Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:27]4[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-])=O)[CH:28]=4)[N:14]3[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#N.C[O-].[Na+].C(O)(=O)C>CO.CC(O)=O.[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:27]4[CH:32]=[CH:31][C:30]5[N:33]=[C:37]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=6)[NH:34][C:29]=5[CH:28]=4)[N:14]3[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3ccc(N)c([N+](=O)[O-])c3)cc3ccc(N4CCN(C)CC4)cc32)cc1
Reactant: N#Cc1ccccn1
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc4nc(-c5ccccn5)[nH]c4c3)cc3ccc(N4CCN(C)CC4)cc32)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 26.9 %

Procedure:
The 4-[6-(4-Methyl-piperazin-1-yl)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-2-nitro-phenylamine (0.5 g, 0.99 mmol), was dissolved in 7:3 MeOH/HOAc (100 ml), and hydrogenated in the presence of 5% palladium on carbon (100 mg), overnight. The solution was then filtered through celite, washed with methanol (50 ml), and evaporated. The resulting diamine was dissolved in methanol (20 ml). To this was added a solution of 2-cyanopyridine (154 mg, 1.5 mmol) that had been treated (immediately before) with sodium methoxide (0.15 mmol) in methanol (2 mL) at 40° C. for 1.5 hour under nitrogen. To this mixture, acetic acid (0.21 ml, 3.8 mmol) was added. This mixture was heated at 80° C. overnight under nitrogen followed by cooling to room temperature, and removing the solvents under reduced pressure. Next the residue treated with a 5% aqueous ammonia solution, incubated at 5° C. over one day, decanted the aqueous layer, washed well with water. Resulting light tan solid was isolated and washed with ether to give the product 150 mg (15% yield). The material while not completely pure, could be taken to next step.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].[CH2:7]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:45])[C@@H:19]([NH:29][C:30]([C:32]2[CH:37]=[C:36](Cl)[N:35]=[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:33]=2)=[O:31])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13]1)=[O:11])[CH3:8].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:7]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:45])[C@@H:19]([NH:29][C:30]([C:32]2[CH:37]=[C:36]([S:4][CH2:1][CH2:2][CH3:3])[N:35]=[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:33]=2)=[O:31])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: CCCS
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-propanethiol (11 μl) was added to a suspension of NaH (4 mg) in anhydrous DMF (0.3 ml) at 0° C. After 1 h stirring at 0° C., 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (50 mg) dissolved in DMF (0.1 ml) was added. The mixture was allowed to warm to RT and was stirred at RT until completion. A NaHCO3 solution was added and the resulting mixture was extracted with DCM. The org. phases were dried (Na2SO4) and evaporated off. The crude was directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Cl:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(OCc2ccccc2)ccc1Br
Reaction time: 23 h

Procedure:
To a mixture of 4-bromo-3-chlorophenol (2.5 g), potassium carbonate (2.165 g) and N,N-dimethylformamide (26 mL), benzyl chloride (1.8 mL) was added under cooling with ice. Raising the temperature to the ambient level, the system was stirred for 23 hours. The reaction mixture was poured in saturated saline solution and the product was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, and dried over anhydrous magnesium sulfate. Distilling the solvent off, the remaining crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=10:1) to provide 4-benzyloxy-1-bromo-2-chlorobenzene (3.029 g).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].Cl>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ncnc3cc[nH]c23)c(F)c1
Temperature: 120 °C
Yield: 85.6 %

Procedure:
To a suspension of 27 (0,400 g, 2,60 mmol) [G. B. Evans, R. H. Furneaux, et. al J. Org. Chem., 2001, 66, 17, 5723-57301] in diphenylether (25 ml) was added 2-fluoro-4-nitrophenol (614 mg, 3.90 mmol) and HCl (2N in Et2O) (0.19 ml, 3.90 mmol). The reaction mixture was heated at 120° C. for 4 hours, cooled to room temperature and concentrated under reduced pressure, to afford title compound 243 (610 mg, 86% yield) as a black solid. MS (m/z): 274.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:18]([O:25][C:26](=[O:28])[NH2:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:18]([O:25][C:26](=[O:28])[NH:27][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: Brc1cc(Br)cc(-c2nc3ccccc3o2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C(Nc1cc(Br)cc(-c2nc3ccccc3o2)c1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
2-(3,5-Dibromo-phenyl)-benzoxazole (0.4 g, 1.10 mmol), carbamic acid benzyl ester (0.17 g, 1.10 mmol), cesium carbonate (0.74 g, 2.30 mmol), Xantphos (46.0 mg, 0.08 mmol) and Pd(dba)2 (62.0 mg, 0.74 mmol) were placed into a dry two-neck flask, which was then flushed with nitrogen. 1,4-Dioxane (5.0 mL) was added into the flask, and the reaction mixture was degassed with argon at room temperature for 40 min. The mixture was heated to 60° C. and stirred for 18 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 5:1/hexanes:ethyl acetate to give (3-benzoxazol-2-yl-5-bromo-phenyl)-carbamic acid benzyl ester (0.22 g, 46%) as a yellow solid.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[NH:58]1[CH2:63][CH2:62][CH:61]([NH:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:74])([F:73])[F:72])[CH:66]=2)[CH2:60][CH2:59]1>CN(C)C=O.ClCCl.O1CCCC1>[F:74][C:71]([F:72])([F:73])[C:67]1[CH:66]=[C:65]([NH:64][CH:61]2[CH2:60][CH2:59][N:58]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:23])([F:2])[F:22])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:63][CH2:62]2)[CH:70]=[CH:69][CH:68]=1
Reactant: FC(F)(F)c1cccc(NC2CCNCC2)c1
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (26 mg; 0.08 mmol, prepared in accordance with Example 3), diisopropylethyl amine (26 μL; 0.15 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (28 mg; 0.08 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of piperidin-4-yl-(3-trifluoromethyl-phenyl)-amine hydrochloride (21 mg; 0.08 mmol, prepared in accordance with Example 80) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 4 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (14 mg; 0.03 mmol). The structure was confirmed using Protocol I-B. Calculated mass=543; observed mass=543; HPLC retention time=5.20 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[N-:16]=[N+:17]=[N-:18].[Na+]>CS(C)=O>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:16]=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCCCCCCCBr
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCCCCCCCCCN=[N+]=[N-]
Temperature: 66 °C
Yield: 97.4 %

Procedure:
A mixture of 13.3 g of methyl 11-bromoundecanoate and 3.12 g of sodium azide in 50 mL of DMSO was heated at 66° C. under nitrogen for 2 days. The reaction mixture was cooled down and mixed with 200 mL of ice water. The aqueous layer was extracted with ether (1×100 mL, subsequently 3×50 mL). The organic layers were combined, washed twice with 25 mL of brine and dried over Na2SO4. Removal of the solvents in vacuo gave 11.2 g of a yellow oil. Purification by column chromatography (silica gel; petroleum ether (40-60° C.)/ether=9:1 (v/v)) gave 10.94 g of the pure product as a colorless oil, which was stored at 4° C. to prevent degradation. 1H NMR (300 MHz, CDCl3): δ 3.65 (s, 3H); 3.24 (t, 2H, J=7.0 Hz); 2.29 (t, 2H, J=7.5 Hz); 1.65-1.53 (m, 2H); 1.42-1.21 (m, 14H) ppm. 13C NMR (75 MHz, CDCl3): δ 174.24; 51.44; 51.37; 34.04; 29.35; 29.27; 29.15; 29.07; 28.80; 26.66; 24.89 ppm. IR (neat, cm−1): 2929 (m); 2856 (m); 2096 (s); 1741 (s).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[CH3:18].[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][C:11]=1[CH3:18]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C=O)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(CO)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylbenzaldehyde (32 mg, 0.071 mmol) synthesized in Example 51 was dissolved in methanol (3.0 mL), and sodium borohydride (5 mg, 0.132 mmol) was added, followed by stirring at 0° C. for 4 hours under nitrogen atmosphere. The reaction solution was brought to room temperature, a saturated aqueous ammonium chloride solution (10 mL) was added, and extraction was carried out with ethyl acetate (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-75%) to afford the desired compound (26 mg, yield 81%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:23])=[C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:16]=2)[C:11](=[O:24])[N:10]([O:25]CC2C=CC=CC=2)[C:9]1=[O:33]>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:23])=[C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:16]=2)[C:11](=[O:24])[N:10]([OH:25])[C:9]1=[O:33]
Reactant: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Agent: [Pd]
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccccc2F)c(=O)n1O
Yield: 88.5 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.03 g) with 1-(2-fluorophenyl)-6-fluoro-3-benzyloxy-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example W-1, 0g, 0.22 mmol) provided 0.07 g of the title compound as a solid, mp 235-237° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:32]#[N:33])=[C:4]([C:21]2[CH:22]=[N:23][C:24]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:25][CH:26]=2)[C:5]([O:18][CH2:19][CH3:20])=[C:6]([CH:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH:7]=1.Cl>O1CCOCC1>[NH2:10][CH:8]([C:6]1[C:5]([O:18][CH2:19][CH3:20])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:30])[CH3:31])=[O:28])=[N:23][CH:22]=2)[C:3]([C:32]#[N:33])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1c(C(C)N)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The tert-butyl [1-(5-chloro-4-cyano-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxyphenyl)ethyl]carbamate from the above step (0.04 g, 0.085 mmol) was treated with 4 M HCl in dioxane (4 mL) and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo to give 5-{3-[1-aminoethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamide as a semi-solid residue (0.05 g, 100%). LCMS calculated for C19H22ClN4O2 (M+H)+: m/z=373.1. found: 373.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([N:25]2C(=O)C4C(=CC=CC=4)C2=O)=[N:20][CH:19]=[CH:18]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1c1nccc2cc(O[C@H]3CCCN(Cc4ccccc4)C3)ccc12
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1nccc2cc(O[C@H]3CCCN(Cc4ccccc4)C3)ccc12
Temperature: 50 °C

Procedure:
To a solution of the above (S)-2-[6-(1-benzylpiperidin-3-yloxy)isoquinolin-1-yl]-isoindole-1,3-dione (20 mg, 43 μmol) in ethanol (2 ml) was added hydrazine monohydrate (−3 μL, 65 μmol). The mixture was heated at 50° C. for 2 h then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give (S)-6-(1-benzylpiperidine-3-yloxy)isoquinolin-1-yl amine El-MS: m/z=334.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:1]
Reactant: OCc1nc2ccccc2s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.4 %

Procedure:
5.47 g of manganese dioxide were added at room temperature to a solution of 2.26 g of 2-hydroxymethylbenzothiazole in 20 ml of acetone. The resulting mixture was stirred under reflux for 5 hours, at the end of which time the temperature of the mixture was cooled to room temperature and the mixture was left to stand for 14 hours. A further 3.06 g of manganese dioxide were then added and the resulting mixture was stirred under reflux for 6 hours. At the end of this time, the reaction mixture was cooled to room temperature and then filtered. The resulting filtrate was concentrated by evaporation under reduced pressure, petroleum ether was added to the thus obtained crude crystalline solid and the mixture was filtered. The filtrate was then concentrated to about half its volume causing precipitation of a crystalline solid which was filtered off and dried in vacuo to give 432.6 mg (yield 19.3%) of the title compound as a solid having a melting point of 69° to 70° C.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:34][C:35]4[CH:44]=[C:43]5[C:38]([CH:39]=[CH:40][CH:41]=[N:42]5)=[CH:37][CH:36]=4)=[N:18][CH:19]=[C:20]([C@H:22]([N:24]4[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]4)[CH3:23])[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O.[C:64]([OH:70])([C:66]([F:69])([F:68])[F:67])=[O:65]>>[F:67][C:66]([F:69])([F:68])[C:64]([OH:70])=[O:65].[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:34][C:35]3[CH:44]=[C:43]4[C:38]([CH:39]=[CH:40][CH:41]=[N:42]4)=[CH:37][CH:36]=3)=[N:18][CH:19]=[C:20]([C@H:22]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)[CH3:23])[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4cccnc4c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cnc2Nc2ccc3cccnc3c2)n1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
A brown solution of (R)-N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)quinolin-7-amine (170.8 mg, 0.225 mmol) and trifluoromethanesulfonic acid (0.2 mL, 2.252 mmol) (10% v/v with TFA) in TFA (2.0 mL) was stirred at 75° C. for 1.5 h. The reaction mixture was subsequently cooled to 25° C. and concentrated in vacuo. The residue was taken up in CH2Cl2 (50 mL), and the resulting solution was washed with saturated aqueous sodium bicarbonate (40 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). All organic layers were then combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Luna 5 μm C18, 30×150 mm, 45 mL/min, 10 to 100% CH3CN/H2O (plus 0.1% TFA, both solvents)) to provide (R)-N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)quinolin-7-amine 2,2,2-trifluoroacetate (52.0 mg, 0.082 mmol, 36.5% yield) as a yellow-orange solid. 1H NMR (400 MHz, d4-MeOH) δ 9.52 (d, J=1.8 Hz, 1H), 9.18 (d, J=2.5 Hz, 1H), 8.99 (d, J=8.2 Hz, 1H), 8.96 (dd, J=5.6, 1.3 Hz, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.25 (d, J=9.2 Hz, 1H), 8.04 (dd, J=9.0, 2.0 Hz, 1H), 7.83 (dd, J=8.0, 5.7 Hz, 1H), 4.70 (q, J=7.0 Hz, 1H), 3.55 (br. s., 4H), 2.94 (s, 3H), 2.65 (s, 4H), 2.58 (s, 3H), 1.89 (d, J=6.8 Hz, 3H). 19F NMR (376 MHz, d4-MeOH) δ −77.36 (s, 3F). m/z (ESI, +ve) 520.2 (M+H)+.
Reaction SMILES: CI.[CH2:3](OCC)C.[Mg].[CH3:9][C:10]1([CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([CH3:18])([CH3:17])[C:11]1=[O:19]>>[CH3:3][C:11]1([OH:19])[C:12]([CH3:18])([CH3:17])[CH2:13][CH2:14][CH2:15][CH2:16][C:10]1([CH3:20])[CH3:9]
Reactant: CC1(C)CCCCC(C)(C)C1=O
Reactant: CCOCC
Agent: [Mg]
Solvent: CI
Product: CC1(C)CCCCC(C)(C)C1(C)O
Yield: 55.3 %

Procedure:
A mixed solution of methyl iodide (23.90 g, 0.16 moles)/dried diethyl ether (10 ml) was dropped into a mixture of magnesium (2.90 g, 0.12 moles)/dried diethyl ether (20 ml) in 1 hour while stirring under water-cooling conditions. The mixture was stirred for 48 hours at room temperature and subjected to separation by filtration. Into the resulting filtrate was dropped a mixed solution of 2,2,7,7-tetramethylcycloheptanone (16.80 g, 0.10 mole)/dried diethyl ether (30 ml) in 30 minutes while stirring at room temperature. The mixture was stirred at room temperature for 48 hours. The resulting reaction mixture was treated in the same manner as in Example 1 to obtain 10.20 g (yield 55.3%) of the captioned compound. This compound was a white solid having a woody, earthy camphoraceous and patchuli oil-like odor.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
Cis-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.46 g, 6.42 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.257 g, 6.42 mmol) dissolved in water (2 mL) was added over 5 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.4 mL, 6.53 mmol) was added over 1 min and stirring continued at −40° C. for 1 h 15 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 35 min. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. The residue was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-60% Acetonitrile in H2O/MeCN/Acetic Acid 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.62 g, 72%) was isolated as a colorless foam. 1H NMR (400 MHz, cd3od) δ 1.90-2.10 (m, 4H), 2.65-2.80 (m, 2H), 3.04 (p, 1H), 3.19-3.34 (m, 1H), 3.44 (s, 3H), 3.94 (ddd, 1H), 4.32-4.44 (m, 1H), 5.85 (s, 1H), 6.78-6.90 (m, 2H), 7.09-7.20 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:8]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]1=O.[C:20]1([CH2:26][C:27]([NH2:29])=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.CN(C)C=O.O>[CH2:26]([C:27]1[S:28][C:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=2[N:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=S)Cc1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCC(Br)C2=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)COc1cccc2c1CCc1sc(Cc3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 14 h
Yield: 21.5 %

Procedure:
A solution of ethyl [(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate (2.16 g, 6.61 mmol) and phenylthioacetamide (1.00 g, 6.61 mmol) in a mixture of ethanol (25 mL) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 14 hours and, then, refluxed for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate=1:5) to provide ethyl [(2-benzyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (540 mg). To a solution of this compound (0.54 g, 1.42 mmol) in a mixture of tetrahydrofuran (16 mL) and methanol (4 mL) was added 1N-hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to provide 320 mg of the title compound Yield 14%.