Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].C(=O)(OC(C)(C)C)[O:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O.N1C=CN=C1.C(OCC)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C>[O:7]=[C:2]1[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9]
Reactant: O=C1COCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Morpholin-3-one (35 g, 346.2 mmol) was slurried in dry THF (350 ml). Tert-butoxycarbonyl tert-butyl carbonate (105.8 g, 111.4 mmol) was added, followed by DMAP (4.2 g, 34.6 mmol). The mixture began to degass rapidly over 30 minutes. The resulting orange solution was stirred at ambient temperature for 24 hrs. The mixture was then cooled in an ice bath and imidazole (23.57 g, 346.2 mmol) was added. After stirring for 30 minutes ethyl acetate (500 ml) was added. The organic phase was separated and washed with 1% (v/v) HCl (500 ml), then sat NaHCO3 (500 ml), then brine (200 ml), dried (MgSO4), filtered and concentrated. The crude was purified through a plug of silica gel, eluting with ethyl acetate. The filtrate was evaporated to give an oil. 40/60 pet ether (200 ml) was added slowly with stirring to generate a white solid. The mixture was aged for 30 minutes, cooled briefly in an ice bath and filtered, washing with 40/60 pet ether. Tert-butyl 3-oxomorpholine-4-carboxylate was obtained as a white solid which was dried under vacuum (52.7 g, 76%); 1H-NMR (CDCl3) 1.47 (9H, s), 3.68 (2H, m), 3.82 (2H, m), 4.15 (2H, s); MS ES(+) 145.8 (M+-tBu).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]1=[O:13].C([O-])([O-])=O.[K+].[K+].[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Br>CC(C)=O>[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26][O:12][C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[C:7](=[O:13])[CH:8]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1cc(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a solution of 1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one (from Step 2 EXAMPLE 107) (0.92 g, 4.2 mmol) and K2CO3 (1.2 g, 8.4 mmol) in acetone (62 mL) was added 2,4-difluorobenzyl bromide (1.3 g, 6.3 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled room temperature, concentrated under reduced pressure, and the residue was partitioned between water and EtOAc. The organic solution was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 95:5 methylene chloride/methanol) to provide 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one as a white solid (1.21 g, 84%): 1H NMR (300 MHz, CDCl3) δ 7.45-7.20 (m, 2H), 7.14 (d, J=8 Hz, 1H), 7.05-6.75 (m, 5H), 6.05 (d, J=3 Hz, 1H), 5.95 (dd, J=5, 3 Hz, 1H), 5.08 (s, 2H), 5.00 (s, 2H).
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:12]([CH:14]=[CH:15][C:16](O)=[O:17])=[O:13].ClC(OCC)=O.N>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:12](=[O:13])[CH:14]=[CH:15][C:16]([NH2:3])=[O:17])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CCN(CC)CC
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: NC(=O)C=CC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
28 ml of triethylamine was dissolved in 600 ml of chloroform, then 49g of 3-(3,4-dichlorobenzoyl)acrylic acid was added. The resulting solution was cooled to 0° C., and 42g of ethyl cloroformate was added. The mixture was warmed to 20° C., stirred for one hour, cooled to 0° C. and then held there while gaseous ammonia was passed into the solution until no further heat of reaction was noted. A precipitate that formed was collected, washed with water and then with acetone to give 4-(3,4-dichlorophenyl)-4-oxo-2-butenamide (4A), as a white solid, m.p.: 208° C. (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A 12 L 3-necked round-bottomed flask was charged with DMF (2L), 5-nitroindazole (200 g, 1.22 mol.) and potassium carbonate (186 g, 1.35 mol). Benzyl bromide (230 g, 1.35 mol) was then added to the stirred suspension at a rate as to maintain the temperature below 40° C. Once the addition was complete the mixture was heated to 75° C. for a further 8 hours, the reaction being monitored by TLC (SiO2, 1:1 ethyl acetate:hexanes). The reaction was then cooled to room temperature, water (2L) added and the resulting slurry stirred at room temperature for 0.5 h. The resulting yellow solids were filtered off and dried at 45° C. and 5 mm Hg vacuum for 48 h. This afforded 424 g of a 1.25:1 mixture of 1- and 2-benzyl-5-nitroindazoles as determined by HPLC analysis (Rt 1-benzyl=14.9 min, Rt 2-benzyl=14.1 min). This material was then split into four approximately 100 g batches and each batch dissolved in acetone (470 mL). Water (156 mL) was then added slowly as a steady stream. After stirring for an additional 1 hour at room temperature the resulting solids were filtered off and vacuum dried. This process afforded a combined total of 126 g (41%) of 1-benzyl-5-nitroindazole, which was 92.1% pure by HPLC analysis, the major contaminant being the 2-benzyl derivative.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1C.[CH2:10]([Li])CCC.[C:15](=[O:17])=[O:16].[OH-].[Na+]>CCCCCC.C(OCC)C.O1CCCC1>[F:8][C:6]1[C:5]([C:15]([OH:17])=[O:16])=[CH:4][CH:3]=[C:2]([F:1])[C:7]=1[CH3:10]
Reactant: [Li]CCCC
Reactant: Cc1ccc(F)cc1F
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(F)ccc(C(=O)O)c1F
Temperature: -50 °C
Reaction time: 20 h

Procedure:
Into a flask equipped with stirrer, dropping funnel, carbon dioxide condenser and gas inlet tube are charged 100 g. (0.78 mole) of 2,4-difluoro-toluene and 500 ml. of dry tetrahydrofuran. The system is flushed with dry nitrogen and cooled (carbon dioxide-acetone bath) to an internal temperature of -50°C. A 585 ml. solution of 15% n-butyllithium (0.935 mole n-butyl-lithium) in hexane is added dropwise into a flask. The resulting dark red-purple solution is maintained at -50°C. for about one hour, and then poured onto a slurry of about 1000 g. of powdered carbon dioxide and about 100 ml. of diethyl ether. After standing for about 20 hours at room temperature the residue is treated with 250 ml. of 2N sodium hydroxide. The caustic layer is washed with toluene, acidified with concentrated HCl, and the white precipitate which forms is recrystallized from hot chloroform to give 2,6-difluoro-m-toluic acid; m.p. 139°-140°C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10](Br)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1.[F-].[Cs+]>O1CCOCC1.C(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C(Br)C(=O)N1Cc1ccccc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(C2=CC(=O)N(Cc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromomaleic anhydride (1 g, 5.7 mmol) and benzyl amine (0.7 mL, 6.8 mmol) in acetic acid (15 mL) was warmed to 50° C. and stirred overnight. The reaction was then cooled to room temperature, diluted with CH2Cl2 (50 mL) and washed with NaHCO3 (3×25 mL) and brine (25 mL). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified using gradient flash chromatography (0-100% ethyl acetate in pet ether) to provide 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (18). 1H NMR (400 MHz, CDCl3) δ 4.71 (s, 2H), 6.87 (s, 2H), 7.26-7.37 (m, 5H). A stirred solution of 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (0.26 g, 1.0 mmol) and p-tolylboronic acid (0.16 g, 1.2 mmol) in dioxane (10 mL) was degassed with a stream of nitrogen for 10 minutes before being treated with CsF (0.39 g, 2.6 mmol) and C12Pd(dppf).CH2Cl2 (0.05 g, 0.06 mmol). The reaction was stirred at room temperature for 1 h then warmed to 40° C. for 1 h. The mixture was then cooled, diluted with CH2Cl2 (30 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified using gradient flash chromatography (0-10% ethyl acetate in pet ether) to provide the title compound 15.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>C1COCC1>[C:8]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([C:23]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=2)=[O:5])[CH:7]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: CON(C)C(=O)c1cccc(-c2ccccc2)c1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cccc(-c3ccccc3)c2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a solution of 38a (FIG. 2) (0.174 g, 0.72 mmol.) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 1.08 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1a as a white solid (43.8%). 1H NMR (CDCl3) δ 8.02 (t, 1H), 7.84-7.74 (m, 2H), 7.64-7.38 (m, 6H), 7.11 (s, 2H), 3.95 (s, 3H), 3.88 (s, 6H); MS (ESI) m/z 371.1 (M+Na)+.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].O.C([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[N:18][N:17]=[N:16]1)C=C>CN(C)C=O>[CH2:1]([N:16]1[N:17]=[N:18][C:19]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[N:15]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCn1nnnc1-c1ccc(-c2ccc(OCOC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1nnc(-c2ccc(-c3ccc(OCOC)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Allyl bromide (0.27 ml, 3.13 mmol) and cesium carbonate (1.02 g, 3.13 mmol) were added to a solution of the obtained compound in N,N-dimethylformamide (5 ml), and the mixture was stirred at room temperature for 1 hour. After water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1) to give a mixture of 1-allyl-5-(4′-methoxymethoxy-1,1′-biphenyl-4-yl)-1H-tetrazole and 2-allyl-5-(4′-methoxymethoxy-1,1′-biphenyl-4-yl)-2H-tetrazole (504 mg, two-step total yield: 71%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH3:10].C[Si]([C:15]#[N:16])(C)C>CO.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[NH2:10][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=1)[C:15]#[N:16]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccc(I)cc1
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Product: N#CC(N)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a stirred solution of 4-iodo-benzaldehyde (7.10 g) in methanol (25 ml) were added sequentially ammonia solution (35 ml, 7 M solution in methanol) and tetraisopropyl orthotitanate (10.9 ml) and the resulting mixture was stirred at r.t. for 2 h. Trimethylsilylcyanide (3.84 ml) was then added dropwise and stirring continued at r.t. for 22 hours. The reaction mixture was poured onto ice-water (100 ml) and after stirring the resulting mixture was filtered through celite, washing with ethyl acetate. The filtrate was concentrated in vacuo and the residue was taken up in ethyl acetate and washed sequentially with distilled water and with saturated brine. The organic phase was then dried over sodium sulphate and concentrated in vacuo to afford (RS)-amino-(4-iodo-phenyl)-acetonitrile (6.41 g, 81%) as a yellow solid. 1H NMR δ (CDCl3, 300 MHz): 7.76 (2H, d, J=7.8 Hz), 7.30 (2H, d, J=7.8 Hz), 4.87 (1H, brs), 1.94 (2H, brs).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].O.C([O-])(O)=O.[Na+]>CCOCC.CCOC(C)=O>[Br:14][CH2:11][C:3]1[C:2]([Cl:1])=[C:7]([CH2:8][CH3:9])[CH:6]=[CH:5][C:4]=1[Cl:10]
Reactant: CCc1ccc(Cl)c(CO)c1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: CCc1ccc(Cl)c(CBr)c1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
The required 2-bromomethyl-1,3-dichloro-4-ethyl-benzene was prepared as follows: To a mixture of 2′,4′-dichloroacetophenone (4.85 g; 25.66 mmol) suspended in diethylene glycol (20 mL) was added KOH (2.37 g; 35.92 mmol) and hydrazine hydrate (2.9 mL). The resulting mixture was heated at 100° C. (for 1 hour) and subsequently overnight, at 200° C. After cooling to RT, the mixture was partitioned between Et2O and water. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes) to afford the product: 2,4-dichloro-1-ethylbenzene (2.24 g). To a solution 2,2,6,6-tetramethylpiperidine (2.36 mL; 14 mmol), dissolved in THF (40 ml) was added a solution of n-BuLi in hexanes (5.6 mL; 2.50 mol/l; 14 mmol), at −78° C. The reaction mixture was stirred for 90 minutes, allowing the temperature to reach 0° C. Subsequently, a solution of 2,4-dichloro-1-ethylbenzene (2.23 g; 12.74 mmol), dissolved in THF (5 mL) was added at −78° C. The resulting mixture was stirred for 2.5 hours. Subsequently, DMF (1.48 mL; 19.11 mmol) was added dropwise and the resulting mixture was stirred for 30 minutes. The reaction was quenched by the addition of a saturated aqueous NH4Cl solution, at −50° C. The resulting mixture was extracted with Et2O. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to afford the crude 2,6-dichloro-3-ethylbenzaldehyde, which was redissolved in MeOH (100 mL). Subsequently, NaBH4 (1.45 g; 38.22 mmol) was added, in small portions, at 0° C. After the addition was complete the mixture was allowed to warm to RT and stirred for one hour. Subsequently, the mixture was cooled to 0° C., water was added, and the MeOH evaporated in vacuo. To the aqueous solution was added a 5% aqueous NaHCO3 solution and Et2O. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:7 followed by 1:1) to afford (2,6-dichloro-3-ethylphenyl)methanol (2.11 g). To a solution of (2,6-dichloro-3-ethylphenyl)methanol (0.79 g; 3.85 mmol) in Et2O (25 mL) was added dropwise PBr3 (0.47 ml; 5.01 mmol), at 0° C., and the resulting mixture was stirred overnight, at RT. Subsequently, water was added, at 0° C., followed by EtOAc en 5% aqueous NaHCO3. The layers were separated and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo to afford 2-bromomethyl-1,3-dichloro-4-ethylbenzene (0.57 g), which was used as such.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.C=O.[BH3-][C:32]#N.[Na+]>CO.O>[CH3:2][N:3]([CH3:32])[CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-[(carbamoylmethoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (115 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (4 mL) cooled down to 0° C. was added hydrochloric acid (12 M, 0.5 mL). The resulting solution was stirred for 1 h at 0° C. and concentrated in vacuo to give 2-[[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide hydrochloride (100 mg, crude) as a light yellow solid. The crude hydrochloride (100 mg) dissolved in methanol (3 mL) was added HCHO (37%, 0.5 mL) and stirred for 1 h at 0° C. Then NaBH3CN (44.35 mg, 0.71 mmol) was added and the resulting solution was stirred for 2 h at room temperature. The reaction mixture was diluted with water, extracted with 3×20 mL of chloroform/i-PrOH. The combined organic layers were concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 53.0% in 13 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide (35 mg) as a white solid. MS (ES): m/z 405 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (1H, s), 5.28-5.21 (1H, m), 3.94-3.88 (3H, m), 3.61-3.56 (2H, m), 3.14-2.97 (2H, m), 2.67-2.54 (2H, m), 2.42-2.31 (10H, m), 2.02 (2H, d), 1.62-1.43 (4H, m).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]([CH2:30][CH2:31][OH:32])([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1.Cl>C(Cl)Cl.O>[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:32][CH2:31][CH2:30][C:18]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[O:19][CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH2:17]2)(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCOC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2(c3ccc(Cl)c(Cl)c3)CN(C(=O)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCO2)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of 2-[4-{[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol obtained in Reference Example 2 (2.3 g, 4.3 mmol) in methylene chloride (23 ml) were added dimethylaminopyridine (0.05 g, 0.43 mmol) and triethylamine (0.9 ml, 6.5 mmol) under a nitrogen stream, the resulting mixture was cooled to 0-5° C., and then a solution of 4-methylbenzenesulfonyl chloride (1.1 g, 5.6 mmol) in methylene chloride (7 ml) was further added dropwise at below 10° C. After stirring at room temperature for 8 hours, water (23 ml) and concentrated hydrochloric acid (1 ml) were added to the reaction mixture, and the resulting mixture was partitioned. The separated organic layer was washed with water (30 ml) and evaporated to dryness. The residue obtained was purified by chromatography on a silica gel column and then crystallized from a mixed solvent of toluene (3.2 ml) and methylcyclohexane (32 ml) under ice-cooling to afford the title compound [1.9 g, yield: 63.9%] as a colorless crystalline solid.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16]Br)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Sc1ccccn1
Reactant: O=C(Nc1nc(CBr)cs1)N(C1CCCCC1)C1CCCCC1
Product: O=C(Nc1nc(CSc2ccccn2)cs1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (L) from 1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and 2-mercaptopyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]1([CH3:54])[CH:45]=[CH:44][C:43]([C:46]2([CH2:52][NH2:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([NH:53][CH2:52][C:46]1([C:43]2[CH:42]=[CH:41][C:40]([CH3:54])=[CH:45][CH:44]=2)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1)=[O:6]
Reactant: Cc1ccc(C2(CN)CCCCC2)cc1
Reactant: Cc1ccc(-c2ccc(Cl)c(C(=O)O)c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C2(CNC(=O)c3cc(-c4ccc(C)nc4)ccc3Cl)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.9 %

Procedure:
To a solution of 2-chloro-5-(6-methyl-pyridin-3-yl)-benzoic acid (73 mg, 0.29 mmol) in N,N-dimethylformamide (4 mL) was added sequentially, stirring at room temperature for 10 minutes after each addition, 1-hydroxybenzotriazole (48 mg, 0.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62 mg, 0.32 mmol), C-(1-p-tolyl-cyclohexyl)-methylamine (60 mg, 0.29 mmol) and triethylamine (31 mg, 0.31 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography to afford the title compound (35 mg). LCMS (m/z) 433.2 M+1.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[C:17]1[S:18][CH:19]=[C:20]([Br:22])[N:21]=1>>[Br:22][C:20]1[N:21]=[C:17]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[S:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Brc1csc(Br)n1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc(Br)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42, using tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 2,4-dibromothiazole (0.124 g, 39%); MS: 377.3 (M+1).