Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[CH3:18].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH2:21]([O:1][C:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[CH3:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCC(C)c1cc(Br)c2nc(C)c(C)c(O)c2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1cc(Br)c2nc(C)c(C)c(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 Grams of 4-hydroxy-6-s-butyl-8-bromo-2,3-dimethylquinoline synthesized in the same way as that described in Example 1 was suspended in 20 ml of dimethylformamide, to which 700 mg of 60% sodium hydride was added under cooling with ice and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added dropwise 3 g of benzyl bromide under cooling with ice and the mixture was allowed to react at room temperature overnight. After the addition of 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate overnight. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane to obtain 2.5 g of 4-benzyloxy-6-s-butyl-8-bromo-2,3-dimethylquinoline. 2.5 Grams of the thus-obtained 4-benzyloxy-6-s-butyl-8-bromo-2,3-dimethylquinoline was dissolved in 25 ml of anhydrous tetrahydrofuran and cooled to −78° C., to which 2.8 ml of a 2.5 M solution of n-butyl lithium in n-hexane was added dropwise and the mixture was stirred for 10 minutes. One ml of methyl formate dissolved in 2 ml of anhydrous tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at 0° C. for 30 minutes. After the addition of 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and a saturated brine and then dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (20:1) to obtain 800 mg of 4-benzyloxy-6-s-butyl-8-formyl-2,3-dimethylquinoline.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][CH2:30][OH:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:33].[Na+]>N([O-])=O.[Na+]>[OH:31][CH2:30][CH2:29][CH2:28][C@@:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][C:17](=[O:32])[N:16]([C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:33])[NH:7][CH:6]=3)=[CH:13][CH:12]=2)[CH3:15])[CH2:21][CH2:20]1
Reactant: [OH-]
Reactant: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: O=N[O-]
Agent: [Na+]
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl -1,3-oxazinan-2-one (40 mg, 0.09 mmol.) was dissolved in 3.5 MH2SO4 (10 mL), and 2 M NaNO2 (10 mL) was added at 0° C. The reaction mixture was stirred at rt for 2 h and treated with NaOH solution. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the residue, which was purified by preparative HPLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). LC-MS Method 2 tR=1.66, min, m/z=433, 455; 1H NMR (CDCl3): 1.36 (m, 2H), 1.50 (m, 3H), 1.68 (m, 2H), 1.92 (m, 2H), 2.10-2.30 (m, 3H), 2.84 (m, 1H), 3.50 (m, 2H), 5.12 (m, 1H), 6.62 (m, 1H), 6.86 (m, 2H), 7.08 (m, 2H), 7.18-7.32 (m, 5H), 7.46 (m, 1H), 7.62 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5](Cl)[C:6](=O)[CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[S:28])=[CH:25][CH:24]=1>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[S:28][C:27]([C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:32])([F:21])[F:33])=[CH:31][CH:30]=2)=[N:29][C:6]=1[CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20])[CH3:2]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)C(=O)CCCOCc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CCCOCc1ccccc1
Yield: 66.5 %

Procedure:
To a solution of 1.15 g of 6-benzyloxy-2-chloro-3-oxo-hexanoic acid ethyl ester in 10 ml of ethanol was added 0.932 g of 4-(trifluoromethyl)thiobenzamide. The reaction mixture was refluxed overnight. The solvent was removed under reduced pressure. The resulting residue was taken into ethyl acetate, washed with water. The aqueous layer was separated and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 90/ethyl acetate 10) to give 1.15 g of 4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.S(Cl)([Cl:21])(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:21])[CH:10]=[N:9]1
Reactant: CC(C(=O)O)c1ccc(-n2cccn2)c(Cl)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 91.2 %

Procedure:
2.5 g (10 mmoles) of 2-[3-chloro-4-(pyrazol-1-yl)phenyl]propionic acid are dissolved in 30 ml of methylene chloride. A solution of 2.01 g (15 mmoles) of sulfuryl chloride in 10 ml of chloroform is added dropwise, with cooling to the resulting solution; heating is effected gradually to room temperature; and this is followed by boiling under reflux for 2 hours. The reaction solution is allowed to cool; the solvent is distilled off; 50 ml of 2 N solution of sodium hydroxide are added to the thus-obtained residue, and boiling up is effected for a few minutes. The reaction solution is extracted with diethyl ether and then acidified with hydrochloric acid. After renewed extraction with diethyl ether, the combined ether phases are dried and evaporated to produce 2.6 g (90% of theory) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid, m.p. 102° to 103° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[SH:13].[C:14](=S)=[S:15].[OH-].[K+]>CCO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[CH:5][C:4]2[S:13][C:14]([SH:15])=[N:2][C:3]=2[CH:8]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)c1ccc2sc(S)nc2c1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
Into a 25 ml round bottomed flask were added 2-amino-4-(trifluoromethyl)benzenethiol hydrochloride (107 mg, 0.43 mmol), CS2 (331 mg, 4.35 mmol), aqueous KOH (127 mg, 2.3 mmol), and EtOH (5 ml). The solution was refluxed under Ar for 2 h, cooled to rt, then treated with Amberlite IR-120(H+) (2 g, 3.8 mmol). The solution was filtered and concentrated to afford the title compound as a white crystalline solid (73.4 mg, 67%). 1H NMR (DMSO-d6) δ=7.46 (s, 1H), 7.61 (d, 1H), 7.93 (d, 1H), 13.99 (br s, 1H); ESIMS: m/z 234 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12]OS(C)(=O)=O)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1)[CH2:22][C:23]#[CH:24].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>ClCCl.C(OCC)(=O)C>[CH2:38]([N:40]([CH2:12][C:8]1[N:7]([CH3:18])[C:6](=[O:19])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([CH2:20][N:21]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:27][CH:26]=3)[CH2:22][C:23]#[CH:24])[CH:4]=2)[N:9]=1)[CH2:41][CH3:42])[CH3:39]
Reactant: CCNCC
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(COS(C)(=O)=O)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C#CCN(Cc1cc2c(=O)n(C)c(CN(CC)CC)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred under argon solution of tert-butyl 4-[N-[7-chloro-2-methanesulphonyloxymethyl-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.230 g, 0.42 mmol) in anhydrous dichloromethane (10 ml) was added diethyl amine (0.306 g, 4.2 mmol). The yellow solution was then stirred at room temperature for 18 hours. The solution was then diluted with ethyl acetate (250 ml) and washed with 5% aqueous sodium carbonate solution (2×100 ml), brine (100 ml), and concentrated in vacuo. Purification by column chromatography, on gradient elution with methanol in dichloromethane (0 to 2%) afforded a white crispy solid which was triturated diethyl ether/hexanes (v/v, 1:2). The white solid was collected by filtration, washed with hexanes and dried in vacuo over P2O5 (0.202 g, 92%), mp 112-113° C.; 1H-NMR (DMSO-d6) 0.95 (t, J=6.9 Hz, 6H, 2×CH2CH3), 1.49 (s, 9H, But), 2.56 (q obscured, J=6.85 Hz, 4H, 2×CH2CH3), 3.62 (s, 3H, N3-Me), 3.70 (s, 2H, 2-CH2), 4.40 (s, 2H, CH2C≡C), 4.79 (s, 2H, 6-CH2), 6.78 (d, J=8.9 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.9 Hz, 2′,6′-ArH), 7.81, 7.86 (2×s, 2H, 5-H, 8-H); MS (FAB, m/z) 523, 525 [(M+H)+, 100%, 40% respectively; Cl isotopic pattern].
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[N:13]4[C:14]=3[C:10]([C:11](=[O:25])[NH:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[N:13]4[C:14]=3[C:10]([C:11]([O:25][CH3:27])=[N:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1noc(C)c1-c1ccc2c(=O)[nH]n3c2c1OCC3c1ccccn1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1nn2c3c(c(-c4c(C)noc4C)ccc13)OCC2c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one (0.03 g, 0.086 mmol) in N,N-dimethylformamide (0.24 mL) at 0° C. was treated with potassium carbonate (0.024 g, 0.172 mmol) followed by dropwise addition of 0.2 M methyl iodide in N,N-dimethylformamide (0.517 mL, 0.103 mmol) and stirred at 0° C. for 30 min. The ice bath was removed and the reaction mixture was stirred for 1 h. The reaction mixture was treated with water (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated and washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give a colorless residue. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) gave Example 6 (10 mg, 30%, first peak to elute) and Example 7 (8 mg, 20%, second peak to elute). Example 6: 1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J=4.4 Hz, 1H), 7.86-7.71 (m, 1H), 7.38-7.29 (m, 1H), 7.29-7.21 (m, 2H), 7.00 (d, J=8.0 Hz, 1H), 5.14 (dd, J=3.4 Hz, 1H), 4.93 (d, J=3.5 Hz, 2H), 3.08 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H); LCMS calculated for C20H19N4O3 (M+H)+: m/z=363.1. found: 363.1. Example 7: 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=4.1 Hz, 1H), 7.82-7.68 (m, 1H), 7.33 (dd, J=7.0, 5.2 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 5.76-5.66 (m, 1H), 4.93-4.73 (m, 2H), 3.99 (s, 3H), 2.27 (s, 3H), 2.11 (s, 3H); LCMS calculated for C20H19N4O3 (M+H)+: m/z=363.1. found: 363.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1Cl)([O-:3])=[O:2].[CH:18]([NH2:22])([CH2:20][CH3:21])[CH3:19].C1(C)C=CC=CC=1>C(O)C>[CH:18]([NH:22][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH2:20][CH3:21])[CH3:19]
Reactant: CCC(C)N
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
One gram of 2,6-dinitro-4-t-butylchlorobenzene was allowed to react with one gram of sec-butylamine by adding the amine dropwise to a refluxing mixture of 50 ml. dry toluene, and the 2,6-dinitro-4-t-butylchlorobenzene. After complete addition, the mixture was refluxed eight hours, cooled to room temperature, the amine hydrochloride filtered off, and toluene and unreacted amine were removed under reduced pressure. The thick material that resulted was dissolved in hot ethanol and the product was crystallized upon cooling to yield N-sec-butyl-2,6-dinitro-4-t-butylaniline melting at 60°-62° C.
Reaction SMILES: O=[C:2]([C:9]1SC=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7]C)=O.S1C=CC=C1C1C=CN=C(N)N=1.C[C:27]1([CH3:35])[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])O1.COC1C=CC(C(O)=O)=CC=1>>[O:34]=[C:29]([C:9]1[CH:2]=[CH:3][C:4]([O:6][CH3:7])=[CH:12][CH:13]=1)[CH2:30][C:31]([O:32][CH2:27][CH3:35])=[O:33]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(=O)CC(=O)c1cccs1
Agent: COc1ccc(C(=O)O)cc1
Agent: Nc1nccc(-c2cccs2)n1
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1

Procedure:
This material is prepared by a method analogous to that described for preparation of ethyl 3-oxo-3-(2-thienyl)propanoate in preparation of 1D, starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and 4-methoxybenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:14][N:15]([CH3:17])[CH3:16])[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.Cl[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[N:14][N:15]([CH3:17])[CH3:16])[N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:22][CH:23]=1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: CN(C)N=C(c1ccccc1O)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)N=C(c1ccccc1OCOc1ccc(Cl)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.7 %

Procedure:
To a solution of the Compound No. 13 (0.20 g, 0.869 mmol) obtained in Example 13 in N,N-dimethylformamide (3 ml) were added α,4-dichloroanisole (0.175 g, 0.989 mmol) and potassium carbonate (0.17 g, 1.23 mmol), and the mixture was stirred at room temperature for 20 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object compound (0.202 g, 0.545 mmol, yield 63%).
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[C:31]2=[O:38])[CH:27]=[CH:28][CH:29]=1.[CH3:39][O:40][CH2:41]I>C1COCC1>[CH3:39][O:40][CH2:41][C:30]1([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)[CH2:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[C:31]1=[O:38]
Reactant: COCI
Reactant: COc1cccc(C2CCCCN(C)C2=O)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCC1(c2cccc(OC)c2)CCCCN(C)C1=O
Reaction time: 1 h

Procedure:
To 1.6 M n-BuLi in hexane (3.38 mL, 5.42 mmol) at 0° C. was added a solution of 2,2,6,6-tetramethyl piperidine (0.91 mL, 5.42 mmol) in anh. THF (10 mL) over 5 min. A solution of 3-(3-methoxy-phenyl)-1-methyl-azepan-2-one (as described in Example 4, Step A) (0.632 g, 2.71 mmol) in anhydrous THF (10 mL) was added and stirred OC for 1 h. Iodomethyl methyl ether (0.275 mL, 3.25 mmol) was added. After stirring for 30 min, the reaction was quenched with H2O, concentrated in vacuo, diluted with EtOAc, washed with 5N HCl (100 mL), water and brine. The organic layer was dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([NH:33][CH2:34][CH:35]5[CH2:37][CH2:36]5)[S:31][CH:32]=4)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:29]=[C:30]([NH:33][CH2:34][CH:35]3[CH2:37][CH2:36]3)[S:31][CH:32]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ccc(-c4csc(NCC5CC5)n4)cc3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(c1CSc1ccc(-c3csc(NCC4CC4)n3)cc1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-{4-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-phenylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.305 g, 0.548 mmol) in dry DCM (12.6 mL) at room temperature add trifluoroacetic acid (12.6 mL) and stir the solution at room temperature overnight. Concentrate in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 DCM/2M ammonia in methanol over 33 min; 95:5 to 90:10 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 7-chloro-6-{4-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-phenylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.215 g, 86%) as an off-white foam.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1C(=O)[C@@H](Br)[C@H](O)COCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-]=[N+]=[N-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](Br)[C@H](O)COCc1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1NC(Cc2ccccc2)CO1
Temperature: 35 °C
Reaction time: 4 h

Procedure:
4(S)-3-[(2R, 3S)-2-Azido-4-benzyloxy-3-hydroxy-butyryl]-4-benzyl-oxazolidin-2-one. To a solution of 4(S)-benzyl-3-[(2S, 3R)-4-benzyloxy-2-bromo-3-hydroxy-butyryl]-oxazolidin-2-one (969 mg, 2.16 mmol) in dimethylformamide (9.0 mL) is added sodium azide (211 mg, 3.25 mmol) and the reaction mixture is stirred at 35° C. for 4 hr. The mixture is diluted with ethyl acetate and washed several times with water, brine and dried over Na2SO4. Filtration and removal of solvents under vacuo gives 4(S)-3-[(2R, 3R)-2-azido-4-benzyloxy-3-hydroxy-butyryl)]-4-benzyl-oxazolidin-2-one as an oil.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=[O:2].[C:13]12(O)[CH2:21][CH:17]([C:18]1([CH3:20])[CH3:19])[CH2:16][CH2:15][C:14]2([OH:23])[CH3:22].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.C1COCC1>[OH:23][C:14]1([CH3:22])[C:15](=[O:2])[CH2:16][CH:17]2[CH2:21][CH:13]1[C:18]2([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccccc1I(=O)=O
Reactant: CC1(O)CCC2CC1(O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(O)C(=O)CC2CC1C2(C)C
Yield: 86 %

Procedure:
o-Iodoxybenzoic acid I (420 mg; 1.5 mmol) was added under stirring in one portion to a solution of pinanediol (170 mg; 1 mmol) in DMSO (3.4 ml) and THF (2.9 ml) at 0° C. After 3 h the reaction was poured in 20 ml of a solution of Na2CO3 (10%) and extracted with diethyl ether (3×10 ml). The combined organic layers were dried over sodium sulfate. The organic solvent was distilled under vacuum. The residue was purified by chromatography (SiO2, dichloromethane) to give after trituration with n-hexane, 145 mg (86%) of 2-hydroxy-pinanone, mp 30°-32° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(OC)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.20 g, 0.006 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (4.06 g, 0.031 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-methoxy-phenoxy)-but-2-enoic acid ethyl ester (2.00 g, 0.006 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (1.12 g, 46%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1.[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[ClH:39].[OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4c([N+](=O)[O-])cccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3c([N+](=O)[O-])cccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(7-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.030 g, 0.058 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(7-nitro-1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.018 g, 62%).