Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:31])[CH:11]=[C:12]([C:29]#[N:30])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-])=O)=[CH:16][CH:15]=1)=[O:8])[CH3:5].[H][H]>[Pd].C(OCC)(=O)C>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:31])[CH:11]=[C:12]([C:29]#[N:30])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])=[CH:18][CH:19]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccc3[N+](=O)[O-])cc2)c(C#N)cn1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3N)cc2)c(C#N)cn1C
Reaction time: 18 h

Procedure:
Add a 1:1 ethanol:ethyl acetate mixture to palladium on carbon (catalytic, 0.30 g) followed by 3(2′-nitro-biphenyl-4-yl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (3.00 g, 8.30 mmol, prepared in example E-9) with stirring. Subject the reaction to an atmosphere of hydrogen gas. After 18 hours, filter and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 332.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[CH2:32][C:33]([O:35][CH3:36])=[O:34].CN(C)C=O.[H-].[Na+]>O>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:25]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:26]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)Cc1cc(OC)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cc(OC)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.2 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.54 g), methyl 2-(2-hydroxy-5-methoxyphenyl)acetate (0.80 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.18 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (1.22 g, 63%) of methyl 2-[5-methoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 160-161° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:21])=[N:16][N:15]=[CH:14]2.[CH2:22]([NH2:24])[CH3:23].C1COCC1.C(Cl)(Cl)Cl>CCOC(C)=O.CN(C)C=O>[CH2:22]([NH:24][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:21])=[N:16][N:15]=[CH:14]3)[CH:4]=1)[CH3:23]
Reactant: CCN
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(C)nncc2c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(C)nncc3c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 15-ml round-bottom flask were added 4-methyl-3-(1-methylphthalazin-6-yl)benzoic acid (51 mg, 183 μmol), hatu (105 mg, 275 μmol), ethylamine (2M solution in THF (275 μl, 550 μmol), and chloroform (1000 μl). 0.5 ml of N,N-Dimethylformamide was next added to the mixture, and the resulting golden yellow solution was stirred at RT for 3 h, during which LC-MS indicated completion of reaction. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. CombiFlash purification (1% to 5% MeOH/CH2Cl2) afforded the title compound (26) as a tan amorphous solid. MS (ES+): 306.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1.O[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[C:31]([C:36]([O:38][CH3:39])=[O:37])[N:32]=[CH:33]3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:36]([O:38][CH3:39])=[O:37])[N:32]=[CH:33]4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)cc2cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of [5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (51 mg, 0.18 mmol), methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate (50 mg, 0.18 mmol) and triphenylphosphine (52 mg, 0.20 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.035 mL, 0.20 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes and then allowed to stand overnight. The mixture was adsorbed onto silica gel and purified by chromatography (silica gel, 0-1.25% methanol in dichloromethane) to afford methyl 7-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (54 mg, 55%). 1H-NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.29-8.14 (m, 2H), 7.75 (d, J=9 Hz, 2H), 7.61-7.50 (m, 3H), 6.96 (d, J=9 Hz, 2H), 4.94 (s, 2H), 3.91 (s, 3H), 2.50-2.46 (m, 1H), 1.21-1.14 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:4]=1.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:34][C:35]1[CH:40]=[C:39]([NH2:41])[CH:38]=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:35]1[CH:40]=[C:39]([NH:41][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:16][CH:15]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Cc1cc(N)ccn1
Reactant: O=C(O)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2ccc(-c3noc(C(F)(F)F)n3)cc2)ccn1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To compound 12b, 4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-benzoic acid, (40 mg, 0.155 mmol) in DMF (516 μL) was added TFFH (82 mg, 0.310 mmol), 2-methylpyridin-4-amine (33.5 mg, 0.310 mmol) and DIPEA (81 μL, 0.465 mmol). The reaction was stirred at 50° C. for 1.5 h. The reaction mixture was subjected to purification by reverse phase prep-HPLC (gradient elution, water/MeCN both containing 0.1% TFA). Fractions containing the desired compound were combined and freeze-dried. The resulting material was dissolved in a mix of ACN/MeOH. They were loaded on a PL-HCO3 MP cartridge (from StratoSpheres™ SPE) and eluted with ACN (3 ml). The eluate was diluted with water (10 ml) and freeze-dried to yield the final compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH:30]1[C:39]2[C:34](=[C:35]([NH:40][NH2:41])[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1>>[CH:30]1[C:39]2[C:34](=[C:35]([N:40]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]6[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]6)(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:41]3)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Reactant: NNc1cccc2cnccc12
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1cccc2cnccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and isoquinolin-5-yl-hydrazine according to the method described for example 91. MS: M=513.4 (M+H)+
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([NH:20][CH3:21])=[O:19])[N:9]=1.[H-].[Na+].[F:24][CH2:25][CH2:26][CH2:27]Br>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:20]([CH3:21])[CH2:27][CH2:26][CH2:25][F:24])=[O:19])[N:9]=1
Reactant: CNC(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Reactant: FCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCF)C(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 22.3 %

Procedure:
To a solution of 1-(2-iodophenyl)-N-methyl-3-isoquinolinecarboxamide (22 mg, 0.06 mmol) in DMF (2 mL) was added 60% NaH (12 mg, 0.30 mmol) in one portion. The mixture was stirred under Ar at room temperature for 40 min. Then, 3-fluoropropyl bromide (22 ul, 0.30 mmol) was added. After stirring under Ar at room temperature for 24 h, the mixture was quenched by adding H2O (7 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, 30% ethyl acetate/hexane, 0.035% Et3N), thereby affording a semisolid (6 mg, 23%), and starting material (17.7 mg). 1H NMR (CDCl3) d 1.96-2.22 (m, 2 H, CH2), 3.16, 3.20 (two s, total 3 H, N-methyl), 3.59-3.85 (m, 2 H, N--CH2), 4.47 (qt, J=79.8, 47.1, 6 Hz, 2 H, CH2F), 7.21 (dt, J=7.5, 0.9 Hz, 1 H, aromatic), 7.36 (dd, J=7.5, 1.5 Hz, 1 H, aromatic), 7.51 (t, J=7.2 Hz, 1 H, aromatic), 7.56 (d, J=3.9 Hz, 2 H, aromatic), 7.69-7.81 (m, 1 H, aromatic), 7.99 (t, J=7.8 Hz, 1 H, aromatic), 8.11, 8.18 (two s, total 1 H, aromatic). HRMS calcd. for C20H18FIN2O: 448.0448. Found: 448.0456.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1([NH:21][C:22]([C:24]2[C:32]3[CH:31]=[C:30]([C:33]4[C:38]([F:39])=[CH:37][N:36]=[C:35](Cl)[N:34]=4)[S:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)=[O:23])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH:17][C:35]2[N:34]=[C:33]([C:30]3[S:29][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:22](=[O:23])[NH:21][CH:18]5[CH2:19][CH2:20]5)[C:32]=4[CH:31]=3)[C:38]([F:39])=[CH:37][N:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3F)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Yield: 80.4 %

Procedure:
4-(3-Aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester (0.557 g, 2.30 mmol) is added to a stirred suspension of 2-(2-chloro-5-fluoropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.400 g, 1.15 mmol) and diisopropylethylamine (0.60 mL, 3.5 mmol) in anhydrous 1,4-dioxane (8 mL) at room temperature under nitrogen. The resultant mixture is heated in an oil bath at 95° C. for 34 hours. At room temperature the mixture is concentrated and chromatographed on silica gel, eluting with CH3OH in dichloromethane: 0-2%, to give 4-{3-[4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-5-fluoropyrimidin-2-ylamino]-propyl}-piperidine-1-carboxylic acid tert-butyl ester (0.512 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: COc1cc(OC)c(-c2nccs2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2nccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 65 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-thiazol-2-yl-benzaldehyde (Ex-55A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp>260° C., 65% yield. 1H-NMR (DMSO-d6) δ 13.33 (bs, 1H), 8.74 (s, 1H), 8.22 (d, J=8 Hz, 2H), 8.04–8.12 (m, 3H), 7.95 (d, J=2 Hz, 1H), 7.82 (d, J=16 Hz, 1H), 7.76 (d, J=3 Hz, 1), 6.94 (s, 1H), 4.14 (s, 3H), 4.05 (s, 1H). HRMS m/z=calc. 396.0906, found 396.0903.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:10]([C:12](O)([CH3:14])[CH3:13])[N:11]=1)=[O:5].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[C:10]([C:12]([CH3:14])=[CH2:13])[N:11]=1)=[O:5]
Reactant: CC(C)(O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Into a solution of Compound 68 (22 mg, 0.05 mmol) in 5 mL of toluene was added dropwise of 0.2 mL of TFA. The mixture was heated to reflux for 30 minutes. After cooled down to room temperature, the reaction was concentrated. The residue was purified by column chromatography on silica gel (10-20% EtOAc in hexanes) to give Compound 68a (20 mg, 95%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[N:4][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[C:34]1(C)C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:34][O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=1[NH:24][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)[N:4]=1
Reactant: Cc1ccccc1
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)O)n3)cc2CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)OC)n3)cc2CC1
Reaction time: 8 h
Yield: 21.6 %

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester (1.168 g, 2.355 mmol) was dissolved in tetrahydrofuran (117 mL, 1440 mmol). Lithium hydroxide (67.7 mg, 2.82 mmol) dissolved in water (23.4 mL, 1.30 mol) was added and the reaction was stirred for 48 hours. The reaction was concentrated under reduced pressure and azetroped twice with toluene. The reaction was then further dried under high vacuum to obtain 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid. 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid (1.55 g, 3.31 mmol) was placed in toluene (40.0 mL, 376 mmol) and methanol (10.0 mL, 247 mmol). 2.00 M of Trimethylsilyldiazomethane in hexane (4.50 mL) was added and the reaction was stirred overnight. The reaction was quenched with acetic acid and then concentrated under reduced pressure. The residue was taken up in DCM (50 mL) and washed with sat. NaHCO3 (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-60% EtOAc/hex as the eluting solvent to obtain 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid methyl ester as a pale yellow solid (344 mg, 21%). m.p.=152-156° C.; LCMS (m/e) 482 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.13 (s, 1H), 8.86 (d, 1H, J=8.6 Hz), 8.14 (s, 1H), 8.09 (d, 1H, J=8.0 Hz), 7.55-7.46 (m, 1H), 7.35 (s, 1H), 7.30-7.22 (m, 1H), 7.14-7.02 (m, 2H), 6.92 (s, 1H), 3.99 (s, 3H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.98-2.89 (m, 4H), 2.80-2.71 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.O=C1C2C(=CC=CC=2)C(=O)[N:24]1[O:33][CH2:34][CH2:35][C@H:36]([O:41][CH3:42])[C:37]([O:39][CH3:40])=[O:38]>[Hg](OC(C)=O)OC(C)=O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2=[C:6]([CH2:8][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[NH:10]/[C:11]/2=[N:24]\[O:33][CH2:34][CH2:35][C@H:36]([O:41][CH3:42])[C:37]([O:39][CH3:40])=[O:38])[N:7]=1
Reactant: COC(=O)[C@H](CCON1C(=O)c2ccccc2C1=O)OC
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCO/N=C1\N[C@@H](c2ccc(F)cc2Br)Cc2nc(N)nc(C)c21)OC
Temperature: 100 °C
Yield: 11.6 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (311, 146 mg, 0.4 mmol), (S)-methyl 4-(aminooxy)-2-methoxybutanoate (46c, 260 mg, 1.6 mmol), Hg(OAc)2 (257 mg, 0.8 mmol) and toluene (2 mL) was heated at 100° C. for 2 h. Cooled to rt, filtered through celite and purified to afford (S)-methyl 4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-methoxybutanoate (23 mg, 12%) as off white solid. MS (ES) [M+H] calculated for C20H24BrFN5O4, 496.09; found 496.20.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:17](OCC)[CH2:18][Br:19])C>>[CH2:1]([O:8][CH:9]1[CH2:10][O:11][CH:17]([CH2:18][Br:19])[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: CCOC(CBr)OCC
Product: BrCC1OCC(OCc2ccccc2)CO1

Procedure:
By the method of Example 38, 2-benzyloxy-1,3-propanediol was reacted with bromoacetaldehyde diethyl acetal to yield 5-benzyloxy-2-bromomethyl-1,3-dioxane; b.p. 130°-133° C/10-4 mm Hg; nD25 1.5395. The nmr spectrum was consistent with the assigned structure and indicated the cis-isomer content was 30 ± 5%, the remainder being trans.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N+:4]=1[O-])#[N:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[N:4]=[C:3]([C:1]#[N:2])[CH:8]=[C:7]([CH3:9])[CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc[n+]([O-])c(C#N)c1
Product: Cc1cc(Cl)nc(C#N)c1
Yield: 80.8 %

Procedure:
A mixture of 2-cyano-4-methylpyridine-1-oxide (4.03 g, 30 mmol) in phosphoryl trichloride (80 mL, 858 mmol) was heated to reflux overnight. The solvent was removed in vacuo. The residue was treated with ice and its pH made basic using saturated NaOH solution at 0° C. The aqueous layer was extracted with DCM (3×). The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo to give the title compound (3.7 g, 81%). ESI-MS m/z [M+H]+ 153.6.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[C:8]2([CH2:10][CH2:9]2)[C:7]1=[O:16].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[O:16]=[C:7]1[NH:6][CH2:12][CH:11]([C:13]([OH:15])=[O:14])[C:8]21[CH2:9][CH2:10]2
Reactant: COc1ccc(CN2CC(C(=O)O)C3(CC3)C2=O)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CNC(=O)C12CC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To an optically active compound of 5-(2,4-dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acid (372 mg) were sequentially added anisole (159 μl) and trifluoroacetic acid (5.6 ml) at room temperature, and the mixture was stirred at 80° C. for 4 hours. This reaction mixture was concentrated under reduced pressure, and diisopropyl ether (10 ml) was added thereto. The precipitated solid was collected by filtration to give the titled compound (144 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=O)[C:2]1=2.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[C:2]1=2
Reactant: CCN(CC)C(=O)COCCc1cccc2ccsc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCOCCc1cccc2ccsc12
Temperature: 5 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
In 14 mL of tetrahydrofuran is dissolved 1.36 g of 2-(2-benzo[b]thiophen-7-ylethoxy)-N,N-diethylacetamide. The solution is cooled to 5° C., and 14 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran is dropwise added thereto. The resulting mixture is stirred at ambient temperature overnight, and then 5.00 mL of 6 mol/L hydrochloric acid is dropwise added, and the resulting mixture is heated under reflux for 30 minutes. After cooling, water and ethyl acetate are added to the reaction mixture, pH is adjusted to 9 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1) to obtain 1.10 g of N-[2-(2-benzo[b]thiophen-7-ylethoxy)ethyl]-N,N-diethylamine as an oily product.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[I:20].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[I:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:13]1[O:21][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=2[N:12]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1I
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2oc(-c3ccncc3I)nc2c1
Temperature: 50 °C
Yield: 80.9 %

Procedure:
To a mixture of 1.81 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-iodoisonicotinamide, 20 ml of tetrahydrofuran and 1.34 g of triphenylphosphine, 2.22 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred while heating at 50° C. for one hour. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.40 g of 2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 29”).