Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][NH:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1.CCN(CC)CC>C(Cl)Cl>[NH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:8][N:7]([CH3:6])[C:1](=[O:4])[CH:2]=[CH2:3])=[CH:10]1
Reactant: CNCc1c[nH]c2ccccc12
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Acryloyl chloride (0.33 mL, 4.10 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (0.60 g, 3.70 mmole) and Et3N (1.03 mL, 7.40 mmole) in CH2Cl2 (30 mL) at 0° C. The reaction was held at 0° C. for ten minutes, then was stirred overnight at RT. The solution was concentrated in vacuo and the residue was diluted with water. The solution was extracted with ethyl acetate, and the combined organic extracts were washed with brine and dried over Na2SO4. The title compound (0.64 g, 80%) was obtained as a light yellow solid: MS (ES) m/e 215 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCl>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOCc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
To a stirred solution of the product of step (a) (1 g) in dichloromethane (20 mL), p -toluenesulfonyl chloride (0.66 g) and triethylamine (0.5 mL) were added and the reaction was stirred at 20° C. for 24 hours. The reaction mixture was diluted with dichloromethane (100 mL) then washed with water (100 mL) and brine (100 mL), dried and the solvent removed in vacuo. Purification by column chromatography on silica gel (Biotage), eluting with 10% ethyl acetate in cyclohexane to give the title compound (1 g). LC retention time 3.37 mins. Mass spectrum m/z 544 [MNH4+]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:33])[CH2:30]CBr.C(=O)([O-])[O-].[K+].[K+]>>[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:18][N:16]1[CH:17]=[C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:13]=[CH:14][C:15]1=[O:19]
Reactant: COC(=O)CCBr
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (example 162, step 3) was reacted with methyl-3-bromopropionate in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=482.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:25]=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21.[CH2:27]([Mg]Br)[CH3:28].C(OCC)C>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([OH:26])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc(N2CCCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(OC)cc1Cl
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a stirred suspension of 10-chloro-1-(2-chloro-4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole-7-carbaldehyde (267 mg, 0.684 mmol) in tetrahydrofuran (7 mL) and a solution of ethyl magnesium bromide in diethyl ether (3.0 M, 274 μL, 0.821 mmol) was added at 0° C. After 15 min, the reaction mixture was quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (137 mg, 0.325 mmol, 48%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Cl)=[C:7]([C:10]#[N:11])[S:6](=[O:13])(=[O:12])[N:5]=1)[CH3:2].C[Si](C)(C)[NH:16][Si](C)(C)C>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:16])=[C:7]([C:10]#[N:11])[S:6](=[O:13])(=[O:12])[N:5]=1)[CH3:2]
Reactant: CCOC1=NS(=O)(=O)C(C#N)=C1Cl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCO
Product: CCOC1=NS(=O)(=O)C(C#N)=C1N

Procedure:
The product from Step A was reacted with hexamethyldisilazane followed by ethanol according to the procedure of Example 5. After recrystallization of the crude product from ethanol, there was obtained pure title compound, mp 228°-229°.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH2:6][CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.[BH4-].[Na+].C(O)C.C(OCC)(=O)C>C(O)C>[OH:20][CH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:5][CH2:6][CH2:7][S:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCCSc1ccncc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a solution of 2.84 g (10.0 mmol) of 4-(2-phthalimidoethylthio)pyridine in 150 ml of ethanol, 3.78 g (100 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10 to give 2.24 g of the desired compound (77.8% yield, colorless crystals), mp. 132°-133° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]([Cl:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:4]=1.C(N(CC)C(C)C)(C)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C)C=O>[C:30]([NH:1][CH2:2][C:3]1[C:12]([Cl:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:4]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(Cl)c(CN)nc1-c1cccc(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Cl)c(CNC(C)=O)nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 6-(aminomethyl)-5-chloro-2-(3-fluorophenyl)nicotinate (0.35 g, 1,2 mmol) was stirred in N,N-dimethylformamide (5 mL) with N,N-diisopropylethylamine (0.41 mL, 2.4 mmol) and acetic anhydride (0.17 mL, 1.8 mmol) was added. The mixture was stirred for 30 minutes at room temperature. Evaporation gave the crude material which was contaminated with the corresponding dechlorinated byproduct (0.4 g, 100%). LCMS calculated for C16H15ClFN2O3 (M+H)+: m/z=337.1. found 336.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:35])=[N:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:35])=[N:29]3)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 300 mg (0.93 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 183 mg (1.03 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.58 ml (1.86 mmol) of titanium tert-butoxide is reacted to give 5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol. 450 mg of crude imine are cyclized in the same way as in Example 130 at −30° C. with 7.6 ml (7.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-65%) yields 77 mg of desired product.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:26][CH3:27])[C:24]=1[OH:25])[CH:18]=[CH:19][C:20]#[N:21].[CH:28](OCC)=[O:29].Cl>O1CCCC1>[CH:28]([C:19](=[CH:18][C:17]1[CH:22]=[C:23]([O:26][CH3:27])[C:24]([OH:25])=[C:15]([O:14][CH3:13])[CH:16]=1)[C:20]#[N:21])=[O:29]
Reactant: CCOC=O
Reactant: COc1cc(C=CC#N)cc(OC)c1O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(C=C(C#N)C=O)cc(OC)c1O
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
A 4.0 ml of n-butyllithium (1.6M) was added to a tetrahydrofuran (20 ml) solution of diisopropylamine (0.9 ml) at -70° C. under nitrogen atmosphere. After 15 minutes, to the solution was added a tetrahydrofuran (8 ml) solution of 1.24 g of 3,5-dimethoxy-4-hydroxycinnamonitrile at -60° C. or less, and the solution was stirred for 1 hour. A 0.7 ml of ethyl formate was added to the solution, and the mixture was further stirred for 1 hour. A 1N hydrochloric acid was added to the mixture and a temperature of the mixture was elevated to room temperature. The mixture was extracted with 250 ml of ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A crystal formed was washed with ethanol to give 430 mg (yield 43.6%) of α-formyl-3,5-dimethoxy-4-hydroxycinnamonitrile. The compound thus obtained was dissolved in 20 ml of tetrahydrofuran- To the solution 3.2 g of carbethoxymethylenetriphenylphosphorane was added. The mixture was stirred at room temperature for 32 hours, and concentrated under reduced pressure. A 80 ml of ethyl ether was added to the residue. The solution was washed with water and 1N hydrochloric acid in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A crystal formed was washed with ethanol to give 320 mg (yield 57.3%) of γ-cyano-6-(3,5-dimethoxy-4-hydroxy)phenyl-2,4-pentadienic acid ethyl ester, which was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and methanol (10 ml). To the solution, an aqueous potassium hydroxide solution (140 mg/5 ml) was added. The mixture was stirred at room temperature for 48 hours, concentrated under reduced pressure. A 70 ml of water was added to the residue. The aqueous solution was washed with ethyl acetate and acidified with conc. hydrochloride. The aqueous layer was extracted with 200 ml of ethyl acetate, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 190 mg (yield 65.1%) of a desired γ-cyano-β-(3,5-dimethoxy-4-hydroxy)phenyl-2,4-pentadienic acid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14](OC)=[O:15])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1coc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1coc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazole-4-carboxylate (1.365 mmol) in tetrahydrofuran (20 ml) was cooled to 0° C., and lithium aluminum hydride in tetrahydrofuran (1.365 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, slowly quenched with water, followed by addition of ammonium chloride solution. The resulting mixture was filtered through celite, and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and solvent removed under reduced pressure. The residue was purified by chromatography, to yield {2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methan-1-ol, a compound of formula (16).
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)=[N:17]2)=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:29])[CH:3]=1.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])=[CH:24][CH:23]=3)=[N:17]2)=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:29])[CH:3]=1
Reactant: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C#Cc1ccc(-c2nn(-c3cc(CNC(=O)C(C)(C)C)c(F)cc3Cl)c(=O)[nH]2)cc1
Yield: 54.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 using N-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-90, 0.100 g, 0.189 mmol), 3,3-dimethylbut-1-yne (0.031 g, 0.378 mmol), TBAF (0.178 g, 0.567 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (3.0 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.10 (s, 9H), 1.30 (s, 9H), 4.30 (d, J=9.0 Hz, 2H), 7.43-7.50 (m, 3H), 7.65 (d, J=9.3 Hz, 1H), 7.78 (d, J=8.1 Hz, 2H), 8.14 (br s, 1H), 12.60 (br s, 1H); MS (m/z): 483.29 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](C(F)(F)F)=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=2[CH:23]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(Cl)[Cl:51]>>[Cl:51][C:3]1[C:2]([Cl:1])=[CH:23][C:6]2[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]([CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[N:9][C:5]=2[CH:4]=1
Reactant: C[Si](C)(C)CCOCn1c(CCCCO)nc2cc(C(F)(F)F)c(Cl)cc21
Reactant: ClCCl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: C[Si](C)(C)CCOCn1c(CCCC=O)nc2cc(Cl)c(Cl)cc21
Reaction time: 4 h

Procedure:
4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butan-1-ol (1.00 g, 2.36 mmol) was dissolved in DCM (30 ml) and Dess-Martin reagent (1.10 g, 2.60 mmol) was added at r.t. The reaction was left for 4 hrs. The reaction was quenched by the addition of 1M Na2S2O3 solution (10 ml), sat. NaHCO3 solution (40 ml) and DCM (80 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×80 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography eluting with EtOAc:heptanes (1:1) as a light orange oil (0.53 g, 38%): MS (ESI+) for C18H24ClF3N2O2Si m/z 422.05 [M+H]+; LC purity 72% (ret. time, 1.81 min); 1H NMR (250 MHz, CHLOROFORM-d) δ ppm −0.21-0.21 (9H, m), 0.77-1.01 (2H, m), 2.17-2.36 (2H, m), 2.64-2.86 (2H, m), 3.02 (2H, td, J=7.39, 3.20 Hz), 3.35-3.74 (2H, m), 5.39-5.60 (2H, m), 7.34-8.18 (2H, m), 9.82 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]1[C:26](B(O)O)=[C:25]([CH3:30])[O:24][N:23]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][C:22]1[C:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[CH:5]3[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:25]([CH3:30])[O:24][N:23]=1
Reactant: CN1C(=O)N(C)C(c2ccccc2)c2cc(Br)ccc21
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)N(C)C(=O)N2C
Temperature: 100 °C

Procedure:
A solution of 6-Bromo-1,3-dimethyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (100 mg, 0.3 mmol) in dioxane (3 mL) is added NaCO3 (50 mg, 0.45 mmol) and 3,5-dimethylisoxazole-4-boronic acid (56 mg, 0.39 mmol) and Pd(dppf)Cl2 then the mixture is refluxed at 100° C. overnight. The reaction is concentrated and is purified by chromatography on silica gel to give product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.CC1(C)C(C)(C)OB([C:45]2[CH:57]=[CH:56][C:48]([CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[CH:47][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:24]([C:4]1[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=[C:2]([C:45]2[CH:46]=[CH:47][C:48]([CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[CH:56][CH:57]=2)[CH:3]=1)=[O:36]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
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
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C

Procedure:
To a stirred solution of tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (1 equiv.) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The reaction was heated at 100° C. for 5 h. After cooling, the reaction mixture was diluted with water, and the product was extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford crude product which was purified by column chromatography over silica gel to afford tert-butyl 4-((5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)(methyl)amino)piperidine-1-carboxylate
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]>CN(C=O)C>[CH:20]([C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[O:16][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:21]
Reactant: O=Cc1cccc(O)c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cccc(C=O)c2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 1.2 g portion of 4-fluorobenzonitrile and 1.0 g of potassium carbonate were added to 25 ml DMF solution of 1.2 g of 3-hydroxybenzaldehyde and stirred overnight with heating at 100° C. The reaction solution was poured into ice water, and then work-up and purification were carried out in the standard method to obtain 1.6 g of 4-(3-formylphenoxy)benzonitrile as an oily substance. EI: 223.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[CH2:10]([S:12]([C:15]1[CH:16]=[C:17]([C:25](Cl)=[O:26])[C:18]2[O:23][CH2:22][CH2:21][O:20][C:19]=2[CH:24]=1)(=[O:14])=[O:13])[CH3:11]>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:25]([C:17]1[C:18]2[O:23][CH2:22][CH2:21][O:20][C:19]=2[CH:24]=[C:15]([S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])[CH:16]=1)=[O:26])[CH3:2]
Reactant: CCS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)CC)cc2c1OCCO2
Yield: 60.1 %

Procedure:
In a similar manner 58 g of 1-ethyl-2-aminomethylpyrrolidine was reacted with 131 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride to give, after treatment and purification, 103.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide (M.P.: 118°-119° C.; yield: 60.2%). 100 g of the base produced was dissolved in 220 ml of acetone and then the solution was filtered on carbon black and a solution of 9.5 g of hydrochloric acid in acetone was added. The resulting hydrochloride crystals were dried off, washed with acetone and then dried. 96 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride was produced (M.P.: 148°-150° C.; yield: 88.2%).
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.[Br:14][C:15]1[C:16]([Cl:23])=[CH:17]C(C)=[N+:19]([O-])[CH:20]=1.CO>C(Cl)Cl>[Br:14][C:15]1[C:16]([Cl:23])=[CH:17][C:7]([CH2:6][OH:11])=[N:19][CH:20]=1
Reactant: Cc1cc(Cl)c(Br)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: OCc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
3.0 mL trifluoroacetic anhydride were added dropwise at 10° C. to 2.6 g (12 mmol) 5-bromo-4-chloro-2-methylpyridine-1-oxide in 30 mL DCM. The reaction mixture was stirred for 5 days at RT. After the addition of MeOH the reaction mixture was evaporated down, the residue was combined with 15% potassium carbonate solution and extracted several times with EtOAC. The combined organic phases were dried on sodium sulphate and evaporated down.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[C:23]1([C:29]2[N:30]=[C:31]([NH:40][CH2:41][CH2:42][CH3:43])[S:32][C:33]=2[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+].O>CN(C)C=O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][N:40]([C:31]2[S:32][C:33]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:29]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:30]=2)[CH2:41][CH2:42][CH3:43])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCCNc1nc(-c2ccccc2)c(CCC(=O)OC)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1nc(-c2ccccc2)c(CCC(=O)OC)s1
Yield: 77.8 %

Procedure:
To a solution of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (433 mg) and methyl 3-[4-phenyl-2-[N-(1-propyl)amino]-5-thiazolyl]propionate (400 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 55.2 mg) at 0° C. and the mixture was stirred at said temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-N-(1-propyl)amino]-4-phenyl-5-thiazolyl]propionate (595 mg, yield 78%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).