Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([O:36]C)=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.O[Li].O>O1CCOCC1.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34]([OH:36])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a solution of methyl 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylate (60 mg, 0.10 mmol) in dioxane/H2O (11 mL/5 mL) was added LiOH.H2O (12.3 mg, 0.30 mol), and the mixture was stirred at 100° C. for 2 hours. After concentrated, the resulting residue was dissolved in H2O, 1 N HCl was added until pH reached 3, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was removed by distillation to provide 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid (41 mg, yield: 70%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.36 (s, 1H), 8.26 (s, 1H), 8.13˜8.16 (m, 2H), 8.09 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.42˜7.46 (m, 2H), 7.25˜7.27 (m, 1H), 7.09 (s, 1H), 6.92˜6.96 (m, 1H), 6.28 (s, 2H), 3.30 (s, 3H), 2.98 (d, 3H). MS (M+H)+: 602.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=1.C[Si](C)(C)[O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]([C:10]1[CH:9]=[CH:8][C:7]([N:6]([N:4]2[CH:3]=[N:2][N:1]=[CH:5]2)[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([OH:17])=[CH:19][CH:20]=2)=[CH:14][CH:13]=1)#[N:12]
Reactant: C[Si](C)(C)Oc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(N(C(=O)c2ccc(O)cc2)n2cnnc2)cc1
Yield: 36.1 %

Procedure:
A mixture composed of 10.43 g of 4-[N-(1,2,4-triazol-4-yl)amino]benzonitrile, 7.9 ml of triethylamine, and 56 ml of methylene chloride was stirred under cooling with ice, and a mixture composed of 23.7 g of 4-(trimethylsilyloxy)benzoyl chloride and 28 ml of methylene chloride was added dropwise thereto, followed by stirring at room temperature for 1 hour. Dilute hydrochloric acid was added to the reaction mixture, followed by stirring at room temperature overnight. After the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, the product was extracted with tetrahydrofuran-diethyl ether (1:1). After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (using a 4:1 mixture of chloroform and acetone as the eluent) to obtain 6.2 g of N-(4-cyanophenyl)-4-hydroxy-N-(1,2,4-triazol-4-yl)benzamide.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH2:15])[CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH3:3].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28]([NH:15][C:10]3[CH:9]=[CH:8][C:7]4[CH2:6][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:14][CH2:13][C:12]=4[CH:11]=3)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: CN(C)CC1CCc2cc(N)ccc2C1
Product: CN(C)CC1CCc2cc(NC(=O)c3cc(-c4ccc(Cl)cc4)c[nH]3)ccc2C1

Procedure:
Following preparation as described in WO 03/087046, 6-((dimethylamino)-methyl)-5,6,7,8-tetrahydronaphthalen-2-amine was converted to the title compound (8 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (25 mg) following the procedure described in step C of Example 1. MS (ESI) 408 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=[C:6]2[N:5]([CH2:22][CH3:23])[C:4](=[O:24])[C:3]=1[N:25]=O.N.C(O)C.[O-]S(S([O-])=O)=O.[Na+].[Na+]>O>[NH2:25][C:3]1[C:4](=[O:24])[N:5]([CH2:22][CH3:23])[C:6]2[N:7]([N:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=2)[C:2]=1[NH2:1]
Reactant: CCn1c(=O)c(N=O)c(N)n2nc(COCc3ccc(OC)cc3)nc12
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCn1c(=O)c(N)c(N)n2nc(COCc3ccc(OC)cc3)nc12
Temperature: 25 °C
Yield: 83.2 %

Procedure:
At ambient temperature, 1.5 g of 7-amino-4-ethyl-2-[(4-methoxybenzyloxy)methyl]-6-nitroso-s-triazolo[1,5-a]pyrimidin-5-one are added to 64 ml of aqueous ammonia solution (25%) and 13 ml of ethanol and dissolved therein. At 30-35° C. a solution of 3.3 g of Na2S2O4 in 30 ml of water is added dropwise. The resulting mixture is stirred at ambient temperature until the reaction is complete (about 3-4 hours). After cooling in an ice bath, the crystals obtained are suction filtered and dried. 1.2 g of 6,7-diamino-4-ethyl-2-[(4-methoxybenzyloxy)methyl]-s-triazolo[1,5-a]pyrimidin-5-one are obtained, which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:9]2[S:18][CH:19]=[CH:20][C:8]=2[CH:7]=1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:39]N1C(=O)CCC1=O.C(OCC)(=O)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:9]2[S:18][C:19]([Br:39])=[CH:20][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2ccsc2n1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(Br)sc2n1C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 16 h
Yield: 34.5 %

Procedure:
To 6-tert-butoxycarbonyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (0.09 g, 0.31 mmol) as a solution in dichloromethane (1 mL) was added TBAF (1M THF, 0.46 mL) followed by N-bromosuccinimide (NBS) (0.07 g, 0.4 mmol). The resulting mixture was allowed to stir at 23° C. for 16 h, after which time the entire reaction mixture was placed directly on a silica gel column. Flash column chromatography (20% ethyl acetate in hexanes) afforded 6-tert-butoxycarbonyl-2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (0.04 g, 36% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH2:16][CH:17]=[CH2:18])(O)[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Br:8].C(N(SN(CC)CC)CC)C.[F-:34].[F-].[F-].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([F:34])([CH2:16][CH:17]=[CH2:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: C=CCC1(O)C(=O)N(c2ccc(Br)c(Cl)c2)N=C1C(F)(F)F
Reactant: [F-]
Agent: CCN(CC)SN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCC1(F)C(=O)N(c2ccc(Br)c(Cl)c2)N=C1C(F)(F)F
Temperature: -3 °C
Reaction time: 1 h

Procedure:
4 g of 1-(3-chloro-4-bromophenyl)-3-trifluoromethyl-4-allyl-4-hydroxy-5-pyrazolone in 200 ml of methylene chloride were cooled to -10° C. and 2.7 ml of trifluoride diethylaminosulfide were added all at once. The mixture was stirred for one hour at -10° C./-3° C. 120 ml of a saturated solution of sodium bicarbonate were added and stirring was carried out for 10 minutes, followed by decanting, washing with water, drying and bringing to dryness. The residue was chromatographed on silica and eluted with a hexane-methylene chloride mixture (8-2) to obtain 1.1 g of 1-(3-chloro-4-bromophenyl)-3-trifluoromethyl-4-fluoro-4-allyl-5-pyrazolone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:34][Si](CC)(CC)CC)[CH2:16][NH:17][C@H:18]([CH3:33])[CH2:19][C:20]2[C:28]3[C:23](=[C:24]([C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[CH:11][C:10]=1[NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:34])[CH2:16][NH:17][C@H:18]([CH3:33])[CH2:19][C:20]2[C:28]3[C:23](=[C:24]([C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[CH:11][C:10]=1[NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CN[C@H](C)Cc1c[nH]c2c(C(=O)OC)cccc12)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)NC[C@H](O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Temperature: 40 °C
Reaction time: 9 h
Yield: 91.6 %

Procedure:
To a solution of methyl 3-[(2R)-2-({(2R)-2-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenyl}-2-[(triethylsilyl)oxy]ethyl}amino)propyl]-1H-indole-7-carboxylate (400 mg, 0.601 mmol) in methanol (20 ml) is added a solution of potassium hydroxide (336 mg, 6.01 mmol) in water (2.0 ml), and the mixture is stirred at 40° C. for 9 hours. The reaction solution is neutralized with 1N hydrochloric acid at 0° C., and thereto is added a pH standard solution (pH 6.8, 5.0 ml). The resultant is purified by reversed phase column (octadecylsilyl, water/methanol 95/5→40/60) to give the title compound (296 mg, yield: 92%).
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1)C>CC(C)=O>[OH:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH:5]=[O:4])=[CH:13][CH:12]=1
Reactant: CCOC(COc1ccc(CO)cc1)OCC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2M HCl (4 mL) was added to a solution of (4-(2,2-diethoxyethoxy)phenyl)methanol (example 1, step g) (0.9 g) in acetone (20 mL) and the resulting mixture was stirred for 16 h at room temperature. The reaction was concentrated in vacuo and the resulting aqueous solution extracted with ethyl acetate (3×20 mL). The combined organic solutions were dried over magnesium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a clear gum, which was used directly in the next step. Yield 0.50 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]O.P(Br)(Br)[Br:12].COC(C)(C)C>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][Br:12]
Reactant: BrP(Br)Br
Reactant: OCc1cc(Br)ccc1Cl
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Clc1ccc(Br)cc1CBr
Temperature: 0 °C
Yield: 156.3 %

Procedure:
To a solution of 2.08 g (9.39 mol) of 5-bromo-2-chlorobenzylalcohol in 30 ml of dry diethyl ether was added dropwise 1.27 g (4.23 mmol) of phosphorous tribromide with ice-cooling. The mixture was stirred with ice-cooling for 3 hours and stirred at room temperature for 1.5 hours. To the reaction solution were added ice water and then tert-butyl methyl ether. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium bicarbonate and water, then dried and concentrated. The solid residue (1.99 g) was subjected to silica gel column chromatography (eluted with n-hexane) to obtain 1.88 g of 5-bromo-2-chlorobenzylbromide as flocculent crystals.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Mg].II.CN([CH:26]=[O:27])C.Cl>C1COCC1.ClCCl>[C:1]12([C:11]3[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH:26]=[O:27])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CN(C)C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
11.09 g (37 mmoles) of 2-(1-adamantyl)-4-bromo anisole dissolved in 85 ml of THF are slowly added to 1 g of magnesium and an iodine crystal. At the beginning of the addition, the reaction mixture is heated until the reaction begins, then the remainder of the solution is added in a manner to maintain a regular reflux. This reaction mixture is heated at reflux for 30 minutes after the end of the addition at which point 2.70 g (37 mmoles) of dry DMF are added. The reaction mixture is then stirred for 30 minutes without heating and then poured into 300 ml of mixture of 2N aqueous HCl and dichloromethane.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].C[O-].[Na+].[Na].Cl.[OH:10][N:11]=[C:12]1[CH2:16][CH2:15][NH:14][CH2:13]1>CO>[ClH:1].[OH:10][N:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:3](=[NH:4])[CH2:2][Cl:1])[CH2:13]1
Reactant: N#CCCl
Reactant: ON=C1CCNC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(CCl)N1CCC(=NO)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.44 ml of chloroacetonitrile was added to a solution of sodium methoxide, prepared by dissolving 16 mg of metallic sodium in 2.8 ml of absolute methanol, and the mixture was stirred at room temperature for about 30 minutes. 950 mg of 3-hydroxyiminopyrrolidine hydrochloride were then added, and the mixture was stirred for a further 2 hours. After completion of the reaction, the solvent was distilled off and the concentrate mixed with anhydrous ether, giving a crystalline product. The crystals were collected by filtration and washed with ether, giving 1.15 g of 2-(3-hydroxyiminopyrrolidin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:31])[CH:5]=[C:6]([Cl:30])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH:28]=O)=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[F:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Cl:30][C:6]1[CH:5]=[N+:4]([O-:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[F:32])=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: Nc1ccccc1F
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNc3ccccc3F)s2)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.7 %

Procedure:
A stirred solution of [(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-formylthiophene-2-carboxylate (128 mg, 0.265 mmol) in dichloromethane (5 mL) was added with 2-fluoroaniline (29 mg, 0.265 mmol) followed by glacial acetic acid (0.015 mL, 0.265 mmol). The reaction was stirred at room temperature for 6 h. Sodium triacetoxyborohydride (140 mg, 0.662 mmol) was added and the reaction was stirred at room temperature for 18 h. Water was added to quench the reaction and the organic layer was washed with brine, passed through a hydrophobic frit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in DCM, to afford the title compound (50 mg, 32%) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:46])[C@H:3]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C:4](=[O:40])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:28]=[C:27]3[C:29]4[C:30]5[C:24]([CH2:25][CH2:26]3)=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][C:20]=5[CH2:19][CH2:18][C:17]=4[CH:16]=2)=[CH:13][N:14]=1.Br[C:48]1[NH:52][C:51]([C@@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:50][CH:49]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CS(C)=O.CCOC(C)=O.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].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>[CH3:44][O:43][C:42]([NH:41][C@@H:3]([CH:2]([CH3:46])[CH3:1])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:16]=[C:17]3[C:29]4[C:30]5[C:20](=[CH:21][C:22]([C:48]6[NH:52][C:51]([C@@H:53]7[CH2:57][CH2:56][CH2:55][N:54]7[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:50][CH:49]=6)=[CH:23][C:24]=5[CH2:25][CH2:26][C:27]=4[CH:28]=2)[CH2:19][CH2:18]3)=[CH:13][N:14]=1)=[O:40])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)CCc2cc(B5OC(C)(C)C(C)(C)O5)cc(c2-4)CC3)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)CCc2cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc(c2-4)CC3)[nH]1)C(C)C
Temperature: 100 °C
Yield: 33.8 %

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (139 mg, 0.22 mmol) and (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (77 mg, 0.24 mmol) were dissolved in dioxane (2 mL) and DMSO (2 mL). Pd(dppf)2Cl2 (16 mg, 0.022 mmol), Pd(PPh3)4 (25 mg, 0.022 mmol), and K2CO3 (2M in H2O, 0.33 mL, 0.66 mmol). The tube was sealed and heated to 100° C. for 20 h. The mixture was cooled to rt, diluted with EtOAc, and washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (54.5 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a mixture of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (1.5 g, 5.5 mmol) and Cs2CO3 (2.2 g, 6.6 mmol) in DMF (6 mL) was added methyl iodide (5150 μL, 8.3 mmol). The mixture was stirred at room temperature for 4 h, diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After removal of solvent, the residue was washed with hexane to yield 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (1.1 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.44 (s, 1H), 3.92 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)CCC.O>CN(C=O)C.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>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:42]2[S:43][CH:44]=[CH:45][CH:46]=2)[CH:3]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(O)(c1cccc(-c2cccs2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-(3-Bromophenyl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.70 g) and a solution of tri-n-butyl(2-thienyl)tin (1.31 ml) in DMF (10 ml) were deaerated and tetrakis(triphenylphosphine)palladium(0) (110 mg) was added. The mixture was stirred under an argon atmosphere at 80° C. for 4 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed twice with water and then with saturated brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chomatography (eluent, hexane:ethyl acetate=6:1→3:1). Recrystallization from ethyl acetate-hexane gave the title compound (1.32 g) as colorless powder crystals.
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][C@@H:6]([NH:13][C:14](=[O:45])[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([NH:28][C:29]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH:26]=[CH:27][C:20]=2[O:19][C@@H:18]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[Li+].[OH-]>>[CH2:32]([NH:31][C:29](=[O:30])[NH:28][C:25]1[CH:26]=[CH:27][C:20]2[O:19][C@@H:18]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:17][N:16]([CH2:15][C:14]([NH:13][C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][C:4]([OH:46])=[O:3])=[O:45])[C:22](=[O:23])[C:21]=2[CH:24]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)C[C@@H](NC(=O)CN1C[C@H](c2ccccc2)Oc2ccc(NC(=O)NCc3ccccc3)cc2C1=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C[C@@H](NC(=O)CN1C[C@H](c2ccccc2)Oc2ccc(NC(=O)NCc3ccccc3)cc2C1=O)c1ccccc1
Yield: 87.5 %

Procedure:
Hydrolysis of (R,S)-3-{2-[7-(3-benzyl-ureido)-5-oxo-2-phenyl-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-phenyl-propionic acid ethyl ester (0.15 g, 0.24 mmol) in the presence of aqueous LiOH, as described in Example 1, yielded (R,S)-3-{2-[7-(3-benzyl-ureido)-5-oxo-2-phenyl-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-phenyl-propionic acid (0.125 g, 0.21 mmol): mp. 138-140° C.; MS (ISP) 593 (M+1)+.
Reaction SMILES: OC(C(F)(F)F)=O.[C@H:8]12[CH2:14][C@H:11]([NH:12][CH2:13]1)[CH2:10][N:9]2[C:15]([C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[NH:23][N:22]=1)=[O:16].[O:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](=[O:45])[C:42](O)=[O:43].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:34]1[CH:33]=[CH:32][C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[CH:18][C:17]=1[C:15]([N:9]1[CH2:10][C@@H:11]2[CH2:14][C@H:8]1[CH2:13][N:12]2[C:42](=[O:43])[C:41]([C:37]1[O:36][CH:40]=[CH:39][CH:38]=1)=[O:45])=[O:16]
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1C[C@@H]2C[C@H]1CN2
Reactant: O=C(O)C(=O)c1ccco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)c1ccco1
Temperature: 25 °C
Reaction time: 60 h
Yield: 51.7 %

Procedure:
4-(3-((1S,4S)-2,5-diazabicyclo[2,2,1]heptane-2-carbonyl)-4-fluorobenzyl)phthalazin-1 (2H)-one TFA salt (200 mg, 0.41 mmol), 2-(furan-2-yl)-2-oxoacetic acid (352 mg, 2.52 mmol), DIPEA (0.63 ml, 3.78 mmol), and HATU (320 mg, 0.84 mmol) were mixed in DMF (30 ml). After the resulting reaction mixture was stirred at room temperature for 60 h, the reaction mixture was partition between DCM and water (100 ml each). The aqueous phase was extracted with DCM (100 ml), and the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:3) to afford the desired product (106 mg, 50.5%) as a light yellow solid.