Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20](=O)[CH2:19]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23][C:18]([CH3:27])([CH3:17])[CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(F)cc2)CC(C)(C)C1
Yield: 80.5 %

Procedure:
The general McMurry coupling procedure described for 14 was followed. To a stirred suspension of zinc powder (13.0 g, 0.2 mol) in THF (400 mL) was slowly added TiCl4 (11 mL, 0.10 mol) via a syringe at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 1 h. A solution of (4-fluorophenyl)(4-hydroxyphenyl)methanone (4.32 g, 0.02 mol) and 3,3,5,5-tetramethylcyclohexanone (9.26 g, 0.06 mol) in THF (100 mL) was added to the reaction mixture. The reaction mixture was heated at reflux for an additional 2 h. Standard work-up followed by purification gave 5.450 g (80%) of compound 231 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=5.7 Hz, 1H), 7.12 (d, J=5.7 Hz, 1H), 7.04 (d, J=8.7 Hz, 2H), 6.97 (dd, J=8.7 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 4.68 (s, 1H), 1.99 (s, 2H), 1.96 (s, 2H), 1.31 (s, 2H), 0.95 (s, 6H), 0.94 (s, 6H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:13]=1)[CH:11]=O>CO.[Pt]>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:13]=1)[CH2:11][NH:4][CH:1]1[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CC(C)c1ccc(Cl)cc1C=O
Agent: [Pt]
Solvent: CO
Product: CC(C)c1ccc(Cl)cc1CNC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Cyclopropylamine (3.26 g, 0.057 mol) was added to a solution of 5-chloro-2-isopropylbenzaldehyde (II) (10 g, 0.054 mol, 99.3 GC % by area) in methanol (100 ml) and the mixture was stirred at room temperature for 1 hour. Platinum on activated carbon (0.2 g, 5% Pt, dry) was subsequently added, the reaction vessel was flushed with nitrogen and pressurized to 6 bar with hydrogen at a maximum of 25° C. for 8 hours. The contents of the autoclave were filtered through Celite, washed with methanol and the solvent was distilled off under reduced pressure. N-(5-Chloro-2-isopropylbenzyl)cyclopropanamine (9.8 g, 96.8 GC-% by area, 78.0% of theory) was obtained as a light-yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3cnccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)sc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylthieno[2,3-c]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (209 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (169 mg, 86%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.Cl.[NH2:28][NH:29][C:30]([NH2:32])=[O:31].Cl.O/N=C(/C1C=CC(OCCOC2C=CC3C(=CC=CC=3)C=2)=CC=1)\C(O)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])/[C:4](=[N:28]/[NH:29][C:30]([NH2:32])=[O:31])/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1
Reactant: NNC(N)=O
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Agent: Cl
Agent: O=C(O)/C(=N\O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: c1ccncc1
Product: COC(=O)/C(=N/NC(N)=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 50 °C
Yield: 29.5 %

Procedure:
A mixture of 4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (1.75 g) in pyridine (25 mL) was warmed to dissolve and added semicarbazide hydrochloride (0.7 g). The stirred mixture was heated at 50° C. for 4 hours, cooled, acidified with hydrochloric acid and extracted twice with dichloromethane. The organic layers were washed with dilute hydrochloric acid, combined, dried (Na2SO4), filtered and evaporated to provide a crude mixture of (E) and (Z) isomers. The crude mixture was separated by HPLC (dichloromethane-tetrahydrofuran; 9:1) and the more polar component was crystallized from dichloromethane-methanol to provide 0.6 g of (E)-alpha-[(aminocarbonyl)hydrazono]-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid methyl ester as a colorless solid, mp 180°-181° C.
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][N:18]2[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30](C(OC(C)(C)C)=O)[CH:31]=[CH:32][C:25]=12)=[O:12])[CH3:2].Cl>CO>[ClH:9].[O:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][N:18]2[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[CH:32][C:25]=12)=[O:12])[CH3:2]
Reactant: COc1ccc(Cl)cc1NC(=O)Nc1cccc2c1CCN2Cc1ccnc2c1ccn2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc2c1CCN2Cc1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 184.9 %

Procedure:
1-(2-Methoxyl-5-chlorophenyl)-3-{1-[1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-2,3-dihydro-1H-indol-4-yl}urea (500 mg, 0.92 mmol) was added to a 25% HCl in methanol solution. The resulting reaction mixture was stirred at rt overnight, then concentrated to afford the product 1-(2-methoxyl-5-chlorophenyl)-3-[1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-2,3-dihydro-1H-indol-4-yl]urea hydrochloride (412 mg, 93%).
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:20])[CH:9]=2)[N:4]=[CH:3]1.[C:21]1(=[O:35])[N:25]([CH2:26][C:27](Cl)=[O:28])[C:24](=[O:30])[C:23]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:22]12>N1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:10]1[CH:9]=[C:8]([F:20])[CH:7]=[CH:6][C:5]=1[N:4]([CH:3]=[N:2][NH:1][C:27](=[O:28])[CH2:26][N:25]1[C:21](=[O:35])[C:22]2[C:23](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:24]1=[O:30])[C:27](=[O:28])[CH2:26][N:25]1[C:24](=[O:30])[C:23]2[C:22](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21]1=[O:35])=[O:19]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: NN1C=Nc2ccc(F)cc2C1(O)c1ccccc1Cl
Solvent: c1ccncc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 3-amino-6-fluoro-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with α-phthalimidoacetyl chloride to give 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-fluorophenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH3:20])=[C:15]([CH3:19])[C:16]=1[O:17][CH3:18])=[O:11])[CH3:2].C([O-])(=O)/C=C/C([O-])=[O:25].[N+]([O-])([O-])=O.[Ce].[NH4+].N>S(=O)(=O)(O)O.ClCCl.CO>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH:20]=[O:25])=[C:15]([CH3:19])[C:16]=1[O:17][CH3:18])=[O:11])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1sc(C)c(C)c1OC
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)c1sc(C=O)c(C)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±) N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-methoxy-4,5-dimethylthiophene-2-carboxamide, fumarate (3 g) in dilute sulphuric acid (100 ml concentrated sulphuric acid in 500 ml water) was added ammonium cerium nitrate (17.56 g) in one portion. After stirring at room temperature for 0.5 hours and then cooling to 0° C., 0.88 ammonia solution (235 ml) was added dropwise to give a neutral solution. This was extracted several times with dichloromethane, the organic extracts combined and washed with water, dried over magnesium sulphate and the solvent removed in vacuo to give a light brown oil. Column chromatography on silica eluting with 10% methanol in dichloromethane gave the pure free base of the title compound, fumarate salt, m.p. 122°-123° C. (ex ethyl acetate-ethanol as recrystallising solvent).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:22]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:22])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccc(SC)cc1C(=O)O
Solvent: O
Product: CCn1ncc2c(Cl)c3cc(SC)ccc3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-(methylthio) anthranilic acid (4.5 g) and POCl3 (20 mL) was refluxed overnight. The reaction mixture was poured into water, then ice was added. The mixture was extracted with CH2Cl2 and then the CH2Cl2 layer was evaporated. The residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate/hexane to afford 2.4 g of 1-ethyl-4-chloro-6-(methylthio)-1H-pyrazolo[3,4-b]quinoline, m.p. 120°-121° C.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-:11])=O)=[CH:7][CH:6]=1)(=O)C.[Na+].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:13][CH:12]=2)[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CC(=O)Oc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(O)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of sodium 4-acetoxybenzoate (1.0 g, 5.4 mmol) in thionyl chloride (15 mL) was heated at reflux for 1 h (the mixture became homogeneous). The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (150 mg, 0.77 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (180 mg, 0.73 mmol) and triethylamine (150 μL, 1.1 mmol) in methylene chloride (20 mL) . After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in 99.5% ethanol (15 mL) and concentrated hydrochloric acid (5 mL) was added. After 17 h, the pH was adjusted to 8 and the solvent evaporated in vacuo. The residue was partitioned between water and chloroform. The organic phase was separated, dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 70 mg (26%) of the title compound as an oil: [α]21D −17° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 365 (24, M+).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25](O)=[O:26])(=[O:3])[NH2:2].Cl.[CH3:29][N:30]1[CH2:33][CH:32]([NH2:34])[CH2:31]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:34][CH:32]4[CH2:33][N:30]([CH3:29])[CH2:31]4)=[O:26])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CN1CC(N)C1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Agent: Cl
Product: CN1CC(NC(=O)c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#CC(C)(C)O)cc2-3)C1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.06 g) was reacted with 1-methylazetidin-3-amine hydrochloride similar to as described in Example 2 to afford 13.4 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(1-methylazetidin-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 442 (M)+. 1H NMR (400 MHz, DMSO) δ 11.76 (d, J=6.7 Hz, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.41 (s, 1H), 7.90 (s, 1H), 7.01 (d, J=10.5 Hz, 1H), 5.48 (s, 1H), 5.01-4.93 (m, 2H), 4.55-4.49 (m, 2H), 4.37 (dd, J=13.4, 6.7 Hz, 1H), 3.58 (t, J=7.2 Hz, 2H), 2.84 (t, J=7.1 Hz, 2H), 2.24 (s, 3H), 1.49 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:26][O:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:26][O:27][CH3:28])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COCCl
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(I)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(I)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 76.3 %

Procedure:
A mixture of N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (4.75 g, 10 mmol), chloromethyl methyl ether (1.14 ml, 15 ml), potassium carbonate (2.76 g, 20 mmol) and acetone (50 mL) was refluxed for 8 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=3:1), and recrystallized (n-hexane/ethyl acetate) to give the title compound (3.96 g, 76.3%) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:52][CH2:53][N:54]([CH2:57][CH3:58])[CH2:55][CH3:56]>CN(C=O)C.CCOC(C)=O>[CH2:53]([N:54]([CH2:57][CH3:58])[CH2:55][CH2:56][N:24]1[CH2:25][CH2:26][CH2:27][C@@H:22]([N:18]2[C:19]3[C:14](=[CH:13][C:12]([C:9]4[CH:10]=[N:11][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:43])=[CH:7][C:8]=4[C:34]4[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=4)=[CH:21][CH:20]=3)[C:15](=[O:33])[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:17]2)[CH2:23]1)[CH3:52]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCNC2)cn1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCN(CCN(CC)CC)C2)cn1
Temperature: 100 °C
Yield: 17.5 %

Procedure:
(R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate (Example 262, 0.100 g, 0.16 mmol) was taken up in DMF (2 mL), K2CO3 (0.112 g, 0.81 mmol) and 2-chloro-N,N-diethylethanamine hydrochloride (0.031 g, 0.18 mmol) were added. The mixture was heated to 100° C. overnight then the reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with brine twice and water twice, then the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel using (dichloromethane-methanol) to give (R)-ethyl 1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.020 g, 17%).
Reaction SMILES: [Cl-:1].C([O:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]3[CH2:21][CH2:20][CH2:19][N+:15]3=2)[CH:11]=1)C1C=CC=CC=1>CO.[Pd]>[Cl-:1].[OH:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]3[CH2:21][CH2:20][CH2:19][N+:15]3=2)[CH:11]=1
Reactant: c1ccc(COc2ccc3c(c2)cn2[n+]3CCC2)cc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Product: Oc1ccc2c(c1)cn1[n+]2CCC1
Yield: 83.3 %

Procedure:
2,3-Dihydro-7-benzyloxy-1H-pyrazolo[1,2-a]indazolium chloride (6 g) obtained in Examples 1 and 2 was dissolved in methanol (100 ml) and catalytically reduced by adding 10% palladium-charcoal (0.6 g) to the solution, to give 3.5 g of 2,3-dihydro-7-hydroxy-1H-pyrazolo[1,2-a]indazolium chloride. After recrystallization from isobutanol, the product had a melting point of 278° to 279° C. (decomposition).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C@@H:31]([C:33]2[CH:34]=[C:35](B(O)O)[C:36]([F:39])=[N:37][CH:38]=2)[CH3:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])(=O)C.[K+]>O1CCOCC1.ClCCl.O.[Cl-].[Na+].O>[F:39][C:36]1[N:37]=[CH:38][C:33]([C@H:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[CH2:30][CH2:29]2)[CH3:32])=[CH:34][C:35]=1[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2cc([C@@H](C)N3CCN(C(=O)OC(C)(C)C)CC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C
Yield: 76.9 %

Procedure:
A glass microwave reaction vessel was charged with 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.250 g, 0.989 mmol) and (R)-5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (0.489 g, 1.385 mmol) in dioxane (3 mL). Then A-Phos (0.070 g, 0.099 mmol), potassium acetate (0.291 g, 2.97 mmol) and water (0.5 mL) were added into the reaction mixture. The reaction mixture was stirred and heated in a CEM Explorer Microwave at 120° C. for 10 min (120 watts, Powermax feature on). The mixture was diluted with dichloromethane (10 mL), water (10 mL) and brine solution (5 mL). The organic layer was collected by extracting with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude material as a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica-gel column (40 g) eluting with 100% ethyl acetate to give tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (0.400 g, 0.761 mmol, 77% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.20-8.29 (m, 3H) 5.78 (dd, J=10.37, 2.35 Hz, 1H) 3.76 (s, 1H) 3.55 (d, J=6.65 Hz, 1H) 3.34 (s, 5H) 2.82 (s, 3H) 2.33 (d, J=5.09Hz, 5H) 1.95-2.13 (m, 3H) 1.56-1.81 (m, 5H) 1.33-1.40 (m, 9H). m/z (ESI, +ve ion) 526.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[N:6][CH:7]=1.[CH3:29][N:30]([CH2:35][C:36](O)=[O:37])[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:3]1[C:2]([N:1]2[C:36](=[O:37])[CH2:35][N:30]([CH3:29])[CH2:31][C:32]2=[O:33])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[N:4]=1
Reactant: Nc1cnc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl
Reactant: CN(CC(=O)O)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)N(c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1 mmol of [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine, and 2 mmol of methyliminodiacetic acid, 4 mmol of HBTU, and 5 mmol of N,N-diisopropylethylamine were added to solution and stirred for six hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain 1-[4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]-4-methylpiperazine-2,6-dione.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:18](=[S:19])[N:17]3[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:18](=[S:19])[N:17]3[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[CH:11]2[OH:20])=[C:4]([F:21])[CH:3]=1
Reactant: COc1cc(N2C(=O)C3CCCCN3C2=S)c(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(N2C(=S)N3CCCCC3C2O)c(F)cc1Cl
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
32.9 g (0.10 mol) of 8-(4-chloro-2-fluoro-5-methoxyphenyl)-7-oxo-9-thioxo-1,8-diazabicyclo[4.3.0]nonane were dissolved in 250 ml of ethanol. 5.7 g (0.15 mol) of sodium borohydride were added in portions at a rate such that the temperature was kept at 30° C. When the addition was complete, the mixture was stirred for a further 30 minutes at 30° C. and poured into 600 ml of ice-water. The precipitate was filtered off under suction, dried and recrystallized from methanol. 24.9 g (75% of theory) of 8-(4-chloro-2-fluoro-5-methoxyphenyl)-7-hydroxy-9-thioxo-1,8-diazabicyclo[4.3.0]nonane were obtained in the form of colorless crystals having the melting point 208°-215° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])[O:14][N:13]=2)=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][C:34](=[O:36])[CH3:35]>>[O:36]=[C:34]([CH3:35])[CH2:33][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:10]=3)[CH:16]=2)[CH:18]=1
Reactant: COCCOc1ccc(-c2cc(-c3cccc(C(=O)O)c3)on2)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCOc1ccc(-c2cc(-c3cccc(C(=O)OCC(C)=O)c3)on2)cc1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
In a 25 ml round flask, 150 mg (0.44 mmol) of 3-{3-[4-(2-methoxy-ethoxy)-phenyl]-isoxazol-5-yl}-benzoic acid are dissolved. Then, 122 mg (0.88 mmol, 4 eq.) of K2CO3 and 49 mg (0.53 mmol, 1.2 eq.) of 1-chloro-propan-2-one are added and the suspension heated to 55° C. under nitrogen. After 48 h, the reaction is cooled to room temperature and the solvent evaporated. Chromatographic purification (10 g SiO2; eluent: hexane/ethyl acetate 1:0 to 4:6) yields the title compound as a white solid. Mass spectrum: m/z (M+H)+: 396.0