Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([F:1])[CH:3]=1
Reactant: CON
Reactant: Cc1ccc(C=O)cc1F
Agent: Cl
Product: CON=Cc1ccc(C)c(F)c1
Yield: 94 %

Procedure:
Reaction of 3-fluoro-4-methyl-benzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 1-A gave the title oxime ether as a clear oil (94% yield). 1HMR indicated a 9:1 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 2.28 (3H, broad s, CH3), 3.97 (3H, s, OCH3), 7.15-7.29 (3H, m, aromatics), 7.99 (1H, s, CH).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=[O:28])[CH:25]=5)[NH:20][CH:19]=4)[CH2:12][CH2:11]3)[C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+]>C(O)C.O>[OH:28][CH2:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[C:4]3[CH:3]=[CH:2][NH:1][C:9]=3[CH:8]=[CH:7][N:6]=2)[CH2:11][CH2:12]1
Reactant: O=Cc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1

Procedure:
A solution of 2 mmol of the compound obtained in Step 4 in 50 ml of ethanol is treated with 2.2 mmol of sodium borohydride for 24 hours. The solvent is evaporated off under reduced pressure and the residue obtained is taken up in water and then extracted with dichloromethane. The organic phase is dried and filtered and then concentrated under reduced pressure, enabling the expected product to be obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:16][C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:17]=2[CH3:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(C(=O)O)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C)Cc2ccccc2C1
Yield: 86.4 %

Procedure:
2-Amino-indane-2-carboxylic acid ethyl ester (250 mg, 1.2 mmol), 2,3-dimethyl-benzoic acid (183 mg, 1.2 mmol) and HATU (555 mg, 1.46 mmol) are taken in a vial, evacuated and refilled with nitrogen. Anhydrous DMF (2 mL) is added and stirring is initiated. After a few min, DIPEA (0.302 mL, 1.82 mmol) is added and stirred at RT overnight. Analysis by tlc of the reaction mixture (silica, 50% EtOAc/heptanes) indicates complete consumption of the starting amine. Water (10 mL) is added, extracted with EtOAc (3×5 mL), dried over Na2SO4, concentrated and the crude product is chromatographed on a 25 g silica gel column using 20-50% EtOAc in heptane as a gradient to afford 2-(2,3-dimethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (350 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]#[N:7].[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:8]1[CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]#[N:7])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: CCCCOc1ccc(C#N)cc1OC
Product: CCCCOc1cc([N+](=O)[O-])c(C#N)cc1OC
Temperature: 30 °C

Procedure:
3-methoxy-4-n-butoxybenzonitrile (1.282 g, 6 mmol) and nitric acid (6 mL) were added into a round bottom flask, heated to 30° C. to react for 2 h, poured into ice-water; after complete stirring, the solution was filtered, washed with water and air-dried to yield 1.495 g of light yellow solid product with a recovery rate of 96%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32][CH2:33][CH3:34])=[CH2:31])CCC.N#N>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([C:30]([O:32][CH2:33][CH3:34])=[CH2:31])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23]
Reactant: CC(c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Temperature: 95 °C

Procedure:
A solution of 6-chloro-3-[1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (80 mg, 0.23 mmol) and tributyl(1-ethoxyvinyl)stannane (0.234 mL, 0.69 mmol) in 15 mL DMF was purged with N2 for 30 min and then tetrakis-(triphenylphosphine)-palladium (80 mg, 0.069 mmol) was added, and the solution was heated at 95° C. for overnight. Then the reaction was quenched with water, extracted with EtOAc for three times. The organic layers were combined, washed with KF solution and brine, dried over Na2SO4. Solvent was evaporated and the crude product (80 mg, 90%) was used in the next step without further purification. LCMS (method C): [MH]+=384.0, tR=4.67 min
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH3:13].[C:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([OH:16])=[O:15]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.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>[F:8][C:6]1[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]([O:12][CH3:13])=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:14]([OH:16])=[O:15])[CH:22]=2)[CH:7]=1
Reactant: COc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cccc(B(O)O)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: C1COCCO1
Product: COc1c(-c2cccc(C(=O)O)c2)cc(F)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 41.7 %

Procedure:
1-Bromo-5-fluoro-2-methoxy-3-nitro-benzene 2c (16.18 g, 64.7 mmol), 3-carboxyphenylboronic acid (13.88 g, 77.7 mmol) and tetrakis(triphenylphosphine)palladium (3.73 g, 3.2 mmol) were dissolved in the solvent mixture of 65 mL of aqueous sodium carbonate (2 N) and 300 mL of 1,4-dioxane. The reaction mixture was heated to reflux at 120° C. for 24 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and diluted with 150 mL of hydrochloric acid (6 N) and 200 mL of ethyl acetate. The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5′-fluoro-2′-methoxy-3′-nitro-biphenyl-3-carboxylic acid 2d (7.86 g, yield 41.7%) as a yellow solid.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N[CH2:17][C:18]([O:20][C:21]([CH3:31])([CH3:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:19].[Cl-].[Cl-].[Ca+2]>C(Cl)Cl>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][CH2:17][C:18]([O:20][C:21]([CH3:31])([CH3:30])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)OC(=O)CN
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(Cc1ccc(Cl)cc1)OC(=O)CN=C(c1ccccc1)c1ccccc1
Yield: 63 %

Procedure:
Benzophenone imine (0.8 g, 2.9 mmol) and finely ground 1-(4-chlorophenyl)-2-methyl-2-propyl glycinate hydrochloride and 10 ml of CH2Cl2 were stirred at room temperature over night with the exclusion of moisture (CaCl2 tube). The reaction mixture was filtered to remove NH4Cl, and evaporated to dryness. The residue was taken up in 10 ml of ether, washed with water and dried. Filtration and removal of the solvent were followed by flash chromatography on SiO2 saturated with NH3 (methanol/NH3) with hexane: ethyl acetate 97:3 as eluent to yield 0.8 g (63%) of 1-(4-chlorophenyl)-2-methyl-2-propyl N-(diphenylmethylene)glycinate. 1H NMR (CDCl3, 60 MHz) δppm 7.5(m, 10, arom), 4.2(s, 2, N-CH2), 3.1(s, 2, benzylic), 1.5(s, 6, C(CH3)2).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[C:5]([C:12](OC)=[O:13])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+].Cl>O1CCCC1.CCCCCC.O>[Cl:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[C:5]([CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nn(C)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cn1cc2c(CO)ccc(Cl)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
To a solution of methyl 7-chloro-2-methyl-2H-indazole-4-carboxylate (4.10 g, 18.3 mmol) in tetrahydrofuran (100 mL) was added a solution (1 M, 54.8 mL, 54.8 mmol) of diisobutylaluminum hydride in hexane at −78° C., and the mixture was stirred for 20 min. The reaction mixture was warmed to room temperature, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture at 0° C. An aqueous sodium hydroxide solution (1 N, 20 mL) was added, and the mixture was stirred at 0° C. for 10 min. The reaction mixture was acidified with 6 M hydrochloric acid (10 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (3.40 g, yield 95%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:21][CH2:22][CH:23]1[O:30][CH2:29][CH2:28][O:27][CH:24]1[CH2:25]I>C1COCC1>[CH2:29]1[CH2:28][O:27][C:23]2([CH2:24][CH2:25][C:1]3([C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[CH2:21][CH2:22]2)[O:30]1
Reactant: ICCC1OCCOC1CI
Reactant: C1=Cc2ccccc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCC21CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of indene (0.84 g, 7.3 mmol) in THF at 0° C. was added lithium bis(trimethylsilyl)amide (14.6 ml, 14.6 mmol). After 30 minutes of stirring the anion was cannulated into a solution of 1,5-diiodo-3-ethylenedioxypentane (2.79 g, 7.3 mmol) prepared as described in J. Am. Chem. Soc. 1990, 9001-9003). The reaction mixture was stirred for 1 h and then warmed to room temperature over night. The reaction mixture was concentrated and purified by flash chromatography (silica gel, hexane/ethyl acetate 10:1) to give the title compound (1.2 g, 4.9 mmol).
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:5]2=[C:4]([C:12]([NH:14][C@@H:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:16]([NH:18][CH3:19])=[O:17])=[O:13])[N:3]=1.CC(C)(C)[C@H](NC(C1N=C(C#CC2C=CC=CC=2)N2CCN(C)CC=12)=O)C(NC)=O.C[Si](Cl)(C)C.C([Mg]Cl)(C)C.[CH:64](=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C1COCC1>[CH3:21][C:20]([CH3:23])([CH3:22])[C@H:15]([NH:14][C:12]([C:4]1[N:3]=[C:2]([CH:64]([OH:71])[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[N:6]2[CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:5]=12)=[O:13])[C:16]([NH:18][CH3:19])=[O:17]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C)CC2)C(C)(C)C
Reactant: O=Cc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: CNC(=O)[C@@H](NC(=O)c1nc(C#Cc2ccccc2)n2c1CN(C)CC2)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](NC(=O)c1nc(C(O)c2ccccc2)n2c1CN(C)CC2)C(C)(C)C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
Under a nitrogen atmosphere (S)-3-bromo-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (Compound 203) (0.050 g, 0.13 mmol) was dissolved in THF and trimethysilylchloride (0.045 g, 0.41 mmol) was added. The resulting solution was stirred for 3 hours. Isopropylmagnesium chloride solution (2M in THF, 0.27 mL, 0.54 mmol) was added dropwise at 0° C. and the mixture was stirred for 15 minutes, then benzaldehyde (0.028 g, 0.26 mmol) was added at 0° C. and the resulting mixture was stirred cold for 40 minutes. The mixture was quenched at 0° C. with NH4Cl saturated solution, stirred for 10 min and concentrated. The reaction mixture was then extracted repeatedly with 20% i-PrOH/DCM and the combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by prep LC/MS using 5-95% gradient acetonitrile/water with 0.1% formic acid. The resulting material was filtered through Strata SCX SPE tube to give (0.010 g, 18%) of Compound 295 as a free base. 1H-NMR (400 MHz, CD3OD) δ: 1.05 (s, 9H), 2.43 (s, 3H), 2.75 (m, 5H), 3.69 (m, 1H), 3.88 (m,2H), 4.09 (m, 1H), 4.32 (s, 1H), 7.53 (t, 2H), 5.97 (m 1H), 7.29 (m, 1H), 7.38 (m, 4H); LCMS (+ESI) m/z 414.2 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][C:38]([C:44]#[N:45])=[CH:37][C:36]=1[NH:46][C:47](=O)[CH2:48][N:49]([CH2:51][CH2:52][OH:53])[CH3:50]>C1COCC1.CCOC(C)=O.O>[Cl:34][C:35]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][C:38]([C:44]#[N:45])=[CH:37][C:36]=1[N:46]1[CH2:47][CH2:48][N:49]([CH3:50])[CH2:51][C:52]1=[O:53]
Reactant: CN(CCO)CC(=O)Nc1cc(C#N)cc([N+](=O)[O-])c1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2cc(C#N)cc([N+](=O)[O-])c2Cl)C(=O)C1
Reaction time: 0.17 h
Yield: 35.3 %

Procedure:
To a solution of triphenylphosphine (252 mg, 0.959 mmol) in THF (2 mL) was added DIAD (0.187 mL, 0.959 mmol). The reaction mixture was stirred for 10 min. Then a solution of N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(methyl)amino)acetamide (120 mg, 0.384 mmol) in THF (2 mL) was added drop wise. The reaction mixture was then stirred at room temperature for 2 h. LC-MS indicated the desired peak, but the reaction was about ˜80% complete. It was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography (0-100% EtOAc in Hexanes, 12 g) gave 4-chloro-3-(4-methyl-2-oxopiperazin-1-yl)-5-nitrobenzonitrile (40 mg) as a off-white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=2)[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:27]=1.C(N(CC)CC)C.O>CS(C)=O>[F:21][C:19]([F:22])([F:20])[C:16]1[N:17]=[CH:18][C:13]([O:12][C:11]2[CH:10]=[C:9]([CH:25]=[CH:24][CH:23]=2)[CH:8]=[C:5]2[CH2:6][CH2:7][N:2]([C:33]([NH:32][C:28]3[N:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[O:34])[CH2:3][CH2:4]2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cn1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)nc3)c2)CC1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A solution of 5-(3-(piperidin-4-ylidenemethyl)phenoxy)-2-(trifluoromethyl)pyridine hydrochloride (0.100 g), phenyl pyridazin-3-ylcarbamate (0.070 g, 1.2 equiv), and triethylamine (0.083 mL, 2.2 equiv) in dimethyl sulfoxide (2 mL, 0.13 M) was heated to 65° C. for 2 h. The reaction was cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/dichloromethane) to give the title compound as a white foam (0.089 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (2H, t, J=5.5 Hz), 2.56 (2H, t, J=5.6 Hz), 3.60 (2H, t, J=5.8 Hz), 3.69 (2H, t, J=5.8 Hz), 6.37 (1H, s), 6.92 (2H, m), 7.07 (1H, d, J=7.6 Hz), 7.30-7.46 (3H, m), 7.62 (1H, d, J=8.8 Hz), 8.25 (1H, d, J=8.2 Hz), 8.45 (1H, d, J=2.5 Hz), 8.76 (1H, d, J=1.9 Hz).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C=O)C>[C:13]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:3][CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6]
Reactant: O=C1OCCC1O
Reactant: BrCc1ccccc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCC1OCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (0.43 g, 10.8 mmol) is added portionwise to a solution of α-hydroxy-γ-butyrolactone (1 g, 9.8 mmol) in DMF (15 ml) at 0° C. under a nitrogen atmosphere. 2-Bromomethylbiphenyl (2.42 g, 9.8 mmol) is then rapidly added. The reaction medium is stirred for 2 hours at room temperature and is then treated by adding 1N hydrochloric acid solution (10 ml). The aqueous phase is extracted with ethyl acetate (2×20 ml) and the combined organic phases are washed with water (4×15 ml), dried over sodium sulphate, filtered and concentrated. After purification by flash chromatography (2/1 heptane/EtOAc), the expected compound is obtained in the form of a colourless oil (1.32 g, 50%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][N:17]2[C@@H:11]([CH2:12][NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]1([C:30]2[CH:47]=[CH:46][CH:45]=[CH:44][C:31]=2[C:32]([NH:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][N:17]2[C@@H:11]([CH2:12][N:13]([C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32](=[O:33])[C:31]4[CH:44]=[CH:45][CH:46]=[CH:47][C:30]=4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:43][CH:42]=3)[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H]2CNc3ccccc3C(=O)N2C1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3C(=O)N2C1
Yield: 95.2 %

Procedure:
The same procedures used in Example 25 were repeated using (2R, 11aR)-2-(tert-butyldimethylsilyloxy)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo [2,1-c][1,4]benzodiazepin-5-one prepared in Reference Example 27 and 4-[(2-phenylbenzoyl)amino]benzoic acid to thus give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]([OH:21])=[O:20])[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]([OH:21])=[O:20])[CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C(O)[C@H]1CCCNC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC[C@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Yield: 62.8 %

Procedure:
(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidine-3-carboxylic acid was prepared by reacting 4-fluoro-2-methoxy-1-nitro-benzene (342 mg, 2.0 mmol) with (S)-Piperidine-3-carboxylic acid (258 mg, 2.0 mmol) at 80° C. in DMF using K2CO3 (608 mg, 2.20 mmol) as a base scavenger. After 16 h the reaction was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous phase was acidified with 1N HCl to pH 4-5. The resulting yellow solid was filtered, rinsed with water, and air dried overnight to yield 352 mg (63%) of (S)-1-(3-Methoxy-4-nitro-phenyl)-piperidine-3-carboxylic acid as a yellow solid. LC/MS (E/I+) 281.08 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:3]=1[C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)c2c(O)cc(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Then, 100 ml of an ethyl acetate solution of 10.0 g of 2'-hydroxy-4,4',6'-trimethoxychalcone was added to a suspension of 2.0 g of 5% palladium/carbon in 50 ml of ethyl acetate, in which a hydrogen gas had been sufficiently absorbed in advance, and the mixture was stirred at room temperature for 1 hour in a hydrogen gas atmosphere. After the reaction, the reaction mixture was filtered and the solvent was removed from the filtrate by distillation, and the obtained residue was recrystallized from a mixed solvent of methanol and ethyl acetate to obtain 9.3 g (yield=93.0%) of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone in the form of a colorless needle.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:50]=[CH:49][C:28]([C:29]([N:31]([CH3:48])[C@:32]([CH3:47])([C:37]([NH:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[O:38])[C:33]([NH:35][CH3:36])=[O:34])=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=O.Cl.[F:52][CH2:53][CH2:54][O:55][CH:56]1[CH2:59][NH:58][CH2:57]1.C(=O)([O-])O.[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C.O>[F:52][CH2:53][CH2:54][O:55][CH:56]1[CH2:59][N:58]([CH2:15][C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH3:48])[C@:32]([CH3:47])([C:37]([NH:39][O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)=[O:38])[C:33]([NH:35][CH3:36])=[O:34])=[O:30])=[CH:49][CH:50]=3)=[CH:21][CH:22]=2)[CH2:57]1
Reactant: FCCOC1CNC1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CN3CC(OCCF)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77.1 %

Procedure:
Sodium triacetoxyborohydride (0.10 g) was added to a solution in NMP (1.5 mL) of (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.15 g) as obtained in Example 16-(1) and 3-(2-fluoroethoxy)azetidine hydrochloride (63 mg) as obtained in Example 16-1-(2), under ice cooling in a nitrogen atmosphere. The mixture was stirred for 40 minutes at room temperature. Water and ethyl acetate were added, and the mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium hydrogen carbonate, whereafter the organic layer was isolated. The extract was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/acetone=80/20→50/50) to obtain (2S)-2-[{4-[(4-{[3-(2-fluoroethoxy)azetidin-1-yl]methyl}phenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow oil) (0.14 g, 81%).