Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.C(N(CC)CC)C.[C:39]([O:42][CH2:43][C:44](Cl)=[O:45])(=[O:41])[CH3:40]>O1CCCC1>[C:39]([O:42][CH2:43][C:44]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:12]=3)=[N:6][N:5]2[CH:31]=1)=[O:45])(=[O:41])[CH3:40]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)ccc2n1
Yield: 73.6 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.487 mmol), triethylamine (101 μL, 0.730 mmol), 2-chloro-2-oxoethyl acetate (63 μL, 0.584 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 385, the title compound (183 mg, 74%) was obtained as a gray powder.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[C:13]([C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:23]1[O:25][CH2:24]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:24][CH:23]([OH:25])[CH2:22][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]([C:17]([CH3:20])([CH3:21])[CH2:18][CH3:19])=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1O
Reactant: c1ccc(OCC2CO2)cc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1OCC(O)COc1ccccc1
Temperature: 135 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of 10 g (35 mmol) of 2,4-dihydroxy-5-(1,1-dimethylpropyl)benzophenone, 5.8 g (38 mmol) of phenyl glycidyl ether, 1.3 g (3.5 mmol) of ethyltriphenylphosphonium bromide in 30 ml of xylene is stirred at 135° C. for 3 h. The reaction mixture is cooled and then filtered over Prolith rapid bleaching earth. The residue which remains after concentrating by evaporation is distilled in a bulb tube (250° C./0.1 mbar). 10.5 g (69%) of the compound are obtained as a viscous yellow liquid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:7]=[CH:6]2)[CH3:2].[F-].[NH4+]>C1COCC1.CO>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The Indole 9 (2.2 g, 7.29 mmol) was dissolved in THF (20 mL) and a solution of ammonium fluoride (NH4F; 1.4 g, 37.8 mmol) in MeOH (20 mL) was added and stirred for 72 hours at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 2N H3PO4, dried over MgSO4, filtered and evaporated to give compound 10 as an off white solid (1.06 g; M+1=146.2).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4](=[O:8])[CH2:5][C:6]#[N:7].[OH-].[Na+].Cl.[NH2:14]O.Cl>C(O)C.O>[NH2:7][C:6]1[CH:5]=[C:4]([C:3]([CH3:10])([CH3:9])[CH2:2][OH:1])[O:8][N:14]=1
Reactant: NO
Reactant: CC(C)(CO)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CO)c1cc(N)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
A mixture of 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile from Step B (1 g, 7.09 mmol), sodium hydroxide (378 mg, 9.45 mmol), and hydroxylamine hydrochloride (656 mg, 9.43 mmol) in a mixture of ethanol (100 mL) and water (100 mL), was heated at 60° C. for 22 h. After cooling to rt, concentrated HCl (1 g) was added and stirred at 50° C. for 2 h followed by 80° C. for a further 1 h. After concentration under reduced pressure, the mixture was treated with 30% sodium hydroxide solution and extracted with chloroform (3×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4, and filtered. Concentrated under reduced pressure, followed by purification via recrystallisation from diethyl ether, afforded 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol as a colorless solid (600 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 5.64 (s, 1H), 3.65 (s, 2H), 2.30 (brs, 2H), 1.31 (s, 6H); LC-MS (ESI) m/z 156 (M+H)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc(Cl)cc1

Procedure:
Reaction of 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (4-chloro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=432.9 (M+H)+
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][CH:37]=1>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35]([C:36]3[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=3)=[O:43])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C)nc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (90 mg, 0.2 mmol) in 2.0 mL of THF under nitrogen atmosphere at −78° C. was added drop-wise 0.3 mL (0.6 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 10 min at −78° C. followed by warming to room temperature and stirred at that temperature for 30 min. The mixture was cooled to 0° C. (ice water) and a solution of N-methoxy-6, N-dimethyl-nicotinamide (72 mg, 0.4 mmol) in 1 mL of THF was added. The mixture was stirred at room temperature for 3 hours, quenched with 1M HCl and neutralized with 1M NaOH until pH was 9. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was purified by flash column (silica gel, 50% ethyl acetate in hexane) to afford 36 mg of 4-chloro-N-[5-chloro-2-(6-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS: (M+H)/z=534.0.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.CN1CCOCC1.[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>C(Cl)Cl>[CH3:37][C:27]1[CH:28]=[C:29]([S:33]([NH:1][C:2]2[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:5]([CH:8]([CH3:9])[CH3:10])=[CH:6][CH:7]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)c1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C(C)C)n(CC(=O)OC(C)(C)C)c2=O)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
3-Amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (assumed to be 3.37 mmol), as prepared in the preceding step, and N-methylmorpholine (1.0 mL, 9.1 mmol) were dissolved in methylene chloride (20 mL) and cooled to 0° C. A solution of m-toluenesulfonyl chloride (0.67 g, 3.5 mmol) in methylene chloride (5 mL) was added and the reaction stirred at ambient temperature for 16 hours. After evaporation in vacuo, the crude product was dissolved in methylene chloride, washed with 10% aqueous citric acid, saturated NaHCO3, and brine, dried over MgSO4, and filtered. The evaporated filtrate gave the title compound (1.24 g, 88%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ7.65 (m, 2H), 7.58 (br s, 1H), 7.46 (d, 1H, J=7.8 Hz), 7.33 (m, 2H), 6.08 (d, 1H, J=7.9 Hz), 4.69 (s, 2H), 2.67 (m, 1H), 2.38 (s, 3H), 1.41 (s, 9H), 1.22 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH2:9]([NH2:19])[C:10]1[CH:18]=[CH:17][C:16]2[O:15][CH2:14][O:13][C:12]=2[CH:11]=1>CO>[O:15]1[C:16]2[CH:17]=[CH:18][C:10]([CH2:9][NH:19][C:4](=[N:3][C:1]#[N:2])[S:5][CH3:6])=[CH:11][C:12]=2[O:13][CH2:14]1
Reactant: CSC(=NC#N)SC
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CO
Product: CSC(=NC#N)NCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 88 %

Procedure:
1.6 g (10.94 mmol) of dimethyl cyanocarbonodithioimidate and 2.0 g (13.23 mmol) of piperonyl amine were dissolved in methyl alcohol, and then stirred for 30 minutes. After completion of the reaction, the produced solid was filtered, and then washed with water and methyl alcohol, thus obtaining 2.4 g (95% yield) of a desired compound of Formula 3.
Reaction SMILES: [C:1](=[O:4])([O-])N.[CH3:5][O:6][C:7]1[C:12]2[N:13]=[C:14]([NH:16][C:17](=[O:19])[OH:18])[S:15][C:11]=2[CH:10]=[CH:9][CH:8]=1>>[CH3:5][O:6][C:7]1[C:12]2[N:13]=[C:14]([NH:16][C:17](=[O:18])[OH:19])[S:15][C:11]=2[C:10]([N:13]2[CH2:14][CH2:1][O:4][CH2:11][CH2:12]2)=[CH:9][CH:8]=1
Reactant: NC(=O)[O-]
Reactant: COc1cccc2sc(NC(=O)O)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)O)nc12
Yield: 58 %

Procedure:
Carbamate formation using the same procedure as for (4-methoxy-benzothiazol-2-yl)-carbamic acid methyll ester yields the product as off-white solid in 58% yield. MS: m/e=324 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:20])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1(I)[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C.CCOCC.[Ag-]=O>[CH:21]1([O:18][C:17](=[O:19])[CH:16]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: IC1CCCC1
Reactant: O=C(O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: O=[Ag-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(OC1CCCC1)C(Cc1ccc(OCc2ccccc2)cc1)OC1CCCC1
Temperature: 55 °C
Yield: 17 %

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (1.0 g, 3.67 mmol), cyclopentyl iodide (7.2 g, 36.7 mmol) and silver (I) oxide (4.25 g, 18.3 mmol) in DMF (15 mL) was heated at 55° C. under N2 for 72 h. The reaction mixture was cooled, diluted with Et2O and filtered through hyflo. The filtrate was extracted with water and the organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 10:1 hexanes:acetone to afford 0.255 g (17%) 3-(4-benzyloxy-phenyl)-2-cyclopentyloxy-propionic acid cyclopentyl ester. Rf=0.67 (1:1 hexanes:acetone). 1H NMR.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3]1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][N:2]1[C:6]([C:7]([NH:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:9])=[CH:5][C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3]1
Reactant: NN1CCOCC1
Reactant: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)NN2CCOCC2)n(C)n1
Yield: 71 %

Procedure:
As described for example 160c, 1-methyl-3-((5-methyl-3-(pyridin-2-yl)isoxazol-4-yl)methylamino)-1H-pyrazole-5-carboxylic acid (80 mg; 255 μmol) was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (101 mg, 71%) which was obtained as a white solid. MS: m/e=398.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.OS(O)(=O)=O.[CH3:18]O>O>[CH3:18][O:11][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1n[nH]c2ccccc12
Temperature: 80 °C

Procedure:
To indazole-3-carboxylic acid (40 g, 247 mmol) suspended in methanol (700 mL) was added concentrated H2SO4 (10 mL) slowly while stirring the mixture. The mixture was stirred and refluxed at 80° C. for 24 h. The mixture was cooled, filtered, and concentrated under reduced pressure to afford a pale yellow solid. The solid was suspended in water (700 mL), crushed to fine powder, collected by filtration, and rinsed with water (˜400 mL). The product was suspended in toluene, and evaporated to dryness under reduced pressure, affording indazole-3-carboxylic acid methyl ester as a pale yellow solid (45 g, >95% pure). (m/z): [M+H]+ calcd for C9H8N2O2 177.07; found, 177.0. 1H-NMR (CD3OD, 300 MHz): δ (ppm) 8.0 (1H, d), 7.5 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 3.9 (3H, s).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:12]1[CH:13]=[C:14]([CH2:31][NH:32][CH3:33])[CH:15]=[CH:16][C:17]=1[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C1C(=O)N(O[C:44]([CH2:46][CH2:47][N:48]2[C:53](=[O:54])[CH:52]=[CH:51][C:49]2=[O:50])=[O:45])C(=O)C1>C(#N)C>[O:54]=[C:53]1[CH:52]=[CH:51][C:49](=[O:50])[N:48]1[CH2:47][CH2:46][C:44]([N:32]([CH2:31][C:14]1[CH:15]=[CH:16][C:17]([Sn:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH3:22])=[C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:5])([F:6])[F:7])[C:2]([F:1])([F:34])[F:35])[CH:13]=1)[CH3:33])=[O:45]
Reactant: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CN(C)C(=O)CCN2C(=O)C=CC2=O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Compound 14 (86 mg, 138 μmol) was dissolved in anhydrous acetonitrile (2 mL) and 3-(Maleimido)propionic acid N-hydroxysuccinimide ester (44 mg, 166 mmol) was added. The mixture was stirred overnight at room temperature, the solvent removed under reduced pressure and the residue purified over silica gel using chloroform/methanol (98/2) as eluant to give 86 mg (111 μmol, 81% yield) of a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.OC1C=CC(C([O:19][CH2:20][C:21]2[CH:26]=CC=CC=2)=O)=CC=1.C1(C)C(S(OC[C@H]2OC2)(=O)=O)=CC=CC=1.C(C1OC1)Br>>[O:19]1[CH2:20][C@H:21]1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: BrCC1CO1
Agent: Cc1ccccc1S(=O)(=O)OC[C@@H]1CO1
Product: COC(=O)c1ccc(OC[C@@H]2CO2)cc1
Yield: 90 %

Procedure:
The same procedure of Reference Example 4 was repeated except that methyl 4-hydroxybenzoate was used in lieu of benzyl 4-hydroxybenzoate, and (S)-(+)-glycidyl toluenesulfonate was used in lieu of epibromohydrin to give the title compound (yield 90%).
Reaction SMILES: [CH:1](=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH:14]O>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C(O)C>[CH3:2][CH:1]1[O:14][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: OO
Reactant: CC=C(C(=O)OCC)C(=O)OCC
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)OC1C
Temperature: 80 °C
Yield: 74.1 %

Procedure:
A mixture of 50 grams (0.27 mole) of diethyl ethylidenemalonate, 455 grams (4.02 moles) of 30% hydrogen peroxide, 17.6 gram (0.053 mole) of sodium tungstate dihydrate and 400 milliliters of ethanol was stirred and heated at 80° C. for one hour, cooled to room temperature and stirred for an additional hour. Ethanol was removed under reduced pressure and the produce extracted into dichloromethane (3×200 milliliters), the extract then water-washed, dried (MgSO4), filtered and solvent removed to give the crude product. Vacuum distillation gave 40.45 grams (0.20 mole) of diethyl 3-methyloxirane-2,2-dicarboxylate having a boiling point of 120° C. at 4millimeters of Hg.
Reaction SMILES: CS([O:5][CH:6]1[CH:11]([CH3:12])[CH2:10][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:8][CH:7]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=O)=O.C(N(CC)CC)C.C[C:38]([O:41]C(OC(OC(C)(C)C)=O)=O)(C)C>N1C=CC=CC=1>[CH3:12][CH:11]1[CH:6]2[CH:7]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:38](=[O:41])[O:5]2)[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH2:10]1
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(NC(=O)OC(C)(C)C)C1OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC2C1OC(=O)N2C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 66 %

Procedure:
A solution of (+/−)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (1.0 equiv.) in pyridine (0.2 M) was heated in the microwave at 110° C. for 10 min. The orange reaction was then concentrated under vacuo, the crude was dissolved in ethyl acetate and water, the organic phase was dried with sodium sulfate and concentrated under vacuo. The crude material was dissolved in DCM (0.2 M), triethylamine (1.8 equiv.) was added, followed by Boc2O (1.2 equiv.). The reaction was stirred for 40 min, then concentrated to dryness. The crude material was purified via silica gel column chromatography eluting with hexane and ethyl acetate (1:1) to afford (+/−)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate as a white foam in 66% yield. LC/MS=376.0 (M+H), LC: 3.424 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][C:26]1[C:27](=[O:33])[NH:28][N:29]=[C:30]([CH3:32])[CH:31]=1>>[CH3:32][C:30]1[CH:31]=[C:26]([CH2:25][NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[C:27](=[O:33])[NH:28][N:29]=1
Reactant: Cc1cc(CN)c(=O)[nH]n1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1cc(CNC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)c(=O)[nH]n1
Yield: 83 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using 4-aminomethyl-6-methyl-2H-pyridazin-3-one instead of aminomethyl-isoxazolidin-3-one to the title compound (SiO2, heptane:ethyl acetate:methanol=20:80:0 to 0:90:10, 231 mg, 83%) which was obtained as a white solid. MS: m/e=432.3 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]1[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][C@@H:18]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:24]=[C:23]1[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][C@H:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:17]1[NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH2:8]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Yield: 99.9 %

Procedure:
N2-[tert-Butoxycarbonyl]-N1-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-leucinamide (64f) (83 mg, 0.177 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid and kept at ambient temperature for 1 h. The solution was evaporated and the residue dissolved in ethyl acetate. The solution was extracted in succession with saturated aqueous sodium bicarbonate and brine then the organic solution was dried, filtered and evaporated to afford the title compound (65 mg, 99%) as a yellow oil. MS APCI, m/z=368 (M+1). LC/MS: 1.63 min.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH2:30])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:35][CH2:36][O:37][CH2:38][CH2:39]Cl>CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:14]=3)=[CH:11][C:10]([S:27]([N:30]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCOCCCl
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(S(=O)(=O)N2CCOCC2)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To a solution of compound 1 (300 mg, 0.68 mmol) in dry DMF (5 mL) was added NaH (60%, 60 mg, 1.50 mmol) at 0° C. and the mixture was stirred at 0° C. for 10 min. 2-chloro-1-(2-chloroethoxy)ethane (97 mg, 0.68 mmol) and KI (113 mg, 0.68 mmol) was added and then this mixture was stirred overnight at rt, quenched with water and extracted with EA. The organic layer was washed with brine twice, concentrated and purified by CC (PE/EA=4/1) to give compound 44 (70 mg, 21%) as a white solid. 1H-NMR (CDCl3, 300 MHz) δ: 0.60-0.70 (2H, m), 0.95-1.03 (3H, m), 1.23-1.40 (3H, m), 1.36 (18H, s), 1.49-1.52 (3H, m), 2.52 (3H, s), 3.02-3.05 (4H, m), 3.73-3.78 (6H, m), 6.35 (1H, s), 7.15 (2H, d, J=1.8 Hz), 7.41 (1H, t, J=1.8 Hz). MS Calcd.: 514; MS Found: 515 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH3:16][OH:17]>>[CH3:16][O:17][C:11](=[O:12])[C:6]1[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=1[F:13])[C:8]([OH:10])=[O:9]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: CO
Product: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Reaction time: 2 h
Yield: 98 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser and a stirrer, 20 g (0.091 mol) of the tetrafluorophthalic anhydride prepared in Example 3 and 40 ml of methanol were charged, and the mixture was stirred for 2 hours under reflux. After completion of the reaction, methanol was distilled off to obtain 22.5 g of 3,4,5,6-tetrafluorophthalic acid-monomethyl ester. The yield was 98.0%.