Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:23]C)[N:13]3[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:9]([NH2:25])[N:8]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(OCCC2CC2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
2-[(2-Cyclopropylethyl)oxy]-8-(methoxy)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (0.1259 g) was dissolved in methanol (5 mL) and added 4N hydrogen chloride in 1,4-dioxane (2 mL). The reaction was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to give a solid which was then suspended in water (1 mL) and small quantity of methanol (2-3 mL). This was then neutralised (to pH 7) by the addition of 2N sodium hydroxide. The suspension was evaporated to near dryness under reduced pressure and then suspended the solid in water (3 mL). The solid was filtered off under suction and washed with a few drops of methanol before being air-dried under suction. This material was then dried to constant weight under vacuo at 50° C. to give the title compound (94 mg).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][C:5](O)([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.[Cl-].[NH4+]>N1C=CC=CC=1>[F:1][C:2]1([F:19])[CH2:7][CH2:6][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)C1(O)CCC(F)(F)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C1=CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzyl 4,4-difluoro-1-hydroxycyclohexanecarboxylate (1.8 g, 6.66 mmol) in 13 ml of pyridine was added phosphorous oxychloride (1.12 g, 7.33 mmol). The resulting solution was stirred under nitrogen at room temperature for 18 hours, and then poured into 70 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with 2 molar hydrochloric acid solution and brine and then dried over sodium sulfate. Filtration and concentration under vacuum afforded the crude product which was purified by chromatography on silica gel eluting 2% ethyl acetate in hexanes to give benzyl 4,4-difluorocyclohex-1-ene-1-carboxylate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([F:44])([F:43])[F:45])=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: FC(F)(F)Oc1ccc(Sc2ccc(Br)cc2)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(OC(F)(F)F)cc3)cc2)c1C
Yield: 55.9 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(4-(trifluoromethoxy)phenylsulfanyl)benzene (0.214 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-fluoro-3-methyl-4-[4-(4-trifluoromethoxyphenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.154 g, 55%) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[Si](C)(C)CC[Si]2(C)C)=[C:4]([O:17][CH3:18])[CH:3]=1.[Mg].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:17][CH3:18])[CH:3]=2)([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1cc(Br)ccc1N1[Si](C)(C)CC[Si]1(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Bromo-2-methoxy-phenyl)-2,2,5,5-tetramethyl-[1,2,5]azadisilolidine (250 mg, 1.0 equiv) was dissolved in anhydrous THF (4 ml) under an argon atmosphere. A 1M suspension of magnesium in THF (0.941 ml, 1.33 equiv) was added dropwise at room temperature, and the mixture was stirred for 2 hours. It was then transferred via cannula to a room temperature solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (145 mg, 1.0 equiv), and the mixture was heated to reflux 2 hours. Cooled to room temperature and quenched with water. Partitioned between EtOAc/water. Dried over sodium sulfate and concentrated. Purified by preparative TLC, 40% EtOAc/hexane. Obtained 4-(4-amino-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a purple foam, 52 mg. LCMS (E/I+) 323 (M+H). NMR 1H (CDCl3) 6.95 (s, 1H), 6.83 (d, J=5.82 Hz, 1H), 6.62 (d, J=5.73 Hz, 1H), 3.92-4.05 (m, 2H), 3.88 (s, 3H), 3.17-3.30 (m, 2H), 1.89-2.10 (m, 2H), 1.68-1.74 (m, 2H), 1.46 (s, 9H), 1.23 (s, 1H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:30])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.[OH:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][C:36]=1[O:43][CH3:44].C(N(CC)CC)C>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:40][CH2:39][C:38]4[CH:41]=[CH:42][C:35]([OH:34])=[C:36]([O:43][CH3:44])[CH:37]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:30])=[C:23]([CH3:29])[CH:24]=1
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: COc1cc(CN)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)COc2ccc(Cl)cc2C)C3)ccc1O

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 75 (0.3 mmol), 4-hydroxy-3-methoxybenzylamine hydrochloride (2.2 eq.) and triethylamine (2.4 eq.) in the manner of Example 68, m.p. 167-168° C. MS [(+)ESI, m/z]: 546 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Sn](Cl)(Cl)(Cl)Cl.[CH3:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:18]=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:18]1[N:19]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[C:20]2[C:25]([C:17]=1[CH3:16])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cn(N2C(=O)c3ccccc3C2=O)c2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C(=O)c2ccccc2F)n(N2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.91 ml of 2-fluorobenzoyl chloride in 50 ml of dry DCM was cooled in an ice/salt bath. To the solution was added 0.86 ml (1.91 g) of tin (IV) chloride. The mixture was stirred at -5° to 0° C. for 10 minutes after which was added 2.0 g of 2-(3-methyl-1H-indol-1-yl)-1H-isoindole-1,3-(2H)dione. The reaction mixture was stirred at 0° C. for 1 hour, allowed to warm to room temperature, cooled again in an ice bath, poured onto ice, extracted twice with ethyl acetate, washed with water, brine, dried (Na2SO4), filtered and concentrated to a green-yellow solid (2.67 g). The solid was chromatographed on silica gel, eluting with 15% acetone/heptane to provide 1.99 g of a solid, which was recrystallized from ethanol, m.p. 197°-199° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:21][CH2:22][C:23]([O:25][C:26](C)(C)[CH3:27])=[O:24])[CH:11]=[C:12]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1)=[O:5])C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][C:4]([OH:5])=[O:3])[CH:13]=[C:12]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CCc1cc(CCC(=O)OC(C)(C)C)cc(Oc2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1cc(CCC(=O)O)cc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
A solution of t-butyl 3-[3-(2-ethoxycarbonylethyl)-5-(3-pyridyloxy)phenyl]propanoate (Preparation 29; 7.8 g) in dichloromethane (100 ml) was treated with trifluoroacetic acid (20 ml) and the resulting solution stirred at room temperature for 20 hours and then evaporated under vacuum. The residue was azeotroped twice with toluene, and then ether (ca 100 ml) and pyridine (ca 10 ml) were added sequentially. This mixture was washed with water and then the combined aqueous washings extracted with ethyl acetate. The organic solutions were combined, washed with water, dried (MgSO4) and evaporated under vacuum to provide an oil, which crystallised on trituration with an ether: hexane mixture to give the title compound (6.56 g), m.p. 85°-87° C. Found: C, 66.67; H, 6.04; N, 3.90. C19H21NO5 requires C, 66.46; H, 6.16; N, 4.08%.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[F:8][C:9]1[CH:10]=[C:11]([C:33](O)=[O:34])[C:12]2[CH2:13][C:14]([CH3:32])([CH3:31])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[NH:16][C:17]=2[CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[C:12]2[CH2:13][C:14]([CH3:31])([CH3:32])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH:20]=3)[NH:16][C:17]=2[CH:18]=1
Reactant: CC1(C)Cc2c(cc(F)cc2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(cc(F)cc2C(=O)NS(C)(=O)=O)NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (200 mg, 5.0 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (494 mg, 5.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (200 mg, 0.52 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-methanesulfonamide (48 mg, 20%) as a white solid: LC/MS m/e calcd for C23H28FN3O4S (M+H)+: 462.56, observed: 462.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[CH2:36]Cl.CC#N.O>C(O)=O>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[CH2:36][N:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[C:13]=2[N:12]=[C:11]1[C:14](=[O:25])[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1
Reactant: ClCc1n[nH]c2ccc(Cl)cc12
Reactant: COC(=O)c1cccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2Cc2n[nH]c3ccc(Cl)cc23)CC1

Procedure:
1-(5-Chloro-1H-indazol-3-ylmethyl)-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid was prepared by a procedure according to example 81 starting from 200 mg (0.58 mmol) 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester and 116.8 mg (0.58 mmol) 5-chloro-3-chloromethyl-1H-indazole. Hydrolysis of the resulting ester and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compound as its formiate in form of a white amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([CH:23]=[CH2:24])[C:20]3[C:19](=[O:25])[CH2:18][CH2:17][C:16]([CH3:27])([CH3:26])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[CH3:26][C:16]1([CH3:27])[C:15]2[CH:14]=[C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:10][CH:9]=3)[CH:22]=[C:21]([CH:23]=[CH2:24])[C:20]=2[C:19](=[O:25])[CH2:18][CH2:17]1
Reactant: C=Cc1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1C(=O)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(=O)CCC2(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
A solution of [4-(8,8-dimethyl-5-oxo-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 70, 0.082 g, 0.22 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of lithium hydroxide (1.5 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1.5 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated aqueous ammonium chloride solution and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow solid (0.065 g, 82%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:14]([O:26][CH3:27])=[CH:15][C:16]3[N:22]([CH3:23])[C:21](=[O:24])[O:20][CH2:19][CH2:18][C:17]=3[CH:25]=2)[N:3]=1.[NH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([NH:33][CH3:34])=[O:32].C(O)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[CH3:27][O:26][C:14]1[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=3[C:31]([NH:33][CH3:34])=[O:32])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:25][C:17]2[CH2:18][CH2:19][O:20][C:21](=[O:24])[N:22]([CH3:23])[C:16]=2[CH:15]=1
Reactant: COc1cc2c(cc1Nc1ncc(C(F)(F)F)c(Cl)n1)CCOC(=O)N2C
Reactant: CNC(=O)c1ccccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)N(C)C(=O)OCC3)ncc1C(F)(F)F
Yield: 29 %

Procedure:
2-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-Amino-N-methyl-benzamide (85 mg, 0.56 mmol;) was stirred in isopropyl alcohol (5.00 mL, 65.3 mmol;) with 10-camphorsulfonic acid (150 mg, 0.63 mmol;) at 120° C. in microwave for 30 min×3. The reaction mixture was concentrated and then extracted with DCM (20 mL) and washed with sat. NaHCO3 (20 mL) followed by water. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on ISCO flash system (0-100% Hex:EtOAc) to obtain the product as one of multiple peaks by UV. The fractions were concentrated and triturated in Et2O to obtain a filterable solid (25 mg, 29%). mp: 210-212° C. (soft 150), MS (ESI+): 517 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 10.85 (s, 1H), 8.42 (s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.71 (s, 1H), 7.52 (d, J=8 Hz, 1H), 7.43 (t, J=8 Hz, 1H), 7.13 (t, J=8 Hz, 1H), 6.70 (s, 1H), 6.19 (br s, 1H), 4.42 (t, J=6 Hz, 2H), 3.92 (s, 3H), 3.40 (s, 3H), 3.04 (d, J=5 Hz, 3H), 2.76 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:16](=[O:23])[C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7]2=[O:15].C(=O)(O)[O-].[Na+:28]>>[Cl:1][C:2]1[C:11]2[NH:10][C:9]([C:12]([O-:14])=[O:13])=[CH:8][C:7](=[O:15])[C:6]=2[CH:5]=[C:4]2[C:3]=1[NH:19][C:18]([C:20]([O-:22])=[O:21])=[CH:17][C:16]2=[O:23].[Na+:28].[Na+:28]
Reactant: O=C(O)c1cc(=O)c2cc3c(=O)cc(C(=O)O)[nH]c3c(Cl)c2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C([O-])c1cc(=O)c2cc3c(=O)cc(C(=O)[O-])[nH]c3c(Cl)c2[nH]1

Procedure:
The diacid prepared in Example 7 is dissolved in hot 4% sodium bicarbonate. Upon cooling, the disodium salt precipitates and is collected by filtration. Recrystallization from water gives a yellow solid melting above 310° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6](C=O)[C:5]([OH:10])=[CH:4][CH:3]=1.CO[CH:13]([O:16][CH3:17])[O:14][CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CO.[Cl-].[Na+].O>[Br:1][C:2]1[CH:9]=[CH:6][C:5]([OH:10])=[C:4]([CH:13]([O:14][CH3:15])[O:16][CH3:17])[CH:3]=1
Reactant: COC(OC)OC
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: COC(OC)c1cc(Br)ccc1O

Procedure:
To a solution of 5-bromosalicylaldehyde (4.00 g, 19.90 mmol) in methanol (50 ml) were added orthoformic acid trimethyl (9.70 g, 10.00 ml, 91.41 mmol) and TsOH.H2O (38.04 mg, 0.20 mmol), followed by reacting them at room temperature for 1 hour. Following neutralization with potassium carbonate (55.28 mg, 0.40 mmol), the solution was cleansed with brine and 5%-sodium hydrogen carbonate (=1:1, 50 ml) and extracted with pet ether (×2). A pool of the organic layer thus formed was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in a vacuum to prepare the object compound (white, solid, 4.92 g, 100%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.FC(F)(F)S(O[CH2:15][CH2:16][F:17])(=O)=O>>[F:17][CH2:16][CH2:15][N:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]1=[O:8]
Reactant: O=S(=O)(OCCF)C(F)(F)F
Reactant: O=c1cc(I)cc[nH]1
Product: O=c1cc(I)ccn1CCF

Procedure:
1-(2-fluoroethyl)-4-iodopyridin-2(1H)-one was prepared from 4-iodopyridin-2(1H)-one and 2-fluoroethyl trifluoromethanesulfonate following a procedure analogous to that described in Example 20 Step 1.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:36][CH3:37])=[C:11]([NH:13][C:14](=[O:35])[C:15](=[N:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([N+]([O-])=O)[C:22]=2[O:33][CH3:34])[C:16](=[O:18])[CH3:17])[CH:12]=1)(=O)C.CN1C(=O)CCC1.Cl>O>[NH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:36][CH3:37])=[C:11]([NH:13][C:14](=[O:35])[C:15](=[N:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[O:33][CH3:34])[C:16](=[O:18])[CH3:17])[CH:12]=1
Reactant: COc1ccc(CCNC(C)=O)cc1NC(=O)C(=NNc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1OC)C(C)=O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc([N+](=O)[O-])ccc1NN=C(C(C)=O)C(=O)Nc1cc(CCN)ccc1OC
Temperature: 112 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
The product described in the previous step, N-[5-(2-acetamidoethyl)-2-methoxyphenyl]-2-[(2-methoxy-4-nitronitrophenyl)-hydrazono]-3-oxobutyramide (4.6 g) was mixed with 150 mL of NMP and 20 mL of concentrated HCl and heated at 112° C. for 6 hours. The reaction mixture was poured into 1000 mL of water and left overnight. The resulting precipitate was filtered off, washed with water and then with a dilute aqueous NaHCO3 solution to a neutral pH, and finally dried in a vacuum to give 4.0 g (95.2%) of N-[5-(2-aminoethyl)-2-methoxyphenyl]-2-[(2-methoxy-4-nitro-phenyl)-hydrazono]-3-oxo-butyramide (AePY74) as a yellow powder. 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][O:5][N:6]=1.C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([Cl:25])=[CH:19][C:18]=1[C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1.CCCCCCC>S(Cl)(Cl)=O.CN(C)C=O.CC#N.N1C=CC=CC=1>[NH2:33][C:27]1[N:28]=[C:29]([NH:32][C:7]([C:3]2[C:2]([CH3:1])=[N:6][O:5][N:4]=2)=[O:9])[CH:30]=[CH:31][C:26]=1[C:18]1[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=1[Cl:16]
Reactant: Cc1nonc1C(=O)O
Reactant: COc1cc(Cl)cc(-c2ccc(N)nc2N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: COc1cc(Cl)cc(-c2ccc(NC(=O)c3nonc3C)nc2N)c1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 18 %

Procedure:
4-Methyl-1,2,5-oxadiazole-3-carboxylic acid (0.3 g, 2.34 mmol) was stirred in thionyl chloride (10 ml) at 50° C. for 18 hours. A further 3 ml oxalyl chloride and 2 drops of dimethylformamide were added and the reaction stirred for a further 1.5 hours at 50° C. The reaction was concentrated in vacuo and azeotroped with dichloromethane. The residue (0.134 g, 0.915 mmol) was dissolved in CH3CN (1.83 ml) and added to a solution of 3-(2,5-dichloro-3-methoxyphenyl)-pyridine-2,6-diamine (Preparation 4, 0.200 g, 0.704 mmol) in anhydrous pyridine (10 ml). The reaction was heated at 60° C. for 24 hours. A further 0.88 equivalents of the acid chloride in CH3CN (0.091 g, in 1.2 ml) was added and the reaction stirred for a further 24 hours at 60° C. The reaction was partitioned between dichloromethane and a saturated aqueous solution of NaHCO3 before drying over Na2SO4 and concentrating in vacuo. The residue was purified by silica gel column chromatography eluting with 5:95 to 30:70 ethyl acetate:heptane to afford the title compound (0.050 g, 18% yield).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([O:11]CC)=O)=[N:4][CH:3]=1.[NH3:14]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([NH2:14])=[O:11])=[N:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(Br)c(=O)[nH]1
Reactant: N
Solvent: CCO
Product: NC(=O)c1ncc(Br)c(=O)[nH]1
Temperature: 50 °C

Procedure:
To a solution of ethyl 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxylate (4, 0.2 g, 0.81 mmol) in ethanol (4 mL), liquid ammonia (4 mL) was added dropwise at room temperature. The reaction mixture was heated at 50° C. for 16 h. TLC showed consumption of starting material. Solvent was removed under reduced pressure and the residue was treated with methanol (1 mL) and filtered. The solid was washed with diethyl ether and dried under reduced pressure to afford 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxamide (5) as off white solid. Yield: 0.14 g, 76%; MS (ESI) m/z 218.87 [M+1]+.