Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:22])[CH:14](Cl)[C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH3:11].CCN(CC)CC>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[S:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:15]=1[C:16]([F:17])([F:18])[F:19])=[O:22])[CH3:11]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(=S)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cccnc2)nc1C(F)(F)F
Temperature: 150 °C

Procedure:
To a 20 mL microwave tube was added thionicotinamide (0.552 g, 4.0 mmol), ethanol (15 mL) and 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (1.75 g, 8 mmol). The tube was capped and heated in a microwave at 150° C. for 10 min. The reaction mixture was cooled to ambient temperature and Et3N (1.7 mL, 12 mmol) was added. The tube was capped and heated in a microwave at 130° C. for 1 min. After cooling to ambient temperature the solvent was evaporated and the crude reaction mixture was directly subjected to silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as an orange oil which subsequently solidified (0.885 g, 73%): IR (KBr) 2988, 1737, 1712 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.21 (dd, J=2.5, 0.8 Hz, 1H), 8.77 (dd, J=5.0, 1.7 Hz, 1H), 8.33 (dt, J=8.0, 2.2 Hz, 1H), 7.47 (ddd, J=11.8, 4.7, 0.8 Hz, 1H), 4.45 (q, J=14.3, 7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H); ESIMS m/z 303 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].Cl>C(OCCO)C.[Cl-].[Na+].O.O>[CH3:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[CH:5]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Product: Cc1cc(Nc2cccc([N+](=O)[O-])c2)nc(N)n1
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-4-chloro-6-methyl-pyrimidine (A8) [10.04 g, 69.93 mmol] and 3-nitroaniline 99.95 g, 72.02 mmol) in 2-ethoxyethanol (300 mL) was added c.HCl (30 mL), and the resulting solution was refluxed for ˜16 h. After this time, the reaction mixture was allowed to cool to room temperature, and then diluted with brine and H2O. The resulting suspension was filtered through a Celite pad, and the solid material thus collected re-dissolved in MeOH, and filtered through a pad of Celite. Solvent was removed under reduced pressure to give diamine E1 as an amorphous beige solid, which was used without further purification: 1H NMR (400 MHz, DMSO): δ 12.97 (br s, 1H, pyrimidinyl-N+—H), 11.03 (s, 1H, ArNHAr), 8.52 (s, 1H, ArH), 8.31 (d, J=7.83 Hz, 1H, ArH), 7.97 (ddd, J=8.20, 2.19, 0.72 Hz, 1H, ArH), 7.83 (v br s, 2H, ArNH2), 7.66 (t, J=8.21 Hz, 1H, ArH), 6.25 (s, 1H, ArH), 2.31 (s, 3H, ArCH3); LCMS (APCI+): 246 (100%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][C:16]([CH3:23])([CH3:22])[CH:17]3O[CH:18]32)=[CH:13][CH:12]=1)#[N:10].O>CS(C)=O>[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][C:16]([CH3:23])([CH3:22])[CH:17]=[C:18]2[N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])=[CH:13][CH:12]=1)#[N:10]
Reactant: O=C1CCCN1
Reactant: CC1(C)Cc2ccc(C#N)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)C=C(N2CCCC2=O)c2cc(C#N)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.18 g of 80% dispersion in oil) in dry dimethylsulphoxide (5 ml) was added 2-pyrrolidinone (0.51 g) in dimethylsulphoxide (5 ml) and the mixture was then stirred at room temperature, under nitrogen, for 1 hour. A solution of 7-cyano-1,2-epoxy-3,3-dimethyl-1,2,3,4,-tetrahydronaphthalene (1.0 g) in dimethylsulphoxide was then added dropwise, and the solution stirred for 18 hours at room temperature. The mixture was then poured into water and extracted into ethyl acetate. The combined organic layers were washed with water, then brine, and dried over sodium sulphate. Removal of drying agent and solvent, followed by chromatography of the residue on a silica gel column eluted with ethyl acetate-pentane (1:1), gave the title compound as a solid, which recrystallised from 60°-80° petrol-ethyl acetate (5:1) as yellow prisms (0.25 g) having mp 131°-2° C.;
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(Cl)(Cl)Cl.C(#N)C>[NH:11]1[CH:15]=[N:14][C:13]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[N:12]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(Cc2nc[nH]n2)cc1

Procedure:
A solution containing alpha-bromo-4-tolunitrile (19.6 g) and 1,2,4-triazole (30.5 g) in a mixture of chloroform (250 mL) and acetonitrile (50 mL) is stirred at reflux for 15 hours. The solution is cooled and washed with 3% aqueous sodium bicarbonate (200 mL) and the organic solution is then dried (MgSO4) and evaporated. The residue is chromatographed on silica gel (300 g). Elution with chloroform/isopropanol (10:1) affords 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile, m.p. 77°-79°, which forms a hydrochloride salt, m.p. 200°-205°, when its solution in ethyl acetate is treated with ethereal HCl.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[N+:30]([C:33]1[O:37][C:36]([CH:38]=O)=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:38][C:36]3[O:37][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=3)=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccc([N+](=O)[O-])o2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccc([N+](=O)[O-])o2)c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with 5-nitro-2-furaldehyde (65) (0.282 g, 2 mmol) afforded, after workup, a purple oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/hexane as the eluant to obtain 0.85 g (1.61 mmol, 81%) of 76 as a brown gum; IR (CH2Cl2) 3440, 1698, 1622, 1528, 1470, 1350, 1215, 1100, 1012, 810 cm-1 ; 1H NMR (CDCl3) δ 1.09 (d, J=6.2 Hz, 3H), 1.23 (d, J=6.2 Hz, 3H), 2.33 (s, 6H), 3.35 (s, 3H), 3.55-3.59 (m, 2H), 4.17-4.21 (m, 2H), 4.94 (septet, J=6.2 Hz, 1H), 5.09 (s, 1H), 6.20 (s, 1H), 7.34-8.29 (m, 7H); 13C NMR (CDCl3) δ 19.49, 19.59, 21.92, 22.18, 40.22, 58.85, 62.91, 67.36, 70.73, 103.11, 103.88, 113.84, 116.76, 118.98, 120.73, 122.43, 128.83, 131.37, 144.54, 145.28, 147.09, 149.47, 150.02, 151.63, 166.83, 167.31. Anal. Calcd for C26H29N3O9 : C, 59.20; H, 5.50. Found: C, 59.47; H, 5.74.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.O.[NH2:11][NH2:12]>O1CCOCC1.O>[C:8]([C:4]1[CH:3]=[C:2]([NH:11][NH2:12])[CH:7]=[CH:6][N:5]=1)#[N:9]
Reactant: NN
Reactant: N#Cc1cc(Cl)ccn1
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(NN)ccn1

Procedure:
4-Chloro-2-cyanopyridine (1 g) was dissolved in hydrazine monohydrate (1 ml) and 1,4-dioxane (10 ml), and stirred overnight under reflux. The reaction solution was diluted with water (30 ml) and extracted repeatedly with ethyl acetate. The organic layer was concentrated to obtain the title compound as a crude product, which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:42][CH:43]([CH3:52])[C@H:44]([NH2:51])[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:51][C@@H:44]([CH:43]([CH3:52])[CH3:42])[CH2:45][N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CC(C)[C@H](N)CN1CCCC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](CN1CCCC1)NC(=O)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
4-Chlorobenzoic acid (1.061 g, 6.78 mmol), TBTU (2.25 g, 7.01 mmol) and DIPEA (20.3 mmol) was mixed in DMF (25 mL). After 10 min was (S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-amine (0.962 g, 6.16 mmol), which is commercially available, added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (1.48 g, 82%). 1H NMR (400 MHz, CDCl3) δ 0.97, 1.80, 1.94-2.32, 2.47-2.76, 2.80-3.01, 4.13, 6.66, 7.41, 7.80. Total no of protons: 23. LCMS (M+H)+: 295.
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:22].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.O>[CH2:15]([O:14][C:7]1[C:8]2[NH:9][C:10](=[O:13])[S:11][C:12]=2[C:4]([C:1](=[O:3])[CH2:2][Br:22])=[CH:5][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)sc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)sc12
Temperature: 80 °C
Yield: 93.3 %

Procedure:
To a solution of 7-acetyl-4-(benzyloxy)-1,3-benzothiazol-2(3H)-one (68 mg) in dry THF (3 ml) under nitrogen, was added phenyltrimethylammonium tribromide (90 mg) and the mixture heated at 80° C. under nitrogen for 2 h. The mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a 5 g silica SPE cartridge, eluting with stepped gradient of 10% to 100% ethyl acetate-cyclohexane mixtures, to give the title compound (49 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:29]1([CH2:35][CH:36]([OH:38])[CH3:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:26][C:23]1[C:22]([CH2:27][O:38][CH:36]([CH3:37])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:20][CH:19]=2)[O:25][N:24]=1
Reactant: CC(O)Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COC(C)Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 17, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-phenyl-propan-2-ol.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[CH3:10][NH:11][NH2:12]>C(O)CC>[NH2:6][C:5]1[N:11]([CH3:10])[N:12]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CNN
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CCCO
Product: Cn1nc(C(C)(C)C)cc1N
Temperature: 25 °C
Yield: 65.3 %

Procedure:
To a solution of 12.5 g (0.1 mol) of 4,4-dimethyl-3-oxopentanenitrile in 50 cm3 of n-propanol were added, at room temperature, 4.6 g (0.1 mol) of methylhydrazine. The reaction medium was maintained at reflux for 1 hour and then cooled to room temperature. The white solid obtained was filtered off on a sinter funnel and then washed with isopropyl ether. After drying under vacuum at 40° C., 10 g of the expected product were obtained in the form of a beige solid, the melting point of which was 157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH3:28]I>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH:23]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(-c3ccncc3)sc2-c2ccc(OC)cc2)cc1
Reactant: CI
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-c2nc(C3=CCN(C)CC3)sc2-c2ccc(OC)cc2)cc1
Reaction time: 48 h

Procedure:
A solution of 4,5-bis(4-methoxyphenyl)-2-(4-pyridyl)thiazole (1.78 g) and methyl iodide (2.96 ml) in a mixture of chloroform and methanol (5:2) (28 ml) was allowed to stand at ambient temperature for 2 days. The reaction mixture was evaporated in vacuo and the residue containing 4-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]-1-methylpyridinium iodide was dissolved in a mixture of methanol (20 ml). To the resulting solution was added portionwise sodium borohydride (0.54 g) with stirring at 5° to 10° C. The reaction mixture was stirred for one hour at the same temperature. Water was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was dissolved in chloroform and washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was recrystallized from a aqueous methanol to give 4,5-bis(4-methoxyphenyl)-2-(1-methyl-1,2,5,6-tetrahydro-4-pyridyl)thiazole (0.16 g).
Reaction SMILES: [CH3:1][S:2][CH3:3].[F:4][C:5]([F:14])([F:13])[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].ClN1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2][CH2:3][C:9]1[CH:10]=[CH:11][CH:12]=[C:6]([C:5]([F:4])([F:14])[F:13])[C:7]=1[NH2:8]
Reactant: CSC
Reactant: Nc1ccccc1C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1cccc(C(F)(F)F)c1N
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
Dimethylsulfide, 16 ml, was syringed all at once into a solution of 25.0 grams (g) of 2-(trifluoromethyl)aniline in 400 milliliters (ml) of methylene chloride. The reaction solution was cooled to 15° C. and 29.0 g of N-chlorosuccinimide was added in small portions over a 20 minute period at such a rate that the reaction temperature did not exceed 20° C. The reaction mixture was stirred at 15° C. for 15 minutes, then 30.4 ml of triethylamine was added dropwise over 15 minutes at such a rate that the temperature did not exceed 15° C. After an additional five minutes of stirring, the reaction was refluxed overnight, allowed to cool to room temperature, washed with two 200 ml portions of 10% sodium hydroxide, the organic phase separated, dried with magnesium sulfate and filtered. The remainder of the solvent was distilled off to yield 35.8 g of the crude desired product which was used without any additional purification in subsequent reactions.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@@H:2]([C:6]([OH:8])=O)[CH2:3][CH2:4][CH3:5].[NH2:19][C@H:20]([C:25]([NH:27][C@H:28]([C:39]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:44])=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CO.CN(C)C=O>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@@H:2]([C:6]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:39]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:44])=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reactant: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CO
Product: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a solution of Z-(D)-Nva-OH(380 mg), H-Leu-Arg(NO2)-Pro-Gly-NH2 (690 mg.) and HONB (300 mg.) in 5 ml. of dimethylformamide is added 340 mg. of DCC at 0°C with stirring. The mixture is stirred for 2 hours at 0°C and for additional 10 hours at room temperature. The reaction mixture is filtered to remove the formed dicyclohexyl-urea, and the filtrate is evaporated to dryness. The resulting residue is dissolved in 100 ml. of chloroform and the solution is washed with 4 % aqueous sodium bicarbonate solution and water. The washed solution is dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is then triturated with a mixture of ethylacetate (25 ml.) and ether (25 ml.) to give a white powder, which is collected by filtration and reprecipitated from ethanol-ether: yield, 1.12 g., [α]D23 -50.5°(c=1.1 in Methanol), Rf1 =0.32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:24]=3)=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.[OH-].[Li+].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:24]=3)=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-{1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl}benzoate (may be prepared as described in Description 113; 372 mg, 0.85 mmol) in tetrahydrofuran (25 ml) was added lithium hydroxide (60.8 mg, 2.54 mmol), water (5 ml) and the mixture was refluxed for 4 hours. The mixture was evaporated under reduced pressure on a buchi. The residue was taken up into water (10 ml) and acidified using 2M aqueous HCl to pH 1. The solid formed was filtered, washed with water and dried in air under vacuum to yield the title compound as a light brown solid. 170 mg.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[CH:10]1([C:13]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:46])[N:23]([C:39]5[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=5)[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:25]4)=[CH:20][CH:19]=3)ON=2)[CH2:12][CH2:11]1>>[CH:10]1([C:13]2[O:3][N:2]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:46])[N:23]([C:39]5[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=5)[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[N:25]4)=[CH:20][CH:19]=3)[CH:17]=2)[CH2:12][CH2:11]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)CCCCc1nc2cc(-c3cc(C4CC4)no3)ccc2c(=O)n1-c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCCCc1nc2cc(-c3cc(C4CC4)on3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A solution of 8A (27 mg, 0.053 mmol) and hydroxylamine hydrochloride (4.3 mg, 0.062 mmol) in pyridine (1 mL, 10 mmol) was stirred at 60° C. for 7 h. The reaction was then stirred at at 110° C. for 16 h. The reaction was quenched with 0.1N HCl and diluted with DCM. The organic layer was removed and the aqueous phase was extracted with DCM (3×). The combined organics were concentrated. The residue was purified by flash chromatography (0% to 20% (12 min) to 70% (10 min) EtOAc/hexanes) to yield an inseparable mixture of tert-butyl 5-(7-(3-cyclopropylisoxazol-5-yl)-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pentanoate and regioisomer tert-butyl 5-(7-(5-cyclopropylisoxazol-3-yl)-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pentanoate (17 mg; Yield=63%), MS (M+H)=504.3.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:13][C:14]([OH:16])=[O:15].Cl>CS(C)=O.O>[CH2:1]([O:9][CH2:13][C:14]([OH:16])=[O:15])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCl
Reactant: OCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)COCCc1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
To a stirred mixture of phenethyl alcohol (1.0 g, 8.18 mmol) in DMSO (16 mL) under nitrogen flow, NaH (0.39 g, 16.37 mmol) was added in one portion and the mixture was stirred at 60° C. for 10 min. Following the addition of chloroacetic acid (0.77 g, 8.18 mmol), the reaction mixture was heated at 80° C. for 3 h. The cooled mixture was then poured into H2O and the aqueous phase acidified to pH 1.0 with a 2.0 N HCl solution. The aqueous phase was then extracted with EtOAc (3×20 mL), and the combined organic phase washed with brine and dried over Na2SO4 to afford the title compound (1.11 g, 75%), which was used in the following step without further purification. 1H NMR (DMSO-d6): δ 2.83 (t, J=7.0 Hz, 2H), 3.67 (t, J=7.0 Hz, 2H), 4.00 (s, 2H), 7.15-7.32 (m, 5H), 12.64 (s, 1H).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12](=[N:16][OH:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:18]([NH:22][C:23]([O:17][N:16]=[C:12]1[C:13](=[O:15])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: O=C1C(=NO)c2ccccc2-c2ccccc21
Reactant: CCCCN=C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)ON=C1C(=O)c2ccccc2-c2ccccc21
Yield: 99.3 %

Procedure:
22.3 g (0.1 mole) of 9,10-phenanthrene-dione-9-oxime are reacted with 12 ml (0.11 mole) of n-butyl isocyanate in 100 ml of chloroform in the presence of 0.2 ml of triethyl amine for an hour. The reaction mixture is heated to boiling for half an hour and evaporated in vacuo. Thus 32 g of 9,10-phenanthrene-dione-9-(n-butyl-aminocarbonyl)-oxime are obtained in the form of a yellowish brown oil, yield 99%.
Reaction SMILES: [C:1]([NH:4][CH:5](P(OC)(OC)=O)[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].C1CCN2C(=NCCC2)CC1.[O:27]1[CH:31]=[CH:30][C:29](C=O)=[C:28]1C=O>C(Cl)(Cl)Cl>[O:27]1[C:31]2[CH:30]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[N:4]=[CH:1][C:2]=2[CH:29]=[CH:28]1
Reactant: O=Cc1ccoc1C=O
Reactant: COC(=O)C(NC(C)=O)P(=O)(OC)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2occc2cn1
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
Methyl (acetylamino)(dimethoxyphosphoryl)acetate (2.34 g, 9.8 mmol) is dissolved in CHCl3 (40 mL), treated with DBU (1.46 mL, 9.8 mmol), stirred for 5 min then added dropwise to a 0° C. solution of furan-2,3-dicarbaldehyde (1.65 g, 8.9 mmol) in CHCl3 (80 mL). The mixture is stirred for 2.5 h as the cooling bath expires then 5.5 h at RT and finally 24 h at 50° C. The mixture is concentrated in vacuo to a yellow oily-solid (6.66 g). The crude material is chromatographed over a standard 100 g slurry-packed silica gel, eluting with 65% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 1.30 g (82%) of methyl furo[3,2-c]pyridine-6-carboxylate as a yellow solid. MS (EI) m/z: 177 (M+).
Reaction SMILES: [N+:1]([CH:4]([CH:10]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-])=O.Cl.[Cl:25]CCl>C(O)C.[Pd]>[ClH:25].[NH2:1][CH:4]([CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C1c2ccccc2Oc2ccccc21)[N+](=O)[O-]
Reactant: ClCCl
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)C1c2ccccc2Oc2ccccc21

Procedure:
Ethyl α-nitro-9H-xanthene-9-acetate (7.5 g, 24 mmol) is dissolved in 150 mL of ethanol and 2 mL of concentrated hydrochloric acid and hydrogenated over 1.0 g of 20% palladium on carbon (53 hours, 51 pounds per square inch (psi)). The filtered solution is stripped of solvent and washed with dichloromethane. This gives 4.83 g of the title compound. An additional crop, 0.61 g is obtained after cooling the dichloromethane wash. The crops are combined and used in the next step.