Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:11](N(OC)C)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[CH:24]([Mg]Br)=[CH2:25].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:17][CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:11](=[O:12])[CH:24]=[CH2:25])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A solution of 2-[3-fluoro-4-(methylsulfanyl)phenyl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (1.33 g) in tetrahydrofuran (15.6 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 15.6 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 4 hr and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.12 g, yield 93%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:8]([Cl:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:8]([Cl:11])=[CH:9][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 3-acetamido-6-chlorobenzotrifluoride (908 mg, 3.82 mmol) in concentrated H2SO4 (4 mL) at 0° C. was added dropwise 70% HNO3 (0.5 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature 3 h, and it was poured into ice water (15 g). The precipitate was collected by filtration, affording 990 mg (91%) of crude 3-acetamido-6-chloro-4-nitrobenzofluoride. It was crystallized. from EtOH/H2O to give 770 mg of pure compound as yellow needles. 1H NMR (CDCl3): δ2.326 (s, 3H), 8.345 (s, 1H), 9.293 (s, 1H), 10.222 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCOCC>C(#N)C>[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CCc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of methyl 3-(4-bromoacetylphenyl)propionate (380 mg) in acetonitrile (4 ml) was added dropwise over 15 minutes to a stirred solution of 1-(4-pyridyl)piperazine (450 mg) in acetonitrile (10 ml) and the mixture stirred overnight. The mixture was then filtered and the filtrate concentrated in vacuo to give an oil. Purification by flash chromatography on silica eluting first with dichloromethane then 5% v/v methanol/dichloromethane gave a solid. Trituration with ether gave the title compound, 172 mg, as a solid: m.p. 141°-143° C.; NMR(d6DMSO) δ8.15(2H,d), 7.92(2H,d), 7.37(2H,d), 6.83(2H,d), 3.89(2H,s), 3.59(3H,s), 3.37(4H,t), 2.93(2H,t), 2.69(2H,t), 2.65(4H,t); m/e 368(M+H)+ ; calculated for C21H25N3O3. 0.25H2O: C, 67.8; H, 6.9; N, 11.3. found: C, 67.8; H, 6.9; N,11.1%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=C([CH:30]=[C:31]([F:33])C=1)C#N>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[C:31]([F:33])[CH:30]=[C:21]([C:20]#[N:19])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Reactant: N#Cc1cc(F)cc(Br)c1
Product: Cc1ccc(Nc2cc(F)cc(C#N)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromo-5-fluorobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=351.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.C(N(CC)CC)C.[Br:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1>[Br:21][CH2:22][CH2:23][C:24]([N:9]1[CH2:8][C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)=[O:25]
Reactant: COc1ccc2c(c1)CNCCS2
Reactant: O=C(Cl)CCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(=O)CCBr)CCS2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.250 g) and triethyl amine (0.53 g) in THF (10 ml) at 0° C. was added dropwise 3-bromopropionic chloride (0.444 g). The resulting mixture was stirred at 0° C. for 1 hour and at room temperature overnight. After dilution with ethyl acetate, the organic phase was washed with saturated NaHCO3/H2O and H2O. After drying over sodium sulfate and filtration, removal of solvent gave to the product.
Reaction SMILES: O.O.O.O.O.O.O.[S:8]([O-:11])([O-:10])=[O:9].[Na+:12].[Na+].Br[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1>O1CCOCC1.O>[O:18]1[CH2:19][CH2:20][CH:16]([CH2:15][S:8]([O-:11])(=[O:10])=[O:9])[CH2:17]1.[Na+:12]
Reactant: O=S([O-])[O-]
Reactant: BrCC1CCOC1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)([O-])CC1CCOC1
Reaction time: 18 h
Yield: 57 %

Procedure:
Sodium sulfite heptahydrate (6.10 g) was added to a solution of 3-(bromomethyl)tetrahydrofuran (2.0 g) [see Preparation 9] in 1,4-dioxane (9 ml) and water (9 ml). The reaction mixture was then heated under reflux and stirred for 18 hours, cooled and the solvent removed under reduced pressure. The resulting solid was dissolved in water and concentrated to a low volume. The solid formed was then collected to afford sodium tetrahydrofuran-3-ylmethanesulfonate (1.30 g) as a white solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:21]=1[Mg]Br.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8](=[O:11])[C:21]1[C:20]([F:19])=[CH:25][C:24]([F:26])=[CH:23][C:22]=1[F:27])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc(F)c([Mg]Br)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1c(F)cc(F)cc1F)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 5.7 g) in tetrahydrofuran (30 mL), 2,4,6-trifluorophenylmagnesium bromide (0.24 M solution in THF; 100 mL) was added dropwise at −40° C. over one hour, and the reaction solution was stirred at −40° C. for 12 hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the solution. The reaction solution was heated to room temperature, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=1:1) to obtain 6.2 g of ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(2,4,6-trifluorophenyl)pentanoate. A solution of 4 N hydrochloric acid in ethyl acetate (30 mL) was added to a solution of the resulting ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(2,4,6-trifluorophenyl)pentanoate in ethyl acetate (30 mL), and the solution was stirred for 12 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 10% palladium-carbon (100 mg) was added to a solution of the residue in ethyl acetate (20 mL) and ethanol (10 mL), and the reaction solution was stirred in a hydrogen atmosphere at 1 atm for 21 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 4.34 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)#[N:2].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15]N.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.NCCCCN.CC[O-].[Na+]>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][C:1]2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:2]=2)=[CH:6][CH:7]=1
Reactant: NCCCCN
Reactant: N#CCCc1ccncc1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: c1cc(CCC2=NCCCCN2)ccn1
Yield: 93.6 %

Procedure:
The mixture of 4-[2-cyanoethyl]pyridine (1.32 g, 0.01M), 1,4-diaminobutane (0.88 g, 0.01M) and 1,4-diaminobutane di-p-toluenesulfonate (4.32 g, 0.01M) was heated at about 190° to about 200° C. for 4 hrs. The residue was stirred with ethanol (20 ml) which contained EtONa (0.02M) and filtered. The filtrate was concentrated and distilled at 0.07 mmHg and a temperature of about 180° to about 200° C. to give 4,5,6,7-tetrahydro-2[2-(4-pyridyl)ethyl]-1H-1,3-diazepine (1.9 g, 93% yield).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:15])[C@H:12]([OH:14])[CH3:13])[CH2:6][CH2:5]1)[CH3:3].CN(C=O)C.[F:21][C:22]([F:55])([F:54])[C:23]1[CH:24]=[C:25]2[C:31]([C:32]3[C:37]([C:38]#[N:39])=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=3)=[CH:30][N:29](S(C3C=CC(C)=CC=3)(=O)=O)[C:26]2=[N:27][CH:28]=1.[OH-].[Li+]>C1COCC1>[C:38]([C:37]1[C:32]([C:31]2[C:25]3[C:26](=[N:27][CH:28]=[C:23]([C:22]([F:54])([F:21])[F:55])[CH:24]=3)[NH:29][CH:30]=2)=[N:33][C:34]([NH:1][C@@H:2]([C@H:4]2[CH2:5][CH2:6][C@H:7]([NH:10][C:11](=[O:15])[C@H:12]([OH:14])[CH3:13])[CH2:8][CH2:9]2)[CH3:3])=[N:35][CH:36]=1)#[N:39]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)Nc2ncc(C#N)c(-c3c[nH]c4ncc(C(F)(F)F)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trans-(R)—N-(4-((R)-1-aminoethyl)cyclohexyl)-2-hydroxypropanamide (45 mg, 0.21 mmol) was dissolved in THF (6 mL) and DMF (2 mL) and stirred over 4 Å molecular sieves for 10 minutes. 4-(5-(trifluoromethyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (131.9 mg, 0.2100 mmol) was added. The reaction mixture was stirred under nitrogen at ambient temperature for 18 hours. The molecular sieves was removed by filtration and washed with EtOAc. The filtrate was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue dissolved in tetrahydrofuran (6 mL). Lithium hydroxide (840.0 μL of 1 M, 0.8400 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The crude mixture was partitioned between ethyl acetate and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (19 mg, 18% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]4[C:27]3=[O:36])[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2ncc[nH]2)n1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2nccn2CCCCCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-Methyl-2-pyridyl)imidazole (2.16 g) and sodium t-butoxide (1.57 g) in 50 mL dry DMF was added N-(6-bromohexyl)phthalimide (4.72 g). The resulting solution was stirred at room temperature for 3 h and then at 60° C. for 3.5 h. The solution was poured into H2O (80 mL) and then extracted three times with EtOAc (3×100 mL). The combined EtOAc extract was dried with anhydrous Na2SO4, and then evaporated to dryness. The product was purified by a silica gel column using EtOAc as the eluent. Yield: about 4.2 g.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[N:23]1[CH:24]=[CH:25][N:26]2[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][C:27]=12>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:30]3[CH:29]=[CH:28][C:27]4[N:26]([CH:25]=[CH:24][N:23]=4)[CH:31]=3)[C:16]2=[CH:15][N:14]=1
Reactant: OB(O)c1ccc2nccn2c1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5nccn5c4)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (16.7 mg, 0.0400 mmol)(Example 3, Step 4) and imidazo[1,2-a]pyridin-6-ylboronic acid (Combi-Blocks, Cat. No. BB-3457). LCMS (M+H)+=409.0.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:16][C:17]3[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(Cl)Cl>[C:1]1([C:7]2[C:12]([C:13]([O:15][C:33]3[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=3)=[O:14])=[C:11]([O:16][C:17]3[N:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[N:22]=3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cc(OC)nc(Oc2cccc(-c3ccccc3)c2C(=O)O)n1
Solvent: ClCCl
Product: COc1cc(OC)nc(Oc2cccc(-c3ccccc3)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step G, using equimolar amounts of 6-phenyl-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid, 4-nitrophenol, and dicyclohexylcarbiimide in methylene chloride, yielding 4-nitrophenyl 6-phenyl-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:26].[F:34][C:35]1[CH:57]=[CH:56][C:38]([CH2:39][N:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[N:42]=[C:41]2[NH:49][CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:37][CH:36]=1>>[CH3:33][O:32][C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH:50]([NH:49][C:41]3[N:40]([CH2:39][C:38]4[CH:56]=[CH:57][C:35]([F:34])=[CH:36][CH:37]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:51][CH2:52]2)([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]1=[O:26]
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3ccccc3)C2=O)cc(OC)c1OC
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Product: COc1cc(CN2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccccc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 2.6 using 1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (10 mmol) and (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (10 mmol) to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19]O)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1>C(#N)CC>[CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19][N:49]3[CH2:50][CH2:51][CH:46]([C:43]4[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][CH:44]=4)[CH2:47][CH2:48]3)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C1CN(Cc2ccccc2)c2ncc(CO)cc2N1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(Cc2ccccc2)c2ncc(CN3CCC(c4ccc(Cl)cc4)CC3)cc2N1
Temperature: 90 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.37 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered and dried in vacuum to afford the title compound (69.9 mg, 42%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.56 (s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.30-7.37 (m, 6H), 7.23-7.30 (m, 3H), 7.00 (d, J=2.0 Hz, 1H), 4.71 (s, 2H), 3.85 (s, 2H), 3.33 (s, 3H), 2.89 (d, J=11.4 Hz, 2H), 1.99 (t, J=10.6 Hz, 2H), 1.67-1.78 (m, 2H), 1.48-1.66 (m, 2H). [M+H] calc'd for C, 11; H, 15; Cl, 2; N, 447; found, 447.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].O[C:6]([C:9]1[CH:14]=[C:13]([CH:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[O:16][SiH:17]([CH3:19])[CH3:18])[CH:12]=[C:11]([CH:24](C(C)(C)C)[O:25][SiH](C)C)[CH:10]=1)([CH3:8])[CH3:7]>ClCCCl.[I-].[Zn+2].[I-]>[C:1]([O:4][C:6]([C:9]1[CH:10]=[C:11]([CH2:24][OH:25])[CH:12]=[C:13]([CH:15]([C:20]([CH3:22])([CH3:21])[CH3:23])[O:16][SiH:17]([CH3:19])[CH3:18])[CH:14]=1)([CH3:8])[CH3:7])(=[S:3])[CH3:2]
Reactant: CC(O)=S
Reactant: C[SiH](C)OC(c1cc(C(O[SiH](C)C)C(C)(C)C)cc(C(C)(C)O)c1)C(C)(C)C
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: CC(=S)OC(C)(C)c1cc(CO)cc(C(O[SiH](C)C)C(C)(C)C)c1
Temperature: 50 °C

Procedure:
404 μl of thioacetic acid and 376 mg of zinc iodide are added to 1 g of 1-(1-hydroxy-1-methylethyl)-3,5-bis[(tert-butyl)dimethylsilanyloxymethyl]benzene in solution in 4.7 ml of 1,2-dichloroethane. The mixture is heated at 50° C. for 40 min. After returning to AT, the salts are removed by filtration, the organic phase is concentrated under RP and the residue is purified by flash chromatography on silica (Biotage 40+M) using a gradient from 0 to 30% AcOEt in heptane. 248 mg of 1-[3-[(tert-butyl)dimethylsilanyloxymethyl]-5-(hydroxymethyl)phenyl]-1-methylethyl thioacetate are thus obtained.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[C:7](N(OC)C)=[O:8].Cl.O>O1CCCC1>[Br:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[C:7](=[O:8])[CH3:1]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Cl)ccc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(Cl)ccc1Br
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (4.26 mL of a 1.4M solution in tetrahydrofuran/toulene, 5.97 mmol) was added dropwise to a stirred solution of 2-bromo-5-chloro-N-methoxy-N-methylbenzamide (0.554 g, 1.99 mmol) in tetrahydrofuran (20 mL) at approximatately 0° C. After 1 h, 1N hydrochloric acid (5 mL) was added and the resulting biphasic mixture was stirred vigorously for about 10 min. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0–10% ethyl acetate/hexanes as eluent) provided the title compound as a colorless oil.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](Cl)=[CH:6][C:5]=1[NH:12][C:13](=[O:24])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH3:15].[H-].[Na+].Cl.C1C[O:32][CH2:31]C1>>[Cl:10][C:9]1[CH:8]=[C:7]([O:32][CH3:31])[CH:6]=[C:5]2[C:4]=1[C:3](=[O:25])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:15])[C:13](=[O:24])[NH:12]2
Reactant: C1CCOC1
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C2(C)C(=O)Nc3cc(OC)cc(Cl)c3C2=O)cc1
Reaction time: 10 h
Yield: 41 %

Procedure:
To a solution of 4,6-dichloro-2-[2-(4-methoxy-phenyl)-propionylamino]-benzoic acid methyl ester (1.00 g, 2.62 mmol) in dry THF (30 mL) was added NaH (0.32 g, 7.86 mmol, 60% dispersed in mineral oil) at room temperature. The reaction mixture was stirred for 10 hours at reflux temperature, and then poured into 1N HCl aqueous solution. The resulting mixture was extracted with ethyl acetate (100 mL×2). The organic layer was washed with brine (100 mL) and water (100 mL×2), dried over anhydrous MgSO4, and concentrated in vacuo. The objective compound (0.36 g, 41%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=2:1): 1H NMR (200 MHz, CDCl3) δ 1.71 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.46 (d, J=1.6 Hz, 1H, ArH) 6.56 (d, J=1.6 Hz, 1H, ArH), 6.77 (dd, J=6.9 Hz, 2.0 Hz, 2H, ArH), 7.14 (dd, J=6.9 Hz, 2.0 Hz, 2H, ArH), 8.77 (br s, 1H, NH); m.p. 222-224° C.; MS(EI) m/e 345 [M+], 162, 134, 119, 91; HRMS m/e cacld. for C18H16NO4Cl 345.0768, found 345.0759.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:19]>C(#N)C>[CH2:24]([N:23]([CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:31])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCOC(=O)CCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CCCCN(CC(=O)OCC)Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
Under a nitrogen atmosphere, triethylamine (1.73 ml, 0.01243 mol) and ethyl 5-bromovalerate (1.72 ml, 0.0109 mol) were added to a solution of N-benzylglycine ethyl ester (2.0 g, 0.0103 mol) in acetonitrile (40 ml) at room temperature, and the resulting mixture was heated at 60° C. After 1 hour, the mixture was refluxed. After 9 hours, the mixture was concentrated under reduced pressure, and the resulting residue was extracted with water (200 ml) and ethyl acetate (200 ml×2) and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain ethyl 5-[benzyl(2-ethoxy-2-oxoethyl)amino]pentanoate (1.2473 g, 37%).