Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH3:30][CH:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=O>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:30][CH:31]([CH3:32])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:8][CH:9]=1
Reactant: CCCCCCCCCC(C)C=O
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)C=Cc1ccc(OC)cc1
Yield: 52.8 %

Procedure:
Starting from (4-methoxyphenyl)methyltriphenylphosphonium bromide (6.00 g, 13.0 mmol, 1.0 equiv.), KtBuO (14 mL, 14.2 mmol, 1.1 equiv., 1M in THF) and 2-methylundecanal (2.86 g, 15.5 mmol, 1.2 equiv.), 1.98 g (53%) of the title compound was obtained after purification by flash chromatography on SiO2 (hexane/EtOAc 99:1) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[NH2:26])[C:19]([O:21][CH3:22])=[O:20])=[O:12])=[O:7])=[CH:4][CH:3]=1.[N:29]1([C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH:32]=[CH:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[NH:26][CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:34]([N:29]3[CH2:33][CH:32]=[CH:31][CH2:30]3)=[O:35])=[CH:43][CH:42]=2)[C:19]([O:21][CH3:22])=[O:20])=[O:12])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N)c(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c1
Reactant: O=Cc1ccc(C(=O)N2CC=CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NCc2ccc(C(=O)N3CC=CC3)cc2)c(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
660 mg (1.63 mmol) of methyl 3-[((4-chlorobenzoyl)ethoxycarbonylmethylamino)methyl]-4-aminobenzoate and 431 mg (2.1 mmol) of 4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzaldehyde were dissolved in 10 ml of dichloromethane. 0.185 ml (3.26 mmol) of acetic acid was added to the solution, and they were stirred at room temperature for 30 minutes. 860 mg (4.1 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[CH:26]=[CH:25][C:24]1=[O:29])=[O:19]>O1CCCC1>[C:24]1(=[O:29])[N:23]([CH2:22][CH2:21][O:20][C:18]([N:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]2=[O:8])=[O:19])[C:27](=[O:28])[CH:26]=[CH:25]1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(Cl)OCCN1C(=O)C=CC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=CC(=O)N1CCOC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
500 mg (3.84 mmol) 5-fluorouracil were dissolved in 100 ml of tetrahydrofuran and diluted with 505 mg (696 μl; 4.99 mmol) of triethylamine. To this solution, 1016 mg (4.99 mmol) of 2-maleinimidoethyl chloroformate, dissolved in 100 ml of tetrahydrofuran, were added drop-wise and the set-up was stirred for 15 h at room temperature. Then, the solvent was removed under the water jet vacuum and the residue purified using column chromatography (LOBAR®-column; running medium: acetic acid/hexane 1.5/1; yield: 61%); melting point: 132° C., Rf-value: 0.64 (diol; acetic acid/hexane 2/1)
Reaction SMILES: S(Cl)(Cl)(=O)=O.Br.C[O:8][C:9](=[O:33])[CH:10]([NH:16][S:17]([C:20]1[CH:32]=[CH:31][C:23]2[O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:22]=2[CH:21]=1)(=[O:19])=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>ClCCl.C(N(CC)CC)C>[CH:21]1[C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]=2[CH:31]=[CH:32][C:20]=1[S:17]([NH:16][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:23](=[O:24])[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=1)[CH2:21][CH3:20])[C:9]([OH:8])=[O:33])(=[O:18])=[O:19]
Reactant: COC(=O)C(CCCCN)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Agent: Br
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C(=O)NCCCCC(NS(=O)(=O)c1ccc2oc3ccccc3c2c1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The appropriate sulfonyl chloride (1.5 equivalents, 0.18 mmol) and 70 mg of a morpholino-resin (prepared according to Booth and Hodges, Supra., 1997) were mixed in 1 mL dichloromethane in each of 10 different vials. One milliliter of a 0.12 M stock solution of 6-amino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid methyl ester hydrobromide in triethylamine was added to each of the vials. The vials were sealed and shaken for 16 hours at room temperature. An excess of an amino-resin and an isocyanato-resin (also both prepared according to Booth and Hodges, Supra, 1997) was added to each vial and shaken for 16 hours to quench unreacted starting materials. Each reaction was filtered through a plug of glass wool, and the resins were washed with 2 mL tetrahydrofuran. The filtrate was evaporated under a stream of nitrogen, and the residue in each vial was redissolved in 1 mL dioxane. One milliliter of a 0.6 M aqueous solution of lithium hydroxide was added, and the resulting mixtures were shaken for 16 hours. Each reaction was washed with diethyl ether, and the aqueous layer was then acidified with 1 molar hydrochloric acid. The reactions were extracted with ethyl acetate and evaporated under a stream of nitrogen to leave the expected products. The compounds were analyzed by LC/MS to determine purity and presence of expected molecular ion.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][CH3:20])[N:11]=[C:10]([CH3:21])[N:9]=1)([CH3:3])[CH3:2].[H-].[Na+].COS(OC)(=O)=O.[CH3:34][O:35][CH2:36]COC>C(CNCC=O)=O.CN(C=O)C>[CH:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[C:13]([C:14](=[CH:34][O:35][CH3:36])[C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][CH3:20])[N:11]=[C:10]([CH3:21])[N:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1c(OC)nc(C)nc1Oc1cccc(C(C)C)c1
Reactant: COCCOC
Agent: O=CCNCC=O
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1c(OC)nc(C)nc1Oc1cccc(C(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A solution of methyl 4-(3-isopropylphenoxy)-6-methoxy-2-methyl-pyrimidin-5-yl-acetate (8.6 g, 26 mol) in 1,2-dimethoxyethane (20 ml) and N,N-diformylmethylamine (8 ml) is added at 5° C. to a suspension of NaH (1.6 g, 80% in oil, 52 mol) in DMF (30 ml). The mixture is stirred for 4 hours at room temperature. Dimethylsulfate (3.7 ml, 39 tool) is added at 0° C and stirring is continued for 3 hours. Dilution with ether, washing with brine and chromatography on silicagel (eluent hexane/ethyl acetate 3:1) gives methyl α-[4-(3-isopropylphenoxy )-6-methoxy-2-methyl-pyrimidin-5-yl]-β-methoxyacrylate as a colorless oil (7.2 g, 74%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH:45]([CH3:47])[CH3:46])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH:45]([CH3:47])[CH3:46])[CH:43]=[N:42][CH:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4C(C)C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4C(C)C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-isopropylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.0 g) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (388 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-isopropylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (634 mg) (Compound 384) as yellow amorphous.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[C:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([CH3:12])[CH2:10][O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[CH2:13]([C:9]1([CH3:12])[C:8]2[CH:20]=[CH:21][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[O:11][CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.5 %

Procedure:
A mixture of 3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (300 mg, 1.06 mmol) obtained in Example 4(B), sodium hydroxide (260 mg, 6.5 mmol), ethanol (10 ml) and water (1 ml) in tetrahydrofuran (10 ml), is stirred for 12 h at room temperature. The reaction medium is acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried (Na2SO4), and concentrated in a rotary evaporator. The product is obtained as a white solid (300 mg, 100%). Mp: 165° C.
Reaction SMILES: [Zn](CC)[CH2:2]C.C(O)(C(F)(F)F)=O.C(I)I.[CH2:16]=[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl>[CH3:16][C:17]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:2][CH2:18]1
Reactant: CC[Zn]CC
Reactant: C=C(C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Solvent: ClCCl
Product: CC1(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ZnEt2 (165 mL, 169 mmol) in DCM (160 mL) at 0° C. was added a solution of TFA (6.5 mL, 85 mmol) in DCM (80 mL) dropwise and the mixture was stirred at 0° C. for 30 min. Then to above mixture was added CH2I2 (6.6 mL, 85 mmol) in DCM (80 mL) dropwise and the mixture was stirred at 0° C. for 20 min, followed by adding dropwise a solution of prop-1-en-2-ylbenzene (5.0 g, 42.3 mmol) in DCM (80 mL). The mixture was stirred at rt for 30 min, quenched by brine (100 mL), extracted with DCM (2×100 mL) and the combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA=1/0 to 100/1) to afford compound P43a (3.4 g, 60%) as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[C:16]1([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C:7]([NH:6][CH2:5][C:4]([OH:22])=[O:3])=[O:8])=[N:10][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)cn1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cn1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a stirred solution of 5-phenylamino-pyridine-2-carboxylic acid (0.26 g, 0.00121 mol) in DMF (2 mL) was added DIPEA (0.471 g, 0.00364 mol), HOBt (0.196 g, 0.00145 mol) and EDCI.HCl (0.278 g, 0.00145 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.203 g, 0.00146 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.32 g (88%) of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester. LCMS: 300.13 (M+1)+, 97%. To a stirred solution [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester (0.32 g, 0.00107 mol) in a mixture of THF (5 mL), methanol (10 mL) and H2O (2 mL) was added LiOH.H2O (0.134 g, 0.00321 mol) at ambient temperature and the resulting mixture was stirred for 2 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.26 g (90%) of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])(=O)=O.[Mg+2].CCN(CC)CC>>[CH2:12]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol), benzaldehyde (2.36 g, 22.3 mmol) and MgSO4 (1.33 g) in 1,2-dicholoroethane (300 mL) and Et3N (30.1 mL, 22.3 mmol) at RT was added NaHB(AcO)3. The mixture was stirred (RT, 16 h) and filtered. The solution was washed with saturated NaHCO3 (200 ml), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with MeOH-DCM (0-10%) to afford tert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23%). Mass calculated for C14H22N2O2=250.34. found: [M+H]+=251.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:23]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as Working Example 2, morpholine (1.64 ml, manufactured by Tokyo Kasei) was condensed with Boc-L-phenylalanine (5.00 g) to give Boc-L-phenylalanylmorpholine (6.00 g) as a white powdery product (yield 95%). Taking a portion (2.00 g) of this product, the Boc group was deprotected with TFA, followed by concentration to dryness. The concentrate was dissolved in water, and the solution was allowed to pass through IRA-402 (Cl type, 250 ml, manufactured by Amberlite Inc.), and the solution was concentrated and lyophilized to give L-phenylalanylmorpholine hydrochloride (1.68 g) as a white powdery product (yield: quantitative). A portion (923 mg) of this product was dissolved in dichloromethane (23 ml). To the solution were added, under ice-cooling, (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate produced in Working Example 1 (Compound 1, 1.00 g), HOBT (507 mg), WSC (719 mg) and triethylamine (1.02 ml). The mixture was stirred for 14 hours at room temperature. The reaction mixture was concentrated, to which was added ethyl acetate. The mixture was washed with a 10% aqueous solution of citric acid, water, a saturated aqueous solution of sodium hydrogen carbonate, a 2% aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous saline solution, respectively, followed by drying over anhydrous sodium sulfate, which was concentrated. The concentrate was subjected to a silica gel column chromatography (100 ml). The column was subjected to elution with solutions prepared by adding ethyl acetate to hexane in sequence. The eluate with 60% to 70% (v/v) ethyl acetate was concentrated to give the above-titled compound (Compound 8; 940 mg) as a white powdery product (yield 54%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:17]=[CH:18][C:19]4[C:23]([CH:24]=3)=[N:22][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=4)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]O)[N:6]2[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:52]>O1CCCC1>[CH2:25]([N:21]1[CH:20]=[C:19]2[C:23]([CH:24]=[C:16]([C:8]3[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][Br:52])[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:17]=[CH:18]2)=[N:22]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncnn2c(CCCCO)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12

Procedure:
To a cooled (0° C.) solution of 4-(4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4)triazin-7-yl]butan-1-ol (2.54 g, 6.16 mmol) and triphenylphosphine (2.42 g, 9.24 mmol) in tetrahydrofuran (30 mL) was added carbon tetrabromide (2.45 g, 7.39 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@@H:11]([C@@H:13]([OH:26])[CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([O:26][C@H:13]([CH2:14][O:15][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:19])[CH3:18])[C@@H:11]([CH3:12])[NH:10][C:9](=[O:27])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:38][CH:39]=1)([O-:30])=[O:29]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)[Si](OC[C@H](O)[C@@H](C)NC(=O)OCc1ccccc1)(C(C)C)C(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](C)NC(=O)OCc1ccccc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
Benzyl {(2R,3R)-3-hydroxy-4-[(tripropan-2-ylsilyl)oxy]butan-2-yl}carbamate (7.00 g, 17.7 mmol) synthesized in Example (89b) was dissolved in toluene (80 mL), and 4-nitro benzoic acid (6.10 g, 36.5 mmol) and triphenylphosphine (11.85 g, 45.2 mmol) were added, followed by cooling to 0° C. Under nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 20.3 mL, 44.7 mmol) was added dropwise over 10 minutes, and stirring was carried out at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-15%) to afford the desired compound (7.90 g, yield 82%) as a yellow liquid.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33](O)=[O:34])=[CH:23][N:22]=1>>[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])=[CH:23][N:22]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Reactant: Cc1ncc(C(=O)O)c(-c2ccccc2)n1
Product: Cc1ncc(C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c(-c2ccccc2)n1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-4-phenyl-pyrimidine-5-carboxylic acid. LC-MS (basic): tR=1.31 min; [M+H]+=453.2.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22].[C:25](Cl)(=[O:27])[CH3:26].O>O1CCCC1>[C:25]([CH:20]([C:13]1[C:12]([F:11])=[CH:17][C:16]([F:18])=[CH:15][C:14]=1[F:19])[C:21]([O:23][CH3:24])=[O:22])(=[O:27])[CH3:26]
Reactant: COC(=O)Cc1c(F)cc(F)cc1F
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C(C)=O)c1c(F)cc(F)cc1F
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a commercially obtained tetrahydrofuran solution of lithium bis(trimethyl-silyl)amide (1.0 M, 21.0 mL), stirred under a nitrogen atmosphere and cooled to an internal temperature of −65° C., was added dropwise over 30 minutes a solution of methyl 2,4,6-trifluorobenzeneacetate (i.e. the product of Step A) (2.04 g, 10.0 mmol) dissolved in dry tetrahydrofuran (10 mL). The reaction mixture was stirred for an additional 30 minutes, and then while maintaining the −65° C. temperature, a solution of freshly distilled acetyl chloride (0.80 mL, 11 mmol) in dry tetrahydrofuran (3 mL) was added dropwise. The reaction mixture was allowed to warm slowly to ambient temperature, and then water (30 mL) was added. The resultant mixture was extracted with ethyl acetate (60 mL). The aqueous phase was acidified with 1 N hydrochloric acid and extracted with ethyl acetate (60 mL). Only the first extract was retained, because thin layer chromatographic analysis showed the second extract to contain apparent polar impurities besides additional desired product. The initial organic phase was further washed with 1 N hydrochloric acid, water and brine, dried over MgSO4, and concentrated to provide the title product as a clear oil (1.86 g).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH:20]=O)=[CH:17][CH:18]=2)[CH:13]=[N:12]1>>[NH:11]1[C:19]2[C:14](=[CH:15][C:16](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:5]4[C:4]/3=[CH:9][CH:8]=[CH:7][N:6]=4)=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: O=C1Cc2cccnc2N1
Product: O=C1Nc2ncccc2/C1=C\c1ccc2[nH]ncc2c1
Yield: 95.3 %

Procedure:
The title compound (50 mg, 95%) was synthesized as an orange solid according to the method described for Example A67 using 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and 1H-indazole-5-carbaldehyde (29.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H, NH), 11.20 (s, 1H, NH), 8.21 (s, 2H), 8.09 (d, J=5.2 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 6.91 (dd, J=8.0 Hz, 5.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.1.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: Cc1ccnc(CCl)c1
Agent: Cl
Product: Cc1ccnc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)c1
Yield: 75.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-(chloromethyl)-4-methylpyridine (0.53 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g) was obtained.