Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C=C(C(Cl)=O)C=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:39]=[C:40]([C:44]([N:46]=[C:47]=[S:48])=[O:45])[CH:41]=[CH:42][CH:43]=1>C1(C)C=CC=CC=1.C(O)C>[F:49][C:37]([F:36])([F:50])[C:38]1[CH:39]=[C:40]([C:44]([N:46]=[C:47]=[S:48])=[O:45])[CH:41]=[CH:42][CH:43]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:47]([NH:46][C:44](=[O:45])[C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:37]([F:36])([F:50])[F:49])[CH:39]=2)=[S:48])=[CH:31][CH:30]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C(N=C=S)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(C(F)(F)F)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
3-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 85%).
Reaction SMILES: [CH2:1]([N:8](C(OC(C)(C)C)=O)[CH2:9][CH:10]([O:29][CH3:30])[C:11]1[C:20]2[C:15](=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([C:25]([F:28])([F:27])[F:26])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:38]>O1CCOCC1>[ClH:38].[CH2:1]([NH:8][CH2:9][CH:10]([O:29][CH3:30])[C:11]1[C:20]2[C:15](=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([C:25]([F:28])([F:27])[F:26])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN(Cc1ccccc1)C(=O)OC(C)(C)C)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: Cl
Solvent: C1COCCO1
Product: COC(CNCc1ccccc1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To N-Benzyl-N-tert-butoxycarbonyl-β-methoxy-2,8-bis(trifluoromethyl)-4-quinolineethanamine (113 mg, 0.21 mmol) in dioxan (1 mL) was added HCl (4-M in dioxan, 0.25 mL, 1 mmol) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo, triturated with ether and filtered to give the title compound (54 mg, 60%) as a white solid: mp 232-233° C.; NMR δH (400 MHz, DMSO-d6) 3.17-3.41 (2H, m), 3.34 (3H, s), 4.19 (1H, d, J 13.8 Hz), 4.22 (1H, d, J 13.8 Hz), 5.78 (1H, dd, J 9.26, 2.1 Hz), 7.36-7.46 (3H, m), 7.53-7.62 (2H, m), 8.00 (1H, t, J 8.0 Hz), 8.03 (1H, s), 8.42 (1H, d, J 7.7 Hz), 8.80 (1H, d, J 8.62 Hz); Anal. Calcd for C21H18F6N2O.HCl: C, 54.26; H, 4.12; N, 6.02. Found C, 54.04; H, 4.30; N, 5.79.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](OB(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.O.C(O)C>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: OB(O)Oc1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccc(-c2ccc3ccccc3c2)c1
Reaction time: 7 h
Yield: 84.6 %

Procedure:
A mixture of 10.00 g (=47.33 mmol) of 2-bromonaphthalene, 7.95 g (=56.82 mmol) of 3-fluorophenylboric acid, 9.81 g (=70.98 mmol) of K2CO3, 3.81 g (=11.82 mmol) of tetrabutylammonium bromide, 1.00 g (=1.42 mmol) of dichlorobis(triphenylphosphine) palladium(II), 0.76 g (=2.84 mmol) of triphenylphosphine and a 100 ml mixed solvent of toluene/water/ethanol in a ratio of 1:1:1 was stirred for 7 hours with reflux. The reaction mixture obtained was extracted twice with toluene. The extract was washed thrice with water and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained black solid of 15.40 g was purified with silica gel chromatography using heptane/toluene in a ratio of 5:1 as the eluent, thereby obtaining a white solid of 10.98 g. The white solid was recrystallized with a mixed solvent of Solumix/heptane in a ratio of 1:1 to obtain 8.90 g of 2-(3-fluorophenyl)naphthalene as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH:17]1([NH2:23])CCC[CH2:19][CH2:18]1.C(#N)C=C>C1(C)C=CC=CC=1.C(O)(=O)C.COC1C=CC(O)=CC=1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH:7]([CH2:19][CH2:18][C:17]#[N:23])[C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NC1CCCCC1
Agent: COc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: C=CC#N
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(=O)C(CCC#N)C1
Temperature: 90 °C
Yield: 813.7 %

Procedure:
4-(dimethylamino)-4-phenylcyclohexanone (2.17 g, 10 mmol) was added to a solution of cyclohexylamine (109 mg, 1 mmol), glacial acetic acid (26 mg, 0.43 mmol) and 4-methoxyphenol (26 mg, 0.21 mmol) in 10 ml of toluol. The mixture was heated to 90° C. (bath temperature) and mixed with acrylonitrile (4 ml, 60.8 mmol) within 2 h. The batch was then heated to 120° C. After 3 h the heating was removed and the batch mixed with 1N NaOH (20 ml) after RT was reached. The mixture obtained was extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with water and then dried over MgSO4. The residue (2.2 g) obtained after removal of the solvent solidified upon standing and was mainly composed of the initial ketone and a more non-polar product compared to this. One of the two possible diastereoisomers of the ketone was obtained with a yield of 400 mg (14%) in the form of an oil by means of chromatographic purification [silica gel 60 G (10 g); cyclohexane/ethyl acetate 1:10 (120 ml)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:27]=[C:11]3[N:12]=[C:13]([CH3:26])[C:14]([C@H:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])=[C:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O[C:32]([CH3:35])([CH3:34])[CH3:33])(=O)C>C(Cl)Cl.CCOCC>[C:32]([O:25][C@@H:20]([C:14]1[C:13]([CH3:26])=[N:12][C:11]2[N:10]([N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:27]=2)[C:15]=1[CH2:16][CH:17]([CH3:19])[CH3:18])[C:21]([O:23][CH3:24])=[O:22])([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1CC(C)C
Reactant: CC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1CC(C)C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.059 g, 0.152 mmol) and tert-butyl acetate (1 ml, 7.40 mmol) in CH2Cl2 (3 mL) was added 70% perchloric aci (0.039 ml, 0.456 mmol) at rt. After 2 h, the reaction was diluted with Et2O (50 mL), washed with sat. Na2CO3 (2×5 mL), dried (Na2SO4), filtered and concentrated to give yellow solid which was purified by prep-HPLC to afford (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.0357 g, 0.080 mmol, 52.9% yield) as brown paste. 1H NMR (500 MHz, CDCl3) δ: 7.97 (t, J=1.7 Hz, 1H), 7.86 (dt, J=7.6, 1.3 Hz, 1H), 7.40-7.31 (m, 2H), 6.79 (s, 1H), 5.36 (s, 1H), 3.70 (s, 3H), 3.53 (dd, J=13.4, 7.6 Hz, 1H), 3.14 (dd, J=13.4, 7.0 Hz, 1H), 2.69 (s, 3H), 2.65-2.54 (m, 1H), 1.25 (s, 9H), 1.03 (d, J=6.7 Hz, 3H), 0.98 (d, J=6.7 Hz, 3H). LCMS (M+H) calcd for C24H31ClN3O3: 444.21. found: 444.3.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl.[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:17]=O)[CH2:12][CH2:11][CH2:10][CH2:9]1.C([BH3-])#N.[Na+]>CO>[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:17][NH:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1nc[nH]n1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2nc[nH]n2)cc1OC1CCCC1
Yield: 22.7 %

Procedure:
To a stirred solution of 3-amino-1,2,4-triazole (1.5 g, 0.018 mol), 7.5 ml of 1N HCl, and 50 ml of methanol was added 3-cyclopentyloxy-4-methoxybenzaldehyde (3.3 g, 0.015 mol) and sodium cyanoborohydride (0.945 g, 0.015 mol). A precipitate formed slowly and after 20 hours the precipitate was filtered and recrystallized from methanol (135 ml) to give 1.0 g (0.0034 mol, 23%) of the title compound, mp 203-204° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH:10](O)[C:11]([F:14])([F:13])[F:12])[N:4]([CH3:16])[C:3]=1[CH3:17].S(Cl)(Cl)=O.[BH4-].[Na+]>C(#N)C.CO>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH2:10][C:11]([F:12])([F:13])[F:14])[N:4]([CH3:16])[C:3]=1[CH3:17]
Reactant: Cc1c(Cl)c(=O)c(O)c(C(O)C(F)(F)F)n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: Cc1c(Cl)c(=O)c(O)c(CC(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
3-Chloro-5-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (300 mg, 1.10 mmol) was suspended in 10 mL of acetonitrile and thionyl chloride (398 μL, 5.50 mmol) was added dropwise. The reaction was stirred at room temperature. After 2 hours, the reaction was concentrated. The crude was diluted with 10 mL of methanol and sodium borohydride (329 mg, 8.80 mmol) was added in small portions. After 15 hours, the reaction was filtered and the filtrate was concentrated in vacuo. The resulting solid was dissolved in methanol and ethyl acetate added, filtered and concentrated. The crude product was purified by column chromatography on silica gel using a mixture of 30% EtOAc in MeOH as eluant. Fractions rich in product were combined and evaporated to dryness. The residue product was recrystallised from methanol/ethyl acetate to give 3-chloro-5-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (172 mg) as a white solid. Yield=61%; 1H NMR (MeOD-D4, 90 MHz) δ (ppm): 4.1 (q, J=9.0 Hz, 2H), 3.99 (s, 3H) and 2.77 (s, 3H); MS m/z 256 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)[CH3:2].[C:13]([O:17][C:18](=[O:23])[CH:19](Br)[CH2:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:23])[CH:19]([S:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:12])[N:7]=1)[CH2:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1csc(S)n1
Product: CCOC(=O)Cc1csc(SC(CC)C(=O)OC(C)(C)C)n1

Procedure:
The title compound was obtained by an operation similar to that of Example 2 and using (2-mercapto-1,3-thiazol-4-yl)acetic acid ethyl ester synthesized in Example 1 and 2-bromobutanoic acid tert-butyl ester to give 2-{[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]thio}butanoic acid tert-butyl ester, followed by operations similar to those of Examples 3, 4 and 34.
Reaction SMILES: [F:1][C@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH:12]=2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1>CC(C)=O>[F:1][C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH:12]=2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: C[C@]12CCC(=O)C=C1[C@H](F)C[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C=C1[C@@H](F)C[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
6β-Fluoroandrost-4,9(11)-diene-3,17-dione (IV, Example 9, 10.5 g) is suspended in acetone (50 ml) and stirred at 20°-25°. Anhydrous hydrochloric acid is bubbled through for approximately one min. After stirring at 20°-25° for 5.5 hr the mixture is cooled in an ice bath and filtered using suction filtration. The solids collected by filtration are rinsed with cold acetone to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)C=O.[O:28]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[OH:1][C:2]1[C:3]([C:8]([NH:39][C:38]2[CH:37]=[CH:36][C:35]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:41][CH:40]=2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ncccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1ncccc1O
Reaction time: 8 h
Yield: 40.5 %

Procedure:
3-Hydroxypicolinic acid (1.39 g, 10.0 mmol) and 1.95 g (12.0 mmol) of carbonyldiimidazole were mixed into anhydrous N,N-dimethylformamide (hereinafter referred to as “DMF”) to prepare a suspension (30 ml). An anhydrous DMF solution (25 ml) of 1.85 g (10.0 mmol) of 4-phenoxyaniline was added dropwise to this suspension, and the reaction was allowed to proceed at room temperature overnight. Water (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the dried organic layer was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 1.24 g (yield 41%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1>>[CH3:8][CH:4]1[NH:3][CH:2]([CH3:1])[CH2:7][N:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:5]1
Reactant: CC1CNCC(C)N1
Reactant: N#Cc1ccc(Cl)nc1
Product: CC1CN(c2ccc(C#N)cn2)CC(C)N1

Procedure:
This compound was synthesized from 2,6-dimethyl-piperazine and 6-chloronicotinonitrile as described for example 39 step 1 (90 mg, crude) and it was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=2.0 Hz, 1H), 7.60 (dd, J=9.0 Hz, J=2.3 Hz, 1H), 6.60 (d, J=9.3 Hz, 1H), 4.27 (d, J=12.8 Hz, 2H), 2.96-2.88 (m, 2H), 2.52 (dd, J=12.4 Hz, J=10.9 Hz, 2H), 1.16 (d, J=6.3 Hz, 6H)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[C:7]([O:15][CH3:16])[CH:6]=2.[CH2:23]([C@H:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]>C(Cl)Cl.CN(C=O)C>[CH2:23]([C@H:25]([NH:32][C:12]([C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[CH:8][CH:9]=2)[N:4]=[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:2]=1[CH3:1])=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: COc1ccc2c(C(=O)Cl)c(C)c(-c3ccccc3)nc2c1
Reactant: CC[C@H](N)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(C)c(-c2ccccc2)nc2cc(OC)ccc12)c1ccccc1
Reaction time: 12 h

Procedure:
Prepared as described in Ex. 1, starting from 1.27 g ( 4.09 mmol) of crude 3-methyl-7-methoxy-2-phenylquinoline-4-carbonylchloride, 0.55 g (4.09 mmol) of (S)-(−)-a-ethylbenzylamine and 1.71 ml (12.27 mmol) of TEA in 24 ml of dry CH2Cl2 and 1 ml of DMF to help solubility. The reaction mixture was stirred 12 hours at room temperture.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1.CCOC(C)=O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[C:20]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1
Reactant: Oc1ccc(Cl)cc1C1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (10 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-chloro-2-cyclohexylphenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (80 ml), washed with H2O (2×40 ml) and brine (60 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-2-cyclohexylphenoxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][N:15]3C(=O)C4=CC=CC=C4C3=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CCN(Cc2ccc(F)cc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCC1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A mixture of N-[2-[1-(4-fluorobenzyl)piperidin-4-yl]ethyl]phthalimide (12.7 g) and hydrazine hydrate (2.02 ml) in ethanol (150 ml) was refluxed for 2 hours. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was chromatographed on alumina eluting with chloroform and the fractions containing the object product were collected and evaporated to give 2-[1-(4-fluorobenzyl)piperidin-4-yl]ethylamine (4.5 g) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2[S:14][C:15]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[Cl:26])=[N:16][C:12]=2[CH:11]=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[C:13]2[S:14][C:15]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[Cl:26])=[N:16][C:12]=2[CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc2nc(-c3c(Cl)cc(C#N)cc3Cl)sc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)c(-c2nc3ccnc(N)c3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
A mixture of [2-(2,6-dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-carbamic acid tert-butyl ester (0.48 g, 1.14 mmol) and TFA (2 mL) in DCM (8 mL) was stirred at room temperature for 2 hours then concentrated to dryness under reduced pressure. The resultant residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M ammonia in isopropanol. The relevant fractions were combined and concentrated under reduced pressure to afford the title compound as a pale yellow solid (0.309 g, 82% yield). 1H NMR (300 MHz, CDCl3): δ 8.21 (d, J=5.8 Hz, 1H), 7.77 (s, 2H), 7.50 (d, J=5.8 Hz, 1H), 4.94 (s, 2H). LCMS (Method D): RT=2.04 min, m/z: 321 [M+H+].
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:18][O:17][C:8]2[CH:9]=[CH:10][C:11]3[NH:12][C:13](=[O:16])[O:14][C:15]=3[C:7]=2[O:6]1)=[N+]=[N-].[H][H].Cl>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[O:6][C:7]2[C:8](=[CH:9][CH:10]=[C:11]3[NH:12][C:13](=[O:16])[O:14][C:15]3=2)[O:17][CH2:18]1
Reactant: [H][H]
Reactant: [N-]=[N+]=NC[C@H]1COc2ccc3[nH]c(=O)oc3c2O1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC1COc2ccc3[nH]c(=O)oc3c2O1

Procedure:
(8S)-8-(Azidomethyl)-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-2(3H)-one (2.86 g, 11.5 mmole) in methanol (60 mL) was treated for 24 hours on a Parr shaker with 60 psi of hydrogen in the presence of 0.43 g of 10% Pd/C and 3.0 mL of 4 N isopropanolic HCl. The catalyst was removed by filtration through celite and was washed with additional methanol. The filtrate was evaporated in vacuum to give 2.12 g (68%) of the (S)-enantiomer of the title compound as a beige solid, m.p.>250° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].COC1C=CC(C=O)=CC=1.[OH-].[Na+]>C(OCC)C.C(OCC)(=O)C>[OH:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: COC(=O)[C@@H](COC1CCCCO1)NC(=O)OC(C)(C)C
Agent: COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CO)COC1CCCCO1
Temperature: 25 °C

Procedure:
To a 3 L three neck flask fitted with a thermometer, magnetic stirrer, under argon was added 2 (128 g, 0.42 mol) in diethyl ether (1.5 L). A clear yellow solution formed after one hour of stirring at room temperature. The solution was cooled to 10° C. with an ice/water bath. Lithium borohydride (9.3 g, 0.42 mol) was added in three portions over 30 minutes to keep the temperature below 18° C. The reaction mixture was warmed to 32° C. and was complete after 60 min by TLC (EtOAc:Hexanes; 3:7, anisaldehyde dip reagent). The reaction mixture was transferred to a 4 L flask and stirred vigorously while 1M NaOH (350 mL) was added slowly to pH 11 and stirred an additional 30 min. Ethyl acetate (500 mL) was added to the mixture and stirred 5 min. The layers were separated. The organic layer was washed with brine (1×600 mL) and dried over granular Na2SO4 (100 g) for 15 min. The mixture was filtered and concentrated under reduced pressure overnight to 109 g (94%) of product 3 as a waxy white crystalline solid. 1H NMR (60 MHz, CDCl3) δ 5.0-5.3 (br m, 1H), 3.2-4.6 (m, 8H), 2.4-3.0 (m, 1H), 1.3-1.7 (m, 15H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:4][CH2:3]1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.Cl>C(#N)C>[Cl:34][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[C:9]([CH2:15][N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)[CH:10]=3)=[CH:25][CH:26]=[N:27]2)=[CH:32][CH:31]=1
Reactant: CN1CCN(Cc2cc(N)ccc2N2CCN(C)CC2)CC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CC#N
Product: CN1CCN(Cc2cc(Nc3ccnc4cc(Cl)ccc34)ccc2N2CCN(C)CC2)CC1
Yield: 47.9 %

Procedure:
4-(4-methylpiperazin-1-yl)-3-[(4-methylpiperazin-1-yl)methyl]aniline (68 mg, 0.22 mmol) and 4,7-dichloroquinoline (44 mg, 1 eq) were refluxed overnight in 10 mL of acetonitrile with 0.66 mL of HCl 1M. The reaction mixture was then evaporated and purified by preparative thin-layer chromatography (DCM/MeOH/NH4O/18/210.1) to yield expected compound as a pale yellow solid (49 mg, 48% yield). m/z (ESI) 465.2 [M+H]+.