Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CC(NC(=[O:8])C)C1.Br[CH2:10][CH2:11][O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[CH:25][C:26]=3[O:31][CH3:32])[N:21]=2)=[CH:15][C:14]=1[CH3:35].[CH2:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])C>CN(C=O)C>[C:39]([N:38]1[CH2:36][CH:42]([CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[NH:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][C:24]([O:33][CH3:34])=[CH:25][C:26]=4[O:31][CH3:32])[N:21]=3)=[CH:15][C:14]=2[CH3:35])[CH2:41]1)(=[O:8])[CH3:40]
Reactant: CC(=O)NC1CNC1
Reactant: CCN(CC)CC
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCC4CN(C(C)=O)C4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of N-azetidin-3-yl-acetamide (17) (1.99 mmol) and 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (18) (1.00 mmol) in anhydrous DMF (10 mL) was added triethylamine (3 mL). The reaction mixture was stirred at room temperature for 3 days under nitrogen. The solvent was evaporated under reduced pressure, water (50 mL) was added, and the precipitated solid was filtered off. The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by the Simpliflash system (0-5% 7 N ammonia in methanol and CH2Cl2 as eluent) to give the title compound 19 as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][CH:18]([F:35])[O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:32](=[O:33])[C:29]4[CH:28]=[CH:27][C:26]([C:23]5[CH:22]=[CH:21][C:20]([O:19][CH:18]([F:35])[F:17])=[CH:25][N:24]=5)=[CH:31][CH:30]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(OC(F)F)cn2)cc1
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(OC(F)F)cn4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-[5-(difluoromethoxy)-2-pyridyl]benzenecarboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH3:1][CH:2]=[CH:3][CH:4]=[CH:5][CH:6](O)[CH2:7][CH3:8].[O-2].[Al+3].[O-2].[O-2].[Al+3]>>[CH3:1][CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7][CH3:8].[CH2:2]([CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=[CH2:8])[CH3:1]
Reactant: CC=CC=CC(O)CC
Agent: [Al+3]
Agent: [O-2]
Product: C=CC=CC=CCC
Product: CC=CC=CC=CC

Procedure:
F. Woods and A. Viola, J. Amer. Chem. Soc. 78 (1956), 4380-4383, report that 2,4-octadien-6-ol is dehydrated at from 300° to 310° C. over aluminum oxide to give 1,6-dimethyl-1,3,5-hexatriene or 1-ethyl-1,3,5-hexatriene. If the reaction is carried out at from 450° to 500° C. instead of at from 300° to 310° C., substituted cyclohexadienes are obtained which are converted into mixtures of o-xylene and ethylbenzene only after dehydration over palladium/active charcoal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH2:25]([S:27][CH2:28][C:29]#[CH:30])[CH3:26]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:30]#[C:29][CH2:28][S:27][CH2:25][CH3:26])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCSCC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCSCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1

Procedure:
A mixture of N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 5 (1.5 g), propargyl ethyl sulfide (1.04 g, 10.4 mmol), copper iodide (0.125 g), and dichlorobis(triphenylphosphine)-palladium(II) (0.462 g) in diethylamine are stirred at room temperature overnight. The reaction mixture is then concentrated in vacuo, and the residue is suspended in water (100 mL) and extracted with four 50-mL portions of EtOAc. The combined organic layers are then dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (elution with 5-10%MeOH/CH2Cl2) yielded the title compound as a solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]([C:14]1[CH:37]=[CH:36][C:17]([O:18][C@@H:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@@H:20]2[NH:28][C:29](OC(C)(C)C)=O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCCC1.C(O)C.C(Cl)(Cl)[Cl:47]>>[ClH:47].[O:7]([C:14]1[CH:37]=[CH:36][C:17]([O:18][C@@H:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@@H:20]2[NH:28][CH3:29])=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Oc2ccccc2)cc1
Product: Cl

Procedure:
The title compound was prepared in a similar manner to Example 12 from LiAlH4 (760 mg, 20 mmol), (±)cis-1-[(4-phenoxy)phenoxy]-2-tert-butoxycarbonylaminoindane (1.39 mg, 3.3 mmol) and tetrahydrofuran (40 ml). After a reaction time of 3 h the reaction was worked up as previously described and subjected to column chromatography on silica gel eluting with 2% ethanol in chloroform to afford a pale pink oil (951 mg) which was converted to the HCl salt and crystallised to afford the title compound as a white solid. m.p. 188°-190° C. (from methanol-diethyl ether).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]3[N:19]=[N:20][N:21]([CH3:22])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:23]([F:26])([F:25])[F:24].CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C1COCC1.C(Cl)Cl>[C:17]([C:15]1[C:14]2[N:19]=[N:20][N:21]([CH3:22])[C:13]=2[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:36](=[O:38])[CH3:37])=[C:6]([C:23]([F:25])([F:24])[F:26])[CH:7]=2)[N:16]=1)#[N:18]
Reactant: CC(=O)Cl
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCN)c(C(F)(F)F)c3)cc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(4-(2-Aminoethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo-[4,5-c]pyridine-4-carbonitrile (0.276 mmol, 0.1 g) and Hunig's base (0.828 mmol, 0.137 ml, 0.107 g) were stirred in THF (1 ml) at 0° C. acetyl chloride (0.552 mmol, 0.039 ml, 0.043 g) was added and the reaction was allowed to warm to room temperature and stirred for 1 hour. The resulting residue was taken up in DCM and washed with water. The organic was concentrated at reduced pressure. The resulting residue was purified by silica chromatography, eluting with DCM—3% MeOH/DCM to afford N-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)acetamide. (0.024 g)
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[N:10]=[C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:12][CH:13]=1)=[O:8])C.Cl>O1CCCC1.O>[C:18]([O:17][C:15]([NH:14][C:11]1[S:12][CH:13]=[C:9]([C:7]([OH:8])=[O:6])[N:10]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(C(=O)O)cs1
Yield: 93.6 %

Procedure:
Lithium hydroxide monohydrate (20.16 g, 0.48 mol) was added to a stirred solution of 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid ethyl ester (52.35 g, 0.192 mol) in a mixture of tetrahydrofuran (800 mL) and water (200 mL). The mixture was stirred over night. 1 N Aqueous hydrochloric acid (480 mL) was added and the reaction mixture concentrated in vacuo to remove tetrahydrofuran. The mixture was then diluted with water and filtered. The solid was washed with water, ether and dried overnight to give 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid (43.9 g, 94%).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1.O.[C:20](=O)([O-])[O-].[Na+].[Na+]>CO>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:20])=[O:12])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Add concentrated sulfuric acid (7 mL) to a solution of commercially available 4-bromo-2-nitrobenzoic acid (25.0 g, 102 mmol) in methanol (150 mL), and heat at reflux for 16 hours. Cool the reaction to room temperature and pour into water (500 mL) and adjust the pH of the suspension to 9 with solid sodium carbonate. Extract the solution with ethyl acetate (2×250 mL), then combine the organic extracts and wash with brine (100 mL), dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a pale amber oil, which crystallizes upon standing (20.5 g, 78%)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br-:1].[CH:8]([O:7][C:5]([CH2:4][CH2:3][CH2:2][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:6])([CH3:10])[CH3:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)CCCBr
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 40 °C
Yield: 57.4 %

Procedure:
Isopropyl 4-bromobutyrate (16.0 g, 76.5 mmol) and triphenylphosphine (20.0 g, 76.5 mmol) in toluene (160 ml) were heated at reflux under nitrogen for 39 h. The mixture was allowed to cool (to approx 40° C.), filtered and the solid was washed with toluene (3 ×25 ml). The product was dried under vacuum to give a white solid (20.7 g, 57%); m.p. 198° C. (onset by DSC); 1H NMR (200 MHz, CDCl3) δ ppm 7.85-7.60 (15 H, m), 4.89 (1 H, heptet, J 6), 3.96-3.70 (2 H, m), 2.75 (2 H, t, J 6), 1.95-1.75 (2 H, m) and 1.13 (6 H, d, J 6).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH2:10]([O:12][C:13](=[O:19])[C:14](OCC)=[O:15])[CH3:11].CC[O-].[Na+]>>[CH2:10]([O:12][C:13](=[O:19])[C:14](=[O:15])[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]([CH3:9])[CH3:1])[CH3:11]
Reactant: CC(=O)CCCC(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCCC(C)C
Temperature: 25 °C
Yield: 46.8 %

Procedure:
6-Methyl-2-heptanone (0.9981 g, 7.80 mmol) and diethyloxalate (1.06 mL, 7.80 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 2.6 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 16. The crude material was purified with 1:1 Hexanes:CH2Cl2 to obtain 0.8342 g (46.9%) of 16. 1H (CD3OD, 400 MHz): δ 6.36 (1H, s), 4.30 (2H, q, J=7.1 Hz), 2.50 (2H, t, J=7.3 Hz), 1.68-1.59 (2H, m), 1.61-1.50 (1H, m), 1.33 (3H, t, J=7.1 Hz), 1.25-1.17 (2H, m), 0.89 (6H, d, J=7.0 Hz) ppm. 13C (CD3OD, 100 MHz): δ 204.41, 166.93, 163.28, 102.66, 63.29, 41.89, 39.41, 28.92, 23.65, 22.89, 14.33 ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:27][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]([NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[CH:22]=3)=[O:19])[CH2:15][CH2:16]2)=[C:7]2[N:8]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Cc1cc(NC(=O)CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)on1
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5cc(C)no5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 6.5 h

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(3-methylisoxazol-5-yl)acetamide (0.036 g, 0.09 mmol) and ethanol (3 ml) was added p-anisaldehyde (0.024 g, 0.18 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared 1M aqueous solution of Na2S2O4 (0.36 ml, 0.36 mmol). The reaction mixture was stirred at 70° C. for 6.5 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, and the free-running powder was placed on a 10 g silica isolute column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1), and 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.008 g, 18%). 1H-NMR (500 MHz, DMSO-d6) 2.19 (s, 3H, isoxazole CH3), 2.73 (s, 4H, piperazine N(CH2)2), 3.32 (s, 2H, NCH2CO), 3.73 (s, 4H, piperazine N(CH2)2), 3.83 (s, 3H, OCH3), 6.18 (s, 1H, isoxazole C—H), 7.11 (d, J=8.9 Hz, 2H) and 8.13 (d, J=8.8 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4OMe), 8.09 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.43 (br s, 1H, CONH), 13.38 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=[O:3].Br.[OH2:13]>CS(C)=O>[Cl:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[O:13])[CH:9]=[CH:8][C:7]=1[Cl:10]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: O
Agent: Br
Solvent: CS(C)=O
Product: O=CC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3,4-dichloroacetophenone (5.39 mmol, 1.02 g) was dissolved in dimethyl sulfoxide (13 mL), and 48% hydrobromic acid (1.83 mL) was gradually added at room temperature. The mixture was stirred overnight at 60° C., and then the reactor was cooled to room temperature. The reaction solution was poured into water (50 mL) at 0° C. and stirred for about 1 hour. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a pale yellow solid (0.780 g, yield 71%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].[C:13](O)(=O)[CH2:14][CH2:15][C:16]#[CH:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[CH2:16]([C:17]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH3:11])[N:12]=1)[CH2:15][C:14]#[CH:13]
Reactant: COc1ccccc1C(N)=NO
Reactant: C#CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C#CCCc1nc(-c2ccccc2OC)no1
Temperature: 80 °C
Reaction time: 3 h
Yield: 36.4 %

Procedure:
In a reactor tube, a mixture of N′-hydroxy-2-methoxybenzamidine (598 mg, 3.6 mmol), 4-pentynoic acid (350 mg, 3.6 mmol), HOBT (0.55 g, 3.6 mmol) and EDCI.HCl (1.03 g, 5.4 mmol) in dioxane (7.4 mL) was stirred at R.T for 3 h. After this time the mixture was heated at 80° C. overnight in a reaction block. The mixture was concentrated and the crude product was purified by flash chromatography (Prepacked column 25 g with DCM as eluent) to afford 299 mg of 5-(but-3-ynyl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole (36%) as yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:25]1[O:29][N:28]=[CH:27][N:26]=1)[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:19][C:20]([O:22]CC)=[O:21])=[N:9]1.[OH-].[K+].C(O)(=O)C>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:25]1[O:29][N:28]=[CH:27][N:26]=1)[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[N:9]1
Reactant: CCOC(=O)Cc1nn(C(c2ccccn2)c2ncno2)c(=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)Cc1nn(C(c2ccccn2)c2ncno2)c(=O)c2ccccc12

Procedure:
To a solution of ethyl 3(2-pyridyl-1,2,4-oxadiazol5-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate (1.0 g) in methanol (10 ml) was added 20% aqueous KOH (0.5 ml) and the mixture refluxed for 30 minutes. Evaporation of excess methanol gave an orange residue. The residue was dissolved in water, acidified with acetic acid (1 ml) and the precipitated solid was collected and crystallized from isopropanol to yield the product (0.53 g; m.p. 196°-200° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:40][CH:41]([CH2:43][C@H:44]([OH:48])[C:45](O)=[O:46])[CH3:42]>C(Cl)Cl>[OH:48][C@@H:44]([CH2:43][CH:41]([CH3:42])[CH3:40])[C:45]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:46]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of L-leucine methyl ester hydrochloride (1.97 g) dissolved in DCM (32 mL) was added NMM (1.9 mL) and the mixture was stirred for 5 minutes before being cooled to 0° C. HOBt (4.0 g), EDAC (3.8 g) and L-α-hydroxyisocaproic acid (1.35 g) were then added sequentially to the reaction mixture. After 30 minutes at 0° C., the reaction was allowed to warm to room temperature and continued stirring overnight. The reaction mixture was concentrated and the resulting crude product was dissolved in EtOAc and washed 2×1.2N HCl, 2× saturated NaHCO3, brine, dried (MgSO4) and concentrated to yield the desired product (2.32 g, 82%). 1H NMR (300 MHz, CDCl3) δ 0.93-0.96 (m, 12H), 1.50-1.67 (m, 5H), 1.82-1.93 (m, 1H), 3.73 (s, 3H), 3.83 (bs, 1H), 4.11-4.18 (m, 1H), 4.57-4.64 (m, 1H), 7.07 (d, 1H).
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[CH3:23][C:24]([OH:29])([C:27]#[CH:28])[CH2:25][OH:26]>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:22])[C:2]([C:28]#[C:27][C:24]([OH:29])([CH3:23])[CH2:25][OH:26])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)CO
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C1CC1)CO
Yield: 50 %

Procedure:
10-bromo-3-cyclopropyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yne-1,2-diol via General Procedure E to yield 21 mg (50%) of (±)-3-cyclopropyl-10-(3,4-dihydroxy-3-methyl-but-1-ynyl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[NH:10][C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:10]2[C:11]3=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]([F:20])=[C:19]3[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[Cl:22])[C:9]2=[O:21])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(Br)cc1Cl
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(Br)cc3Cl)c3c(F)c4ncoc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.26 mmol) in DCM (10 mL) was added triethylamine (80 mg, 0.78 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (71 mg, 0.39 mmol) and DMAP (15 mg). After stirring at room temperature for 1 h, the reaction was treated with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (20 mL×2). The combined organic phase was washed with water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (120 mg, 87.2% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.39-7.11 (d, 2H), 7.05, (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).
Reaction SMILES: C1(CCl)C=CC=C(CCl)C=1.C(O[CH:15]([O:22]C(=O)C)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=O)C.[C:26]([O-])(=[O:28])C.[Na+].[Cl-].[Na+]>ClC1C=CC=CC=1.O.C(N(CC)CC)C>[C:16]1([CH2:15][OH:22])[CH:21]=[CH:20][CH:19]=[C:18]([CH2:26][OH:28])[CH:17]=1
Reactant: CC(=O)OC(OC(C)=O)c1ccccc1
Reactant: CC(=O)[O-]
Agent: ClCc1cccc(CCl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1
Solvent: CCN(CC)CC
Product: OCc1cccc(CO)c1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
In a manner similar to that in Example 1, m-xylylene dichloride was converted into m-diacetoxymethylbenzene at 97° to 101° C. in 3 hours by use of a reactant mixture comprising 100 parts of m-xylylene dichloride (97.6% purity), 100 parts of anhydrous sodium acetate, 125 parts of monochlorobenzene, and 2 parts of triethylamine. To the reaction mixture was added 250 parts of warm water to dissolve the by-product sodium chloride. The mixture was left standing at 80° C. to allow it to settle in two layers. To the monochlorobenzene layer which had been freed from the catalyst amine by removing in the same manner as in Example 1, were added 46 parts of sodium hydroxide and 310 parts of water to allow the saponification to proceed at 94° C. for 2 hours. After saponification, the reaction mixture was neutralized with 3N hydrochloric acid and left standing at 82° C. to allow the mixture to settle in two layers. The aqueous layer containing m-xylylene glycol, was added at 80° C. 50 parts of monochlorobenzene to extract impurities. After separation, m-xylylene glycol was extracted from the purified aqueous layer with n-butyl acetate in the same way as in Example 1. The n-butyl acetate layers obtained by repeating batchwise extraction three times were combined, distilled to recover ethyl acetate, and dried in vacuo to obtain 76.0 parts of m-xylylene glycol (melting point, 53.5° - 55° C.) in a yield of 98.7%.