Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:11]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C1CCCCC(=O)O1
Solvent: CCOC(C)=O
Product: O=C(O)CCCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
28 g of finely powdered p-nitrophenol were added to 25.6 g of adipic anhydride and the mixture was stirred at room temperature overnight, whereupon the contents of the flask solidified. The mass was melted, whilst stirring, and the melt was dissolved in 350 ml of ethyl acetate. The solution was extracted several times with water and the ethyl acetate was distilled off in vacuo. The residue was recrystallised three times from acetonitrile. Yield: 45.2 g (85% of theory) of melting point 104°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH2:19][O:20][CH3:21])[CH2:17][CH3:18])[C:10]=1[N+:22]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH2:19][O:20][CH3:21])[CH2:17][CH3:18])[C:10]=1[NH2:22]
Reactant: CCC(COC)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(COC)Nc1nccc(-c2ccc(Cl)cc2Cl)c1N
Yield: 57 %

Procedure:
[4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.25 g, 0.67 mmol) and Na2S2O4 (0.95 g, 5.45 mmol) were treated substantially as described in Part E of Example 9 to yield 0.13 g (56%) of 4-(2,4-dichloro-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 340.3 [(M+H)+, 100].
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:35][C:24]4([CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[CH2:23]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:35][C:24]4([CH2:27][NH:26][CH2:25]4)[CH2:23]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:36])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CC2(CNC2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.23 %

Procedure:
(Z)-tert-butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.13 g) was dissolved in DCM (1.5 mL). The reaction mixture was cooled to 0° C. and CF3COOH (1.5 mL) was added. The reaction mixture was allowed to warm to room temp. where it was stirred for 4 h. The reaction mixture was concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.100 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (Yield 95.23%). 1H NMR (400 MHz, DMSO) δ 9.49 (s, 1H), 8.52-8.5 (m, 3H), 8.32 (s, 1H), 7.44-7.42 (d, 1H, J=10.4 Hz), 5.97-5.94 (d, J=10.4 Hz, 1H), 4.37-3.93 (m, 8H); LCMS calcd for C18H16F6N5O [M+H]+ 432.34. found 432.29 at retention time 2.256 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[CH:13][CH:12]=1)(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[CH:15][CH:16]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: NCC(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Yield: 42.3 %

Procedure:
A slurry of 0.166 g (0.44 mmol) of {[4-(3-fluoro-benzyloxy)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester in 1 ml diethyl ether is treated with 3 ml of a saturated solution of gaseous hydrochloric acid in diethyl ether. The mixture is refluxed for 4 h, poured on water and made basic by addition of a saturated sodium carbonate solution. Extraction with ethyl acetate yields a yellowish solid which is dissolved in about 1 ml of diethyl ether and treated with a few drops of a saturated solution of gaseous hydrochloric acid in diethyl ether. The precipitate is filtered to give 0.051 g (37%) of a colorless solid. MS: m/e=275.2 (M++H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C:10](=[N:13]O)[CH2:9]2)=[CH:4][CH:3]=1.N.CO>[Ni].O>[C:5]1([C@H:8]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: ON=C1CC[C@H](c2ccc(Br)cc2)C1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: NC1CC[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 32 h
Yield: 92.1 %

Procedure:
A solution of Example 1C (10 g, 39.4 mmol) and 7M NH3/MeOH (100 mL) was added to Ra—Ni 2800, water slurry (40.0 g, 682 mmol) in a 50 mL pressure bottle. The mixture was stirred at room temperature for 32 hours at 30 psi. HPLC indicated complete reaction. The mixture was filtered through a nylon membrane, concentrated, and diluted with MTBE (300 mL) and 2N NaOH (150 mL). The layers were separated and the organic layer was washed with water (100 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated to afford the title compound (5.86 g, 36.3 mmol, 92%). MS (LCMS) m/z 162 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][C:9]2=[N:12]O)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][CH2:10][CH:9]2[NH2:12])=[CH:6][CH:7]=1
Reactant: ON=C1CCC1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC1CCC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
To a solution of 2-(4-chlorophenyl)cyclobutanone oxime (200 mg, 1 mmol) in methanol (5 ml) was added MoO3 (205 mg, 1.4 eq.) and sodium borohydride (394 mg, 10 eq) at 0° C. After stirring at rt for 2 h the solvent was evaporated. A mixture of H2O and CH2Cl2 was added. Organic phase was separated, washed with brine, dried and concentrated in vacuo. 120 mg of product-amine was isolated as a mixture of cis and trans isomers 2:1. The crude product without purification was used for the next reaction.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.[OH:29][C:30]1[C:38]2[N:37]=NNC=2C=[CH:32][CH:31]=1.C(N(CC)CC)C.NCC(O)CC>C(Cl)Cl.O>[CH2:10]([O:9][C:7](=[O:8])[NH:1][CH2:2][CH2:3][C:4](=[O:6])[NH:37][CH2:38][CH:30]([OH:29])[CH2:31][CH3:32])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CCC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(O)CNC(=O)CCNC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A mixture comprising Z-Beta-Ala-OH (9.0 g, 40.3 mmol), EDCI.HCl (10.0 g, 52.4 mmol), hydroxybenzotriazole (5.45 g, 40.3 mmol), triethylamine (7.3 ml, 52.4 mmol) in DCM (150 ml) is stirred at 0° C. for 30 minutes. 1-amino-2-butanol (4.2 ml, 44.3 mmol) is added in one portion and stirring continues for 1 hour. The reaction mixture is diluted with water (150 ml) and extracted with dichloromethane (2×150 ml) The organic layers are combined, dried over MgSO4, filtered and concentrated in vacuo to yield a crude white solid. The product is purified by chromatography on silica eluting with ethanol-ethyl acetate (1:10) to give the titled compound.
Reaction SMILES: [O:1]([C@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>[Fe](Cl)(Cl)Cl.C(OCC)(=O)C>[C:14]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:4]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)[C@@H](C)Oc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl[Fe](Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)Oc1ccc(C(C)=O)cc1
Yield: 80 %

Procedure:
A mixture of 36 g (0.2 mol) of methyl (R)-2-phenoxypropionate (enantiomeric excess 94-95%), 81.6 g (0.8 mol) of acetic anhydride, 6.5 g (0.04 mol) of iron(III) chloride and 100 ml of ethyl acetate was heated at 70°-75° C. for 6 hours. The diluent and excess acetic anhydride were then removed under reduced pressure, after which the crude product was subjected to vacuum distillation. Yield: 80% (94-95% enantiomeric excess).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:23]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.[CH3:36][O:37][C:38](=[O:44])[CH:39]([CH3:43])[C:40](O)=[O:41]>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:36][O:37][C:38](=[O:44])[CH:39]([CH3:43])[C:40]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][CH:27]=1)=[O:41]
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
HOBt (245 mg, 1.8 mmol), DMAP (370 mg, 3.0 mmol), EDCI.HCl (348 mg, 1.8 mmol) followed by biphenyl-4-ylamine (307 mg, 1.8 mmol) were added to a stirred solution of 2-methyl-malonic acid monomethyl ester (200 mg, 1.5 mmol) in DMF (3 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution and concentrated under reduced pressure to afford 330 mg (77%) of N-biphenyl-4-yl-2-Methyl-malonamic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22](O)=[O:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH3:33][N:34](C)[CH:35]=O>C(Cl)Cl>[N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22]([N:34]([CH3:35])[CH3:33])=[O:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: CC(=O)S[C@H]1C[C@@H](CC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](CC(=O)N(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-carboxymethyl-4-acetylthiopyrrolidine (125 mg) was dissolved in 1 ml of dry methylene chloride, and 0.1 ml of oxalyl chloride and a catalytic amount of dimethylformamide were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was distilled to remove the solvent, and dry benzene was added to the residue, followed by distillation of benzene. After two times repetition of the above procedure, the resulting residue was dissolved in 2 ml of dry methylene chloride. The resultant mixture was added to a solution of 45 mg of dimethylamine in 1.5 ml of dry methylene chloride and 0.2 ml of dry tetrahydrofuran under nitrogen stream at 0° C., followed by stirring at the same temperature for 30 minutes. The reaction mixture was diluted with methylene chloride, washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2R,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonylmethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](=O)[CH3:16])=[C:13]([OH:18])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH3:16])=[C:13]([OH:18])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCc1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of 1-[6-benzyloxy-2-hydroxy-3-(5-methyl-7-nitroindan-4-yloxy)phenyl]ethanone (1.081 g) in dichloromethane (18 mL) were added triethylsilane (0.955 mL) and trifluoroacetic acid (6 mL). The mixture was stirred at room temperature overnight. Adding water, the reaction mixture was stirred for 30 min and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from dichloromethane and hexane to give the title compound (663 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1
Reactant: O=[N+]([O-])c1ccc2occc2c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2occc2c1

Procedure:
To a solution of all of the 5-nitrobenzofuran in 90% ethanol (50 ml) kept at reflux were added small portions of Fe powder (in total 2.5 g) and concentrated HCl (in total 0.1 ml) during 10 min. The mixture was refluxed for another hour. The inorganic precipitates were filtered off and the mixture was poured onto brine and ethyl acetate (250 ml). work-up of the organic phase afforded 1 g of crystalline 5-aminobenzofuran derivative.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:18]1[N:19]=[CH:20][C:21]3[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Yield: 84 %

Procedure:
6-bromo-2-isoquinolin-3-yl-chromen-4-one oxime was prepared using the method D, (step 2) illustrated in example 1C. 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (50 mg, 0.12 mmol) was treated with a 1M solution of titanium tetrachloride (0.35 ml, 0.35 mmol) in dichloromethane (3 ml) to yield 6-bromo-2-isoquinolin-3-yl-chromen-4-one oxime (37 mg, 85%) as a yellow solid after recrystallization in hot chloroform. The compound was isolated as a 98/2 mixture of Z/E oxime isomers.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]([CH3:30])[C:27]([OH:29])=O)=[CH:23][C:22]=4[F:33])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C[N:35]1CCOCC1.ClC(OCC(C)C)=O.CO.ClCCl>COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][C@@H:26]([C:27](=[O:29])[NH2:35])[CH3:30])=[CH:23][C:22]=3[F:33])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(N)=O
Temperature: -10 °C
Yield: 60.1 %

Procedure:
To a stirred solution of (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid (0.25 g, 0.55 mmol) in ethylene glycol dimethyl ether (20 mL) at −10° C. was added N-methyl morpholine (0.06 mL, 0.55 mmol) followed by dropwise addition of isobutyl chloroformate (0.071 mL, 0.55 mmol). The turbid solution was stirred at −10° C. 10 min. Ammonia gas was bubbled through the reaction mixture 10 min, which was then warmed to room temperature and stirred a further 15 min. The reaction mixture was partitioned between chloroform and water. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford a white solid. Flash column chromatography (1% methanol/dichloromethane) yielded 0.15 g of a white solid (60% yield).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[O:10])=[N:6][CH:7]=1.[CH3:21][O-:22].[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:20][O:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[NH:11][C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([O:22][CH3:21])=[CH:7][N:6]=1)=[O:10]
Reactant: COc1ccc(C)cc1NC(=O)Nc1cnc(Br)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cnc(NC(=O)Nc2cc(C)ccc2OC)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 13 %

Procedure:
To a stirred solution of 1-(5-bromo-pyrazin-2-yl)-3-(2-methoxy-5-methyl-phenyl)-urea (47 mg; 0.14 mmol) in N-methyl pyrrolidinone (300 μL) was added sodium methoxide (0.5 mmol). The reaction was heated to 100° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), brine (30 mL), then dried (MgSO4), and filtered. The crude product was purified using a 0.5 mm prep plate eluting with hexane and ethyl acetate (1:1) to yield a yellow solid (13% yield). 1H NMR (400 MHz, CDCl3) δ8.12 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 6.80 (dd, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 2.38 (s, 3H). LRMS (ESI, Positive) m/e 289.10 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1)[CH3:2].[H-].[Na+].I[CH3:19].O>C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1)[CH3:19])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)c1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of (3-bromo-4-methoxy-phenyl)-acetic acid ethyl ester (1.45 g, 5.12 mmol, 1.00 eq.) in THF (18 mL), sodium hydride (60% dispersion in mineral oil, 225 mg, 5.63 mmol, 1.10 eq.) was added. The reaction mixture was stirred at r.t. for 30 min. Iodomethane (0.34 mL, 5.38 mmol, 1.05 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. Water was carefully added. THF was removed in vacuo. The residue was extracted with AcOEt (2×). The org. layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 25 fractions of 40 mL, Heptane 100% to Heptane+15% AcOEt) to yield the title compound as a yellow oil.
Reaction SMILES: Cl.[C:2]([NH:6][C:7](=[O:14])[C@@H:8]1[CH2:12][C@H:11]([Cl:13])[CH2:10][NH:9]1)([CH3:5])([CH3:4])[CH3:3].[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:35]([OH:39])[C:36](O)=[O:37])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C@H:35]([OH:39])[C:36]([N:9]1[CH2:10][C@@H:11]([Cl:13])[CH2:12][C@H:8]1[C:7]([NH:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:14])=[O:37])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
680 mg (2.23 mmol) of (4S)-1-t-butoxycarbonyl-N-t-butyl-4-chloro-L-prolinamide (prepared as described in Preparation 2) were treated with 10 ml of a 4N solution of hydrogen chloride in dioxane, in order to eliminate the t-butoxycarbonyl group and give (4S)-N-t-butyl-4-chloro-L-prolinamide hydrochloride. The whole of the hydrochloride thus obtained and 880 mg (1.99 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) were dissolved in 5 ml of dimethylformamide, and the solution was cooled with ice. 420 mg (2.58 mmol) of diethyl cyanophosphate, followed by 640 mg (6.40 mmol) of triethylamine, were then added to the ice-cooled mixture, and the mixture was stirred for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with a 10% w/v aqueous solution of citric acid and then extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by preparative thin layer chromatography using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 850 mg of the title compound as a colorless powder, melting at 107°-109° C.
Reaction SMILES: CC(C1N=NC(NN)=CC=1)(C)C.[CH3:13][C:14]([C:17]1[N:22]=[N:21][C:20]([NH:23][N:24]=[C:25]([C:27]2[S:28][CH:29]=[CH:30][C:31]=2C)[CH3:26])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH3:16][C:14]([C:17]1[N:22]=[N:21][C:20]([NH:23][N:24]=[C:25]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH3:26])=[CH:19][CH:18]=1)([CH3:13])[CH3:15]
Reactant: CC(=NNc1ccc(C(C)(C)C)nn1)c1sccc1C
Agent: CC(C)(C)c1ccc(NN)nn1
Product: CC(=NNc1ccc(C(C)(C)C)nn1)c1cccs1

Procedure:
Other compounds prepared from 1-[6-(1,1-dimethylethyl)-3-pyridazinyl]hydrazine include; from 1.66 g of 3-methyl-2-acetythiophene, 1-(3-methyl-2-thienyl)ethanone[6-(1,1-dimethylethyl)-3-pyridazinyl]hydrazone, yield=1.27 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH:11]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1>[N:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:10]=[C:2]3[C:3]([C:4](=[O:5])[NH:6][C:23](=[O:24])[NH:1]3)=[CH:7][CH:8]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: NC(=O)c1ccc(C(c2ccccc2)n2ccnc2)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2ccc(C(c3ccccc3)n3ccnc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a stirred solution of 4.6 parts of 2-amino-4-[(1H-imidazol-1-yl)phenylmethyl]benzamide in 90 parts of tetrahydrofuran were added 3.52 parts of 1,1'-carbonylbis[1H-imidazole]. The mixture was stirred first overnight at room temperature and then for 48 hours at reflux temperature. The solution was concentrated under reduced pressure and the concentrate was treated with water. The product was extracted with dichloromethane. A white product was precipitated in the dichloromethane layer. This product was filtered off and crystallized from hot acetonitrile. The product was filtered off, washed with acetonitrile and 2,2'-oxybispropane and dried in vacuo at 60°-70° C., yielding 1.77 parts (35.4%) of 7-[(1H-imidazol-1-yl)phenylmethyl]-2,4(1H,3H)-quinazolinedione; mp. 287.2° C. (comp. 29).