Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[CH:4][C:3](=[O:7])[CH2:2]1.[C:8](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9].O.O.O.O.O.[N+]([O-])([O-])=O.[Bi+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(Cl)Cl>[O:7]=[C:3]1[CH2:2][O:1][CH2:6][CH:5]([NH:9][C:8](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: O=C1C=CCOC1
Reactant: NC(=O)OCc1ccccc1
Agent: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: O
Solvent: ClCCl
Product: O=C1COCC(NC(=O)OCc2ccccc2)C1
Yield: 73.5 %

Procedure:
2H-pyran-3(6H)-one (2.33 g, 23.75 mmol), benzyl carbamate (4.31 g, 28.5 mmol), and DCM (2.375 mL) were added to a small vial and stirred vigorously. To the thick syrup was added bismuth(III) nitrate pentahydrate (1.728 g, 3.56 mmol). The vial was capped and the reaction was stirred vigorously overnight. The reaction was diluted with DCM and filtered through a pad of celite. The filtrate was condensed and purified on a 100G SNAP Biotage column (10-100% ethyl acetate in hexane) to give benzyl 5-oxotetrahydro-2H-pyran-3-ylcarbamate (4.35 g, 17.45 mmol, 73.5% yield) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.41 (m, 5H), 5.20-5.28 (m, 1H), 5.05-5.15 (m, 2H), 4.24-4.35 (m, 1H), 4.01-4.06 (m, 1H), 3.89-3.95 (m, 1H), 3.80-3.87 (m, 1H), 2.73 (d, J=5.47 Hz, 1H), 2.64-2.71 (m, 1H).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]3[C:25]=2[CH3:26])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].C(OCC)(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][N:18]2[C:25]([CH3:26])=[C:15]([CH2:14][CH2:13][C:4]3[CH:5]=[CH:6][C:7]4[N:8]=[C:9]([NH:11][CH3:12])[O:10][C:2]=4[CH:3]=3)[N:16]=[C:17]2[CH:22]=1
Reactant: CNC(=O)Nc1ccc(CCc2nc3cc(OC)ccn3c2C)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1nc2ccc(CCc3nc4cc(OC)ccn4c3C)cc2o1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 14.4 %

Procedure:
A mixture of 2-[2-{3-hydroxy-4-(3-methylureido)phenyl}ethyl]-7-methoxy-3-methylimidazo[1,2-a]pyridine (1.9 g) and polyphosphate ester (15 g) was stirred for 1.5 hours at 130° C. To the reaction mixture was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 1 with 6N hydrochloric acid. The separated aqueous layer was adjusted to pH 8 with aqueous potassium carbonate solution. The aqueous mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran with salting-out technique. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was triturated with a mixture of diethyl ether and ethyl acetate, and the resulting precipitate was crystallized from a mixture of methanol, ethyl acetate and isopropyl ether to give 6-[2-(7-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-methylaminobenzoxazole (0.26 g).
Reaction SMILES: CS([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[S:8]1)(=O)=O.[CH3:29][NH:30][CH3:31]>O1CCCC1>[CH3:29][N:30]([CH3:31])[CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[S:8]1
Reactant: CNC
Reactant: CS(=O)(=O)CCC1C=CN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2S1
Solvent: C1CCOC1
Product: CN(C)CCC1C=CN(C(=O)c2ccc(N)cc2)c2ccccc2S1
Temperature: 80 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of 2-(2-methanesulfonylethyl)-5-(4-nitrobenzoyl)-1,5-benzothiazepine as prepared in Example 6 (0.9 g, 2.1 mM) and dimethylamine (40% solution in water, 3.0 ml) in tetrahydrofuran (10 ml) was heated in a sealed tube with stirring in an 80° C. oil bath for 16 hours. The mixture was cooled to room temperature, evaporated to dryness, diluted with water (30 ml) and extracted with ethyl acetate (2×35 ml). The combined ethyl acetate extracts were dried (MgSO4) and evaporated in vacuo to give the desired product (0.78 g, 97%). This product (0.78 g, 2.0 mM) was dissolved in ethanol, and a catalytic amount of 10% Pd/C was added. The mixture was hydrogenated in a PARR apparatus under 30 psi of H2 pressure for 16 hr, filtered through Celite and evaporated in vacuo to give the desired product (0.64 g, 90%). m/z (M+) 356.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.II.O=[I:27](OI(=O)=O)=O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:27][C:4]1[CH:3]=[CH:2][C:1]([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:6][CH:5]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccccc1
Reactant: [O-][I+2]([O-])O[I+2]([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Temperature: 90 °C
Reaction time: 22 h
Yield: 187.5 %

Procedure:
(+,−) Trans-propane-2-sulfonic acid (2-phenyl-cyclopentyl)-amide (0.52 g, 1.47 mmol, prepared in example 1) was dissolved in 30 mL of glacial acetic acid. To this solution was added concentrated sulfuric acid (0.16 mL, 1.61 mmol) at room temperature followed by iodine (0.19 g, 0.74 mmol), and diiodine pentoxide (0.20 g, 0.59 mmol). The reaction was then protected from light and heated to 90° C. and stirred for 22 hours. To the dark brown reaction mixture was slowly added 10% aqueous sodium bisulfite. The mixture was cooled to 0° C. for 1 hour and a light brown solid collected by filtration. The solid was dissolved in warm diethyl ether and washed with water (2×), then saturated sodium bicarbonate (1×). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to give 435 mg (75%) of the title compound. The NMR was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:32]1([S:42](Cl)(=[O:44])=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][CH:33]=4)(=[O:44])=[O:43])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc5ccccc45)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and naphthalene-1-sulfonyl chloride. Purity (ELSD, based on MW=611.7)=81%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH:19]([CH3:21])[CH3:20].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([NH2:34])=[CH:32][C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[N:25]1([C:28]2[C:33]([NH:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:3]=3[CH:19]([CH3:21])[CH3:20])=[CH:32][C:31]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:30][N:29]=2)[CH2:24][CH2:23][O:22][CH2:27][CH2:26]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Solvent: Cc1ccccc1
Product: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 4-chloro-7-fluoro-3-isopropyl-2-(pyridin-2-yl)quinoline (45.0 mg, 0.150 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-3-(1-methylethyl)-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, chloroform-d) δ ppm 8.73 (1H, ddd, J=4.8, 1.7, 0.9 Hz), 7.88 (1H, td, J=7.7, 1.9 Hz), 7.72-7.79 (2H, m), 7.67 (1H, dt, J=7.8, 1.0 Hz), 7.58 (1H, d, J=2.7 Hz), 7.39 (1H, ddd, J=7.4, 4.9, 1.2 Hz), 7.23 (1H, ddd, J=9.4, 8.0, 2.5 Hz), 7.13 (1H, s), 6.11 (1H, d, J=2.5 Hz), 3.83-4.04 (4H, m), 3.67-3.79 (4H, m), 3.49 (2H, ddd, J=12.0, 6.3, 2.6 Hz), 3.25-3.42 (1H, m), 2.97 (2H, ddd, J=11.9, 6.2, 2.6 Hz), 2.85 (4H, t, J=4.8 Hz), 1.52 (3H, d, J=7.2 Hz), 1.12 (3H, d, J=7.0 Hz). Mass Spectrum (ESI) m/e=529.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([C:7]#[N:8])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Temperature: 37.5 °C

Procedure:
About 20% of a solution of p-chlorobenzyl cyanide (0.75 g, 4.94 mmol) and diethyl oxalate (0.87 mL, 6.4 mmol) in tetrahydrofuran (one mL) was added to a stirred suspension of sodium hydride (167 mg, 6.95 mmol) in tetrahydrofuran (4 mL). The mixture was heated at 35-40° C. until H2 evolution began. The remaining mixture was added dropwise over about ten minutes. After H2 evolution ceased, part of the solvent was removed under reduced pressure. The residue was diluted with 10 mL of water, neutralized with dilute sulfuric acid and extracted twice with ethyl acetate. The extract was water washed, dried (MgSO4) and stripped to a light brown solid. This was triturated with hexane, filtered and dried to give 1.17 g, (94%yield) of ethyl 3-(4-chlorophenyl)-3-cyano-2-oxopropanoate.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N:11]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:20]([O:19][C:17]([N:11]1[CH2:16][CH2:15][N:14]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:13][CH2:12]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Clc1nc2ccccc2o1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCN(c2nc3ccccc3o2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A mixture of 2-chlorobenzoxazole (1.00 g, 6.51 mmol), benzyl 1-piperazinecarboxylate (1.43 g, 6.51 mmol), and K2CO3 (1.80 g, 13.0 mmol) in DMF (13 mL) was stirred at 100° C. overnight, cooled, diluted with water, and extracted with EtOAc. The extracts were combined, washed with water and brine, dried over Na2SO4 and concentrated in vacuo to provide the title compound (1.70 g, 77%), characterized by NMR and mass spectral analyses.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([OH:39])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:39][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(O)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(OC)c(OC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 3,4-dimethoxyphenol (0.42 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.57 g, 61%).
Reaction SMILES: C([O:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH2:7][CH2:6]1)(=O)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CCCCCCN1CC[C@@H](OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCN1CC[C@@H](O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C

Procedure:
To a solution of (R)-ethyl 7-(8-acetoxy-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (24.4 mg, 0.049 mmol) in THF (3 ml) and water (1 ml) was added LiOH (6.99 mg, 0.292 mmol). The reaction mixture was heated to reflux for 1.5 h. A further 6 equivalents of LiOH was added and heated continued at reflux for 1 h. After cooling to RT, the pH of the mixture was adjusted to pH below 5 by addition of 2M HCl. The volatile solvent was removed in vacuo. To the residue was added water (10 ml) and the mixture was extracted with ethyl acetate (3×10 ml). The organic phase were combined, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product was carried out by chromatography on silica eluting with 0-100% EtOAc/iso-hexane followed by 0-100% MeOH/DCM. The residue was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH. The basic fraction was concentrated in vacuo and the residue was dissolved in THF (3 ml) and water (1.0 ml) and treated with LiOH (6.99 mg, 0.292 mmol). After stirring at reflux for 1.5 h, the mixture was allowed to cool to RT and acidifed with 2M HCl to pH below 5. The volatile solvent was removed in vacuo. To the residue was added water (10 ml) and the mixture was extracted with ethyl acetate (3×10 ml). The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[N:6]=1.N[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH2:15][NH:1][C:2]2[O:3][CH:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[O:7])[N:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCC1CCCCC1
Reactant: NC1=NC(=O)C(c2ccccc2)O1
Product: O=C1N=C(NCC2CCCCC2)OC1c1ccccc1

Procedure:
Synthesis was performed from 2-amino-5-phenyl-1,3-oxazol-4(5H)-one and aminomethylcyclohexane according to Method G+H.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].COC(=O)C1C=CC(OCC2C(CCCC)=NOC=2C)=NC=1>>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[CH2:12][O:11][C:8]1[N:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Agent: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Yield: 45.2 %

Procedure:
As described for example 10a, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (960 mg, 2.95 mmol) was converted, instead of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (415 mg, 45%) which was obtained as a white solid. MS: m/e=310.1 [M−H]−.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[OH:23][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]1[C:4]([C:3]([NH:2][CH3:1])=[O:10])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNC(=O)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1C(O)c1ccccc1
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 67.5 g. (0.5 mole) N-methyl benzamide and 1200 ml. dry tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5° C. Stirring is initiated and 688 ml. of 1.6 M. n-butyl lithium (1.1 mole) in hexane is added dropwise over about 1 hour maintaining temperature below 8° C. The resulting dilithio salt is stirred at 5° C. for an additional hour and then a solution of 58.5 g. (0.55 mole) of benzaldehyde in 500 ml. tetrahydrofuran is added dropwise in about 1 hour maintaining the temperature between -10° to +10° C. The resulting mixture is stirred at 5° C. for 1 hour longer and 300 ml. of saturated ammonium chloride is added maintaining the temperature at about 10° C. The layers are separated and the organic phase dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give α-hydroxy-N-methyl-α-phenyl-o-toluamide.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:20]2[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Fc1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 0.10 g, 0.40 mmol), 2-chloro-5-fluoro-pyrimidine (0.053 g, 0.40 mmol) and triethylamine (0.11 mL, 0.81 mmol) in DMF (0.5 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (10 CH2Cl2:1-20 IPA:89-70 hexane) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):345.29
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH:19]4[OH:27])[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][N:8]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:5]2=[N:6][CH:7]=1.[CH3:39][CH2:40][N:41](C(C)C)C(C)C.Cl.C(N)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:41][CH2:40][CH3:39])=[O:26])[CH:19]4[OH:27])[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][N:8]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:30])=[O:31])[C:5]2=[N:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(C(=O)O)C4O)n3)c3cc(Cl)cnc32)cc1
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)C1CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1O
Reaction time: 0.5 h

Procedure:
3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-cyclohexanecarboxylic acid, 65b, (0.100 g, 0.179 mmol) was dissolved in DMF (2 mL) and iPr2NEt (0.124 mL, 0.714 mmol) and ethanamine hydrochloride (0.029 g, 0.357 mmol) was added at room temperature. Then HATU (0.081 g, 0.214 mmol) was added to the solution at room temperature. After 30 min, EtOAc was added and the mixture was washed with 1 N HCl, aqueous saturated NH4Cl solution, and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (3.07 g), ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (2.04 g), potassium carbonate (1.22 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carboxylate as colorless crystals (3.20 g, 69%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 150-151° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][C:22]#[N:23]>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:21](/[C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)\[C:22]#[N:23])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: N#CCc1cccs1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3cccs3)cc2c1
Yield: 92.2 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (222 mg) was condensed with 2-thiopheneacetonitrile (123 mg) through Method B (production step 3), to thereby yield the target product (yield: 301 mg, 92%).
Reaction SMILES: NC(N)=O.OO.C([O-])(O)=O.[Na+].[CH2:12]([O:14][C:15](=[O:32])[CH:16]([N:18]1[C:23]2[CH:24]=[C:25](C(=O)C)[CH:26]=[CH:27][C:22]=2[O:21][CH2:20][C:19]1=[O:31])[CH3:17])[CH3:13].[C:33]([O:39]C(C(F)(F)F)=O)([C:35](F)(F)F)=[O:34]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:32])[CH:16]([N:18]1[C:23]2[CH:24]=[C:25]([O:39][C:33](=[O:34])[CH3:35])[CH:26]=[CH:27][C:22]=2[O:21][CH2:20][C:19]1=[O:31])[CH3:17])[CH3:13]
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(C(C)=O)cc21
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Solvent: ClCCl
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(OC(C)=O)cc21
Reaction time: 0.17 h

Procedure:
To a suspension of urea-hydrogen peroxide (5.93 g, 63 mmol) and NaHCO3 (5.93 g, 63 mmol) in DCM (60 mL) at 0° C. was added 2-(6-acetyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (6.14 g, 21 mmol). The reaction mixture was stirred for 10 min and TFAA (5.84 mL, 42 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h and then 3 days at ambient temperature. The reaction mixture was diluted with DCM (60 mL), quenched with saturated Na2S2O3 solution (30 mL) and washed with water (30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 2-(6-acetoxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester, which was used in the next step directly without purification. TLC (eluting with 25% EtOAc/heptane) Rf=0.4.