Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[Li]CCCC>C1COCC1>[Br:8][C:6]1[N:5]=[C:4]([CH3:9])[C:3]([OH:10])=[CH:2][CH:7]=1
Reactant: Cc1nc(Br)cc(Br)c1O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(Br)ccc1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
4,6-Dibromo-2-methylpyridin-3-ol (15.8 g, 59.4 mmol) was dissolved in THF (200 mL). The solution was cooled to −78° C. and n-BuLi (50 mL, 125 mmol, 2.5 M in hexane) was added dropwise keeping the temperature below −78° C. The reaction mixture was allowed to stir at that temperature for 2 hours. The reaction mixture was quenched with water (50 mL) and was neutralized with 2 N HCl. The aqueous mixture was extracted with dichloromethane (2 times). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give 6-bromo-2-methylpyridin-3-ol (10.5 g, 95%) as a yellow oil. 1H-NMR (300 MHz, DMSO) 2.29 (s, 3H), 7.08 (d, 1H), 7.26 (d, 1H), 10.08 (s, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].C1COCC1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:22]([NH:24][CH:25]1[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:35][C:36]#[N:37])[C:26]1=[O:38])=[O:23])=[CH:16]2>CO>[NH2:37]/[C:36](=[N:2]\[OH:3])/[CH2:35][N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH:25]([NH:24][C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([Cl:12])=[CH:21][CH:20]=3)=[O:23])[C:26]1=[O:38]
Reactant: N#CCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N/C(CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21)=N\O
Reaction time: 0.17 h
Yield: 43.8 %

Procedure:
A solution hydroxylamine hydrochloride (147 mg, 2.11 mmol) in MeOH (4 mL) was added to a solution of sodium methoxide in methanol (0.5 M, 4.2 mL, 2.1 mmol) that had been further diluted with methanol (4 mL). After stirring for 10 minutes, THF (4 mL) was added followed by portionwise addition of 5-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-1H-indole-2-carboxamide (Method 11, 400 mg, 1.06 mmol). The reaction mixture was stirred at ambient temperature for 18 h, partitioned between EtOAc (80 mL) and diluted brine (80 mL), filtered and the layers of the filtrate separated. The organic phase was dried (Na2SO4) and the volatiles removed under reduced pressure to give the title material (191 mg, 44%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:16])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)cc1
Yield: 94 %

Procedure:
To a solution of 2-(4-bromophenyl)acetic acid (10 g, 47 mmol) in methanol (100 mL) was dropwise thionyl chloride (0.2 mL) at room temperature. The mixture solution was heated to reflux for 3 hours. Then removed the solvent to dry to gave methyl 2-(4-bromophenyl)acetate as a colorless oil (10 g, 94%). 1H NMR (300 MHz, CDCl3): δ 7.45 (d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 3.70 (s, 3H), 3.58 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:10](=[O:19])[NH:9]2)[CH:5]=CN=1.[F:20]C1C=C(C=CC=1)CP(=O)(OCC)OCC.BrC1C=[N:39][CH:40]=C(C=1)C=O>>[Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[O:11][C:10](=[O:19])[NH:9]2)[CH:5]=[N:39][CH:40]=1
Reactant: CCOP(=O)(Cc1cccc(F)c1)OCC
Reactant: O=C1N[C@H](c2ccnc(Br)c2)[C@@H](c2ccccc2)O1
Reactant: O=Cc1cncc(Br)c1
Product: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cccc(F)c2)O1

Procedure:
Prepared according to the same procedure as (4R,5R)-4-(2-bromopyridin-4-yl)-5-phenyloxazolidin-2-one, starting with diethyl 3-fluorobenzylphosphonate and 5-bromonicotinaldehyde. 1H-NMR (CDCl3, 500 MHz) δ 8.72 (d, J=2.1, 1H), 8.41 (d, J=1.8, 1H), 7.94 (dd, J=2.1, 1.8, 1H), 7.42 (ddd, J=7.9, 7.9, 5.8, 1H), 7.14 (ddd, J=8.6, 8.6, 2.4, 1H), 7.01-7.10 (m, 2H), 6.78 (bs, 1H), 5.27 (d, J=7.3, 1H), 4.81 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 163.2 (d, J=249), 158.5, 152.0, 146.4, 138.5 (d, J=6.7), 136.7, 135.7, 131.1 (d, J=8.6), 121.6 (d, J=17), 116.8 (d, J=21), 113.0 (d, J=22), 84.8, 62.2. Mass spec.: 337.06 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21](O)=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)=[O:30])=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:16])([F:17])[F:18])[CH:7]=1
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Reactant: CC(C)NNC(=O)c1ccco1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccco1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 44 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (174 mg, 0.52 mmol) and furan-2-carboxylic acid N′-isopropyl-hydrazide (90 mg, 0.53 mmol) in DMF (5 ml) was treated with diisopropyl amine (0.235 ml, 1.32 mmol) and PyBroP (370 mg, 0.79 mmol) at room temperature overnight. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-80% ethyl acetate in hexanes gradient to afford the product as a white solid (110 mg, 44%). MS m/e 481.38 (M+H+)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:14][N:13]=[C:12]2[N:4]([C:5](=O)[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:3]1.[OH2:17].[NH2:18][NH2:19]>CCO>[NH2:13][CH2:14][C:2]([CH3:16])([CH3:1])[CH2:3][NH:4][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:17])[NH:19][N:18]=1
Reactant: CC1(C)CN=C2c3ccccc3C(=O)N2C1
Reactant: O
Reactant: NN
Solvent: CCO
Product: CC(C)(CN)CNc1n[nH]c(=O)c2ccccc12
Yield: 58 %

Procedure:
To 2,2-dimethyl-2,3-dihydro-1H-4,9a-diaza-fluoren-9-one (1.5 g, 7.0 mmol) in EtOH (17.5 mL), hydrazine hydrate (0.98 mL) was added and the mixture was heated at reflux for 3½ h. Crystallization provided 0.994 g (58%) of 4-(3-amino-2,2-dimethyl-propylamino)-2H-phthalazin-1-one.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=[O:10])([CH3:3])[CH3:2].S(=O)(=O)([OH:16])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[C:9]([OH:16])=[O:10])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C(C)C)cc1C=O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Isopropyl-2-methoxybenzaldehyde (2.8 g, 15.7 mmol) was dissolved in acetone (40 mL). To this solution was added sulfamic acid (2.29 g, 23.57 mmol) and sodium chlorite (1.71 g, 18.85 mmol) in water (40 mL). The mixture was stirred at rt in an open flask for 12 hrs. The acetone was removed and the mixture was extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated to afford the title compound. MS (DCI/NH4+) m/z 212 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH:13]=[CH2:14])[CH:12]=1)[C:9](=[O:15])[CH2:8][CH2:7][C:6]2([CH3:17])[CH3:16].[N+](=[CH2:20])=[N-].C(OCC)(=O)C>C(OCC)C.CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:13]1([C:11]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[C:10]=2[C:9](=[O:15])[CH2:8][CH2:7][C:6]3([CH3:17])[CH3:16])[CH2:20][CH2:14]1
Reactant: C=[N+]=[N-]
Reactant: C=Cc1cc(OC)cc2c1C(=O)CCC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C2CC2)c2c(c1)C(C)(C)CCC2=O
Temperature: -25 °C
Yield: 83 %

Procedure:
A stirred, cooled (−40° C.) solution of 6-methoxy-4,4-dimethyl-8-vinyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 155, 51.7 g, 7.4 mmol) in diethyl ether (10 mL) was treated with a solution of diazomethane in ether (40 mmol in 50 mL of ether) followed by palladium(II)acetate (0.08 g) and the resulting reaction mixture was warmed to −25° C. when effervescence was observed. The reaction mixture was then filtered through a plug of silica and the filtrate was evaporated to afford a dark brown residue that was subjected to flash column chromatography over silica gel (23-400 mesh) using 20% ethyl acetate in hexane as the eluent to afford the title product as a pale yellow solid (1.5 g, 83%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:7])=[O:18])=[CH:15][N:14]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cl)c1ccc(Cl)nc1

Procedure:
75 Ml. of phosphorous oxychloride and 144 g. of phosphorous pentachloride were added to 100 g. of 6-chloronicotinic acid and intimately mixed. The reaction mixture was slowly heated in an oil bath to 80° over 25 minutes with stirring. The bath temperature was raised to 125° and the solution was stirred and refluxed for 1 hour. After concentration under reduced pressure, anhydrous toluene was added and the solution was concentrated again, finally on the oil pump, to yield 6-chloronicotinoyl chloride as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:26]3[CH2:27][CH2:28][CH2:29][CH:25]3[CH3:24])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC1CCCN1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC1CCCN1c1cc(NC(=O)c2ccc(C(C)(C)O)cc2)nc2ccnn12
Temperature: 25 °C
Yield: 29.7 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol) and 2-methylpyrrolidine (26 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 25-50% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a orange solid (34 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.06 Hz, 3 H) 1.45 (s, 6 H) 1.71-1.81 (m, 1 H) 1.90-2.01 (m, 1 H) 2.03-2.26 (m, 2 H) 3.75-3.91 (m, 1 H) 3.96-4.12 (m, 1 H) 4.96 (br. s., 1 H) 6.27 (d, J=2.27 Hz, 1 H) 6.98 (s, 1 H) 7.61 (d, J=8.34 Hz, 2 H) 7.91-8.09 (m, 3 H) 10.81 (s, 1 H). ESI-MS: m/z 380.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23](O)=[O:24])=[N:11][CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=[O:50].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:26][O:50][C:49](=[O:51])[C:48]([NH:47][C:23]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][N:11]=1)=[O:24])([CH3:53])[CH3:52]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(N)C(=O)O
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (1.0 g, 2.99 mmol) in DMF (20 mL) at room temperature under N2 is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.925 g, 5.97 mmol) and 1-hydroxybenzotriazole (HOBt) (0.806 g, 5.97 mmol). The mixture is stirred for 15 minutes after which α-aminoisobutyric acid (0.917 g, 5.97 mmol) and diisopropylethyl-amine (DIPEA) (1.56 mL, 8.96 mmol) are added. The resulting solution is stirred at room temperature for 16 hours then concentrated under reduced pressure. The resulting brown oil is purified over silica (EtOAc:heptane 1:1) to afford 0.58 g (45% yield) of the desired compound as a colorless solid. 1H NMR (250 MHz, CDCl3) δ ppm 8.13 (1 H, s), 8.02 (1 H, d, J=2.3 Hz), 7.31-7.48 (10 H, m), 6.90 (1 H, d, J=2.3 Hz), 5.19 (2 H, s), 5.10 (2 H, s), 3.74 (3 H, s), 1.58 (6 H, s). HPLC-MS: m/z 435 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1(/[CH:9]=[CH:10]/[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][CH:15]=2)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[CH3:36][O:35][C:33]([CH2:32][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])/[CH:22]=[CH:23]/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:15]=1)=[O:34]
Reactant: COC(=O)CBr
Reactant: O=C(/C=C/c1ccccc1)Nc1ccc(OC(=O)/C=C/c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CN(C(=O)/C=C/c1ccccc1)c1ccc(OC(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.4 %

Procedure:
Sodium hydride (60%, 162 mg, 4.06 mmol) was washed with anhydrous THF (×2) and then suspended in anhydrous THF (20 mL). To this was added (E)-3-phenylacrylic acid 4-[(E)-(3-phenylacryloyl)amino]phenyl ester 11 (1.00 g, 2.71 mmol) followed by methyl bromoacetate (0.51 mL, 5.41 mmol). The reaction mixture was stirred at room temperature for 3 days. It was then diluted with ethyl acetate and washed with brine (×3), dried (Na2SO4) and evaporated. The resultant residue was purified by flash column chromatography on silica gel, eluting with petrol/ethyl acetate (2:1→1:1) and then ethyl acetate, to afford the title compound (0.734 g, 61%). 1HNMR (300 MHz) (CDCl3) δ 3.77 (3H, s), 4.52 (2H, s), 6.43 (1H, d, J=16 Hz), 6.65 (1H, d, J=16 Hz), 7.25-7.40 (7H, m), 7.45 (4H, m), 7.61 (3H, m), 7.75 (1H, d, J=16 Hz) and 7.91 (1H, d, J=16 Hz).
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](Cl)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].O>CC(N(C)C)=O>[C:1]([NH:10][NH:11][C:12](=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: NNC(=O)c1ccccc1O
Reactant: O=C(Cl)c1ccccc1O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(NNC(=O)c1ccccc1O)c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30.4 g of salicylic acid hydrazide are dissolved in 500 ml of dimethylacetamide and 34.8 g of salicylic acid chloride are added dropwise over the course of 70 minutes at 25° - 40° C. The yellow solution is stirred for 3 hours at room temperature and is then poured into 1 liter of water, whereupon white, fine crystals precipitate. The substance is filtered off, washed with water and dried in vacuo at 60° C. The product is purified by recrystallisation from ethylene gylcol monomethyl ether. The N,N'-bis-salicyloyl-hydrazine thus obtained (stabiliser No. 1), melts at 303° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]([OH:39])=O)=[O:34])([CH3:31])([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[C:28]([O:32][C:33](=[O:34])[NH:35][CH2:36][C:37](=[O:39])[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)CNC(=O)OC(C)(C)C)c1ccncc1
Reaction time: 1 h

Procedure:
A solution of 1.1 eq. of 4-(methylamino)pyridine (180, Aldrich, 19,551-0) in anhydrous DMF was stirred under an atmosphere of argon as 1.1 eq. of HOBT and 2.0 eq of DIPEA were added followed by 1.0 eq of N-(tert-butoxycarbonyl)glycine (Bachem, A-1730). The mixture was stirred for 1 hr, cooled in an ice-bath and 1.1 eq. of EDC.HCl was added. The reaction was stirred and allowed to reach rt overnight. Water was added to the reaction mixture and the solvents were evaporated under high vacuum. The residue was dissolved in ethyl acetate, washed with 0.15 M citric acid, sat. aq. NaHCO3, brine and dried over anhydrous Na2SO4. To afford 181.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1.[C:24]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)(=[O:26])[CH3:25].[OH-].[Na+]>ClC(Cl)C.C(OCC)(=O)C.C(O)(=O)C>[C:24]([N:27]1[CH2:32][CH2:31][CH:30]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]
Reactant: COc1cccc(N)c1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COc1cccc(NC2CCN(C(C)=O)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Under ice cooling, sodium triacetoxyborohydride (12.0 g) was added to a liquid mixture of m-anisidine (4.40 g), 1-acetylpiperidin-4-one (5.0 g) and acetic acid (8 ml) in dichloroethane (80 ml). Then the reaction mixtures were stirred at room temperature overnight. The reaction mixtures were diluted with ethyl acetate (200 ml) and a 5 N aqueous solution (35 ml) of sodium hydroxide was added thereto. The organic layer was separated, washed successively with water and brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound (7.80 g) as a brown oil (yield: 87.9%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH:19]=[O:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[CH3:21][Mg]Cl>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([C:3]1([CH2:18][CH:19]([OH:20])[CH3:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC=O)OCC3
Reactant: C[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(C)O)OCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of compound 8 (275 mg, 1.01 mmol) in dry THF (4 mL) was added dropwise over five minutes to a stirred solution of 1M MeMgCl in THF (1.52 mL, 1.52 mmol, 1.5 eq) at 0° C. under argon and allowed to warm slowly to room temperature. After stirring for two hours, another equivalent of 3M MeMgCl in THF (337 μL, 1.01 mmol, 1.0 eq) was added, and the mixture was stirred for an additional hour. The mixture was then diluted with saturated NaHCO3 and extracted three times with EtOAc. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 20:80:EtOAc:Hexane to give a yellow solid (280 mg, 96%): mp 103-104° C. 1HNMR (CDCl3, δ TMS) shows a 2:1 mixture of diastereomers. MS−: m/z 322 (MCl−), 286 ([M−H]−). Anal. (C18H25NO2): C, H, N. The product was carried on to the next step as a mixture of diastereomers.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([OH:53])=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH:54]([C:56](=[O:70])[CH2:57][CH:58]1[CH2:61][CH:60]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[CH2:59]1)[NH2:55]>CN(C=O)C>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:55][NH:54][C:56](=[O:70])[CH2:57][CH:58]1[CH2:61][CH:60]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:66])([CH3:67])[CH3:68])[CH2:59]1)=[O:53])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CC(CC(=O)NN)C1
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)NC1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
HATU (1.6 g, 4.3 mmol) and DIPEA (0.93 g, 7.2 mmol) were added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.0 g, 3.6 mmol), tert-butyl 3-(2-hydrazinyl-2-oxoethyl)cyclobutylcarbamate (0.97 g, 3.9 mmol) in DMF (10 mL) at. The reaction mixture was stirred at 0° C. for 1 hr. The mixture was quenched with saturated sodium chloride (50 mL) and the organic layer was separated. The water layer was exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (50% EtOAc/petroleum ether) to afford tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclobutylcarbamate (1.5 g, 88%). ESI-MS (EI+, m/z): 502 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]([NH2:40])([CH2:38][CH3:39])C.CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:40][CH2:36][CH2:38][CH3:39])=[O:34])=[C:18]([CH3:23])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: CCC(C)N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methyl-aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (48 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propylamine (20 1l) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 30 mg (yield 47%) of the title compound.