Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([C:17](N)=O)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[C:20]1([CH2:26][OH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N12CCCN=C1CCCCC2.Br[N:40]1[C:44](=[O:45])CCC1=O>C(Cl)CCl>[CH3:17][C:2]1([NH:40][C:44](=[O:45])[O:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C(N)=O)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: CC1(NC(=O)OCc2ccccc2)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
To a solution of 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxamide (1.8538 g, 7.04 mmol) and phenylmethanol (7.61 g, 70.4 mmol) in ClCH2CH2Cl (30 ml) cooled at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.18 mL, 21.12 mmol) dropwise, followed by 1-bromopyrrolidine-2,5-dione (1.378 g, 7.74 mmol) in portions. After addition, the resulting yellow mixture was stirred at 0° C. for 15 min, then at rt for 3.5 hrs, After this time, the reaction was determined not to be complete by LCMS analysis and an additional amount of NBS (138 mg) was added. The reaction was then allowed to stir for an additional 2.5 hrs. The reaction mixture was quenched by addition of water (50 mL) and then adjusted to pH=5 with 1N aqueous HCl. The solution was extracted with EtOAc (3×). The combined EtOAc extracts were washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give the product, benzyl 3-methyl-1-(4-nitrophenyl)piperidin-3-ylcarbamate (2.274 g, 6.16 mmol, 87% yield) as a yellow oil. Anal. Calcd. for C20H23N3O4 m/z 369.4, found: 370.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.06 (d, J=9.34 Hz, 2H), 7.37 (d, J=4.40 Hz, 1H), 7.34-7.27 (m, 4H), 6.81 (d, J=9.34 Hz, 2H), 5.09-4.93 (m, 2H), 4.74 (s, 1H), 4.18-4.07 (m, 1H), 3.74-3.62 (m, 1H), 3.11-3.02 (m, 2H), 2.04-1.99 (m, 1H), 1.81-1.68 (m, 2H), 1.58-1.51 (m, 1H), 1.44 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([NH2:16])=[O:15].O.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1.CC(C)=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:3]2[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=3)[S:5][C:4]=2[C:14](=[O:15])[NH:16][C:18]1([CH3:23])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNc1cc(-c2ccncc2)sc1C(N)=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Yield: 13.9 %

Procedure:
A mixture of 3-(methylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (400 mg, 1.72 mmol), p-toluenesulfonic acid monohydrate (150 mg) and acetone (40 mL) in toluene (40 mL) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: dichloromethane=1:9) to afford the title compound (30 mg, yield 6%) as an orange solid:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][NH:17][CH3:18].COCC(O)C>>[CH3:13][N:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)[CH2:15][CH2:16][NH:17][CH3:18]
Reactant: CNCCNC
Reactant: Cc1cc(Cl)c2ccccc2n1
Solvent: COCC(C)O
Product: CNCCN(C)c1cc(C)nc2ccccc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
4-Chloroquinaldine (1.5 g, 5 mmol) was mixed with N,N′-dimethylethylenediamine (2.45 ml, 25 mmol) and 1-methoxy-2-propanol (8 ml) and stirred at 110° C. overnight. The mixture was purified by column chromatography (pre-packed silica column, gradient of heptane/ethyl acetate each containing 1% triethylamine). 0.4 g were obtained (1.75 mmol; 35%). MS (APCI) m/z=230.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6](=O)[CH3:7])[CH3:5].O.[NH2:10][NH2:11]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:6](=[N:10][NH2:11])[CH3:7])[CH3:5]
Reactant: CON=C(C)C(C)=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CON=C(C)C(C)=NN
Yield: 29.8 %

Procedure:
3 g (0.026 mol) of butane-2,3-dione mono-(O-methyl oxime) are heated at 60° C. in 20 ml of ethanol with 2.6 g (0.052 mol) of hydrazine hydrate for 1 hour. The reaction mixture is poured onto water and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. The residue is stirred with petroleum ether and the crystals are filtered off. 1 g (29.7% of theory) of 3-hydrazono-butan-2-one O-methyl oxime is obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH:17]([C:6]1[CH:7]=[C:8]([CH:14]([CH3:16])[CH3:15])[CH:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1)([CH3:19])[CH3:18]
Reactant: NC(N)=S
Reactant: CC(C)c1cc(C(C)C)c(C(=O)CBr)c(C(C)C)c1
Solvent: CCO
Product: CC(C)c1cc(C(C)C)c(-c2csc(N)n2)c(C(C)C)c1
Yield: 25.5 %

Procedure:
A mixture of 2-bromo-1-(2,4,6-triisopropylphenyl)ethanone (13.9 g, 42.7 mmol) and thiourea (3.24 g, 42.6 mmol) in 95% EtOH (60.9 mL) was heated at reflux overnight. The solution was concentrated and added with water (100 mL), saturated aqueous Na2CO3 (10 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure, which was purified by column chromatography on silica gel (33% EtOAc in hexanes as eluant) to give 4-(2,4,6-triisopropylphenyl)thiazol-2-amine (3.28 g) as white solids in 25% yield: 1H NMR (500 MHz, CDCl3) δ 7.03 (s, 2 H), 6.22 (s, 1 H), 4.75 (s, 2 H), 2.89 (m, 1 H), 2.68 (m, 2 H), 1.27-1.14 (m, 18H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.I[C:11]([F:16])([F:15])[CH:12]([F:14])[F:13].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: FC(F)C(F)(F)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Temperature: 70 °C

Procedure:
To a solution of 3-bromo-5-fluorophenol (104 mmol crude), prepared as described in Step 1, Procedure 7, and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was cooled to rt, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina The filtrate was concentrated under reduced pressure to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification. LCMS: RT=1.91 min, [M+H] No Ionizable peak (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.76 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, Purity 100%); NMR: 400 MHz 1H(CDCl3) ppm 7.19 (m, 2 H), 6.92 (d, J=8.35 Hz, 1 H), 5.88 (tt; J=52.95 Hz and J=2.64 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:20]([NH:22]C)[CH3:21])=[CH:5][CH:4]=1.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].[CH2:38](O)C(N)(CO)CO>C(Cl)Cl>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:22][CH:20]([C:10]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH3:21])(=[O:36])=[O:35])=[C:30]([CH3:38])[CH:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(CO)(CO)CO
Reactant: CNC(C)c1nc2ccccc2c(=O)n1-c1ccc(OC)cc1
Solvent: ClCCl
Product: COc1ccc(-n2c(C(C)NS(=O)(=O)c3ccc(C(C)(C)C)cc3C)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a suspension of the 3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one (50 mg, 0.16 mmol) stirring in 2 mL DCM was added TEA (19 mg, 0.19 mmol) followed by the addition of neat 4-tert-butyl-benzenesulfonyl chloride (37 mg, 0.16 mmol). The reaction was allowed to stir at room temperature for 2 h then treated with PS-tris-amine resin (100 mg). The reaction was allowed to stand for 15 min at room temperature after which the resin was removed by filtration. The filtrate was concentrated under vacuum to afford the crude product. The crude residue was purified by flash chromatography (silica gel, 50% EtOAc/Hex) to afford the desired product as an off-white powder (74 mg, 92% yield). 1H-NMR (CDCl3): δ 8.15 (d, 1H), 7.55 (s, 1H), 7.39 (m, 4H), 7.25 (d, 1H), 7.16 (m, 2H), 7.09 (m, 1H), 6.70 (m, 2H), 4.90 (q, 1H), 4.83 (s, 3H), 3.11 (s, 3H), 1.22 (d, 3H), 1.09 (s, 9H); MS (ESI) 506 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:27](=O)[CH3:28])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](/[C:27](=[N:17]/[NH:16][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][C:10]([S:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)/[CH3:28])[CH:26]=1
Reactant: NNC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 50.6 %

Procedure:
4-(morpholinosulfonyl)benzohydrazide (100 mg, 0.350 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (59.8 mg, 0.350 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-4-(morpholinosulfonyl)benzohydrazide (80 mg, 0.177 mmol, 50.6% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (m, 2H), 7.89 (m, 2H), 7.67 (d, 1H, J=2.4 Hz), 7.35 (dd, 1H, J=2.4 & 8.8 Hz), 6.95 (d, 1H, J=8.4 Hz), 3.64 (m, 4H), 2.92 (m, 4H), 2.49 (s, 3H). Mass [M+H]+:438.0
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.NC1C=CC=C2C(N(O)C(=O)C=12)=[O:14].[OH-].[Na+]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: Nc1cccc2c1C(=O)N(O)C2=O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(C=O)cc1
Yield: 62 %

Procedure:
172 mg (1.60 mmol) of 4-toluidine were reacted analogously to Example 1 in the presence of 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide. After a reaction time of 22 hours, the reaction solution was brought to pH 8 with 2M NaOH, extracted with chloroform and examined by NMR spectroscopy. Yield 62% of 4-aminobenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8](CC#N)[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.[C:17]([OH:20])(=[O:19])[CH3:18].S(=O)(=O)(O)O.O1CCOCC1>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH2:18][C:17]([OH:20])=[O:19])[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(CC#N)c(C)nc2c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2cc(CC(=O)O)c(C)nc2c1

Procedure:
Compounds of formula (50), wherein R4 and R5 are as defined in formula (I) and R6 is aryl or heteroaryl, can be prepared as described in Scheme 6. Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be prepared using the procedures described in Synthetic Comm., 17(14):1647–1653 (1987). Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be treated with a reducing agent, such as, but not limited to, lithium aluminum hydride or sodium borohydride, to provide (7-methoxy-2-methyl-3-quinolinyl)methanol. (7-Methoxy-2-methyl-3-quinolinyl)methanol can be treated with a chlorinating reagent, such as, but not limited to, thionyl chloride to provide 3-(chloromethyl)-7-methoxy-2-methylquinoline. 3-(Chloromethyl)-7-methoxy-2-methylquinoline can be treated with sodium cyanide or potassium cyanide to provide (7-methoxy-2-methyl-3-quinolinyl)acetonitrile. (7-Methoxy-2-methyl-3-quinolinyl)acetonitrile can be treated with acid, such as, but not limited to, glacial acetic acid and concentrated sulfuric acid, in water and 1,4-dioxane with heat to provide (7-methoxy-2-methyl-3-quinolinyl)acetic acid. (7-Methoxy-2-methyl-3-quinolinyl)acetic acid can be treated with a reducing agent, such as, but not limited to, B2H6, borane-THF complex, or borane-pyridine complex, to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethanol. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethanol can be treated with methanesulfonyl chloride and a base, such as, but not limited to, triethylamine or diisopropylamine to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate can be treated with an amine of formula (5) to provide amines of formula (47). Amines of formula (47) can be treated with BBr3 to provide hydroxy compounds of formula (48). Hydroxy compounds of formula (48) can be treated with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to provide triflates of formula (49). Triflates of formula (49) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide compounds of formula (50).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([OH:17])=[O:16].[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:12])([CH3:13])[CH3:14])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([O:17][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=1)=[O:16]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)O)C2(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)OCc3cccc(Oc4ccccc4)c3)C2(C)C)cn1
Reaction time: 16 h
Yield: 92.3 %

Procedure:
A mixture of trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl) pyrimidin-5-yl]cyclopropane carboxylic acid (500 mg), 3-phenoxybenzylbromide (552 mg), anhydrous potassium carbonate (304 mg) and acetone (10 cm3) was heated at the reflux temperature for 2 hours with stirring after which it was kept at the ambient temperature for 16 hours. After removing the solid precipitate by filtration the filtrate was concentrated by evaporation under reduced pressure. The residual oil was subjected to high performance liquid chromatography (Gilson) using a silica column and, as eluent, a mixture of dichloromethane (100 parts by volume) and ethyl acetate (2 parts by volume). The product, 3-phenoxybenzyl trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)-pyrimidin-5-yl]cyclopropane carboxylate (800 mg) was obtained as an oil and identification was confirmed by n.m.r. and infra red spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 86 %

Procedure:
As described for example 146d, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mol) was converted, using cyclopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (trituration with tert-butylmethylether, 194 mg, 86%) which was obtained as a white solid. MS: m/e=351.3 [M+H]+.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.O.[C:14](=[O:17])(O)[O-:15].[Na+]>CO>[OH:1][CH2:12][CH2:2][CH2:7][CH2:6][C:5]1([C:14]([O:15][C:2]([CH3:12])([CH3:7])[CH3:3])=[O:17])[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CCCCO)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (4.32 g) produced in Example 41 in methanol (29 mL) was added p-toluenesulfonic acid monohydrate (28 mg), and the mixture was stirred at room temperature for 24 hours. Water and an aqueous saturated sodium bicarbonate solution were added, thereafter, methanol was distilled off, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated to obtain tert-butyl 1-(4-hydroxybutyl)cyclopropanecarboxylate (3.20 g). This was dissolved in acetonitrile (118 mL), a phosphate buffer (pH 6.6, 79 mL) was added, and the mixture was stirred at 40° C. A 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO, 227 mg), an aqueous sodium chlorite solution (sodium chlorite 2.62 g, water 16 mL) and an aqueous sodium hypochlorite solution (0.5%, 16 mL) were added, and the mixture was stirred for 15 hours. After allowing to cool, an aqueous sodium sulfite solution and 2N hydrochloric acid were added, followed by extraction with ethyl acetate. This was reverse-extracted with an aqueous saturated sodium bicarbonate solution, 2N hydrochloric acid was added to make the solution acidic, followed by extraction with ethyl acetate. This was washed with water and an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated to obtain the title compound (3.08 g) having the following physical property values.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:7]=1[CH:8]=[O:9].CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:7]=1[C:8]([OH:21])=[O:9]
Reactant: CC(C)=O
Reactant: O=Cc1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Alternatively, a solution of 4.28 g (15 mmol) of 2-(3,4-dichloro-phenoxy)-5-fluorobenzaldehyde (Preparation no. 5) in 25 mL of acetone was cooled to 5–10° C. and treated via syringe with 5.8 mL (15.6 mmol) of 2.67 M Jones reagent*. After 1 hr at this temperature, the reaction was quenched with 8 mL of isopropanol, allowed to warm to 25° C., and filtered through a pad of d.e. The filtrate was concentrated in vacuo to approximately ¼ volume, diluted with water and extracted several times with CHCl3. The organic layers were washed with water, then with saturated NaCl and finally dried over MgSO4 and concentrated to provide 2-(3,4-dichlorophenoxy)-5-fluoro-benzoic acid as a tan solid, 4.19 g. 1H-nmr (CDCl3, 400 MHz, δ): 7.78 (dd, 1H), 7.38 (d, 1H), 7.27 (m, 1H), 6.98 (m, 2H), 6.81 (dd, 1H). *Jones reagent was prepared from 13.4 g of chromium trioxide and 11.5 mL of concentrated H2SO4, diluted to a final volume of 50 mL with H2O.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH2:11][C:12](OC)=O)=[CH:4][NH:3]1.[C-]#[N:17].[Na+].CS(C)=O>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH2:11][C:12]#[N:17])=[CH:4][NH:3]1
Reactant: COC(=O)Cc1c[nH]c(=O)c2ccoc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1c[nH]c(=O)c2ccoc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
Combine methyl (4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)acetate (4.42 g, 21.3 mmol), sodium cyanide (5.22 g, 106 mmol), and dimethylsulfoxide (44 mL) and heat at 80° C. for 1 hour. Cool to room temperature, pour into ethyl acetate, wash sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dry over magnesium sulfate, filter, and concentrate under reduced pressure to provide the desired compound (3.63 g, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:9]1[S:10][C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:12]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:9]1[S:10][C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:12]([CH2:14][OH:15])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1CO
Reaction time: 15 h
Yield: 81.9 %

Procedure:
Ethyl 2-[bis(tert-butoxycarbonyl)amino]-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole-5-carboxylate obtained in Example (62b) (2.87 g, 5.55 mmol) was dissolved in THF (60 mL). TBAF (1 M solution in THF, 9.3 mL) and acetic acid (0.48 mL, 8.39 mmol) were added, followed by stirring for 15 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=90/10, 70/30) to obtain 1.83 g of the title compound as a white solid (82%).
Reaction SMILES: [CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:47]=[C:46]2[C:42]([C:43]([CH:48]=O)=[CH:44][NH:45]2)=[CH:41][CH:40]=1>>[CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:48][C:43]2[C:42]3[C:46](=[CH:47][C:39]([F:38])=[CH:40][CH:41]=3)[NH:45][CH:44]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3cc(F)ccc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Yield: 36.7 %

Procedure:
Following the procedure described for Example 1(A), Step A, N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide (Preparation 9) (50 mg, 0.099 mmol) was condensed with 6-fluoroindole-3-carboxaldehyde (19.4 mg, 0.119 mmol). Purification by medium pressure chromatography eluting with 50% EtOAc in CH2Cl2 yielded 23.5 mg of N-benzyl-2-[8,9-difluoro-4-(6-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 7.94 (d, 1H), 7.61 (m, 3H), 7.27-7.49 (m, 9H), 6.95 (m, 1H), 6.86 (m, 1H), 6.63 (m, 1H), 4.35-5.0 (m, 5H), 4.20 (m, 1H), 1.23 (m, 6H): MS 647.3 (M+1), 645.3 (M−1).