Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C.[Pd]>[CH2:14]([NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: COCOC1CCN(CCN)CC1
Agent: [Pd]
Solvent: CCO
Product: COCOC1CCN(CCNCc2ccccc2)CC1
Reaction time: 24 h
Yield: 64.8 %

Procedure:
27 g of 1-(2-aminoethyl)-4-methoxymethoxy-piperidine was dropwise added to a solution of 15 g of benzaldehyde in 300 ml of ethanol, at room temperature. The mixture was stirred at the same temperature for 1 day. To the reaction mixture was added 5 g of 10% Pd-C, and the resulting mixture was allowed to absorb hydrogen at room temperature at atmospheric pressure. After a reaction was over, the catalyst was removed by filtration. The filtrate was diluted with ethyl acetate. The dilution was subjected to extraction with 10% hydrochloric acid. The aqueous layer was made alkaline with an aqueous potassium hydroxide solution and then subjected to extraction with ethyl acetate. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 10% methanol-chloroform) to obtain 25.50 g of 1-(2-benzylaminoethyl)-4-methoxymethoxypiperidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>O1CCOCC1>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Reactant: COCCN
Solvent: C1COCCO1
Product: COCCNc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
A mixture of 6-chloro-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 17) (250 mg, 0.59 mmol) and 2-methoxyethylamine (443 mg, 5.9 mmol) in anhydrous 1,4-dioxane (5 ml) was heated at 150° C. for 40 minutes in a sealed vessel under microwave irradiation. The reaction was worked up as described in Example 54 to give the title compound (108 mg, 40%) as a cream solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCOB1[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1.C(=O)([O-])O.[Na+]>COCCOC.O.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>[CH:1]1([C:7]2[C:8]3[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OS(=O)(=O)C(F)(F)F)cccc1-3
Reactant: c1cncc(B2OCCCO2)c1
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: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(-c2cccnc2)cccc1-3
Temperature: 90 °C
Yield: 82 %

Procedure:
To a suspension of methyl 12-cyclohexyl-4-trifluoromethanesulfonyloxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (130 mg, 0.248 mmol), 3-(1,3,2-dioxaborinan-2-yl)pyridine (53 mg, 0.323 mmol) and sodium hydrogen carbonate (62 mg, 0.744 mmol) in 1,2-dimethoxyethane (2 ml) and water (0.75 ml) was added tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol), and the mixture was heated at 90° C. for 3 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to give methyl 12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (92 mg, yield 82%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:36])([F:35])[F:34])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:50][O:51][NH:52][CH3:53].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([N:52]([O:51][CH3:50])[CH3:53])=[O:27])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:35])([F:34])[F:36])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-{4-[2-benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}benzoic acid (115.8 mg, 0.237 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (86 mg, 0.356 mmol), O,N-dimethyl-hydroxylamine hydrochloride (69 mg, 0.711 mmol) and 0.3 mL of triethylamine dissolved in 2 mL CH2Cl2 was stirred at room temperature overnight. The reaction mixture was quenched with 1M HCl(aq) and the crude material was extracted with CH2Cl2. The crude material was purified with flash chromatography using EtOAc/heptane, 3:7, as eluent to afford 17 mg of analytically pure product.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=CC=C[CH:3]=1.[C:15](O)(=O)C(C)(C)C>>[C:9]1([C:1]([C:2]([CH3:3])([CH3:7])[CH3:15])=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)C(=O)O
Reactant: O=C(c1ccccc1)c1ccccc1
Product: CC(C)(C)C(=O)c1ccccc1

Procedure:
This invention will be useful in reactions like: benzophenone and pivalic acid to obtain t-butyl phenyl ketone; 1,3-dichloroacetone and pivalic acid to obtain monochloropinacolone; and cyclopentanone and acetic acid to obtain 2,7-octanedione.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f12) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C:7](=[CH:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([O:19][C:12]1[CH:13]=[CH:14][C:15]2[C@@H:16]3[C:7]([C@H:6]4[C@@:2]([CH2:18][CH2:17]3)([CH3:1])[CH:3]=[CH:4][CH2:5]4)=[CH:8][CH2:9][C:10]=2[CH:11]=1)(=[O:28])[CH3:27]
Reactant: C[C@@]12C=CC[C@H]1C1=CCc3cc(O)ccc3[C@H]1CC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)CC=C1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Yield: 35.1 %

Procedure:
A solution of estra-1,3,5(10),7,16-pentaen-3-ol (5, 192.1 mg, 0.7612 mmol) in anh. pyridine (2.6 mL, 32 mmol) and acetic anhydride (0.36 mL, 3.8 mmol) was stirred 6 h, after which 30 mL of ethyl acetate were added. The mixture was washed with three 10 mL portions of 1N hydrochloric acid+10 mL of saturated sodium bicarbonate+10 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. See Example 15. The residue was washed with 10 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparative TLC (5% ethyl acetate/hexanes on silica gel GF, 1000μ thickness) and recrystallization from aqueous ethanol gave fine white needles (78.6 mg, 0.267 mmol, 35%), m.p. 77-80° C. TLC (4% ethyl acetate/hexanes on silica gel) showed 2 spots at Rf 0.21 and 0.24. (NA-1994A-286A)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:26])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C>[CH:2]([C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:26])[C:12]2[CH:13]=[CH:14][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[CH3:9])=[O:1]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
A reactor is charged with 150 mg (0.42 mmol) of the solid obtained in step 1 and 216 mg (0.5 mmol) of the Dess-Martin reagent in 5 ml acetonitrile. The mixture is stirred at room temperature for 16 hours. The insoluble compounds are filtered and the filtrate is concentrated under reduced pressure. The obtained solid is washed with ethylic ether and pentane to give the required aldehyde (120 mg, 82%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[C:3]=1C.[OH:19][CH2:20][CH2:21][N:22]1[CH:31]=[C:30](I)[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[C:23]1=[O:33]>>[OH:19][CH2:20][CH2:21][N:22]1[CH:31]=[C:30]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:4][CH:3]=2)[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[C:23]1=[O:33]
Reactant: Cc1c(I)c2cccnc2n1C(=O)OC(C)(C)C
Reactant: O=c1c2cnccc2c(I)cn1CCO
Product: O=c1c2cnccc2c(-c2c[nH]c3ncccc23)cn1CCO

Procedure:
Analogously to Example 5, tert-butyl 3-iodo-2-methylpyrrolo[2,3-b]pyridine-1-carboxylate is reacted with 2-(2-hydroxyethyl)-4-iodo-2H-2,7-naphthyridin-1-one, giving 2-(2-hydroxyethyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2H-2,7-naphthyridin-1-one as colourless solid; MS (ESI): 307 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1.O1CCC[CH2:22]1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]([OH:19])[CH3:22])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=Cc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc2ccc(F)cc2nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a stirring mixture of 2-(2-chlorophenyl)-7-fluoroquinoline-3-carbaldehyde (0.7588 g, 2.656 mmol) in tetrahydrofuran (26.56 mL, 2.656 mmol) was added methylmagnesium bromide 3 M in diethyl ether (1.328 mL, 3.984 mmol) dropwise at 0° C. (started at 4:00 pm), and the mixture was allowed to warm to room temperature with stirring over 19 h. The reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×1). The combined orgainc layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)ethanol as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (1 H, d, J=11.0 Hz), 8.20 (1 H, dd, J=8.6, 6.7 Hz), 7.75 (1 H, dd, J=10.6, 2.7 Hz), 7.42-7.66 (5 H, m), 5.39 (1 H, dd, J=57.5, 3.9 Hz), 4.59-4.69 (1 H, m), 1.20 (3 H, dd, J=58.7, 6.3 Hz); LC-MS (ESI) m/z 302.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].C[O:16][C:17]([C@H:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.Cl>>[CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH:9][C:17]([C@H:19]([NH2:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:16])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)[C@H](N)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Reaction time: 24 h

Procedure:
The wet mycelium so obtained is suspended in M/30-phosphate buffer (pH 6.0), containing 7-aminodeacetoxycephalosporanic acid and D-α-phenylglycine methyl ester hydrochloride (0.4 g), at 28° C for 24 hours. The amount of Cefalexin formed in the reaction mixture is 0.095 g when determined by microbiological assay.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:18])=O.[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[CH3:18][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:19]=[C:20]([NH2:22])[S:21][CH:2]=1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(-c2ccccc2)cc(C)c1-c1csc(N)n1
Yield: 27.9 %

Procedure:
A mixture of 2-bromo-1-(3,5-dimethyl-(1,1′-biphenyl)-4-yl)ethanone (2.56 g, 8.44 mmol) and thiourea (0.64 g, 8.44 mmol) in 95% EtOH (12.1 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene (10 mL). The solids were filtered and dried under vacuum to give 4-(3,5-dimethyl-(1,1′-biphenyl)-4-yl)thiazol-2-amine (0.66 g) as yellow solids in 28% yield: 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J=1 Hz, 2 H), 7.43 (t, J=7.5 Hz, 1 H), 7.32 (m, 1 H), 7.25 (s, 2 H), 6.34 (s, 1 H), 5.03 (s, 2 H), 2.24 (s, 6 H).
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.Br[CH2:25][C:26]1[C:37]([C:38]#[N:39])=[C:30]2[N:31]=[C:32]([CH:34]3[CH2:36][CH2:35]3)[O:33][C:29]2=[C:28]([F:40])[C:27]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O>[CH:34]1([C:32]2[O:33][C:29]3[C:30](=[C:37]([C:38]#[N:39])[C:26]([CH2:25][F:1])=[C:27]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:28]=3[F:40])[N:31]=2)[CH2:36][CH2:35]1
Reactant: N#Cc1c(CBr)c(-c2ccccc2)c(F)c2oc(C3CC3)nc12
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(CF)c(-c2ccccc2)c(F)c2oc(C3CC3)nc12
Yield: 59.4 %

Procedure:
Under nitrogen atmosphere at 0° C., tetra(n-butyl)ammonium fluoride (1.0 M tetrahydrofuran solution) (1.50 ml, 1.50 mmol) was added to a tetrahydrofuran (12 ml) solution of 5-bromomethyl-2-cyclopropyl-7-fluoro-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-292) (426 mg, 1.15 mmol), followed by stirring with cooling with water for 1.5 hours. The solvent was evaporated away under reduced pressure, then the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=4:1, v/v) to obtain the entitled compound (212 mg, 59%) as a colorless oil.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][N:5]=1>CO>[Cl:3][C:4]1[N:5]=[CH:6][C:7]([NH2:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(N)cnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
Reduced iron (793 mg) was added to an aqueous solution (25 mL) of ammonium chloride (1.27 g), and the mixture was stirred at room temperature for 5 min. A solution (10 mL) of 2-chloro-3-methyl-5-nitropyridine (816 mg) in methanol was added dropwise over 10 min. The reaction mixture was stirred at 40° C. for 20 min and at 50° C. for 1.5 hr and further refluxed for 1 hr. The reaction mixture was filtered through celite, and celite was washed with methanol. Methanol was mostly removed by concentration under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→7:3) to give the title compound as a solid (yield 280 mg, 42%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:9]([C:11](OCC)=[O:12])=[N:8][CH:7]=1.[BH4-].[Na+]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:9]([CH2:11][OH:12])=[N:8][CH:7]=1
Reactant: CCOC(=O)c1ncc(-c2cccs2)s1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1ncc(-c2cccs2)s1
Yield: 74 %

Procedure:
In substantially the same manner as in Reference Example 111, ethyl 5-(2-thienyl)-2-thiazolecarboxylate was subjected to reduction with sodium borohydride to obtain 5-(2-thienyl)-2-thiazolylmethanol. The yield was 74%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 67-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24](=[O:30])[N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:18]([O:31][CH3:32])[CH:17]=3)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:13](=[O:14])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24](=[O:30])[N:25]5[CH2:26][CH2:27][CH2:28][CH2:29]5)=[C:18]([O:31][CH3:32])[CH:17]=4)[CH2:35][CH2:34][N:11]3[CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCC(=O)N1CCCC1
Reactant: BrCCBr
Product: COc1cc(N2CCn3cc(-c4ccc(Cl)cc4)cc3C2=O)ccc1OCC(=O)N1CCCC1

Procedure:
Following the procedure described in Example 1 step D, 4-(4-chlorophenyl)-N-(3-methoxy-4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)phenyl) 1H-pyrrole-2-carboxamide (11 mg) was alkylated with 1,2-dibromoethane to yield 9.2 mg of the title compound. MS (ESI) 480 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][CH:12]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=2)[CH:14]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccc(Cl)cc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCNc2ccc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)c2)nc1
Temperature: 85 °C
Yield: 58.4 %

Procedure:
To 2-(2,4-dichlorophenyl)-4-fluoro-1-nitrobenzene(32 mgs, 0.1 mmol) in acetonitrile was added 2-(2-aminoethylamino)-5-cyanopyridine (19.2 mgs, 0.1 mmol) and N,N diisopropylethylamine (18 μl, 0.1 mmol), and the mixture was heated to 85° C. over-night. The mixture was partitioned between ethyl acetate and water and the organic layer was dried (MgSO4) and concentrated. Purification on silica gel with 5% methanol in dichloromethane as the eluent yielded 25 mgs of 6-({2-[(2′,4′-dichloro-6-nitro-1,1′-biphenyl-3-yl)amino]ethyl}amino)nicotinonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][OH:6].N1C=CN=C1.[Si:21](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:5][O:6][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
(R)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (2.2 mg, 10 mmol) was dissolved in THF (20 ml). Imidazole (818 mg, 12 mmol) and TBDPS chloride (2.9 ml, 11 mmol) were added. The mixture was stirred at rt overnight. The mixture was then partitioned between CH2Cl2 and water (30 ml/30 ml). The organic layer was concentrated and the residue was purified by column chromatography (6/1, Hexanes/EtOAc) to give (R)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propionic acid methyl ester (3.3 g, 72%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2].F[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.ClCCl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=2)=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2]
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: CCc1ccc(O)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 140 °C

Procedure:
A mixture of 4-(2-ethyl-5-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (100 mg, 0.34 mmol), 2-fluoro-6-trifluoromethylpyridine (68 mg, 0.41 mmol), and potassium carbonate (110 mg, 0.69 mmol) in N,N-dimethylformamide (3 ml) is heated to 140° C. under microwave irradiation for 40 minutes. The mixture is cooled to room temperature, poured into 2M aqueous hydrochloric acid, diluted with dichloromethane and filtered through a phase separation cartridge. The organic phase is collected. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel to give 4-[2-ethyl-5-(6-trifluoromethylpyridin-2-yloxy)phenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([OH:12])=O)[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:20][NH:21][C:22]([C:24]1[N:25]([CH3:30])[N:26]=[CH:27][C:28]=1[NH2:29])=[O:23]>>[CH3:30][N:25]1[C:24]([C:22](=[O:23])[NH:21][CH3:20])=[C:28]([NH:29][C:10]([C:8]2[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)=[O:12])[CH:27]=[N:26]1
Reactant: CNC(=O)c1c(N)cnn1C
Reactant: O=C(O)c1nc(C2CC2)cnc1Nc1cccnc1
Product: CNC(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cccnc2)cnn1C

Procedure:
The product was obtained starting from 6-cyclopropyl-3-(pyridin-3-ylamino)pyrazine-2-carboxylic acid (30 mg, 0.12 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (23 mg, 0.15 mmol) according to the method described in example 64, step 6 as yellow solid (30 mg, 64%).