Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[C:22]2[CH3:34])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[Cl-].[C:69]([C:73]1[CH:78]=[CH:77][C:76]([C@@H:79]([NH3+:81])[CH3:80])=[CH:75][CH:74]=1)([CH3:72])([CH3:71])[CH3:70]>CN(C=O)C>[C:69]([C:73]1[CH:74]=[CH:75][C:76]([C@@H:79]([NH:81][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]4[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:19][CH:18]=2)[C:22]([CH3:34])=[C:23]3[CH3:33])=[O:31])[CH3:80])=[CH:77][CH:78]=1)([CH3:72])([CH3:70])[CH3:71]
Reactant: C[C@H]([NH3+])c1ccc(C(C)(C)C)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
To a mixture of 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (100 mg) in DMF (2 mL) was added DIEA (116 μL) and HATU (88 mg). The mixture was stirred for 5 min, and then (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride (49 mg) was added. The reaction mixture was stirred at rt for 30 min. The completion of the reaction was monitored by anal. HPLC. The solvent was removed in vacuo to obtain the crude which was purified by flash chromatography (AcOEt/Hex 10→100%) to obtain the title compound (120 mg). ESI-MS (m/z): 559 [M+H-tBu]+, 615 [M+H]+, 637 [M+Na]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:40]=[CH:39][NH:38][N:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:37]4[C:36]([CH3:35])=[CH:40][CH:39]=[N:38]4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(CCl)cc2)nn1
Reactant: Cc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3nccc3C)cc2)nn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of [5-({[1-(4-Chloromethyl-benzyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (200 mg, 0.412 mmol), 3-methylpyrazole (33.9 mg, 0.412 mmol) and cesium carbonate (269 mg, 0.825 mmol) in 2 mL of DMF was stirred at 80° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire Prep C18 OBD 5 μm 30×100 mm, Flow 40 mL/min, ACN/water (0.1% TFA) 5/95 over 2 min, then ACN/water (0.1% TFA) 5195-100/0 over 15 min). LCMS (Method A) RtA=1.527; [M+H]+=531.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2N=[N:11][CH:12]=[CH:13][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].C(OC(=O)C1C=CN=[C:22]([CH:26]2[CH2:28][CH2:27]2)C=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2=[C:22]([CH:26]3[CH2:28][CH2:27]3)[N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: CCOC(=O)c1ccnc(C2CC2)c1Cl
Product: CCOC(=O)c1oc2c(C3CC3)nccc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 3-chloro-2-cyclopropylisonicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (7/3) gives the desired product as colorless oil;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([O:12]CC2C=CC=CC=2)=[CH:10][CH:9]=[CH:8][N:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)/C=C/c1ncccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ncccc1O
Yield: 87.9 %

Procedure:
In an autoclave, a solution of 11.5 g of 3-(3-benzyloxy-2-pyridyl)-(2E)-2-propenoic acid methyl ester in 125 ml of methanol is hydrogenated in the presence of 1.15 g of 10% palladium catalyst on activated carbon at an initial pressure of 32 bars for 2 hours at room temperature. The reaction mixture is filtered, the filter residue is washed with methanol and the filtrate is concentrated by evaporation. 6.8 g of 3-(3-hydroxy-2-pyridyl)-propionic acid methyl ester of melting point 94°-96° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])=[O:17])=[CH:13][CH:14]=2)=[O:38])=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Sc2ncc(Br)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(S(=O)c2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
To a stirred solution of 6n (1.0 g, 2.11 mmol) in DCM (50 mL) at 0° C. was added MCPBA (0.364 g, 2.11 mmol) in portions. The resulting mixture was stirred at room temperature for 6 h and then diluted with water and made slightly basic with Na2CO3 solution. The DCM layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried and evaporated to give a residue that was purified by silica gel flash column chromatography (ethyl acetate-methanol 5:1) to give 8g, yield 48%. 1H NMR (400 MHz, DMSO-d6): δ 11.32 (br, s, 1H), 10.38 (br, s, 1H), 9.15 (s, 2H), 8.20 (m, 1H), 7.88 (m, 1H), 7.72-7.80 (m, 6H); EI-MS m/z 489 [M]+, 491 [M+2]+; HRMS calculated for C18H12BrN5O5SNa [M+Na]+: 511.9634, found: 511.9632. Anal. (C18H12BrN5O5S) C, H, N.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[ClH:13].[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36]C(OC)=O)=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24](O)=[C:25](OC)[CH:26]=2)[N:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:60]1([CH2:65][CH2:66][OH:67])[CH:64]=[N:63][CH:62]=[N:61]1>C(Cl)Cl>[ClH:13].[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([OH:36])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:67][CH2:66][CH2:65][N:60]3[CH:64]=[N:63][CH:62]=[N:61]3)=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: OCCn1cncn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(F)c(Nc2ncnc3cc(OCCn4cncn4)ccc23)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
Diethyl azodicarboxylate (244 mg, 1.4 mmol) was added dropwise to a suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol), (prepared as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(1,2,4-triazol-1-yl)ethanol (95 mg, 0.84 mmol), (Ann. Pharm. Fr. 1977, 35, 503-508), in methylene chloride (5 ml). The mixture was stirred for 1 hour at ambient temperature and further triphenylphosphine (184 mg, 0.7 mmol), 2-(1,2,4-triazol-1-yl)ethanol (63 mg, 0.56 mmol) and diethyl azodicarboxylate (122 mg, 0.7 mmol) were added. The mixture was stirred for a further 2.5 hours and the solvent was removed by evaporation. The residue was dissolved in methanol (5 ml) and 2M aqueous sodium hydroxide solution (2 ml) was added. The mixture was stirred for 20 minutes and the mixture was partitioned between ether and water. The aqueous layer was acidified to pH7 with 2M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, and dried under vacuum. The resulting solid was dissolved in methylene chloride/methanol and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The volatiles were removed by evaporation, the solid was resuspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline hydrochloride (180 mg, 56%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][P:11](=[O:15])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:16]>CO.[Pd]>[ClH:16].[CH3:14][P:11]1(=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CP1(=O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CP1(=O)CCNCC1

Procedure:
A solution of 1-benzyl-4-methyl-1,4-azaphosphinane 4-oxide (5 g) in methanol (50 mL) and 3 M HCl (10 mL) with palladium on carbon (10%, 1.0 g) was hydrogenated on a Parr shaker for 24 hours at 60 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure to give a white crystalline solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])=[CH:15][C:14]=3[F:28])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.N1C=CC=CC=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])=[CH:15][C:14]=3[F:28])=[O:9])=[CH:29][CH:30]=1
Reactant: N#CCCCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: N#CCCCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a suspension of the title compound of Example 89 (0.11 g) in 25 mL EtOAc is added triethylamine (0.08 mL) and pyridine (5 mL) to aid dissolution. After 10% Pd/C (50 mg) is added, the reaction is placed under a hydrogen balloon. After 2 hours, the reaction is complete and subsequently filtered over Celite. The filter cake is washed with ethyl acetate. The filtrate is concentrated to give a tan solid which is further dried on the vacuum pump to afford the desired product (0.088 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[CH3:11][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])([CH3:11])[CH3:9])=[N:6][CH:7]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1ncc(Br)cn1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(Br)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 46.1 %

Procedure:
To a solution of 1-(5-bromopyrimidin-2-yl)ethanone (99 mg, 0.50 mmol) in THF (10 mL) was added MeMgBr (1.65 mL, 4.95 mmol) at −78° C. under nitrogen. The formed solution was stirred at −78° C. for 20 min, quenched with satd aq NH4Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give an oil, which was purified by prep TLC (3:1 PE/EtOAc) to give 2-(5-bromopyrimidin-2-yl)propan-2-ol (50 mg, yield: 46.77%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([C:14]#[C:15][Si](C)(C)C)=[CH:11][CH:12]=3)[C:7]([CH3:21])([CH3:20])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.CO.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CCCCCC>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=3)[C:7]([CH3:21])([CH3:20])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CC1(C)CCN(C2CC2)c2ccc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#Cc1ccc2c(c1)C(C)(C)CCN2C1CC1

Procedure:
Following general procedure E and using 1-cyclopropyl-6-trimethylsilanylethynyl -4,4-dimethyl-1,2,3,4-tetrahydroquinoline (Intermediate 52, 0.40 g, 1.34 mmol), methanol and potassium carbonate (0.2 g, 1.47 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.17 g, 56%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]1[CH2:25][CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13][C@@H:12]1[CH2:25][CH2:26][O:27][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@@H](CCO)C1
Reactant: CI
Solvent: CN(C)C=O
Product: COCC[C@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of [(1S,2R,4R)-[4-tert-butoxycarbonylamino-2-(hydroxyethyl)-cyclohexyl]-carbamic acid benzyl ester (0.42 g, 1.07 mmol) in DMF (4 mL) was charged with iodomethane (20 mL) and Ag2O (1.24 g, 5.35 mmol) and stirred at RT for 14 h. The mixture was filtered and the filtrate was diluted with sat. NaHCO3 and minimum EtOAc. The mixture was separated (organic on bottom). The aqueous was extracted with EtOAc, and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford [(1S,2R,4R)-[4-tert-butoxycarbonylamino-2-(methoxyethyl)-cyclohexyl]-carbamic acid benzyl ester (0.255 g). MS found: (M+H)+=429.2.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:45]>C(#N)C.[Cu]Cl.[Cu](Cl)Cl>[Cl:45][C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cl
Reactant: CCOC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 3 h

Procedure:
A solution of 10.99 g of isoamyl nitrite in 10 ml of acetonitrile was added to a mixture of 15.46 g of ethyl 2-[3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]propionate, 6.19 g of copper (I) chloride, 12.61 g of copper (II) chloride, and 120 ml of acetonitrile at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was poured into a mixture of ice and hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 13.16 g of ethyl 2-[3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3, 6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]propionate (compound b-10).
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]([NH:36][NH2:37])=[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.[CH3:45]CN(CC)CC.C(=N)OCC>CC#N>[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]7[O:35][CH:45]=[N:37][N:36]=7)[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: CN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)NN)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Reactant: CCN(CC)CC
Agent: CCOC=N
Solvent: CC#N
Product: CN(c1cc2oc(-c3ccc(F)cc3)c(-c3nnco3)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of N-(5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-3-(hydrazinecarbonyl)benzofuran-6-yl)-N-methylmethanesulfonamide (20 mg, 0.03 mmol) and Et3N (1 mL) in MeCN (5 mL) was added ethyl formimidate (6 mg, 0.05 mmol). Then the mixture was stirred at 110° C. for 2 hours. After the solvent was removed by vacuum, the resulting residue was purified using prep-HPLC to provide Compound 159 (10 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 9.01 (s, 1H), 8.35 (s, 1H), 8.10 (t, J=2.8 Hz, 2H), 7.89 (s, 1H), 7.48 (t, J=2.8 Hz, 2H), 7.15˜7.23 (m, 4H), 7.07 (s, 1H), 6.78 (t, J=2.8 Hz, 1H), 5.98 (s, 2H), 3.29 (s, 3H), 2.89 (s, 3H). MS (M+H)+: 626.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]3[CH2:13][N:14]([C:17]4[CH:18]=[N:19][C:20](F)=[CH:21][CH:22]=4)[C:15](=[O:16])[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH2:24]1[CH:28]2[CH2:29][NH:30][CH2:31][CH:27]2[CH2:26][N:25]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]3[CH2:13][N:14]([C:17]4[CH:22]=[CH:21][C:20]([N:30]5[CH2:29][CH:28]6[CH2:24][N:25]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][CH:27]6[CH2:31]5)=[N:19][CH:18]=4)[C:15](=[O:16])[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2nn(-c3ccc(Cl)cc3)cc2CN1c1ccc(F)nc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc(N4Cc5cn(-c6ccc(Cl)cc6)nc5C4=O)cn3)CC2C1
Temperature: 140 °C
Yield: 61.4 %

Procedure:
To a mixture of Example 34A (20 mg, 0.061 mmol) in DMSO (0.8 mL) was added tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (63 mg, 0.297 mmol). The resulting mixture was irradiated in microwave reactor at 140° C. for 30 min. The sealed tube was heated at 140° C. for 3 h and allowed to cool down to room temperature. The reaction mixture was subjected to filtration. The solid collected was further washed with MeOH (5 mL) and dried under vacuum to give product (19.5 mg) as light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.60 (s, 9H), 2.90-3.05 (m, 2H), 3.20-3.50 (m, 4H), 3.60-3.80 (m, 4H), 4.77 (s, 2H), 6.42 (d, J=8.8 Hz, 1H), 7.43-7.50 (m, 2H), 7.72-7.76 (m, 2H), 7.89 (s, 1H), 8.07 (dd, J=8.8, 2.7 Hz, 1H), 8.28 (d, J=2.7 Hz, 1H). LCMS, [M+H]+=521.4.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:29])([F:28])[C:5]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:6]=1[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[CH2:14][CH2:15][S:16]2)=[CH:11][CH:10]=1>CCO>[F:29][C:4]([F:3])([F:28])[C:5]1[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:6]=1[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([OH:19])[CH2:14][CH2:15][S:16]2)=[CH:11][CH:10]=1
Reactant: O=C1CCSc2cc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCSc2cc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
To a solution of NaBH4 (93.1 mg) in EtOH (15 mL) was added dropwise a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-2,3-dihydro-4H-thiochromen-4-one (1.0 g) in EtOH (5 mL) at 0° C. The reaction mixture was warmed to 25° C., followed by stirring for 3 hours. The reaction liquid was concentrated under reduced pressure and to the residue were added DCM (20 mL) and then saturated aqueous NH4Cl (30 mL) at 0° C., followed by stirring for 1 hour and extracting with DCM three times (30 mL×3). The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 60:40) to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}thiochroman-4-ol (845 mg) as a white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:35]([NH:37][CH2:38][C:39]([NH:41][C@H:42]([C:52]([NH:54][CH2:55][C:56]([NH:58][C@H:59]([C:70]([N:72]1[CH2:79][CH2:78][CH2:77][C@H:73]1[C:74]([NH2:76])=[O:75])=[O:71])[C@@H:60]([CH3:69])[O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:57])=[O:53])[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:40])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:17][C:18](=[O:20])[NH2:19])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:87]([C:109]([O:111][C:112]([CH3:115])([CH3:114])[CH3:113])=[O:110])[C@H:88]([C:106](O)=[O:107])[CH2:89][CH2:90][CH2:91][NH:92][C:93](=[NH:105])[NH:94][S:95]([C:98]1[CH:104]=[CH:103][C:101]([CH3:102])=[CH:100][CH:99]=1)(=[O:97])=[O:96]>>[NH:87]([C:109]([O:111][C:112]([CH3:114])([CH3:113])[CH3:115])=[O:110])[C@H:88]([C:106]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:35]([NH:37][CH2:38][C:39]([NH:41][C@H:42]([C:52]([NH:54][CH2:55][C:56]([NH:58][C@H:59]([C:70]([N:72]1[CH2:79][CH2:78][CH2:77][C@H:73]1[C:74]([NH2:76])=[O:75])=[O:71])[C@@H:60]([CH3:69])[O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:57])=[O:53])[CH2:43][O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:40])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:17][C:18](=[O:20])[NH2:19])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:107])[CH2:89][CH2:90][CH2:91][NH:92][C:93](=[NH:105])[NH:94][S:95]([C:98]1[CH:104]=[CH:103][C:101]([CH3:102])=[CH:100][CH:99]=1)(=[O:97])=[O:96]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](COCc2ccccc2)C(=O)NCC(=O)N[C@H](C(=O)N2CCC[C@H]2C(N)=O)[C@@H](C)OCc2ccccc2)[C@@H](C)OCc2ccccc2)[C@@H](C)OCc2ccccc2)cc1
Yield: 72.2 %

Procedure:
By using 8.35 g of Boc-Thr(Bzl)-Asn-Thr(Bzl)-Gly-Ser(Bzl)-Gly-Thr(Bzl)-Pro-NH2 and 3.30 g of Boc-Arg(Tos)-OH, and the same procedure as in Reference 15 was repeated to obtain 7.60 g (yield: 70.5%) of the above-mentioned objective product. Melting point: 120°-132° C.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20](/[CH:24]=[CH:25]/[C:26]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH2:10][C:8]3[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=3)[N:12]=2)=[O:27])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(Cl)c3)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-chloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=392.14.