([C:40]([OH:42])=[O:41])CC1C=C2C(C=CC=C2)=CC=1.[C:43]1([CH3:49])[CH:48]=CC=C[CH:44]=1>>[C:43]([O:42][C:40](=[O:41])[CH2:28][N:18]([C:1]([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[NH:19][CH3:20])([CH3:49])([CH3:48])[CH3:44]
Reactant: Cc1ccccc1
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CNNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNN(CC(=O)OC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 70 %

Procedure:
1 L, two-necked, round-bottom-flask was fitted with a glass stopper and reflux condenser connected to a calcium tube. A solution of N-Fmoc-N′-methyl hydrazine (20 g, 75 mmol) in toluene (300 mL) was added. A solution of t-butylbromo acetate (22 g, 111 mmol) in toluene (50 mL) was added slowly. Cs2CO3 (49 g, 149 mmol) was added slowly. Nal (11 g, 74 mmol) was added slowly with vigorous stirring. The reaction mixture was stirred at reflux temperature over 1 day. The product mixture was filtered and extracted with EA (500 mL). The solution was dried over sodium sulfate and evaporated in vacuo. The product was purified by chromatography with hexane:EA=2:1 solution to give (N-Fmoc-N′-methyl-hydrazino)-acetic acid t-butyl ester (19.8 g, 70%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[ClH:17].[NH4+:18].[Cl-]>C(Cl)Cl.CO>[ClH:17].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:18])=[NH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCCOCc1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: N=C(N)CCCOCc1ccccc1
Reaction time: 144 h

Procedure:
A solution of 4-benzyloxybutyronitrile (16.5 g.) and EtOH (8.6 g.) in CH2Cl2 (100 ml.) was saturated with HCl gas at 0° and the mixture kept at 0° for 6 days. The resulting suspension was evaporated to dryness in vacuo and the residue was slurried with dry ether. The insoluble solid was added to 40% aqueous K2CO3 (120 g.) at 0° and the oil which separated was extracted with CH2Cl2 (2×100 ml.). The CH2Cl2 layer was washed with a little water, brine and then dried to give the crude imidate (14 g.). This was stirred with NH4Cl (3.5 g.) in MeOH (100 ml.) for 24 hours and the solution was evaporated to give a crude sample (14.6 g.) of 4-benzyloxybutanamidine hydrochloride.
Reaction SMILES: C[Mg]Cl.[C:4]([O:8][C:9](=[O:24])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]1)([CH3:7])([CH3:6])[CH3:5].[CH2:25]([SiH](CC)CC)C.FC(F)(F)C(O)=O>O1CCCC1>[C:4]([O:8][C:9](=[O:24])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:25])=[CH:18]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC[SiH](CC)CC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1n1ccc(C=O)c1
Agent: C[Mg]Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1ccn([C@@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c1
Reaction time: 3 h
Yield: 27.2 %

Procedure:
Methylmagnesium chloride solution (3 M in tetrahydrofuran, 0.23 ml, 0.68 mmol) was added at −78° C. to a solution of trans-[2-(3-formyl-pyrrol-1-yl)-cyclohexyl]-carbamic acid tert-butyl ester (example 26a, 100 mg, 0.34 mmol) in tetrahydrofuran (2 ml), then after 3.5 h the reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4), and evaporated. This crude material (103 mg) was dissolved in dichloromethane (2 ml) and treated with triethylsilane (58 mg, 0.50 mmol) and trifluoroacetic acid (190 mg, 1.67 mmol). The reaction mixture was allowed to reach 0° C. over 3 h, then evaporated and the residue chromatographed (SiO2, heptane-ethyl acetate gradient) to afford the title compound (27 mg, 28%). Yellow solid, MS (ISP) 293.2 (M+H)+.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[CH:11]=[C:12]([C:15]([OH:17])=O)[O:13][CH:14]=2)=[N:3][CH:2]=1.C1CN([P+](ON2N=[N:42][C:37]3[CH:38]=[CH:39][CH:40]=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[F:58][C:59]([F:68])([F:67])[CH2:60]NCCC1CC1>CN(C=O)C>[CH:38]1([CH2:37][N:42]([CH2:60][C:59]([F:68])([F:67])[F:58])[C:15]([C:12]2[O:13][CH:14]=[C:10]([C:4]3[C:5]4[CH:9]=[CH:8][NH:7][C:6]=4[N:1]=[CH:2][N:3]=3)[CH:11]=2)=[O:17])[CH2:39][CH2:40]1
Reactant: FC(F)(F)CNCCC1CC1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)c1cc(-c2ncnc3[nH]ccc23)co1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1cc(-c2ncnc3[nH]ccc23)co1)N(CC1CC1)CC(F)(F)F
Yield: 7.2 %

Procedure:
35 mg [0.153 mMols] of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carboxylic acid was dissolved in 1.5 mL of DMF and stirred with 120 mg [0.22 mMols] of PyBOP, 50 μL [46 mg, 0.46 mMols] of N-methylmorpholine, and 50 mg [0.26 mMols] of N-(2,2,2-trifluoroethyl) N-2-cyclopropylethylamine overnight at ambient temperature. The solvent was removed under a nitrogen stream at 30° C. and residue dissolved in methanol with several drops of TFA to protonate the amines present. The crude material was purified via C18 silica utilizing a gradient of water/acetonitrile/TFA as an eluent 5%-95%. The product, 4 mg of a beige powder (after lyophilization of filtrates) was obtained; yield 9.5%.
Reaction SMILES: [CH:1]([C:3]([C:5]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:6]=1[O:13]C)=[O:4])=[CH2:2]>C(#N)C.O>[C:3]([C:5]1[C:6](=[O:13])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)(=[O:4])[CH:1]=[CH2:2]
Reactant: C=CC(=O)c1cc(OC)ccc1OC
Solvent: O
Solvent: CC#N
Product: C=CC(=O)C1=CC(=O)C=CC1=O

Procedure:
To a stirred solution of 2,5-dimethoxyphenyl vinyl ketone (2.5 g, 0.013 mole) in 25 ml of acetonitrile at 0° C. was added dropwise over 3 minutes an aqueous solution of (NH4)2Ce(NO2)6 (17.9 g, 0.033 mole) in 30 ml of water. After the addition, the dark brown mixture turned to yellowish-brown within 5 minutes. At that point, the mixture was poured into water and extracted with methylene chloride. The methylene chloride portion was washed twice with water and then with brine. After drying (MgSO4), the solvent was removed to give a brown oil, which was purified by column chromatography on silica gel, using diethyl ether/hexane (1/1) as eluant. The product was obtained as a reddish/orange, semi-solid residue; 0.8 g; IR (neat) 1670 cm-1 ; NMR (CDCl3) δ5.95 (d, 1H); 6.5-7.2 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[H][H]>CO.[Pd].C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=CCCc1ccccc1)CCCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(CCCc1ccccc1)CCCc1ccccc1
Yield: 98 %

Procedure:
A solution of ethyl-2-(3-phenylpropyl)-5-phenyl-2-pentenoate in methanol (10 mL) was added to a suspension of 10% palladium on carbon (0.112 g) in methylene chloride (10 mL) and the mixture was hydrogenated under 60 psi of hydrogen for 6 h. The catalyst was removed by filtration through a pad of celite and the solvent was removed under reduced pressure to give ethyl-2-(3-phenylpropyl)-5-phenyl-pentanoate (0.787 g, 98%). The crude product was not purified further but used directly in the next step. 1H NMR (300 MHz, CDCl3): δ 1.25 (t, 3 H, J=7.1), 1.60 (m, 8 H), 2.39 (m, 1 H), 2.61 (t, 4 H, J=7.3), 4.14 (q, 2 H, J=7.1), 7.24 (m, 10 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C1N=CN(C(N2C=NC=C2)=O)C=1>CCN(CC)CC>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:15]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CCc1ccc(O)cc1

Procedure:
3-(4-Hydroxyphenyl)propionic acid (2.49 g, 15 mmol) was reacted with glycine ethyl ester hydrochloride in the presence of CDI and Et3N as described in Example 21 Part A. After removal of the solvent the residue was dissolved in CHCl3 and washed with 1N HCl, saturated NaHCO3 solution and saturated NaCl solution. After drying (MgSO4) and removal of the solvent in vacuo crude title ester remained (2.44 g) as a viscous oil. NMR indicated this contained a major impurity but it was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]3[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]3)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:31]([O:30][C@@H:3]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]3[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]3)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:10][CH:11]=1)[CH2:2][Cl:1])(=[O:33])[CH3:32]
Reactant: CC1(C)OC[C@H](COc2ccc(C(C)(C)c3ccc(OC[C@H](O)CCl)cc3)cc2)O1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H](CCl)COc1ccc(C(C)(C)c2ccc(OC[C@H]3COC(C)(C)O3)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of (S)-1-chloro-3-(4-(2-(4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (850 mg, 1.95 mmol) in anhydrous pyridine (6.0 mL) were successively added acetic anhydride (280 μL, 2.93 mmol) and catalytic amount of DMAP. After 3 h, the reaction mixture was quenched with an aqueous solution of sodium chloride and stirred for 15 min, and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and filtered. Solvents were evaporated, and the resulting crude material was used without further purification.
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:11])([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:19](Cl)(=[O:29])[C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22](Cl)=[O:23].C1(=O)NC(=O)C2=CC=CC1=C2>ClCCl>[F:1][CH2:2][C:3]([N:11]1[C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[C:19]1=[O:29])([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: C=CCC(N)(CF)C(=O)OC
Agent: O=C1NC(=O)c2cccc1c2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(CF)(C(=O)OC)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of methyl 2-fluoromethyl-2-amino-4-pentenoate (2.10 g, 13 mmol) and triethylamine (3 g) in dry dichloromethane, phthaloyl dichloride (2.37 g, 11.7 mmol) is added with ice cooling. After stirring overnight, at room temperature, the solution is washed with water and 1 N HCl. Drying and removal of solvent by evaporation gives a residue, consisting mainly of the iso-phthalimide. The residue is dissolved in dry dichloromethane, two equivalents of triethylamine are added, and the mixture is refluxed overnight. Work-up as described above gives the title compound as an oil (3.0 g).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:19][N:10]2[C:11]3[CH:12]=[CH:13][C:14]([Br:18])=[CH:15][C:16]=3[CH:17]=[C:9]2[C@H:8]1[N:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:21])(=O)=O.[N-]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:54](CC)CC)C.[C:59]([O:63][C:64]([O:66]C(OC(C)(C)C)=O)=O)([CH3:62])([CH3:61])[CH3:60]>CN(C=O)C.O>[CH2:22]([N:20]([CH3:21])[C@@H:8]1[C:9]2=[CH:17][C:16]3[CH:15]=[C:14]([Br:18])[CH:13]=[CH:12][C:11]=3[N:10]2[CH2:19][C@@H:7]1[CH2:6][NH:54][C:64](=[O:66])[O:63][C:59]([CH3:62])([CH3:61])[CH3:60])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN(Cc1ccccc1)[C@@H]1c2cc3cc(Br)ccc3n2C[C@@H]1COS(C)(=O)=O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)[C@@H]1c2cc3cc(Br)ccc3n2C[C@@H]1CNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
The crude material from Step 3 was dissolved in DMF (5 mL) and treated with NaN3 (234 mg, 3.6 mmol). The mixture was heated at 80° C. for 2 h. To the mixture was added H2O (1 mL) and triphenylphosphine (524 mg, 2 mmol). The mixture stirred at 80° C. for 1 h. After cooling the mixture to room temperature, triethylamine (0.5 mL, 3.6 mmol) and di-tert-butyldicarbonate (436 mg, 2.0 mmol) were added sequentially. The mixture was stirred at room temperature for 1 h. The mixture was concentrated and chromatographed on silica gel (0-8% MeOH in CH2Cl2) to afford the product (300 mg, 35%).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH:5]([OH:7])[CH3:6].Cl.[NH2:27][OH:28].C[O-].[Na+].Cl>CO.C(Cl)Cl.CCOC(C)=O>[OH:7][CH:5]([CH3:6])[CH:4]([NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[C:3](=[O:2])[NH:27][OH:28]
Reactant: NO
Reactant: COC(=O)C(NC(=O)c1ccc(C#Cc2ccccc2)cc1)C(C)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)C(NC(=O)c1ccc(C#Cc2ccccc2)cc1)C(=O)NO
Reaction time: 2 h
Yield: 54.9 %

Procedure:
A solution of tolanoic-Thr methyl ester (4) (2.34 g, 7.0 mmol) in MeOH (20 ml) and DCM (30 ml) was added to a cooled (−10° C. bath) suspension of hydroxylamine HCl salt (4.81 g, 70.0 mmol) and NaOMe (4.16 g, 77.0 mmol) in MeOH (30 ml). Follow reaction by LCMS. After stirring for 2 hours, the reaction seems to stall at 50% completion. Add an additional 1 equivalent of NaOMe (0.416 g). After 3 hours, the reaction was 75% complete. Add an additional 0.5 equivalent of NaOMe (0.21 g). After 4 hours, the reaction was 90% complete. Add an additional 0.15 equivalent of NaOMe (0.064 g) for a total of 12.65 equivalents of NaOMe. The pH of the reaction was between 11-12 and had reacted about 95% completion. The reaction was diluted with EtOAc (500 ml) and washed with sat aq. NaHCO3 (2×60 ml), 50% diluted brine (60 ml), sat brine (60 ml), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in minimal DMA. The product was purified by prep. HPLC using a reverse phase Ultro 120 C18 column running a 2% gradient (AcCN/water, 0.1% TFA). The purified fractions were lyophilized to dryness. The product as the TFA salt was dissolved in AcCN/water (50:50) (80 ml), 1N aq. HCl (13 equivalent) and lyophilized again to give 1.3 g of white powder in 55% yield and >97% purity.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:38])[C:11]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5([NH:31]S(C(C)(C)C)=O)[CH2:30][O:29][CH2:28]5)=[CH:23][CH:22]=4)=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:13][C:14]=3[C:5]2=[N:4][N:3]1COCC[Si](C)(C)C.Cl.O1CCOCC1>CO>[NH2:31][C:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:11]3[C:10](=[O:38])[C:9]4[CH:8]=[CH:7][N:6]5[C:2](=[O:1])[NH:3][N:4]=[C:5]5[C:14]=4[O:13][C:12]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=2)[CH2:30][O:29][CH2:28]1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)n(COCC[Si](C)(C)C)nc45)c3=O)cc2)COC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)[nH]nc45)c3=O)cc2)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a stirred solution of 2-methyl-propane-2-sulfinic acid (3-{-4-[3,6-dioxo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl]-phenyl}-oxetan-3-yl)-amide (46 mg, 0.07 mmol) in MeOH (6 mL) was added a solution of HCl in dioxane (4 M, 0.14 mL, 0.56 mmol) at RT. After 1 h, the reaction mixture was evaporated to dryness. The residue was suspended in DCM (5 mL), cooled in an ice bath, and TFA (1 mL) was added. The mixture was stirred at RT for 1 h before evaporating to dryness. The residue was dissolved in MeOH and loaded on to a 2 g SCX-2 cartridge. The cartridge was washed with MeOH before eluting with 2 M NH3 in MeOH solution. The eluent was collected and evaporated. The resulting residue was subjected to flash chromatography (SiO2, gradient 10 to 30% 2 M NH3/MeOH in DCM) to afford the title compound (15 mg, 52%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.81 (d, J=7.2 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.44-7.36 (m, 5H), 7.22 (d, J=8.2 Hz, 2H), 6.97 (d, J=7.2 Hz, 1H), 4.70 (d, J=6.1 Hz, 2H), 4.66 (d, J=6.1 Hz, 2H). LCMS (Method E): RT=2.35 min, [M+H]+=427.
Reaction SMILES: Cl[C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.Cl.[NH2:20][OH:21].[H-].[Na+].O>N1C=CC=CC=1.CN(C=O)C>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:2]=2[O:21][N:20]=1
Reactant: NO
Reactant: COc1ccc(C(=O)c2ccccc2F)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc2c(-c3ccccc3F)noc2c1
Temperature: 60 °C

Procedure:
2-chloro-2'-fluoro-4-methoxybenzophenone (15.5 g) is refluxed for three hours in 150 ml of pyridine containing 10.0 g of hydroxylamine hydrochloride. The pyridine is removed in vacuo and the residue is distributed between ether and 5% HCl. Drying and evaporation of the organic phase gives an isomeric mixture of oximes. The mixture is dissolved in 50 ml of DMF and is added to a suspension of 1.5 g NaH in 30 ml of DMF. After warming at 60° C. for 30 minutes the reaction mixture is poured into H2O and extracted with ether. Concentration under reduced pressure gives a solid. Recrystallization from ether gives 3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 101°-103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(N)cc(C(=O)O)c1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Nc1cc(NCc2ccccc2)cc(C(=O)O)c1

Procedure:
15.2 g. (0.1 mol) of 3,5-diaminobenzoic acid was placed in a 500 ml. round bottom flask to which 200 ml of methanol was added. To the round bottom flask 10.3 g. (0.1 mol) of benzaldehyde was added. The solution was stirred for several minutes. While the solution stirred 3.77 g. (0.06 mol) sodium cyanoborohydride was added slowly. After 5 hours the solution was filtered and then concentrated to dryness. The reaction mixture was dissolved in 200 ml. of 2M hydrochloric acid. The acid solution was extracted twice with 200 ml. ethyl acetate. The ethyl acetate solutions were combined and back washed with 200 ml. distilled water, and then dried over sodium sulfate. The solution was concentrated to dryness and 4.58 gm. of product was collected. The product was then purified by column chromatography using a solution of tetrahydrofuran/ethanol/water/ammonium hydroxide in the following ratio--10:3:1:0.04 as the eluent. Structural verification was obtained by carbon magnetic resonance, proton magnetic resonance and infra-red analysis.