Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][N:14]([C:16](=[O:18])[CH3:17])[OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=[O:24]>N12CCCN=C1CCCCC2.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][N:14]([C:16](=[O:18])[CH3:17])[O:15][C:23](=[O:24])[NH:22][CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: CC(=O)N(O)Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)ON(Cc1ccc(OCc2ccccc2)cc1)C(C)=O
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A mixture of N-(4-benzyloxybenzyl)acetohydroxamic acid (1.35 g), methyl isocyanate (0.65 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene catalyst (1 drop) in tetrahydrofuran (10 ml) was stirred for 3 hours then left overnight to provide N-(4-benzyloxybenzyl)-O-methylcarbamoylacetohydroxamic acid (1.35 g) m.pt. 101°-102° [from ethyl acetate-light petroleum (b.pt. 60°-80°)].
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].C(=O)(O)O.N[NH:13][C:14]([NH2:16])=[NH:15].C(=O)(O)O.[NH2:21][C:22]([NH2:24])=[NH:23]>O>[C:1]([O-:7])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[NH2:15][C:14]([NH2:16])=[NH2+:13].[NH2:23][C:22]([NH2:24])=[NH2+:21]
Reactant: N=C(N)NN
Reactant: O=C(O)CC(=O)O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Product: NC(N)=[NH2+]
Product: O=C([O-])CC(=O)[O-]
Temperature: 90 °C

Procedure:
Malonic acid (200.0 g, 1.922 mol) was weighed into a 2-liter beaker with a magnetic stir bar and dissolved in 1500 ml of distilled water. Aminoguanidine bicarbonate (313.9 g, 2.31 mol) and guanidine carbonate (138.5 g, 0.769 mol) were added in portions with stirring as to avoid bubbling over the sides of the beaker due to the evolution of carbon dioxide during the reaction. The reaction was stirred at room temperature overnight (approximately 24 hours). The water was removed from the reaction mixture in vacuo with heating to approximately 90° C. for 4 hours. The product was recovered as a crystalline white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1
Reactant: CCOC(=O)CCCCl
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 105 °C
Yield: 53 %

Procedure:
Ethyl 4chlorobutyrate (0.154 ml, 1.1 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1 mmol), (prepared as described for the starting material in Example 2), and anhydrous potassium carbonate (690 mg, 5 mmol) in DMF (10 ml). The mixture was stirred and heated at 105° C. for 4 hours then allowed to cool. The mixture was diluted with methylene chloride and the insolubles were removed by filtration. The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (1008/1). The purified product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(3-ethoxycarbonylpropoxy)-6-methoxyquinazoline (230 mg, 53%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C[CH2:66][N:67](C(C)C)[CH:68]([CH3:70])[CH3:69].CNC(C)C>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:16]4[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:67]([CH:68]([CH3:70])[CH3:69])[CH3:66])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: CNC(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CC(C)N(C)C(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (120 mg, 0.29 mmol), PyBOP® (150 mg, 0.29 mmol), DIEA (152 μL, 0.87 mmol) in CH2Cl2 (5 mL) was stirred at RT for 10-15 minutes. To this solution of activated acid was added N-methylpropan-2-amine (30 μL, 0.29 mmol). The reaction mixture was stirred at RT for 3 h and concentrated in vacuo. The crude product was purified using prep HPLC (method 5-25-50_80 mins) and was further washed with ethyl ether and drops of CH2Cl2 to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropyl-N-methylacetamide. (12 mg, 0.025 mmol, 9%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>CC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18]([N:35]=[N+:36]=[N-:37])=[O:19])=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCC(=O)N=[N+]=[N-]
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
5-Bromo-3-(3-carboxy-propyl)-1H-indole-2-carboxylic acid ethyl ester (1.2 g, 3.40 mmol, 1.0 equiv) (see Example 2) was dissolved in 30 mL of acetone, cooled to −5° C. and triethylamine (0.76 ml, 5.44 mmol, 1.6 equiv) was added. To this cold solution, ethyl chloroformate (0.6 mL, 5.44 mmol, 1.6 equiv) was added dropwise and the mixture was stirred for 30 min at 0° C. A solution of sodium azide (440 mg, 6.8 mmol, 2.0 equiv) in 2 mL of water was added slowly and the mixture was stirred for a further 1 h at 0° C. The reaction mixture was then poured into ice-water (50 mL) and extracted 3×50 mL of diethyl ether. The pooled organic fractions were washed with 1×50 mL of water, 1×50 mL of saturated sodium bicarbonate, 1×50 mL of water, dried (Na2SO4), filtered and evaporated on the rotovap to provide 3-(3-azidocarbonyl-propyl)-5-bromo-1H-indole-2-carboxylic acid ethyl ester (1.28 g, 100%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH:6]1[O:10][O:9][C:7]1=[O:8])([CH2:4]O)[CH3:3].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1.ClCCl>[CH2:13]([O:10][C@@H:6]1[C:2]([CH3:1])([CH3:3])[CH2:4][O:9][C:7]1=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(CO)C1OOC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)COC(=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of D(−)-pantolactone (20.0 g, 153.7 mmol) and sodium hydride (4.4 g, 184.4 mmol) in anhydrous THF was stirred under an atmosphere of nitrogen at room temperature for 1 hour. The resultant mixture was treated with benzyl bromide (31.5 g, 184.4 mmol) and stirred at room temperature overnight. The product mixture was treated with water and diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to purification on silica gel eluting with 0-5% methanol in dichloromethane gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[O:30][CH:29]([OH:34])[CH2:28][CH2:27]2>O1CCCC1.CCCCCC>[OH:34][CH:29]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][N:16]=1)[CH2:28][CH2:27][C:26]1[CH:25]=[C:24]([O:23][CH3:22])[CH:33]=[CH:32][C:31]=1[OH:30]
Reactant: c1cnccn1
Reactant: COc1ccc2c(c1)CCC(O)O2
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(O)c(CCC(O)c2cnccn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (8.5 ml, 50.4 mmol) in 200 ml of anhydrous tetrahydrofuran was cooled to −30° C., n-butyllithium (20 ml of a 2.5 M solution in hexane, 50 mmol) was added dropwise, and the mixture stirred for 30 min at 0° C. After cooling at −70° C., a solution of pyrazine (4.0 g, 49.9 mmol) in 50 ml of anhydrous tetrahydrofuran was added dropwise. After 10 min at −70° C., 6-methoxy-chroman-2-ol (1.8 g, 10.0 mmol) was added and stirring was continued at −70° C. for 1.5 h. The reaction mixture was quenched with 20 ml of water and hydrochloric acid added until pH 5-6 was reached. After extraction with ethyl acetate, the organic layer was washed with water and brine, dried with sodium sulfate and concentrated. The obtained crude orange oil (960 mg) was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1.S(Cl)(Cl)=O.[CH3:19][C@H:20]1[O:25][C@@H:24]([CH3:26])[CH2:23][N:22]([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[CH2:21]1.CCN(C(C)C)C(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:31][NH:30][C:28](=[O:29])[CH2:27][N:22]2[CH2:23][C@H:24]([CH3:26])[O:25][C@H:20]([CH3:19])[CH2:21]2)=[O:14])[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: Cn1ncc2c(C(=O)O)cc(Br)cc21
Reactant: C[C@@H]1CN(CC(=O)NN)C[C@H](C)O1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(CC(=O)NNC(=O)c2cc(Br)cc3c2cnn3C)C[C@H](C)O1
Temperature: 100 °C
Yield: 60.7 %

Procedure:
6-Bromo-1-methyl-1H-indazole-4-carboxylic acid (480 mg, 1.882 mmol) was suspended in thionyl chloride (4.12 ml, 56.5 mmol) and heated to 100° C. for 30 mins. The thionyl chloride was removed in vacuo and excess azeotroped with dry diethyl ether to give a yellow solid. This was dissolved in dry tetrahydrofuran (THF) (15 ml) and 2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetohydrazide (529 mg, 2.82 mmol) and DIPEA (1.315 ml, 7.53 mmol) were added. The reaction mixture was heated to 60° C. for 20 mins. Solvent was removed in vacuo and the residue partitioned between dichloromethane (15 ml) and water (15 ml). The layers were separated and the organic phase concentrated in vacuo to give a green solid which was purified by column chromatography, loading in dichloromethane and purified on Flashmaster 11 silica (Si) 20 g using a 0-100% ethyl acetate-cyclohexane+0-20% MeOH over 30 mins. The appropriate fractions were combined and evaporated in vacuo to afford the title compound as a yellow solid (485 mg). LCMS (Method A) Rt 0.49 min, MH+ 424.
Reaction SMILES: [F:1][C:2]([F:31])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([CH2:22][C:23]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].CO.[BH4-].[Na+].O>C(Cl)Cl>[F:31][C:2]([F:1])([O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH:23]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[OH:24])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=C(CS(=O)(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1)C1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(CC(O)C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Crude 2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazin-1-yl}sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)ethanone (3.60 g, 0.008M) was dissolved in DCM (120 ml) and methanol (40 ml) at ambient temperature and sodium borohydride (334 mg, 0.0088 mol) was added. Stirred for 2 hours, added H2O (250 ml) and extracted with DCM. Collected the organic phase, dried over MgSO4, filtered and evaporated to dryness to yield 2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazin-1-yl}sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)ethanol (3.6 g, 95%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]12[C:17]2=[CH:18][C:19]3[O:23][CH2:22][O:21][C:20]=3[CH:24]=[C:16]2[O:15][CH2:14]1.Br[CH2:26][C:27]1[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:26][C:27]1[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)[C:8](=[O:13])[C:7]12[C:17]2=[CH:18][C:19]3[O:23][CH2:22][O:21][C:20]=3[CH:24]=[C:16]2[O:15][CH2:14]1
Reactant: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2Cc1ccc(C(F)(F)F)o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a suspension of sodium hydride (0.03 g, 0.63 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide (5.00 mL) was slowly added a solution of 5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.10 g, 0.33 mmol) in N,N-dimethylformamide (5.00 mL) at 0° C. After stirring for 15 minutes at 0° C., a solution of 2-(bromomethyl)-5-(trifluoromethyl)furan (0.11 g, 0.49 mmol) in N,N-dimethylformamide (40.0 mL) was added. The resulting mixture was stirred at ambient temperature for 4 h and quenched with water (20.0 mL). The mixture was extracted with ethyl acetate (3×25.0 mL). The combined organic layers was washed with water (50.0 mL) and brine (2×25.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (15-50%) to afford the title compound (0.11 g, 77% yield): mp 96-98° C.; 1H NMR (300 MHz, CDCl3) δ 7.09 (d, 1H), 7.00 (s, 1H), 6.87 (d, 1H), 6.74 (d, 1H), 6.52 (s, 1H), 6.38 (d, 1H), 6.11 (s, 1H), 5.88 (d, 2H), 4.96 (ABq, 2H), 4.80 (ABq, 2H), 2.29 (s, 3H); MS (ES+) m/z 444.2 (M+1).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([C:24]#N)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([OH:28])C.[OH-].[K+]>CCCCCC>[C:18]1([CH:17]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:24]2=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCO
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: N#CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Product: O=C1OC(c2ccccc2)CC(c2ccccc2)C1c1ccccc1

Procedure:
20.8 g (0.1 mol) of chalcone (1,3-diphenyl 1-propenone) are dissolved hot in 12.0 g (0.102 mol) of benzyl cyanide. 60 ml of hexane-absolute alcohol mixture (20-80) are added; the reaction medium is cooled to 0° C. in an ice-salt mixture. The catalyst (8 ml of 2 N ethanol KOH) is then added slowly. Crystallisation intervenes very quickly in the vessel, about 1 hour after the beginning of pouring which lasts 3/4 of an hour. The vessel is then placed in the refrigerator for the night.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:22]([NH:21][CH2:19][CH3:20])=[O:23])[S:3][C:4]=2[CH:10]=1
Reactant: CCN=C=O
Reactant: Nc1nc2ccc(Br)cc2s1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Temperature: 90 °C
Yield: 94 %

Procedure:
A suspension of 2-amino-6-bromo-benzothiazole (6.12 g, 26.2 mmol), triethylamine (7.30 mL, 52.4 mmol, 2.0 eq), and ethyl isocyanate (4.15 mL, 52.4 mmol, 2.0 eq) in 50 mL toluene was heated at about 90° C. for about 15 hours. The precipitate was filtered off, washed with Et2O, and dried under vacuum to give the desired compound 7.39 g (94%). LC/MS 300.0 (M−1); LC retention time 3.01 min.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[H-].[Na+].[CH3:13][O:14][C:15](=[O:18])[CH2:16]Br>CN(C=O)C.O>[CH3:13][O:14][C:15](=[O:18])[CH2:16][N:7]1[C:6](=[O:8])[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=[C:2]1[Cl:1]
Reactant: COC(=O)CBr
Reactant: O=c1[nH]c(Cl)nc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(Cl)nc(Cl)c(Cl)c1=O
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a solution of 2,5,6-trichloro-3H-pyrimidin-4-one (20.0 g, 0.1 mol) in DMF (150 mL) was added NaH (60% in mineral oil, 6.0 g, 0.12 mol) in portions at 0° C. and the mixture was stirred for 30 min. Bromoacetic acid methyl ester (18.3 g, 0.12 mol) was then added, and the reaction mixture was stirred at RT overnight. The solution was diluted with water (800 mL) and extracted with EA (200 mL, 3×). The combined organics were washed with water (800 mL, 3×), washed with brine (500 mL), dried (Na2SO4) and concentrated. The residue was purified by silica chromatography (1:50, EA:PE) to give 6.0 g of the title product (22%). 1H NMR (400 MHz, CDCl3): δ 3.80 (s, 3H), 5.04 (s, 2H). [M+H] Calc'd for C7H5Cl3N2O3, 271. Found, 271.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:24])[CH:19]=[N:20][C:21]=1[O:22][CH3:23].N1C=CC=CC=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:19]=[N:20][C:21]=1[O:22][CH3:23]
Reactant: COc1cc(N)cnc1OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cnc1OC
Yield: 38.3 %

Procedure:
The title compound (1.56 g, 4.60 mmol) was prepared from 2-nitrobenzenesulfonyl chloride (2.66 g, 12.0 mmol), 5,6-dimethoxy-3-pyridinamine (2.04 g, 13.2 mmol) and pyridine (2.9 mL, 36.0 mmol) using the methods of (IntA1), step 1.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:12]([O-])=O.[Na+].N>O.C(O)(=O)C.C(OCC)(=O)C>[N+:9]([C:8]1[CH:7]=[CH:6][CH:5]=[C:3]2[C:2]=1[CH:1]=[N:12][NH:4]2)([O-:11])=[O:10]
Reactant: O=N[O-]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2[nH]ncc12
Reaction time: 72 h

Procedure:
A mixture of 2-methyl-3-nitro-aniline (5.00 g, 32.9 mmol) and a solution of sodium nitrite (2.27 g, 32.9 mmol) in water (7.5 mL) in glacial acetic acid (750 mL) was was stirred for 15 minutes and allowed to stand at room temperature for 3 days. The mixture was concentrated under reduced pressure leaving a pale yellow solid which was dissolved in ethyl acetate (250 mL) and filtered through a plug of silica gel, rinsing with ethyl acetate. The combined ethyl acetate was concentrated under reduced pressure to provide a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.65 (m, 1H), 8.10 (m, 1H), 8.16 (m, 1H), 8.54 (s, 1H), 13.9 (s, 1H); MS (DCI/NH3) m/z 164 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:29]1([C:33]([NH:35][C:36]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:37]=2[C:38]([NH:40][CH2:41][C:42](O)=[O:43])=[O:39])=[O:34])[CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH:18][C:42](=[O:43])[CH2:41][NH:40][C:38](=[O:39])[C:37]1[CH:45]=[C:46]([C:49]([F:51])([F:52])[F:50])[CH:47]=[CH:48][C:36]=1[NH:35][C:33]([N:29]1[CH2:32][CH2:31][CH2:30]1)=[O:34])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCC1
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
(2S,3S)-(2-Amino-3-hydroxy-hex-4-ynyl)-carbamic acid benzyl ester (520 mg, prepared as in WO PCT 0250019) was dissolved in CH2Cl2 (20 ml) and DIEA (0.74 ml) and cooled to 0° C. prior to the addition of {2-[(azetidine-1-carbonyl)-amino]-5-trifluoromethyl-benzoylamino}-acetic acid (684 mg, prepared as in WO PCT 0250019) and HATU (756 mg). After the reaction was stirred overnight at room temperature, the CH2Cl2 was removed and EtOAc was added. The organic layer was washed with saturated NH4Cl solution (aq) brine, dried, filtered, and concentrated. Flashed chromatography of the resulting residue gave (2S,3S)-[2-(2-{2-[(azetidine-1-carbonyl)-amino]-5-trifluoromethyl-benzoylamino}-acetylamino)-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (745 mg). MS found: (M+H)+=590.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[CH:17]1([C:20]([Cl:22])=[O:21])[CH2:19][CH2:18]1>N1C=CC=CC=1>[ClH:22].[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[N:4]=[C:5]([NH:9][C:20]([CH:17]2[CH2:19][CH2:18]2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Solvent: c1ccncc1
Product: CN1CCC(N(C)c2cccc(NC(=O)C3CC3)n2)CC1
Product: Cl
Yield: 73.7 %

Procedure:
Prepare according to procedure in Example 69 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34, 175 mg, 0.794 mmol), cyclopropanecarbonyl chloride (108 μL, 1.19 mmol), and pyridine (15 mL) to yield 190 mg (74%) of the title compound: mass spectrum (ion spray): m/z 289.1 (M+1); Analysis Calc'd for C16H25N4OCl.0.1H2O: C, 58.83; H, 7.78; N, 17.15. Found: C, 58.69; H, 7.71; N, 17.31. mp 258-60° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:18](=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:33])[C:3]=1[C:34]([OH:36])=[O:35].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([O-:41])=[O:40].[NH3+:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([NH:17][C:14]([CH3:16])([CH3:15])[CH2:13][O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH3+:1])=[C:3]([C:34]([OH:36])=[O:35])[C:4]([CH3:33])=[N:5]2)=[O:32].[F:37][C:38]([F:43])([F:42])[C:39]([O-:41])=[O:40]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc2cccc(OCC(C)(C)NC(=O)CCCCCNC(=O)OC(C)(C)C)c2c(N)c1C(=O)O
Solvent: ClCCl
Product: Cc1nc2cccc(OCC(C)(C)NC(=O)CCCCC[NH3+])c2c([NH3+])c1C(=O)O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of 4-amino-5-(2-(6-(tert-butoxycarbonylamino)hexanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylic acid (Example 20a) (59.6 mg, 0.12 mmol) in CH2Cl2 (9.0 mL) was treated with trifluoroacetic acid (1.0 mL) at room temperature. After being stirred at room temperature for 2 h the reaction mixture was evaporated to dryness. The residue was dissolved in H2O (5.0 mL) and the product was isolated by preparative HPLC (RPC18, H2O→CH3CN gradient). The appropriate fractions were collected and evaporated under reduced pressure. The residue was dried in a dessicator over phosphorus pentoxide to give 43.6 mg (58%) of 5-(2-(6-ammoniohexanamido)-2-methylpropoxy)-3-carboxy-2-methylquinolin-4-aminium trifluoroacetate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.98 (s, 1H), 9.40 (s, 1H), 7.88 (t, J=8.3 Hz, 1H), 7.75 (s, 1H), 7.72-7.56 (m, 3H), 7.42 (d, J=7.9 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 4.42 (s, 2H), 2.81 (s, 3H), 2.72-2.60 (m, 2H), 2.08 (t, J=7.3 Hz, 2H), 1.50-1.39 (m, 4H), 1.38 (s, 6H), 1.26-1.14 (m, 2H). MS 404 (M+).