Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13]O>>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: Cl
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 58 °C
Yield: 96 %

Procedure:
3-bromophenylacetic acid (10000 mg, 46.50 mmol) was dissolved in methanol (200 mL) at room temperature and concentrated hydrochloric acid (4 mL) was added. The resulting solution was heated at 58° C. for 2 h then cooled to room temperature at which time the volatiles were removed in vacuo. The crude material was dissolved in ethyl acetate and the solution was carefully poured into a saturated aqueous sodium bicarbonate solution. The phases were separated and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (Biotage) with a gradient of 4 to 35% AcOEt/hexanes to give (3-bromo-phenyl)-acetic acid methyl ester as a colorless oil (10250 mg, 96%). GC-MS (MH+ 230 RT=9.34 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10](CCO)[N:9]=2)[CH:7]=1.C(OC(N1CCCC[C@H]1C(=O)NC1C=CC(C#CC2C(C3C=C(Cl)C=CC=3O)=NNC=2)=CC=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:19][CH:20]=3)=[CH:11][NH:10][N:9]=2)[CH:7]=1
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Agent: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1CCCCN1

Procedure:
Using the same procedure for the preparation of compound 5A, treatment of compound 25A with TFA in methylene chloride gives the title compound 26A as a white powder in similar yield. LCMS (ESI) m/z 421.03 (MH+, 100); HPLC: tR=4.08 min.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH:9]=1)(C)(C)C.N1C=CC=CC=1.F.C(OC([O-])=O)([O-])=O.[Na+].[Na+]>C(#N)C>[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccn(-c2cccc(Cl)c2)c(=O)c1
Agent: F
Agent: O=C([O-])OC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1cc(CO)ccn1-c1cccc(Cl)c1
Reaction time: 3 h

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-1-(3-chlorophenyl)-1H-pyridin-2-one (5.11 g, 14.6 mmol) in acetonitrile (75 ml) in a teflon beaker was added hydrogen fluoride-pyridine (2.5 ml, 87.5 mmol) and stirred for 3 hours. The reaction mixture was neutrallized with solid and aqueous sodium dicarbonate and then the solvent evaporated in vacuo. The resulting solid residue was extracted with EtOAc, dried (MgSO4), filtered and the solvent was evaporated in vacuo. This residue was chromatographed (silica gel, 80-100% EtOAc:hexane gradient elution) to afford the title compound.
Reaction SMILES: [CH:1]1([CH:4]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH3:5])[CH2:3][CH2:2]1.[CH2:12]([O:19][C:20](ON1C(=O)CCC1=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl>[CH:1]1([CH:4]([CH:6]2[CH2:7][CH2:8][N:9]([C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:21])[CH2:10][CH2:11]2)[CH3:5])[CH2:2][CH2:3]1
Reactant: CC(C1CCNCC1)C1CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C1CC1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 91.4 %

Procedure:
Dissolve racemic 4-(1-cyclopropylethyl)-piperidine (1.75 g, 11.42 mmol) and N,N-dimethyl-4-pyridinamine (139.5 mg, 1.14 mmol) in pyridine (15 mL) and dichloromethane (30 mL). Add N-(benzyloxycarbonyloxy)succinimide (3.70 g, 14.84 mmol) and stir the solution for 4 hours. Pour the reaction mixture into 5N HCl and extract twice with EtOAc. Wash the organic extracts with sodium bicarbonate, followed by brine; dry over sodium sulfate; filter; collect the filtrate; and concentrate under reduced pressure. Purify the crude material on a silica gel flash column chromatography using a gradient of 0-20% EtOAc in hexane to give the title compound (3.0 g, 91%) as a clear oil. MS (m/z): 288 (M+1).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.Br[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12]>>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:8][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])=[CH:2][CH:1]=1
Reactant: Nc1ccc(O)cc1
Reactant: CN1CCN(C(=O)CBr)CC1
Product: CN1CCN(C(=O)COc2ccc(N)cc2)CC1

Procedure:
Prepared from p-aminophenol and 1-(bromoacetyl)-4-methylpiperazine by the method of Example 333 to give a product of m.p. 71°-73° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:6][CH2:5]2.[C:17]([Cu])#[N:18]>CN(C=O)C.O>[F:13][C:12]([F:15])([F:14])[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]#[N:18])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:16]
Reactant: N#C[Cu]
Reactant: O=C(N1CCc2cc(Br)ccc21)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)CCN2C(=O)C(F)(F)F
Temperature: 160 °C
Reaction time: 96 h

Procedure:
1-(5-Bromo-2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoroethanone (19 g, 0.0646 mol; see step (ii) above) was dissolved in DMF (50 mL). CuCN (8.68 g, 0.0969 mol) was then added and the reaction mixture was stirred at 160° C. for 4 days, before being cooled to RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate then concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the sub-title compound as a white solid. Yield: 13 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+].CN(C)C=O>O>[N:16]([CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CN(Cc2ccccc2)CCO1
Temperature: 130 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 4-benzyl-2-chloromethylmorpholine (15.0 g), sodium azide (8.6 g), and dimethylformamide (150 ml) is stirred at 130° C. for 2 hours. The reaction mixture is diluted with water and extracted with diethyl ether. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 2-azidomethyl-4-benzylmorpholine (15 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14]>C(N(CC)CC)C.[Cu](I)I.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>[CH:15]1([C:13]#[C:14][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#CC2CC2)ccc1C(=O)O
Temperature: 80 °C
Yield: 71.5 %

Procedure:
Methyl 4-Bromo-2-methylbenzoate (1.0 g, 4.4 mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (43 mg, 5 mol %), followed by PdCl2(PPh3)2 (157 mg, 5 mol %) and ethynylcyclopropane (1.43 ml, 12 mmol). The mixture was heated in a sealed pressure tube at 80° C. for 3 hours. After completion of the reaction, the triethylamine was evaporated and the residue was dissolved in EtOAc and filtered through Celite®. The organic layer was washed with water, brine, and dried (Na2SO4), then filtered and concentrated under vacuum. The residue was purified by column chromatography on sililca gel using EtOAc-hexane (0-100% gradient) as eluent to give the desired product (630 mg). The product was dissolved in 10 mL of MeOH and 10 mL of 2N LiOH and the mixture was refluxed overnight. The MeOH was evaporated and the basic layer was washed with EtOAC, acidified, and re-extracted with EtOAC. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give the desired product as a beige solid (461 mg). m/z 201 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:8]2[CH:9]=[C:10]([B:13]([OH:15])[OH:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[O:4]1)[CH3:2].[H-].[Na+].[CH3:21]I>C1COCC1>[CH2:17]([C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]([B:13]([OH:14])[OH:15])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:21])[C:5](=[O:16])[O:4]1)[CH3:18]
Reactant: CI
Reactant: CCC1(CC)OC(=O)Nc2ccc(B(O)O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(CC)OC(=O)N(C)c2ccc(B(O)O)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 4,4-diethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylboronic acid (4.85 g, 19.50 mmol) in THF (100 mL) at 0° C. was added sodium hydride (3.12 g-60%, 78 mmol). After 10 minutes, methyl iodide (9.7 to mL, 156.0 mmol) was added and the reaction was allowed to warm to room temperature. After one week, the reaction was quenched with ammonium chloride solution (sat.) and extracted with ethyl acetate several times. The organic layers were washed with brine, dried over magnesium sulfate and concentrated. Trituration with ether gave 4,4-diethyl-1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylboronic acid as a yellow solid (3.97 g, 77%). 1H NMR (DMSO-d6): δ 8.03 (s, 2H), 7.78 (dd, J=8.2, 1.3 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 3.28 (s, 3H), 1.99 (m, 4H), 0.78 (t, J=7.4 Hz, 6H). MS (ESI) m/z 264 ([M+H]+); MS (ESI) m/z 262 ([M−H]−); Anal. calcd for C13H18BNO4: C, 59.35; H, 6.90; N, 5.32. Found: C, 58.97; H, 6.98; N, 4.73.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.Br.CC1C([C:22]2[NH:23][CH2:24][CH2:25][N:26]=2)=C(C)NN=1.C(N(CC)CC)C>CN(C=O)C>[NH:26]1[CH2:25][CH2:24][N:23]=[C:22]1[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: NCCCOc1ccc2cc[nH]c2c1
Reactant: Cc1n[nH]c(C)c1C1=NCCN1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1cc2ccc(OCCCNC3=NCCN3)cc2[nH]1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
500 mg (2.6 mmol) of 6-(3-aminopropoxy)indole 23 [prepared in accordance with Example 9.1] are dissolved in 10 ml of DMF together with 0.97 g (3.9 mmol) of 2-(3,5-dimethylpyrazolyl)-4,5-dihydroimidazole hydrobromide and 1.7 ml (11.9 mmol) of triethylamine, and the solution is stirred at 60° C. for 12 hours. After the solution has been evaporated, the crude product is purified by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=1[O:14][CH3:15])=[O:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[CH2:25][NH:24][CH2:23][CH2:22]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]([CH3:16])[C:3]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:24]2[CH2:23][CH2:22][C:21]3[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:25]2)=[CH:8][C:7]=1[O:14][CH3:15])=[O:4]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1cc(C=O)ccc1OC(=O)N(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc2c(cc1OC)CN(Cc1ccc(OC(=O)N(C)C)c(OC)c1)CC2

Procedure:
To a solution of 4-(dimethylaminocarbonyloxy)-3-(methoxy)benzaldehyde (1.02 g) in 1,2-dichloroethane (16 ml) was added 6,7-dimethoxytetrahydroisoquinoline(0.97 g) and sodium triacetoxyborohydride (1.35 g), with stirring. The mixture was stirred at ambient temperature for 1 hr, poured onto ice/sodium carbonate solution and extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash column chromatographed (silica gel), eluting with dichloromethane, 1% and 2% methanol dichloromethane. The appropriate fractions were collected and concentrated to give 0.92 g (50.3%/o) of product. Recrystallization from ethyl acetate gave the analytical sample, mp 126-128° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][CH2:7][C:6]=2[CH:13]=1.C([Li])CCC.CN(OC)[C:21](=[O:23])[CH3:22]>C1COCC1.C(OCC)(=O)C>[C:21]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][CH2:7][C:6]=2[CH:13]=1)(=[O:23])[CH3:22]
Reactant: CC1(C)OCc2cc(Br)ccc2O1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)COC(C)(C)O2
Reaction time: 0.5 h

Procedure:
To the product of step (a) (110 g, 0.46 mol) in 1.0 L of THF at −78° C. was added 236 mL (0.51 mol) of 2.14 M n-butyllithium in hexanes via a dropping funnel. After 30 minutes, N-methyl-N-methoxy acetamide (71 g, 0.69 mol, available from TCI) was added. After 2 hours, the reaction mixture was quenched with water, diluted with 2.0 L of 1.0 M aqueous phosphate buffer (pH=7.0) and extracted once with diethyl ether. The diethyl ether phase was washed once with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a light orange oil. The oil was dissolved in a minimum volume of ethyl acetate, diluted with hexanes, and to give the title compound as a crystalline solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:32])=[C:28](F)[CH:29]=3)[C:24](=[O:33])[N:23]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:22]2=[O:42])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:32])=[C:28]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:29]=3)[C:24](=[O:33])[N:23]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:22]2=[O:42])[CH:18]=[CH:19][CH:20]=1
Reactant: C1CCNC1
Reactant: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)c1
Solvent: CCN(CC)CC
Product: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)cc32)c1
Yield: 86.7 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.077 mL, 0.9 mmol), triethylamine (0.12 mL, 0.9 mmol), and 1-(3-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example E-1, 0.12 g, 0.3 mmol) provided 0.12 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:15][N:16]1[CH2:20][CH:19]2[CH2:21][N:22]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:23][CH:18]2[CH2:17]1>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([N:22]3[CH2:23][CH:18]4[CH:19]([CH2:20][N:16]([CH3:15])[CH2:17]4)[CH2:21]3)=[CH:29][CH:28]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN1CC2CN(c3ccc(N)cc3)CC2C1
Reactant: CCCCOc1ccc(C(=O)O)cc1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CC4CN(C)CC4C3)cc2)cc1

Procedure:
4-Butoxybenzoic acid was reacted with 4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)phenylamine by method E. The product with the molecular weight of 393.53 (C24H31N3O2); MS (ESI): 394 (M+H+) was obtained in this way.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])[CH3:3]
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCCCCCCN1C(=O)c2ccccc2C1=O)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (0.11 g), 1-bromo-6-phthalimidohexane (0.47 g) and potassium carbonate (0.42 g) in N,N-dimethylformamide (5 ml) was stirred overnight at room temperature. The mixture was taken up in ethyl acetate, washed three times with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a white powder of 1-{(2S,3R)-2-hydroxy-5-[2-(6-phthalimidohexyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide (6-1) (219 mg).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:17][C@H:18]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:46])[CH3:45])[C:41](=[O:47])[O:40]1)[CH2:19][N:20]1[C:25]([CH3:27])([CH3:26])[CH2:24][N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][O:36][CH3:37])[C:22](=[O:38])[CH2:21]1.C(OCC)(=O)C>[Cl-].[Na+].O.O>[CH2:6]([O:13][C:14](=[O:15])[NH:17][C@H:18]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:45])[CH3:46])[C:41](=[O:47])[O:40]1)[CH2:19][N:20]1[CH2:21][C:22](=[O:38])[N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][O:36][CH3:37])[CH2:24][C:25]1([CH3:27])[CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COCOc1ccccc1N1CC(C)(C)N(C[C@H](N)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COCOc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OCc2ccccc2)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Reaction time: 2 h
Yield: 96.1 %

Procedure:
206 mg of cesium carbonate (0.63 mmol) was added to a solution of 326 mg of N-{(S)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]-2-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}-2-nitrobenzenesulfonamide obtained in the above reaction (0.53 mmol) and 0.12 ml of thiophenol (content: 95%) (1.1 mmol) in N,N-dimethylformamide (5 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for two hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1-10/1). 49 mg of sodium bicarbonate (0.57 mmol) and 78 μl of benzyloxycarbonyl chloride (0.53 mmol) were added to a solution of 209 mg of 4-{(S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}1-(2-methoxymethoxyphenyl)-5,5-dimethylpiperazin-2-one obtained above (0.48 mmol) in a mixed solvent of ethyl acetate (3 ml) and water (3 ml) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Brine was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 263 mg of {(S)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]-2-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}carbamic acid benzyl ester (yield: 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C(=O)O)CCOCC2)cc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1ccc(C2(C(=O)N3CCOCC3)CCOCC2)cc1
Yield: 87 %

Procedure:
The title compound (3.1 g, 87%) was prepared using 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid, morpholine and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) similarly to the procedure used for example 166. HRMS ESI+ m/z 306.1696 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:23])[CH:29]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(Cl)c4)c3O2)cc1
Yield: 74.6 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.404 g (75%) of (±)-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 101-103° C.; Anal. calcd. for C22H19ClO4S: C, 63.69; H, 4.62. Found: C, 63.59; H, 4.52.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][N:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:22])=O>ClCCl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:22])=[O:8])=[CH:5][N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinic acid (45 g, 235.5 mmol), dichloromethane (540 mL) and DMF (0.910 mL, 11.77 mmol) via syringe. To this solution was added oxalyl chloride (24.51 mL, 282.56 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was concentrated in vacuo to afford the title compound as a brownish semisolid.