Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])[O:2]C(C)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.P([O-])([O-])[O-].[CH2:32](Cl)[C:33](=[CH2:35])[CH3:34]>>[CH:11]([O:10][P:1]([CH2:34][C:33](=[CH2:32])[CH3:35])(=[O:2])[O:6][CH:7]([CH3:8])[CH3:9])([CH3:12])[CH3:13]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: C=C(C)CCl
Agent: [O-]P([O-])[O-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)CP(=O)(OC(C)C)OC(C)C

Procedure:
208 parts of triisopropyl phosphite, 1.5 parts of phenothiazine and 3.4 parts of Ni(CO)4 (corresponding to 2 mol %, based on the phosphite) are heated to 120°-130° C in a nitrogen atmosphere. 99 parts (corresponding to a 10% excess) of methallyl chloride are added dropwise over a period of 5 hours. 68 parts of isopropyl chloride (Bp: 35°-36° C) are distilled off through a column. The product is fractionated in vacuo through a column. Boiling point: 58°-63° C/0.25 Torr; Yield: 155 parts (70.5% of the theoretical): nD20 : 1.4312 Purity according to GC: 97.3%
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=O.[NH2:14][NH2:15].C(OCC)(OCC)(OCC)C>C1(C)C(C)=CC=CC=1>[CH3:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]2[O:7][C:8]([CH3:9])=[N:14][N:15]=2)=[CH:3][C:2]=1[OH:1]
Reactant: NN
Reactant: CCOC(=O)c1ccc(C)c(O)c1
Agent: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc(-c2ccc(C)c(O)c2)o1
Temperature: 150 °C

Procedure:
A suspension of ethyl 3-hydroxy-4-methylbenzoate (3.60 g, 20 mmol) in anhydrous hydrazine (10 mL, 318 mmol) (Aldrich) was heated at reflux (150° C. bath temperature) for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a dry solid. This was suspended in xylene (50 mL) and concentrated under reduced pressure. The resulting solid was suspended in triethyl ortho-acetate (35 mL, 191 mmol) (Aldrich) and heated at reflux (150° C. bath temperature) for 20 hours with removal of ethanol. After cooling, dichloromethane was added and the solid was collected by filtration to give 2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenol as an off-white crystalline material. (Yield 2.28 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>O1CCCC1>[S:14]([O:12][CH:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])(=[O:16])(=[O:15])[CH3:13]
Reactant: CC(O)CCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(CCCc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 5-phenyl-2-pentanol (482 g.; 2.94 moles) in tetrahydrofuran (2250 ml.) at 0° C. was added methanesulfonyl chloride (300 ml.) at such a rate that the internal temperature does not rise above 10° C. (total addition time 4.5 hours). After addition is complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for an additional hour. The reaction mixture was filtered and the supernate concentrated to a light yellow oil (2800 g.) which was dissolved in chloroform (2 liters) and washed with water (4×1 liter), brine (1×1 liter), charcoal treated (50 g.), dried (MgSO4), filtered through diatomaceous earth and concentrated to a light orange oil (687 g., 95% yield). This material was suitable for use without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.F[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][N:20]=1>CS(C)=O.CCOC(C)=O>[I:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)[CH:24]=1
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Reactant: Fc1cc(I)ccn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cn(-c3cc(I)ccn3)ccc2=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one (7.30 g, 31.6 mmol), 2-fluoro-4-iodopyridine (10.56 g, 47.35 mmol), and K2C03 (10.9 g, 79 mmol) in DMSO (80 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2S04), filtered and concentrated. The residue was washed with EtOAc and filtered, and the collected solid dried to give 4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one. 1H-NMR (DMSO, 400 MHz) (5 8.41 (dd, J=8.0, 2.4 Hz, 1H), 8.30 (s, 1H), 8.20 (m, 2H), 7.81 (dd, J−4.0, 0.8 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.28 (d, J=7.6 Hz, 1H), 4.96 (s, 2H), 3.72 (s, 3H). MS (M+H)+ 435.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([N+:19]([O-])=O)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOCC.[Pd]>[NH2:19][C:12]1[CH:11]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(N)c1
Yield: 82.6 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid (56.57, 190.9 mmol) in methanol (250 mL) and palladium/carbon (5.66 g, 10% weight) was hydrogenated with a Parr-shaker overnight at 51 psi. The black mixture was filtered through a pad of Celite, and the filtrate was evaporated to give a brown oil, which was stirred in ether (300 mL) overnight. The ether slurry was filtered to give 2-amino-4-(tert-butoxycarbonylamino-methyl)-benzoic acid as a brown solid (42.0 g, 84% yield). The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:11][N:12]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[C:11]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)#[N:12]
Reactant: Brc1cccc2[nH]ncc12
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2[nH]ncc12
Temperature: 85 °C

Procedure:
4-Bromoindazole (1.0 g, Judkins et al., WO 9641803) and zinc cyanide (0.6 g) were added to N-methylpyrrolidinone (12.5 ml) and placed under an argon atmosphere. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (0.88 g) and the reaction was heated to 85° C. overnight. The reaction mixture was cooled and partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO4), and evaporated to dryness. The product was purified by chromatography on silica gel using ethyl acetate-dichloromethane (5:95) as the eluting solvent to afford 0.581 g pure 4-cyanoindazole.
Reaction SMILES: [CH2:1]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(Cl)(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:10][C:4]1([CH2:1][C:2]#[CH:3])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C1=COCCC1
Reactant: C#CCC1(O)CCCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C#CCC1(OC2CCCCO2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of 2.9 g (21 mmol) of (prop-2-ynyl)cyclohexanol in 10 ml of dry ether was stirred under argon as 0.24 ml (26 mmol) of dihydropyran was added followed by about 5 mg of toluenesulfonic acid. After one hour, tlc (CHCl3, silica gel) analysis indicated that significant starting material remained. Another 0.2 ml of dihydropyran and about 5 mg of toluenesulfonic acid were added. Twice more at one hour intervals, 0.2 ml portions of dihydropyran along with a small amount of toluenesulfonic acid were added to the reaction mixture. It was left to stir under argon at room temperature for 15 hours. Potassium carbonate was then added to the mixture and it was stirred for several minutes before it was washed with water. The wash solution was back extracted with ether and the combined extracts were then washed with brine, dried (Na2SO4) and evaporated in vacuo to yield 4.6 g of 1-(tetrahydropyran-2-yloxy)-1-(prop-2-ynyl)cyclohexane) having the following spectral characteristics: nmr (CDCl3) δ 1.0-2.5 (19H, m), 3.6 (2H, broad m) and 4.65 ppm (1H, broad s); ir (CHCl3) 980, 1030, 1050, 1070, 1120, 1150, 1270, 1450, 2120, (weak) 2760, 2930 and 3300 cm-1.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2(O)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:12]2([C:9]3[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=3)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: Brc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
Solid aluminum trichloride (0.68 mL, 5.1 mmol) was added to a solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (0.40 g, 1.3 mmol) in bromobenzene (5.4 mL, 51.3 mmol) at 0° C. under nitrogen. After being stirred at 0° C. for 4 hours, the mixture was quenched with ice and concentrated under reduced pressure. The mixture was dissolved in 1N LiOH (30 mL) and extracted with EtOAc (2×30 mL). The combined organics were dried with Na2SO4, filtered and concentrated. The crude product was directly taken up in EtOAc (4 mL) and aqueous Na2CO3 solution (2M, 4 mL). Di-tert-butyldicarbonate (0.851 g, 3.9 mmol) was added in one portion. The mixture was stirred at 23° C. overnight. The next day, two layers were separated, and the aqueous layer was further extracted with EtOAc (2×10 mL). The combined organics were dried over Na2SO4, concentrated, and purified by column chromatography (0-40% EtOAc/hexanes) to give tert-butyl 4-(4-bromophenyl)-4-(4-chlorophenyl)piperidine-1-carboxylate (0.302 g, 51% yield). 1H NMR (CDCl3, 400 MHz) δ 7.46 (d, J=7.2 Hz, 2H), 7.32 (d, J=6.9 Hz, 2H), 7.19 (d, J=7.0 Hz, 2H), 7.12 (d, J=7.3 Hz, 2H), 3.54 (br s, 2H), 2.35 (br s, 2H), 1.54 (br s, 2H), 1.43 (s, 11H). LCMS: M+1 452.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][CH2:21][CH2:22][CH3:23])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[CH:40][C:36]=1[C:37](Cl)=O>C(Cl)Cl>[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[CH:40][C:36]=1[CH2:37][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][CH2:21][CH2:22][CH3:23])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCCNc1c(N[C@@H](Cc2ccc(N)cc2)C(=O)O)c(=O)c1=O
Reactant: COc1ccc(C(=O)Cl)c(OC)c1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1c(N[C@@H](Cc2ccc(NCc3ccc(OC)c(OC)c3OC)cc2)C(=O)O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.3 %

Procedure:
To the derivatised resin (5), (120 mg) was added DCM (5 ml), DIPEA (0.1 ml, 0.6 mmol) and 2,3,4-trimethoxybenzoyl chloride (138 mg, 0.6 mmol). The solution was agitated for 12 h at RT then filtered and washed thoroughly with DCM. The resin was treated with 60% trifluoroacetic acid in DCM (1.5 ml) for 3 h with agitation and then filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by preparative HPLC to afford the title compound (0.5 mg).
Reaction SMILES: Br[C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28][C:29]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:30]=1[NH2:31].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOCC>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:7]2[C:2]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:29]=3[CH3:28])=[N:3][C:4]([CH3:27])=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccccc1COc1ccc(S(=O)(=O)c2ccc(C)nc2Br)cc1
Reactant: COc1ccc(N)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2nc(C)ccc2S(=O)(=O)c2ccc(OCc3ccccc3OC)cc2)c(C)c1
Temperature: 70 °C
Yield: 15 %

Procedure:
2-Bromo-3-[4-(2-methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridine from part F (75 mg, 0.167 mmol), 2-methyl-4-methoxyaniline (26 μL, 0.200 mmol), Pd(dba)3 (3 mg, 0.0033 mmol), dppp (3 mg, 0.0067 mmol), and NaOt-Bu (22 mg, 0.234 mmol) were suspended in toluene in a tightly capped conical vial. The reaction mixture was heated at 70° C. for 4.5 h. The mixture was cooled to rt, and diluted with ether. The organic layer was washed with brine (2×), dried over MgSO4, filtered, and concentrated. Purified by preparative TLC (1000 μM silica gel plate, 15% ethyl acetate in hexanes) to furnish the desired product (13 mg, 15% yield) as a pale yellow solid: mp 70–72° C.; 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.77 (d, J=9.2 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.30–7.22 (m, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.90 (d, J=7.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.68 (d, J=9.1 Hz, 2H), 6.53 (d, J=8.0 Hz, 1H), 5.23 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 2.27 (s, 3H), 2.10 (s, 3H); HRMS (ESI) m/z 505.1807 [(M+H)+, calcd for C28H29N2O5S, 505.1797].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[CH:8][C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].[OH:27]S(O)(=O)=O>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:26])[C:4]1[C:9]([C:10](=[O:27])[CH3:11])=[CH:8][C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]
Reactant: COC(=O)c1c(C#C[Si](C)(C)C)cc(F)c(F)c1Nc1ccccc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1c(C(C)=O)cc(F)c(F)c1Nc1ccccc1Cl
Yield: 58 %

Procedure:
A mixture of 2-(2-chlorophenylamino)-3,4-difluoro-6-trimethylsilanylethynylbenzoic acid methyl ester (1.00 g, 2.54 mmol), HgSO4 (761 mg, 2.54 mmol), and concentrated H2SO4 (0.27 mL) in acetone-water (22 mL/4 mL) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo, diluted with EtOAc-THF, and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give the crude material that was purified by silica gel flash column chromatography (8% EtOAc in hexanes) to afford the desired product (496 mg, 58%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[CH:41]=[N:40][C:39]2[NH:38][CH2:37][CH2:36][O:35][C:34]=2[CH:33]=1>>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:32]3[CH:41]=[N:40][C:39]4[NH:38][CH2:37][CH2:36][O:35][C:34]=4[CH:33]=3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Brc1cnc2c(c1)OCCN2
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide and 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. MS (ESI): mass calcd. for C23H24FN3O3S, 441.15; m/z found, 442.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.15-8.12 (m, 1H), 7.80 (d, J=0.9, 1H), 7.72-7.69 (m, 1H), 7.68-7.62 (m, 1H), 7.60-7.54 (m, 2H), 7.39-7.33 (m, 3H), 4.42-4.33 (m, 2H), 3.75-3.69 (m, 2H), 1.09 (s, 9H).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH2:8].C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:30][CH3:31])[C:25]=1[O:26][CH2:27][C:28]#[CH:29])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:20](=[O:21])[C:19]1[CH:23]=[C:24]([O:30][CH3:31])[C:25]([O:26][CH2:27][C:28]#[CH:29])=[C:17]([F:16])[CH:18]=1
Reactant: CC1CCCC1N
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(F)cc(C(=O)NC2CCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.5 %

Procedure:
To a mixture of 1 ml of ethyl acetate and 0.2 g of 2-methylcyclopentylamine hydrochloride was added 0.48 ml of triethylamine and then, a mixture of 0.24 g of 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoyl chloride and 1 ml of ethyl acetate was added dropwise thereto under ice cooling. The mixture obtained was stirred at room temperature for 12 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to obtain 0.21 g of N-(2-methylcyclopentyl)-3-fluoro-5-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 70 of the present invention) represented by the formula:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][N:24]=[C:25]=[O:26].[CH:27]([NH2:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][NH:24][C:25]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:26]
Reactant: CC1=C(CN=C=O)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)N
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC1=C(CNC(=O)NC(C)C)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 750 %

Procedure:
To a solution of the isocyanate from Step 1 in toluene was added 1.2 equivalent of isopropylamine. The reaction mixture was kept under reflux for 1 h. After having been cooled to room temperature, the mixture was diluted with n-hexane to form a yellow precipitate, which was filtered off, and was recrystallized from CH2Cl2, to give the title compound as a yellow solid (750%), mp: 217° C.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]2[CH:6]3[C:13]4([CH2:14][CH2:15][C:4]=2[CH:3]=1)[CH:9]([CH2:10][N:11]([C:16](=[O:18])[CH3:17])[CH2:12]4)[CH2:8][CH2:7]3.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:16]([N:11]1[CH2:12][C:13]23[CH:6]([CH2:7][CH2:8][CH:9]2[CH2:10]1)[C:5]1[CH:19]=[CH:20][C:2]([O:1][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:3][C:4]=1[CH2:15][CH2:14]3)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CC2CCC3c4ccc(O)cc4CCC23C1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2CCC3c4ccc(OC(=O)c5ccccc5)cc4CCC23C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
1-(2-Hydroxy-5,6,6a,7,10,11-hexahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrol-8-yl)-ethanone (Example 5B) (10.0 mg, 0.037 mmol) and triethylamine (15.4 μL, 0.11 mmol) were dissolved in CH2Cl2 (2 mL). Benzoyl chloride (5.1 μL, 0.044 mmol) was added dropwise. The mixture was stirred at rt for 12 hr, quenched with water (2 mL), and extracted with CH2Cl2 (5 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane, providing 11.1 mg (80.4%) of the title compound.
Reaction SMILES: Cl.N1C=CC=CC=1C[N:9]1[C:13]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:12][C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10]1.O1CCOCC1.[Se](=O)=O>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([C:13]2[NH:9][CH:10]=[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:12]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(C(=O)c2ccc(Cl)cc2)n(Cc2ccccn2)c1
Agent: Cl
Agent: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c[nH]c(C(=O)c2ccc(Cl)cc2)c1
Yield: 97.3 %

Procedure:
Ethyl 1-(2-pyridylmethyl)-5-(4-chlorobenzoyl)pyrrole-3-carboxylate hydrochloride (4.05 g.) was combined with 150 ml. of dioxane, 5 ml. of water and 10 g. of selenium dioxide and refluxed for 18 hours. The reaction mixture was filtered, the filtrate diluted with 150 ml. of ether and 150 ml. of water, and equilibrated. The organic phase was separated, back-washed with two 100 ml. portions of water, and concentrated to yield solid ethyl 5-(4-chlorobenzoyl)pyrrole-3-carboxylate (2.7 g., Rf 0.55 on silica gel thin layer chromatography with ethyl acetate-1/hexane-5/5% acetic acid as eluant).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)[O:11][CH2:10]2)=[O:6].[N+:37]([CH3:40])([O-:39])=[O:38].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:36][C:2]([F:1])([F:35])[C:3]([CH2:40][N+:37]([O-:39])=[O:38])([C:26]1[CH:27]=[C:28]([Cl:34])[C:29]([Cl:33])=[C:30]([Cl:32])[CH:31]=1)[CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]1)[O:11][CH2:10]2)=[O:6]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.4 %

Procedure:
To the stirred solution of tert-butyl 5′-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 2, 8.6 g, 15.33mmol) in DMF (215 mL) was added nitro methane (8.20 mL, 153.29mmol) and DBU (2.22 mL, 14.87 mmol) at room temperature. Reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, the reaction mixture was quenched with addition of water (250 mL) and extracted with ethyl acetate (2×300 mL). Combined organic layer was washed with LiCl Solution (2×400 mL) and brine (500 mL). Organic layer was dried over sodium sulfate and concentrated to get crude compound sticky solid (11.23 g). Purification was done by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 10% ethyl acetate in n-hexane to afford light yellow sticky liquid (5.10 g, impure-used as such in next step). 1H NMR (400 MHz, CDCl3) δ: 1.48 (s, 9H), 3.95 (d, J=18.72 Hz, 1H), 4.13-4.18 (m, 3H), 4.33-4.36 (m, 2H), 5.17-5.18 (m, 2H), 5.42 (d, J=12.2 Hz, 1H), 5.58 (d, J=12.16 Hz, 1H), 7.20 (s, 1H), 7.31 (s, 1H), 7.60-7.65 (m 1H), 7.78 (d, J=16.92 Hz, 1H), 7.98-8.00 (m, 1H). LC-MS (m/z): 622.9 (M−H).