Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:13].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl>[Br:12][C:7]1[C:6]2[CH:5]=[CH:4][C:3]3[N:13]=[C:17]([OH:18])[C:16]([OH:20])=[N:1][C:2]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2c(Br)cccc2c1N
Agent: Cl
Solvent: O
Product: Oc1nc2ccc3c(Br)cccc3c2nc1O
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 1,0 g (4,2 mmol) 1,2-diamino-5-bromonaphthalene and 1,2 g (9,5 mmol) oxalic acid dihydrate in 20 ml 4 N hydrochloric acid was refluxed for 2,5 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was dissolved in 200 ml 2 N sodium hydroxide, and reprecipitated with 4N hydrochloric acid (to pH 1-2) to give 820 mg (67%) of pure 7-bromo-2,3-dihydroxybenzo(f)quinoxaline, m.p. >300° C.1H NMR (DMSO-d6 ): 8,6 (1H,d), 7,8 (1H,d), 7,7 (1H,d), 7,4 (1H,d), 7,3 (1H,d).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]([C:37]1[N:38]=[CH:39][N:40](C(OC(C)(C)C)=O)[CH:41]=1)=[CH2:36]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:8]2[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2](/[CH:36]=[CH:35]/[C:37]4[N:38]=[CH:39][NH:40][CH:41]=4)=[CH:3][CH:4]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:10][C:9]=2[CH:20]=1
Reactant: C=Cc1cn(C(=O)OC(C)(C)C)cn1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3c[nH]cn3)cc2)cc1
Temperature: 150 °C
Yield: 79.6 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (50 mg, 0.113 mmol) was dissolved in DMF (2 mL) and triethyl amine (0.474 mL, 3.40 mmol). To the solution was added tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (66.0 mg, 0.340 mmol) and Pd(PPh3)2Cl2 (7.95 mg, 0.011 mmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and sat. NH4Cl. The organic layer was collected (phase separator) and concentrated onto silica gel and the material was purified by column chromatography (SiO2, 0-30% DCM/MeOH) to afford (E)-4-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-imidazole (41 mg, 0.090 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J=1.52 Hz, 1H), 7.51-7.62 (m, 2H), 7.46-7.51 (m, 1H), 7.39 (d, J=9.09 Hz, 2H), 7.32 (d, J=2.53 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H), 7.08 (d, J=16.67 Hz, 1H), 6.76-6.95 (m, 6H), 3.77 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].C[Si](C)(C)[O:16][CH2:17][CH2:18]O[Si](C)(C)C.C(Cl)Cl>FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:8]2[O:16][CH2:17][CH2:18][O:9]2)[CH:10]=1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1
Temperature: -78 °C
Yield: 99.2 %

Procedure:
5-Methoxy-2-nitro-benzaldehyde (30.00 g, 0.1656 mol) and 1,2-bis-trimethylsilanyloxy-ethane (40.6 mL, 0.166 mol) were placed in a 40 mL vial, followed by Methylene chloride (1000 mL, 20 mol). The reaction mixture was then cooled to −78° C., and trimethylsilyl trifluoromethanesulfonate (1 mL, 0.008 mol) was added dropwise under N2. The reaction mixture was allowed to warm up to at 23° C. for 1 day. A solution of saturated K2CO3 (50 mL) was added to quench the reaction, and organic layer was separated. Removal of solvent gave a oily product, which was treated with ether/hexanes to give a pure solid product (37.0 g, 99%). NMR (MeOD) δ: 8.01 (d, J=9.0 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.05 (dd, J=8.9, 2.9 Hz, 1H), 6.49 (s, 1H), 4.85 (s, 3H), 3.91 (s, 4H). MS (M+1): 226.10.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.O.O.O.[C:14]([O-:17])(=[O:16])[CH3:15].[Na+]>O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:14]([O-:17])(=[O:16])[CH3:15]
Reactant: CN(C)C(=N)N=C(N)N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(C)C(=N)NC(=N)N
Yield: 51.6 %

Procedure:
20.0 g (1 equivalent) of metformin hydrochloride, 50 Ml of water, and 19.72 g (1.2 equivalents) of sodium acetate trihydrate were added to a reactor, and stirred. Then the resulting crystal was filtered and washed with acetone, and then dried at 60° C. to obtain 11.72 g of metformin acetate (yield: 51.3%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[N:19]=[C:20]=[O:21]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([NH:19][C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[F:11])=[O:21])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: CCc1cc(Br)ccc1N
Solvent: ClCCl
Product: CCc1cc(Br)ccc1NC(=O)Nc1cc(C)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A solution of 4-bromo-2-ethylaniline (200 mg) in dichloromethane (10 mL) was treated with 1-fluoro-2-isocyanato-4-methylbenzene (151 mg), stirred at room temperature overnight, diluted with hexanes, and filtered. The filter cake provided 227 mg of the desired product. MS (ESI(+)) m/e 351,353 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].CN1CCOCC1>CO>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: CN(C)CCN
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCN(C)C)cc2s1
Yield: 9.6 %

Procedure:
the title compound (11 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), N1,N1-dimethylethane-1,2-diamine (67 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 381.4 (M+1, 50%). Yield=9%.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[N:7]=1)(=[O:4])=[O:3].[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>O1CCOCC1>[CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:24]=[CH:23][C:21]([NH:22][C:29](=[O:30])[NH:28][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[N:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1
Reactant: CC(C)N=C=O
Solvent: C1COCCO1
Product: CC(C)NC(=O)Nc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOCC3)n2)cc1
Yield: 43.8 %

Procedure:
4-[4-(Methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]aniline (70 mg, 0.2 mmol) and isoproylisocyanate (0.1 mL, 1 mmol) were heated in dioxane (2 mL) at 70° C. for 4 hours. The reaction mixture was evaporated and the residue triturated with ethyl acetate. The suspension was filtered and the white solid washed with ethyl acetate and diethyl ether then dried under vacuum at 60° C. overnight to yield the title compound (38 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:20](B(CC)CC)[CH3:21]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4]([CH2:20][CH3:21])[N:3]=1
Reactant: CCB(CC)CC
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CCc1nc(Cl)c(C#N)cc1F

Procedure:
To a vigorously stirred mixture of 2,6-dichloro-5-fluoro-3-pyridinecarbonitrile (15.0 g, 78.5 mmol), potassium phosphate (17.0 g, 74.0 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.5 g, 1.8 mmol) in dry THF (300 ml) at room temperature was added in a stream triethylborane (85 ml of a 1M solution in THF). The resulting mixture was heated at reflux temperature for 16 h, cooled, concentrated, and partitioned between ethyl acetate and water. The resulting crude product obtained from the organics was subjected to flash chromatography using ethyl acetate/hexanes as eluent to give the title compound (8 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4].[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([F:23])=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1F
Temperature: 25 °C
Yield: 3.2 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyrimidine-4-carboxylic acid methyl ester (778 mg, 2.5 mmol) and F-TEDA (974 mg, 2.75 mmol) were combined in acetonitrile and heated at reflux for 4 hours (reaction made little progress after 1 hour). The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, purified by column chromatography, and then purified a second time by preparative HPLC to yield 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropyrimidine-4-carboxylic acid methyl ester (26 mg, 3.2% yield): mp 200-202° C.: 1H NMR (CDCl3): δ 7.62 (dd, 1H), 7.21 (dd, 1H), 5.40 (br s, 2H), 4.02 (s, 3H), 4.0 (d, 3H)
Reaction SMILES: Br[C:2]([CH3:14])([CH3:13])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21].[In]>C1COCC1>[OH:21][C:16]1([C:2]([CH3:14])([CH3:13])[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1
Reactant: CC(C)(Br)C(=O)OCc1ccccc1
Reactant: O=C1CCCCO1
Agent: [In]
Solvent: C1CCOC1
Product: CC(C)(C(=O)OCc1ccccc1)C1(O)CCCCO1

Procedure:
A stirred suspension of benzyl 2-bromo-2-methylpropanoate (0.748 g, 2.91 mmol), tetrahydro-2H-pyran-2-one (0.260 g, 2.60 mmol) and indium (0.341 g, 2.97 mmol) in THF (3 mL) was sonicated for 6 h. The reaction was quenched with sat. NaHCO3 and extracted with ether, then concentrated. The residue was purified by silica gel flash chromatography to afford benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.43 (5H, m), 5.18 (2H, s), 3.51-3.61 (2H, m), 2.41 (2H, t, J=7.10 Hz), 1.56-1.66 (2H, m), 1.35-1.47 (8H, m). Benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate was dissolved in triethylsilane (0.415 mL, 2.60 mmol) and treated with TFA (0.200 mL, 2.60 mmol) and the reaction mixture was stirred at rt for 16 h, then evaporated to dryness to yield benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.41 (5H, m), 5.22 (1H, d, J=12.66 Hz), 5.10 (1H, d, J=12.51 Hz), 3.91-4.01 (1H, m), 3.53 (1H, dd, J=11.22, 1.75 Hz), 3.39 (1H, td, J=11.56, 2.37 Hz), 1.82-1.92 (1H, m), 1.44-1.59 (4H, m), 1.30-1.41 (1H, m), 1.19-1.25 (3H, m), 1.11-1.19 (3H, m). A stirred suspension of 10% Pd—C (16.63 mg) and benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate (82 mg, 0.313 mmol) in EtOAc (5 mL) was stirred under H2 for 6 h, and then filtered and concentrated to yield Cap P-23 (54 mg). 1H NMR (500 MHz, CDCl3) δ ppm 4.09-4.19 (1H, m), 3.48-3.57 (1H, m), 3.33-3.42 (1H, m), 1.88-1.97 (1H, m), 1.71 (1H, d, J=13.12 Hz), 1.47-1.65 (3H, m), 1.29-1.40 (1H, m), 1.23-1.27 (3H, m), 1.14-1.20 (3H, m).
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[O:27])[CH2:22][CH2:21]2)=[O:18])[N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+].Cl>CO>[NH:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[O:27])[CH2:22][CH2:21]2)=[O:18])[N:11]=[N:10]1
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCN(C(=O)OCc3ccc(Cl)cc3Cl)CC2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)OCc2ccc(Cl)cc2Cl)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 2,4-dichlorobenzyl 4-(4-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate (100 mg, 0.180 mmol) in MeOH (1 mL) at RT was added 1M NaOH (0.397 mL, 0.397 mmol). The reaction mixture was allowed to stir for 1 hr. An equivalent of 1M HCl (0.4 ml) was added to neutralise the reaction mixture and the MeOH removed under reduced pressure. The reaction mixture was diluted with EtOAc and water and the organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Trituration with diethyl ether afforded the title product;
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[C:8]([C:18](OCC)=[O:19])[N:7]=1)=O)C.[BH4-].[Na+].[Cl-].[Cl-].[Ca+2]>C1COCC1>[N:12]1([C:10]2[CH:11]=[C:6]([CH2:4][OH:3])[N:7]=[C:8]([CH2:18][OH:19])[CH:9]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cc(N2CCNCC2)cc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OCc1cc(N2CCNCC2)cc(CO)n1

Procedure:
Diethyl-4-piperazinyl-2,6-pyridinedicarboxylate is dissolved in THF and treated with NaBH4 and CaCl2 as per the procedure of Example 51 to give the title compound.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([F:16])[C:13](F)=[C:12]([F:18])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20]([OH:23])[C:21]#[CH:22].[H-].[Na+]>CN(C=O)C>[CH:1]1([CH2:7][NH:8][C:9](=[O:19])[C:10]2[CH:11]=[C:12]([F:18])[C:13]([O:23][CH2:20][C:21]#[CH:22])=[C:14]([F:16])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(NCC1CCCCC1)c1cc(F)c(F)c(F)c1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1c(F)cc(C(=O)NCC2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To 10 ml of DMF were added 0.50 g of N-cyclohexylmethyl-3,4,5-trifluorobenzamide and 0.15 g of propargyl alcohol and to the mixture obtained was added 100 mg of sodium hydride at 0° C. The mixture obtained was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated. The residue was subjected to silica gel column chromatography to obtain 0.49 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3,5-difluorobenzamide (hereinafter, described as the compound 32 of the present invention) represented by the formula:
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([C@@H:10]([CH3:25])[CH2:11]2)=[CH:8][C:7](=[O:26])[CH:6]=[CH:5]1.[CH2:28]([O:30][CH2:31][C:32](Cl)=[O:33])[CH3:29]>>[CH2:28]([O:30][CH2:31][C:32]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([OH:24])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:27])[C:9](=[CH:8][C:7](=[O:26])[CH:6]=[CH:5]2)[C@@H:10]([CH3:25])[CH2:11]3)[CH2:14][CH2:15]1)=[O:33])[CH3:29]
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12
Reactant: CCOCC(=O)Cl
Product: CCOCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
As described in Example 2(a), 15.0 g of 11β,17,21-trihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione is reacted with ethoxyacetic acid chloride, worked up, and purified, thus isolating 15.6 g of 21-ethoxyacetoxy-11β,17-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione, mp 229° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH:18]=3)=[N:8][C:7]=2[NH:6][C:5]1=[O:30])[CH2:2][CH3:3].[F:31][CH:32]([F:37])C(OCl)=O.[Na].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[F:31][CH:32]([F:37])[O:30][C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=4)[CH:18]=3)=[N:8][C:7]=2[N:6]=1
Reactant: CCCn1c(=O)[nH]c2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: O=C(OCl)C(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(OC(F)F)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione (100 mg, 0.24 mmol), Sodium chloro difluoroacetate (47 mg, 0.31 mmol), Cs2CO3 (117 mg, 0.36 mmol) and DMF (2 ml) were stirred at 60° C. for 18 hours. Reaction mixture was cooled and diluted with water (10 ml), solid materials were filtered off and it was purified by preparative HPLC to obtain 2-Difluoromethoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one as off white solid (1 mg, 10%) and
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[Cu][C:14]#[N:15].Cl.C#N>CN(C=O)C.[Cl-].[Na+].O.[Fe](Cl)(Cl)Cl.C(OCC)(=O)C.O>[C:14]([C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1)#[N:15]
Reactant: N#C[Cu]
Reactant: COc1ccc(Br)c2ccsc12
Agent: Cl[Fe](Cl)Cl
Agent: C#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C#N)c2ccsc12
Temperature: 150 °C
Yield: 69 %

Procedure:
To a stirred solution of 4-bromo-7-methoxy benzo[b]thiophene (1.05 g, 4.32 mmol, 1 equiv.) in dry DMF (40 mL) was added copper(I)cyanide (3.885 g, 43.4 mmol, 10 equiv.) and the reaction mixture was heated at 150° C. overnight. The reaction mixture was cooled to ˜120° C. and then solid iron(III)chloride (1.58 g, 9.74 mmol) was added followed by 1 N HCl (CAUTION: HCN evolution—perform in a well vented hood!) The reaction mixture was heated at ˜100° C. for 2 hr before cooling to room temperature. Water, brine, and ethyl acetate were added and the layers were separated. The organic layer was washed with brine (3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue thus obtained was purified via medium pressure liquid chromatography eluting with 10% ethyl acetate/90% hexanes to afford the title compound (564 mg, 69%) as a colorless solid; □H (400 MHz, CDCl3) 4.06 (3H, s), 6.81 (1H, d, J=8 Hz), 7.56 (1H, d, J=6 Hz), 7.65 (1H, d, J=6 Hz), 7.71 (1H, d, J=8 Hz).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]([OH:32])[C@@H:10]([NH:13][C:14]([C@@H:16]([NH:22][C:23]([N:25]3[CH2:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:17][C:18]([F:21])([F:20])[CH3:19])=[O:15])[CH2:11][CH3:12])[O:6][N:5]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]([C@@H:10]([NH:13][C:14]([C@@H:16]([NH:22][C:23]([N:25]3[CH2:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:17][C:18]([F:21])([F:20])[CH3:19])=[O:15])[CH2:11][CH3:12])=[O:32])[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC[C@H](NC(=O)[C@H](CC(C)(F)F)NC(=O)N1CCCOCC1)C(O)c1nc(C2CC2)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@H](CC(C)(F)F)NC(=O)N1CCCOCC1)C(=O)c1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution of Perhydro-1,4-oxazepine-4-carboxylic acid ((S)-1-{(S)-1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-butyl)-amide (110 mg, 0.24 mmol) in dry dichloromethane (20 mL) under N2 is added Dess-Martin periodinane (143 mg, 0.34 mmol). The reaction is stirred at RT for 2 hr, and then dichloromethane (20 mL) is added. The reaction is quenched with a solution of Na2S2O3 (0.26M, 2 mL) and washed with saturated NaHCO3 (20 mL). The aqueous layer is extracted with dichloromethane (2×30 mL). The organic layers are dried (Na2SO4) and concentrated in vacuum. The residue is purified over 12 g silica gel, eluted with ethyl acetate: heptane (gradient 50-100%) to afford Perhydro-1,4-oxazepine-4-carboxylic acid {(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-3,3-difluoro-butyl}-amide (82 mg, 75%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[C:6]([NH:8][NH2:9])=O.[F:19][C:20]1[CH:21]=[C:22]([C:27]2([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32][CH2:31][CH2:30][N:29]=[C:28]2SC)[CH:23]=[CH:24][C:25]=1[F:26]>C(O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([C:27]2([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32][CH2:31][CH2:30][N:29]3[C:6]([C:5]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:8][N:9]=[C:28]23)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COc1cc(C(=O)NN)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCN=C1SC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)c3)nnc21
Temperature: 90 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)benzohydrazide (236 mg) was added to a mixture of ethyl 3-(3,4-difluorophenyl)-2-(methylsulfanyl)-3,4,5,6-tetrahydropyridine-3-carboxylate (300 mg) in ethanol (3 mL) at room temperature, and the mixture was stirred at 90° C. for 2 days. The reaction mixture was diluted with ethyl acetate, the mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (217 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.CCCCCC.[Si](Cl)(CC)(CC)CC.[F:26][C:27]1[N:32]=[CH:31][C:30]([C:33](N(OC)C)=[O:34])=[CH:29][CH:28]=1>C1COCC1>[F:26][C:27]1[N:32]=[CH:31][C:30]([C:33]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[O:34])=[CH:29][CH:28]=1
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1ccc(F)nc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1cncc1C(=O)c1ccc(F)nc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 250-mL round-bottom flask containing 1-methyl-1H-imidazole (1.74 g, 21.2 mmol) and THF (50 mL) at −78° C. under nitrogen was added n-BuLi in hexane (2.5 M, 9.8 mL, 24.5 mmol) dropwise. The resulting mixture was stirred for 1 hour at −78° C., and Et3SiCl (3.20 g, 21.2 mmol) was added. The mixture was stirred for an additional 1 hour at −78° C., and a second portion of n-BuLi (2.5 M, 8.5 mL, 21.3 mmol) was added. After stirring for an additional 1 hour at −78° C., 6-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (3.00 g, 16.3 mmol, Intermediate 21, step b) was added. The mixture was stirred at −78° C. and then allowed to warm up to room temperature. The stirring was continued for 1 hour at room temperature, and then the reaction was quenched by the addition of 20 mL of water. The mixture was diluted with 100 mL of water. The organic layer was separated, and the aqueous layer was extracted with 3×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by chromatography (silica gel column, 1:4 EtOAc/petroleum ether) to give the title compound as a white solid.