Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:12](=[O:13])[C@@:11]3([CH2:25][C:16]4=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]4[CH2:14]3)[N:10]([CH3:26])[C:9]2=[O:27])=CC=1.[N+]([O-])([O-])=O.[NH4+]>CO>[CH3:26][N:10]1[C@:11]2([CH2:25][C:16]3=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]3[CH2:14]2)[C:12](=[O:13])[NH:8][C:9]1=[O:27]
Reactant: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(Cc2ccc(OC)cc2)C(=O)N1C
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)NC(=O)N1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl (6R)-1′-(4-methoxybenzyl)-3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylate (10.0 g, 25.3 mmol) in MeOH (100 mL) at ambient temperature was added eerie ammonium nitrate (27.7 g, 50.6 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The resulting mixture was partitioned between H2O (500 mL) and EtOAc (1 L) and the organic layer was discarded. The aqueous layer was adjusted to pH=7-8 by addition of 1 N aqueous NaOH and extracted further with EtOAc (2×500 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=276.1 (M+1).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[S:22][N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[S:22][N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4nsc(N)n4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Nc1cncc(-c2c[nH]c3ccc(-c4nsc(N)n4)cc23)n1
Temperature: 100 °C
Yield: 28.5 %

Procedure:
To a mixture of tert-butyl (3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.49 g, 0.8 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. The reaction was stirred for 2 h at RT. The solvent was then removed in vacuo and the residue was triturated with Et2O to give 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (0.23 g, 56.2%). MS (ESI, pos. ion) m/z: 506.1 (M+1). To a solution of 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (0.23 g, 0.45 mmol) in 1-4-dioxane (10 mL) was added 10% aq NaOH (5 mL) and the reaction was heated at 100° C. for 2 h. The reaction was quenched with ice cold H2O to give a pale yellow precipitate. The precipitate was filtered, washed with ice cold H2O and dried under vacuum. The crude product was purified with preparative HPLC (eluent: 20-80% AcCN in H2O with 0.1% TFA) to give 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (45 mg, 28.3%). MS (ESI, pos. ion) m/z: 352.1 (M+1); 1H NMR (DMSO-d6, 400 MHz): δ 11.81 (s, 1H), 9.19 (s, 1H), 8.20-8.18 (m, 2H), 7.92 (dd, J=8.4, 1.2 Hz, 1H) 7.86 (brs, 2H), 7.63 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 4.32-4.29 (m, 1H), 1.29 (d, J=6.4 Hz, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[CH:7][C:4]=1[CH:5]=[O:6].[I-].[Na+].[Al+3].[Cl-].[Cl-].[Cl-]>C(#N)C>[OH:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(OC)c(C=O)cc1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Product: COc1cc(O)c(C=O)cc1C
Reaction time: 1 h

Procedure:
The above prepared 2,4-Dimethoxy-5-methyl-benzaldehyde (5.40 g, 30 mmol) was dissolved in 150 mL of acetonitrile and treated successively with sodium iodide (6.74 g, 1.5 eq.) and AlCl3 (4.00 g, 1.0 eq.), and the mixture kept at 80° C. for 1 h. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1), delivered 4.23 g of the title compound as light brown crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]1([CH2:26][OH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:26]([O:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(OCc3ccccc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenyl-methanol to give (1-benzyloxy-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [CH2:1](O)[CH2:2]SCCO.[CH2:8]([N:23]=[C:24]=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)COCCO>[CH2:8]([N:23]=[C:24]=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:1][CH3:2]
Reactant: CCCCCCCCCCCCCCCN=C=O
Reactant: OCCSCCO
Solvent: OCCOCCO
Product: CCCCCCCCCCCCCCCCCN=C=O

Procedure:
Following the procedure described in preparation 4, but using thiodiethylene glycol and n-pentadecylisocyanate, instead of diethylene glycol and n-heptadecylisocyanate, respectively, the title compound of this preparation was obtained in a similar yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCC(=O)c1ccc(O)c(CCC(=O)OCC)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CCCCc1ccc(O)c(CCC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 57 %

Procedure:
To a solution of 3.91 g (11.6 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-hydroxy-δ-oxobenzenepentanoic acid ethyl ester (from example 140) in 50 mL of acetic acid was added 0.5 g of 10% palladium on carbon, and the resulting mixture was shaken at room temperature and 45 p.s.i. in a Parr shaker for 18.5 hr. The mixture was filtered with suction through a Celite pad and the solids washed with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo. The residue was dissolved in 200 mL of ethanol and treated with 5 mL of concentrated sulfuric acid. The resulting mixture was refluxed for 4 hr and then stirred at room temperature overnight. Most of ethanol was removed in vacuo and the residue was worked-up with ether in the usual manner (the combined ether extracts were additionally washed with saturated aqueous sodium bicarbonate solution). The crude product was purified by flash chromatography on 350 g of silica gel, eluting with hexane-ethyl acetate (4:1) to give 2.13 g (56.7%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([CH2:12][CH3:13])[S:11][C:5]=2[N:4]=[CH:3]1.[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[C:10]([CH2:12][CH3:13])[S:11][C:5]=4[N:4]=[CH:3]3)=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: CCc1cc2c(=O)n(N)cnc2s1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: CCc1cc2c(=O)n(NC(=O)CC34CC5CC(CC(C5)C3)C4)cnc2s1

Procedure:
3-Amino-6-ethylthieno[2,3-d]pyrimidin-4(3H)-one and 1-adamantane acetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm. 35 (t, J=7.5 Hz, 1H), 1.64-1.73 (m, 12H), 2.00-2.04 (m, 3H), 2.21 (s, 2H), 2.88 (qd, J=7.5, 1.2 Hz, 1H), 7.17 (t, J=1.2 Hz, 1H), 7.93 (s, 1H), 8.08 (s, 1H) ppm; MS (DCI/NH3) m/z 372 (M+H)+; Elemental Analysis: Calculated for C20H25N3O2S.0.2H2O: C, 64.04; H, 6.83; N, 11.20. Found: C, 63.91; H, 6.68; N, 11.27.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([C:27]1[C:31]([CH:32]2[CH2:35][C:34](=O)[CH2:33]2)=[CH:30][N:29]([C:37]2[C:42]([Cl:43])=[CH:41][C:40]([C:44]([F:47])([F:46])[F:45])=[CH:39][C:38]=2[Cl:48])[N:28]=1)#[N:26].O>C(Cl)Cl>[C:25]([C:27]1[C:31]([CH:32]2[CH2:35][C:34](=[C:20]([Br:24])[Br:21])[CH2:33]2)=[CH:30][N:29]([C:37]2[C:38]([Cl:48])=[CH:39][C:40]([C:44]([F:45])([F:46])[F:47])=[CH:41][C:42]=2[Cl:43])[N:28]=1)#[N:26]
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=C(Br)Br)C1
Temperature: -10 °C
Yield: 81.9 %

Procedure:
Triphenylphosphine (560 mg, 2.14 mmol) was dissolved in 2 ml anhydrous DCM and cooled to -10° C. Carbon tetrabromide (355 mg, 1.07 mmol in 2 ml DCM) was added dropwise to the cooled solution, producing an amber colour. 3-Cyano-4-(3-oxocyclobutyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (200 mg, 0.53 mmol, Example 3) in DCM (2 ml) was added dropwise whereupon the reaction mixture assumed a brown colour. The reaction mixture was warmed to room temperature. After 0.5 hr the mixture was poured into water (20 ml) and extracted with DCM (3×20 ml). The combined organics were washed (brine), dried (Na2SO4), filtered and the solvent removed in vacuo to leave a brown solid. This was purified by silica chromatography (eluting with 50% DCM/hexane) to yield 230 mg of the title compound as a white solid.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].N1C=CC=CC=1.Cl[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18].C1(C)C=CC=CC=1.C(=O)=O.CC(C)=O>ClCCl>[CH:20]([O:19][C:17]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])=[O:18])([CH3:22])[CH3:21]
Reactant: CC(C)OC(=O)Cl
Reactant: O=Cc1ccccc1O
Agent: O=C=O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)Oc1ccccc1C=O
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of salicylaldehyde (10.39 g, 85.08 mmol) and pyridine (7.57 mL, 1.1 eq.) in dichloromethane (40 mL) in a 250 mL round-bottom flask was added a solution of 1M isopropyl chloroformate in toluene (93.60 mL, 1.1 eq.) slowly in 20 minutes to maintain the internal temperature below −25° C. using a cold bath of dry ice/acetone. White precipitate began to form during the addition and more precipitate was seen after the addition was complete. The mixture was removed from the cold bath and stirred for 2 hours with the application of a slow increase of temperature. Subsequently, the reaction mixture was evaporated to half the volume on a rotary evaporator, diluted with ethyl acetate (50 mL), washed with ice cold water (2×100 mL), 1N NaOH (3×50 mL), ice water (2×50 mL) and cold brine (1×100 mL), dried over anhydrous MgSO4 and evaporated on a rotary evaporator to produce 15.85 g (88%) of yellow oil. The carbonate (10.52 g) was distilled in high vacuum to yield 9.32 g of colorless oil (b.p. 101-103° C./0.8 torr). 1H NMR (300 MHz, CDCl3): δ 10.22 (s, 1H), 7.92 (dd, J=2.1, 7.5 Hz, 1H), 7.68 (dt, J=2.1, 7.5 Hz, 1H),7.47 (t, J=7.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 5.04 (m, 1H), 1.45 (d, J=6.3 Hz, 6H).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[CH:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH:15]3OCC[O:26][CH:16]32)[CH2:8]1)C.C(O)(=O)C(C(C(O)=O)O)O.O>O1CCOCC1>[CH:4]([CH2:5][O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[CH:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:26])[CH2:8]1)=[O:3]
Reactant: CCOC(CO[C@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@]2(C)C4OCCOC4C[C@@H]32)C1)OCC
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](OCC=O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 84.7 %

Procedure:
A solution of 7.2 g of 3β-(2,2-diethoxyethoxy)-17-ethylenedioxy-androstane, in 250 ml of dioxane and 250 ml of a saturated solution of tartaric acid was heated at 70° C. for 2 hrs in a nitrogen atmosphere, 100 ml of water were then added and the residue was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using as eluant n-hexane/ethyl acetate 70/30 to give 4.5 g of 3β-formylmethoxy-androstan-17-one as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](I)[CH:8]=[C:7]([I:12])[C:6]=1[O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21](B(O)O)=[CH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+].Cl>C(COC)OC.O.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>[C:1]([C:5]1[CH:10]=[C:9]([C:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH2:22])[CH:8]=[C:7]([I:12])[C:6]=1[O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(I)cc(I)cc1C(C)(C)C
Reactant: C=C(B(O)O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: C=C(c1ccccc1)c1cc(I)c(OC)c(C(C)(C)C)c1
Temperature: 100 °C

Procedure:
A solution of 1-tert-butyl-3,5-diiodo-2-methoxybenzene (4.94 g, 11.87 mmol) in dimethoxyethane (50 mL) and water (30 mL) was treated with 1-phenylvinylboronic acid (2.283 g, 15.43 mmol), tetrakis(triphenylphosphine)palladium(0) (0.686 g, 0.593 mmol) and sodium bicarbonate (2.492 g, 29.7 mmol) followed by heating at 100° C. for 3 hours. 1 N HCl was added and the mixture was extracted with ethyl acetate, then dried (Na2SO4), filtered and concentrated in vacuo to give crude product which was purified by silica gel flash chromatography eluting with 50:1 hexanes/ethyl acetate to give the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[C:5]=2[O:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.C(Cl)Cl.Cl.[CH3:24][NH:25][O:26][CH3:27]>C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+].O>[CH3:27][O:26][N:25]([CH3:24])[C:13](=[O:15])/[CH:12]=[CH:11]/[C:10]1[C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)/C=C/c1cccc2c1OCCO2
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)/C=C/c1cccc2c1OCCO2

Procedure:
A mixture of (trans)-3-(2,3-dihydrobenzodioxin-5-yl)propenoic acid (9.83 g, 47.7 mmol), thionyl chloride (20 mL), and CH2Cl2 (75 mL) was heated to reflux for 1 hr, and then concentrated in vacuo to give a yellow-green solid. This material was dissolved in ethyl acetate (75 mL), and a solution of N,O-dimethylhydroxylamine hydrochloride (9.5 g) in saturated Na2CO3 (100 mL) was added with stirring. The mixture was stirred for 90 min and then diluted with water and ethyl acetate. The ethyl acetate layer was separated and washed twice with water and twice with saturated Na2CO3. The ethyl acetate layer was concentrated in vacuo to give a brown oil. This crude product was chromatographed on silica gel using 1:1 ethyl acetate/methylene chloride as the eluent to give a clear oil that crystallized upon standing (11.1 g, 93.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:19][C:20]#[CH:21])[C:10](=[O:22])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.I[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[NH:32]C(=O)OC(C)(C)C.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>CN(C=O)C.ClCCl.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(OCC)(=O)C>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:19][C:20]3[NH:32][C:31]4[CH:30]=[CH:29][N:28]=[CH:27][C:26]=4[CH:21]=3)[C:10](=[O:22])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Reactant: C#CCN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Agent: I[Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2cc3cnccc3[nH]2)c2ccccc2C1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
57 mg (0.13 mmol) of 4-(4-chlorobenzoyl)-1-(2-propynyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on obtained in step 1 and 50 mg (0.16 mmol) of t-butyl (3-iodopyridin-4-yl)carbamate were dissolved in 5 ml of DMF. 5.6 mg (0.08 mmol) of bis(triphenylphosphine)palladium (II), 1 mg (0.005 mmol) of copper iodide and 0.09 ml (0.64 mmol) of triethylamine were added to the obtained solution, and they were stirred at 100° C. for 1-5 hours. The reaction solution was cooled to 50° C. 0.05 ml (0.32 mmol) of DBU was added thereto, and they were stirred at 50° C. for 30 minutes and then at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 10 ml of dichloromethane. 1.5 ml of trifluoroacetic acid was added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: Cl.O.[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>CO.[Fe]>[Cl:3][C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[NH2:10]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(Cl)c1
Agent: [Fe]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: Nc1ccc(N2CCOCC2)c(Cl)c1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a mixture of concentrated hydrochloric acid (1.0 mL) and water (50 mL) was added iron powder (7.55 g, 135 mmol) in one portion and the mixture was stirred at 65° C. for 15 min. The aqueous layer of the mixture was poured out and a solution of 4-(2-chloro-4-nitrophenyl)morpholine (3.28 g, 13.5 mmol) in MeOH (50 mL) was added to the above processed iron powder. The mixture was acidified to pH 3 with hydrochloric acid and stirred further at 65° C. for 45 min. The mixture was then cooled to rt, adjusted to pH 10 with Et3N and filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (150 mL) and the solution was washed with water (100 mL×3) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (2.05 g, 71%).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[C:13]([N:18]1[C@@H:22]([CH3:23])[C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:20][C:19]1=[O:30])(=[O:17])[CH2:14][CH2:15][CH3:16].C[C@H]1[C@@H](C2C=CC=CC=2)OC(=O)N1.Br[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=1[CH:54]=[CH2:55]>C1COCC1>[CH3:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([CH2:45][C@@H:14]([CH2:15][CH3:16])[C:13]([N:18]2[C@@H:22]([CH3:23])[C@@H:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:20][C:19]2=[O:30])=[O:17])=[C:47]([CH:54]=[CH2:55])[CH:48]=1
Reactant: CCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Reactant: C=Cc1cc(OC)ccc1CBr
Agent: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=Cc1cc(OC)ccc1C[C@@H](CC)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (21.3 mL, 53.3 mmol, 2.5 M in hexane) is added to a solution of diisopropylamine (8.2 mL, 58.1 mmol) in THF (150 mL) at −78° C. and the mixture is stirred at −78° C. for 10 min. A solution of (4S,5R)-3-butyryl-4-methyl-5-phenyloxazolidin-2-one (11.99 g, 48.5 mmol, prepared from (4S,5R)-4-methyl-5-phenyloxazolidin-2-one based on the procedure described in Tetrahedron Letters, 1986, 27, page 3311-3314) in THF (50 mL) is added. The mixture is stirred at −78° C. for 30 min. Finally, a solution of 1-bromomethyl-4-methoxy-2-vinylbenzene (11.1 g, crude) in THF (30 mL) is added. The mixture is stirred at −78° C. for 10 min and warmed to RT over 1 h and is continued to be stirred at RT for 15 h. The mixture is partitioned between EtOAc and sat. NH4Cl solution. The organic extract is dried with MgSO4, concentrated and purified by chromatography to give the title compound as an oil: 1H NMR (CDCl3) δ 0.68 (d, J=7 Hz, 3H), 0.95 (t, J=7 Hz, 3H), 1.52-1.59 (m, 1H), 1.73-1.79 (m, 1H), 2.80-2.85 (m, 1H), 2.98-3.04 (m, 1H), 3.78 (s, 3H), 4.14-4.20 (m, 1H), 4.70-4.75 (m, 1H), 5.34 (dd, J=1.3, 11 Hz, 1H), 5.57 (d, J=7.3 Hz, 1H), 5.63 (dd, J=1.3, 17 Hz, 1H), 6.72 (dd, J=2.5, 8 Hz, 1H), 6.99 (d, J=2.8 Hz, 1H), 7.04 (dd, J=11, 17 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 7.21-7.24 (m, 2H), 7.35-7.40 (m, 3H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH2:14][N:15](C(=O)C)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[OH:1][NH:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH2:14][N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:27]([CH3:26])(=[O:29])=[O:28])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N(Cc1ccccc1)Cc1ccc2cc(C(=O)NO)sc2c1
Product: CS(=O)(=O)N(Cc1ccccc1)Cc1ccc2cc(C(=O)NO)sc2c1

Procedure:
The title compound was prepared in procedures similar to those described for the preparation of 6-[(acetyl-benzyl-amino)-methyl]-benzo[b]thiophene-2-carboxylic acid hydroxyamide. Methanesulfonyl chloride was used instead of acetic anhydride for the preparation of this title compound. 1H NMR (DMSO-d6, 200 MHz) δ 11.46 (brs, 1H), 9.29 (brs, 1H), 7.90-7.76 (m, 3H), 7.36-7.16 (m, 6H), 4.43 (s, 2H), 4.33 (s, 2H), 2.99 (s, 3H). MS (EI): cal'd 389.1 (M−H−), exp 389.2 (M−H−).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28](O)[CH:27]=[N:26]1)([CH3:24])([CH3:23])[CH3:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][O:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:15]=2)[CH:27]=[N:26]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCOCc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)n1ncc(OCc2ccc(COCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.4 %

Procedure:
To solution of the product of Example 5C (437 mg, 1.48 mmol) and 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (250 mg, 1.23 mmol) dissolved in anhydrous THF (12 mL) was added solid PPh3 (485 mg, 1.85 mmol) and diisopropyl azodicarboxylate (DIAD, 0.358 mL, 1.85 mmol). After completion of addition the reaction mixture continued to stir at room temperature. After 20 hours, the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate) to provide the desired product 528 mg, 1.10 mmol) in 89% yield. 1H (CDCl3 7.70 (1H, s), 7.38 (4H, m), 5.30 (2H, s), 4.58, 600 MHz): δ (2H, s), 3.80 (2H, t, J=5.4 Hz), 3.57 (2H, t, J=5.4 Hz), 1.63 (9H, br s), 0.90 (9H, s), 0.07 (6H, s); 13C (CDCl3159.0, 153.7, 138.8, 134.4, 128.3, 127.3, 150 MHz): δ 125.1, 118.5, 72.8, 71.7, 71.6, 66.4, 61.9, 29.7, 27.9, 25.6, −5.1.; HRMS calcd for C24H37ClN2O4Si: 481.228389, found 481.2282.