Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C(O[N:39]1N=N[C:41]2[CH:42]=CC=N[C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:39][CH2:40][CH2:41][CH2:42][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCCN2CCOCC2)cc1

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 4-aminopropyl)morpholine (22.5 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum N-(6-methyl-4′-{[(3-morpholin-4-ylpropyl)amino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide (59.5 mg, 83%). NMR; δH [2H6-DMSO 9.94,(1H, s), 8.55,(1H, t), 8.36,(1H, s), 7.90,(2H, d), 7.78,(1H, t), 767,(1H, dd), 7.60,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.98,(1H, m), 3.56,(4H, t), 3.30,(2H, m), 2.35-2.32,(6H, m), 2.19,(3H, s), 1.69,(2H, m). LCMS: retention time 2.42 min, MH+448.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:19])[C:14](O)=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)=[CH:4][CH:3]=1.[Br-:21].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][C:14]1[C:13]([CH3:19])=[C:12]2[C:17]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][C:10](=[O:20])[O:11]2)=[CH:16][CH:15]=1
Reactant: Cc1c(O)ccc2c(-c3ccc(F)cc3)cc(=O)oc12
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(Br)ccc2c(-c3ccc(F)cc3)cc(=O)oc12

Procedure:
4-(4-fluorophenyl)-7-hydroxy-8-methyl-2-H-chromen-2-one, (4.47 g, 16.5 mol) and triphenylphosphine dibromide (7.68 g, 18.2 mmol) were heated in a sand bath at 320-350° C. for 0.5 h. The cooled mixture was dissolved in dichloromethane, silica gel was added and the mixture was evaporated. Chromatography on silica gel (hexane/EtOAC; 90:10), gave the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[C@@H:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)(=[O:3])[CH3:2].[CH2:41]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:42]#[CH:43].C(N(CC)CC)C>C(Cl)Cl.[Cu]I>[C:1]([O:4][C@H:5]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:43]#[C:42][CH2:41][NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:15][CH:14]=2)[C@@H:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)(=[O:3])[CH3:2]
Reactant: C#CCNS(C)(=O)=O
Reactant: CC(=O)O[C@@H](CC[C@H]1C(=O)N(c2ccc(I)cc2)[C@@H]1c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(F)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H](CC[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 0.5 g (0.742 mmol, 1 equiv) (1S)-3-[(2S,3R)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-(4-iodophenyl)-4-oxoazetidin-3-yl]-1-(4-fluorophenyl)propyl acetate (intermediate of step A), 0.198 g (1.48 mmol, 2 equiv.) N-prop-2-yn-1-ylmethanesulfonamide (i-5), 0.086 g (0.074 mmol, 0.1 equiv.) tetrakistriphenylphosphine palladium(0) and 7 mg (0.04 mmol, 0.05 equiv) copper(I) iodide in 8 mL methylene chloride was deoxygenated by a slow stream of anhydrous nitrogen delivered by a needle through a rubber septum. To the resulting solution was added by syringe 1 mL (7.42 mmol, 10 equiv.) triethylamine. The resulting solution was stirred at room temperature for 4.5 hr at which time the mixture was partitioned 5 mL of a 5% aq. solution of citric acid. The mixture was transferred to a spearatory funnel and extracted with EtOAc (3×5 mL) and methylene chloride (2×5 mL) The combined organic extracts were dried over anhydrous Na2SO4 filtered and the solvent removed under vacuum. The residue was purified by prep. Tlc eluting with EtOAc/hexanes (4/1) followed by further purification by prep. Tlc eluting with EtOAc/hexanes (1/1) to afford the title compound. m/z (ES) 619.0 (M−HOAc+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[O:12]CN=C[C:4]=2[N:3]=1>B(Br)(Br)Br>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1
Reactant: Clc1nc2c(c3ccccc13)OCN=C2
Agent: BrB(Br)Br
Product: Oc1cnc(Cl)c2ccccc12

Procedure:
6-Chloro-1,3-Oxazino[5,6-c]isoquinoline was prepared by the procedure of Miyoko Toyama and Hirotaka Otomasu starting from 1-chloro-4-hydroxy isoquinoline. The starting material: 1-chloro-4-hydroxy isoquinoline (Example 226c) was prepared by the synthetic sequence shown above. MCPBA oxidation of 4-methoxy isoquinoline (Example 222a) was carried as usual to give 79.1% of the corresponding N-oxide (Example 226a). The material was converted into the 1-chloro derivative immediately afterward in POCl3 to give the chloride (Example 226b) in essentially quantitative yield. The crude 1-chloro-4-methoxy isoquinoline was de-methylated in BBr3 at room temperature to give the corresponding 1-chloro-4-hydroxy isoquinoline (Example 226c) after treating the crude BBr3 mixture with anhydrous methanol at room temperature, followed by evaporation to get rid of excess of borate residues. The reaction of Miyoko Toyama and Hirotaka Otomasu gave 266 mg of 6-chloro-1,3-oxazino[5,6-c]isoquinoline (Example 226d, 62.3%) overall yield from 300 mg of 4-methoxy isoquinoline in 4 steps. LC/MS Rt-min ([M−HCHO]H+) [method D]: 2.45 (192). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 5.02 (s, 2 H) 5.41 (s, 2 H) 7.68 (m, 1 H) 7.77 (ddd, J=8.25, 6.91, 1.22 Hz, 1 H) 8.10 (d, J=8.31 Hz, 1 H) 8.26 (d, J=8.56 Hz, 1 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:13]C1C2C=CSC=2C=CC=1.C(OCCCC)=C>[Pd]>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10](=[O:12])[CH2:11][Br:13])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: Brc1cccc2sccc12
Reactant: CC(=O)c1cccc2sccc12
Agent: [Pd]
Agent: C=COCCCC
Product: O=C(CBr)c1cccc2sccc12

Procedure:
1-benzo[b]thiophen-4-yl-2-bromo-ethanone was synthesised from 1-benzo[b]thiophen-4-yl-ethanone (available by the palladium coupling of 4-bromobenzo[b]thiophene with 1-vinyloxy-butane) according to the method in Example 10A(a) (6.8 g, 92%) as an orange oil; 1H NMR (CDCl3): 4.6 (2H, s), 7.4 (1H, t, J=7.8 Hz), 7.65 (1H, d, J=5.7 Hz), 7.95 (1H, dd, J=7.8, 0.9 Hz), 8.1 (1H, dt, J=7.8, 0.9 Hz), 8.3 (1H, dd, J=5.7, 0.9 Hz).
Reaction SMILES: F[C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:14]([C:13]1[CH:16]=[CH:17][C:10]([O:9][C:2]2[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)=[O:15]
Reactant: N#Cc1ccc(F)s1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)s1

Procedure:
Dissolve 5-fluorothiophene-2-carbonitrile (0.541 g, 4.25 mmol) and 4-hydroxybenzaldehyde (0.519 g, 4.25 mmol) in DMF (11 mL). Add K2CO3 (1.469 g, 10.6 mmol) and heat at 100° C. for 1.5 hours. Concentrate the reaction mixture. Take the solid up in ethyl acetate (100 mL) and wash with water (2×25 mL). Dry the organic layer over MgSO4, filter and concentrate. Purify by chromatography eluting with 30% ethyl acetate in hexanes to give the title compound: 1H NMR (CDCl3): 9.96 (s, 1H), 7.98 (dd, J=6.6, 2.2 Hz, 2H), 7.86 (d, J=4.0 Hz, 1H), 7.40 (d, J=2.2 Hz, 2H), 6.96 (d, J=4.0 Hz, 1H); HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=17.4 min, 98.1% purity.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[CH3:14][C:15]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][C:16]=1[NH2:17].C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:21][C:15]=2[CH3:14])[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]=1[CH2:9][CH3:10]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Reactant: Cc1cc(N2CCOCC2)ccc1N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCOCC3)cc2C)nc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (630 mg), 2-methyl-4-(morpholin-4-yl)aniline (500 mg), diisopropylethylamine (900 μL), and N-methylpyrrolidone (5 mL) was stirred at 110° C. overnight. The reactant was left to be cooled, and then water was added thereto, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=8:2→5:5) to obtain 5-chloro-6-ethyl-3-{[2-methyl-4-(morpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide (660 mg) as an orange solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>ClCCl>[CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:36]([O:38][CH3:39])=[O:37])[N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)n1nc(C(=O)NC2CN(C)CCN(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
To a solution of N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (0.92 g) and triethylamine (0.77 g) in dichloromethane (30 ml), methyl chloroformate (0.48 g) is added dropwise at 0° C., and the mixture is stirred at 25° C. for 16 hours. The reaction mixture is washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.7 g) as an oil. The free base thus obtained is converted to the fumarate of the title compound in a usual manner, m.p. 158-160° C. (recrystallized from ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:10][C@H:11]([C:15]([OH:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)#[N:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:10][C@H:11]([C:15]([OH:18])([CH3:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoic acid (3.5 g, 12.4 mmol) in THF (80 mL) were added 4-cyanobenzhydrazide (2.3 g, 14.3 mmol), HOBt (1.70 g, 12.6 mmol), EDC (3.56 g, 18.6 mmol) and Et3N (2.8 mL, 20.1 mmol) at −20° C. sequentially. After addition, the mixture was stirred at −20° C. for 30 min., then room temperature overnight. The reaction was quenched by adding ice-water. After removal of the THF, the residue was extracted with EtOAc (300 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. The filtrate was concentrated and purified by flash chromatography to give the title compound (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-cyanobenzohydrazide (3.47 g, 65%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 9.72 (b, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.6 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 5.55 (d, J=7.2 Hz, 1H), 4.08 (d, J=7.2 Hz, 1H), 2.35 (s, 3H), 1.47 (s, 3H), 1.42 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([SH:14])[C:11]([CH:15]([CH3:17])[CH3:16])=[CH:10][C:9]=1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:4])([CH3:3])[CH3:2].[S:27](Br)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].N1C=CC=CC=1>CCOC(C)=O>[C:22]([O:21][C:19]([NH:18][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:26])=[CH:13][C:12]([S:14][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[C:11]([CH:15]([CH3:16])[CH3:17])[CH:10]=1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: CC(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc1S
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Sc2cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc2C(C)C)cc1

Procedure:
The title compound was prepared according to the General Method 15 using (2-tert-butyoxycarbonylamino-4-isopropyl-5-mercapto-phenyl)-carbamic acid tert-butyl ester (prepared in Example TT-1; 22.1 mmol), tosyl bromide (5.2 g, 22 mmol), pyridine (5 mL), and EtOAc (50 mL). The crude product was purified by flash chromatography (5%-60% EtOAc in hexanes as eluents). 1H-NMR (CDCl3): δ0.97 (s, 6 H), 1.53 (s, 18 H), 2.4 (s, 3 H), 3.2 (m, 1 H), 7.11 (br s, 1 H), 7.22 (d, 2 H), 7.28 (s, 1 H), 7.36 (s, 1 H), 7.5 (d, 2 H), 7.75 (br s, 1 H).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([CH2:11]O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:13][CH2:11][C:8]1[O:9][C:10]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2cccc(F)c2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc2cc(CBr)oc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of (7-fluorobenzofuran-2-yl)methanol (1.38 g, 8.31 mmol), tetrabromomethane (4.41 g, 13.3 mmol) and triphenylphosphine (2.61 g, 9.97 mmol) in dichloromethane (42 mL) was stirred at 0° C. for 2 h and concentrated in vacuo to dryness. The residue was purified by column chromatography (hexanes/ethyl acetate, 49/1) to afford 2-(bromomethyl)-7-fluorobenzofuran (1.85 g, 97%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.34-7.29 (m, 1H), 7.20-7.12 (m, 1H), 7.10-7.02 (m, 1H), 6.82-6.77 (m, 1H), 4.60 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)oc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCO[C@@H]1CN(c2nc(C(=O)O)c(CC)o2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 75.8 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (115c) (0.24 g, 0.48 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (4 mL) and THF (6 mL), to obtain 160 mg of the title compound as a colorless solid (75%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=O)=[CH:9]2.Cl.[CH3:30][O:31][C:32](=[O:56])[C@@H:33]([CH2:35][S:36][C:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:34].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:30][O:31][C:32](=[O:56])[C@@H:33]([CH2:35][S:36][C:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:34][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:28]
Reactant: COC(=O)[C@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)N[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 70.7 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.45 g), S-trityl-D-cysteine methyl ester hydrochloride (0.46 g), 1H-1,2,3-benzotriazol-1-ol (0.26 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.32 g), triethylamine (0.19 mL) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 64 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio) to give the title compound (0.60 g, yield 72%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([CH3:39])[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=C)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=2)=[O:25])=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:42].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:40])[N:7]([C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[O:42])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:28]=2)=[O:25])=[CH:21][CH:22]=1)[CH3:39])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1ccc(NC(=O)Nc2ccc(-n3cnc4c(N(C)C(=O)OC(C)(C)C)ncnc43)cc2)cc1C(F)(F)F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.1 %

Procedure:
In a mixed solution of 10 mL of tetrahydrofuran and 5 mL of water, 324 mg (0.59 mmol) of methyl-(9-{4-[3-(3-trifluoromethyl-4-vinylphenyl)ureido]phenyl}-9H-purin-6-yl)-carbamic acid tert-butyl ester was dissolved, and 200 μL of a 0.1 M osmium tetraoxide aqueous solution and 510 mg (2.38 mmol) of sodium periodate were added thereto, and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The product was purified by a silica gel column (hexane:ethyl acetate=1:2) to obtain 243 mg (75%) of a target product as a white crystal.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=[C:2]([NH:17][C:18]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][NH:24]3)=[CH:20][CH:19]=2)[N:7]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc3cn[nH]c3c2)n1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A mixture of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine (1 g, 3.6 mmol), 6-aminoindazole (0.5 g, 3.7 mmol), tetrahydrofuran (10 ml), and diisopropylethylamine (0.65 ml, 3.7 mmol) was stirred for 1 hour. After concentrating under reduced pressure, the residue was treated with water (25 ml) and stirred for 10 minutes. The solid was filtered, treated with hydrochloric acid (1 M, 10 ml), stirred vigorously for 10 minutes, and filtered. The solid was purified by flash chromatography on silica eluting with 5% methanol-dichloromethane to yield the title compound (600 mg, 45% yield). 1H NMR (DMSO-d6) 13.04 (br s, 1H), 10.90-10.97 (m, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.71 (m, 2H), 7.53 (m, 1H), 7.41 (m, 1H), 7.34 (m, 1H), 2.50-2.54 (m, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:31]=[CH:30][C:19]4[C:20]([C:24]([NH:26][CH:27]5[CH2:29][CH2:28]5)=[O:25])=[C:21]([CH3:23])[O:22][C:18]=4[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1.[CH3:32][NH2:33]>C1COCC1.CS(C)=O>[CH:27]1([NH:26][C:24]([C:20]2[C:19]3[CH:30]=[CH:31][C:16]([O:15][C:9]4[C:8]5[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][NH:33][CH3:32])=[CH:6][CH:7]=5)[N:12]=[CH:11][CH:10]=4)=[CH:17][C:18]=3[O:22][C:21]=2[CH3:23])=[O:25])[CH2:29][CH2:28]1
Reactant: Cc1oc2cc(Oc3ccnc4cc(OCCBr)ccc34)ccc2c1C(=O)NC1CC1
Reactant: CN
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CNCCOc1ccc2c(Oc3ccc4c(C(=O)NC5CC5)c(C)oc4c3)ccnc2c1

Procedure:
A solution of compound 90-1 (100 mg, 0.21 mmol) and 0.3 ml of methylamine 90-J (R′═CH3, R′═H) in THF (2N) in DMSO (2 ml) was heated to 60° C. for 1 hour. The reaction mixture was purified by HPLC (Dionex System) using 10-50% CH3CN/H2O+0.1% AcOH over 30 minutes to give N-cyclopropyl-2-methyl-6-({7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)-1-benzofuran-3-carboxamide 90 (42 mg).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:30]=[C:29](Cl)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1>C(#N)C.O>[Cl:24][C:25]1[CH:30]=[C:29]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (12.58 g, 57.0 mmol) and DIPEA (29.0 mL, 166 mmol) in ACN (104 mL) was added 2,4-dichloro-5-nitropyridine (10.00 g, 51.8 mmol). The resulting mixture was stirred at RT for 24 hours. The reaction mixture was diluted with water and washed with DCM (×2). The combined organic layers were washed with a minimal volume of brine, dried over sodium sulfate, filtered and concentrated in vacuo. After almost complete concentration of solvent, EtOAc was added, and the solid precipitate was collected yielding cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide as a yellow solid (12.97 g, 73.4% yield).