Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:11]=[C:10]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])[CH2:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[N:11]=[C:10]([C:32]([C:34]([F:36])([F:35])[F:37])([C:38]([F:40])([F:41])[F:39])[OH:33])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2ccc(N3CCNCC3)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 216.1 %

Procedure:
5-(2-Chloro-phenyl)-1-[4-(4-BOC-piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (280.0 mg, 0.46 mmol) prepared in Example 426 was added to a saturated solution of hydrochloric acid in ethyl acetate (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 270.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:19])[NH:9][N:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CI.[C:22](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1(C)C=CC=CC=1.O>[CH3:22][O:19][C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]n(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1nn(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-nitro-1-phenyl-1,2-dihydroindazol-3-one (2 g, 7.69 mmol, 1.00 equiv, 98%) in toluene (50 mL), CH3I (4.3 g, 29.68 mmol, 3.86 equiv, 98%), potassium carbonate (1.63 g, 11.58 mmol, 1.51 equiv, 98%), N,N-dimethylformamide (50 mL). The resulting solution was stirred for 1 h at 80° C. in an oil bath. The resulting solution was diluted with water (100 mL). The resulting solution was extracted with dichloromethane (2×50 mL) and the organic layers were combined, then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). The collected fractions were combined and concentrated under vacuum to yield 3-methoxy-6-nitro-1-phenyl-1H-indazole as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[C:28]1(=[O:49])[N:32]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[C:31](=[O:44])[C:30]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:29]12.[OH-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:43][C:40]4[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][N:32]5[C:28](=[O:49])[C:29]6=[CH:48][CH:47]=[CH:46][CH:45]=[C:30]6[C:31]5=[O:44])=[CH:42][CH:41]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Reaction time: 5 h
Yield: 6 %

Procedure:
To a stirred solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl) piperazine (24 g) and 14.5 g of 4-(3-phthalimidopropyloxy)phenol in dimethylsulfoxide (500 ml) at 50° under nitrogen was added sodium hydroxide (1.9 g) in water (15 ml), and the solution was stirred for 5 hours 55°-60°. After standing at room temperature overnight, the reaction was poured into water (1 L) and the oil was extracted using ethyl acetate. The extract dried over sodium sulfate was evaporated in vacuo and the residual material was dissolved in acetonitrile. The supernatant was decanted from some insoluble material and then hydrogen chloride was bubbled into the solution to precipitate the product as the dihydrochloride salt. Methanol was added to the mixture to redissolve the salt and the solution was concentrated until a solid started to precipitate. The solid was collected by filtration to give 2 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2 -[4-(3-phthalimidopropyloxy)phenoxy]ethyl]piperazine as its di-hydrochloride salt, mp 233°-246°. The filtrate was evaporated and the resulting oil was crystallized from methanol yielding an additional 8.3 g of the same material, mp 225°-240°
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[C:28](Cl)(=[O:30])[CH3:29]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:28](=[O:30])[CH3:29])[CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OCC)c1
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-chloro-2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and acetyl chloride.
Reaction SMILES: [NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:18]([O:25][C:26]([NH:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(Br)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To (1R,3R)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate (1.5 g, 5.03 mmol) in acetonitrile (7.2 ml) and water (1.800 ml) was added N-(Benzyloxycarbonyloxy)succinimide (1.254 g, 5.03 mmol) followed by potassium carbonate (0.695 g, 5.03 mmol). The reaction mixture was stirred for 1 hour at room temperature. The solvent was removed and the remaining aqueous slurry was taken up in water and ethyl acetate. The organic layer was removed and washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by flash chromatography to yield (1R,3R)-methyl 1-(benzyloxycarbonylamino)-3-(4-bromophenyl)cyclopentanecarboxylate (1.4 g, 3.24 mmol, 64.4% yield) as an off white gum.
Reaction SMILES: Cl.[N:2]1([C:11]2[CH:12]=[C:13]([CH2:17][NH:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>C(Cl)Cl>[CH2:31]([O:30][C:28]([N:18]([CH3:19])[CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:12]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: CNCc1cccc(N2CCc3ccccc32)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(C)Cc1cccc(N2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
An ice cold rapidly stirred solution of 7.73 g (28.18 mmole) of 3-(1-indolinyl)-N-methyl benzenemethanamine hydrochloride of Example 8b in 150 ml CH2Cl2 was treated dropwise with a solution of 9.9 ml (70.45 mmole, 2.5 equivalents) of triethylamine in 10 ml CH2Cl2. After stirring for three minutes, a solution of 4.0 ml (42.27 mmole, 1.5 equivalents) ethyl chloroformate in 10 ml CH2Cl2 was added dropwise. At the end of the addition the reaction mixture was permitted to warm to room temperature, stirred for 1 hour and stand about 64 hours. Water (200 ml) was added and the organic layer was separated and washed with 2N HCl (200 ml), water (300 ml), brine (300 ml), dried (Na2SO4), and concentrated to give 7.64 g (87.3%) of crude product. Chromatography on silica gel (85 g) using ether-methylene chloride afforded 6.73 g (76.9% overall) of an oil of N-ethoxycarbonyl-3-(1-indolinyl)-N-methylbenzenemethanamine, bp>240° C./0.1 mm.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25])[C:6]1=[O:39])[CH2:2][CH2:3][CH3:4].[NH:40]1[CH:44]=[CH:43][CH:42]=[N:41]1>>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33][C:44]3[CH:43]=[CH:42][NH:41][N:40]=3)[CH:30]=[CH:29][C:28]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25])[C:6]1=[O:39])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2cc(CBr)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Reactant: c1cn[nH]c1
Product: CCCCn1c(=O)c(NC(=O)Nc2cc(Cc3cc[nH]n3)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21

Procedure:
In the same manner as in Example 8 (b), the title compound is prepared from N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2-tert-butyl-5-(bromomethyl)phenyl]urea and pyrazole.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14](=[O:31])[C:15]4[C:16]([O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:17]([O:21]C)[N:18]=[CH:19][CH:20]=4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1.CO.O.[OH-].[Na+]>Br.CC(O)=O>[ClH:1].[NH2:2][C:3]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:14](=[O:31])[C:15]4[CH:20]=[CH:19][NH:18][C:17](=[O:21])[C:16]=4[O:23][C:24]=3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: COc1nccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(=O)[nH]ccc4c3=O)cc2)CCC1
Yield: 70.3 %

Procedure:
A solution of 3-[4-(1-amino-cyclobutyl)-phenyl]-8-methoxy-2-phenyl-pyrano[2,3-c]pyridin-4-one hydrochloride (22 mg, 0.051 mmol) in 33% hydrogen bromide solution in AcOH (0.5 mL) was heated in a microwave oven at 100° C. for 30 min. The reaction mixture was added to a mixture of MeOH (3 mL) and water (3 mL), the pH adjusted to ˜4 by addition of aqueous sodium hydroxide, and chromatographed on a 5 g C18 cartridge {gradient 35 to 70% MeOH in water+1 M HCl (0.12 mL in each 10 mL of eluent)}. Fractions containing product were concentrated in vacuo. The resultant residue was chromatographed on a 5 g C18 cartridge {gradient 35 to 70% MeOH in water+1 M HCl (0.06 mL in each 5 mL of eluent)} to give the title compound (15.1 mg, 71%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.33 (br s, 1H), 8.51 (br s, 3H), 7.48-7.33 (m, 8H), 7.28-7.26 (m, 2H), 6.61 (d, J=6.7 Hz, 1H), 2.60-2.49 (m, 4H), 2.23-2.12 (m, 1H), 1.85-1.74 (m, 1H). LCMS (Method F): RT=6.59 min, [M−H]−=383.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([N:13]2[C:17]3[N:18]=[CH:19][NH:20][C:21](=O)[C:16]=3[CH:15]=[N:14]2)[CH:12]=1>>[Cl:3][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C:11]3[CH:12]=[C:7]([F:6])[CH:8]=[CH:9][C:10]=3[CH3:23])[N:14]=[CH:15][C:16]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(F)cc1-n1ncc2c(=O)[nH]cnc21
Product: Cc1ccc(F)cc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
Phosphorus oxychloride (5442 μl, 58.39 mmol) was added to 1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (Intermediate AK2) (713 mg, 2.92 mmol), at ambient temperature. The resulting mixture was heated to 100° C. and stirred for 4 hours. The mixture was allowed to cool to ambient temperature. The reaction mixture was evaporated to near dryness. Dissolved into toluene, evaporated, dissolved, in toluene and evaporated to dryness again. The solid was dried under vacuum to give crude product. This was partitioned between EtOAc (70 mL), and water (25 mL). The organic phase was dried (MgSO4), evaporated, then dried under vacuum to afford the product (732 mg, 95%). 1H NMR (400 MHz, DMSO) δ 2.13 (3H, s), 7.52-7.42 (2H, m), 7.64-7.58 (1H, m), 8.83 (1H, s), 8.96 (1H, s); m/z (ES+) (M+H)+=263; HPLC tR=2.39 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:13]1[S:12][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:10])[F:9])[O:5][N:4]=2)=[CH:15][CH:14]=1)=[O:21]
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1
Yield: 54 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 2-methoxybenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (15 then 25%) as eluant to afford product as a yellow-tinted oil (100 mg, 54%). 1H NMR (CDCl3) 2.39 (d, J=1.3, 3H), 3.82 (s, 3H), 7.01-7.08 (m, 2H), 7.27-7.54 (m, 4H). 13C NMR 8.0, 55.9, 111.9, 115.9 (q, J=151), 120.7, 128.2, 129.0, 129.6, 132.7, 135.0, 136.3, 147.1, 155.4 (q, J=41), 157.3, 158.0, 188.2. 19F NMR −63.1. LC/MS 7.50 min, [M+1]+ 368.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:18][OH:19])[CH2:13][C:12](OC)([O:14]C)[CH2:11]2)[CH:5]=[C:4]([Cl:20])[N:3]=1.Cl.N.CO>CC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:18][OH:19])[CH2:11][C:12](=[O:14])[CH2:13]2)[CH:5]=[C:4]([Cl:20])[N:3]=1
Reactant: COC1(OC)CC(CO)(CNc2cc(Cl)nc(N)n2)C1
Agent: Cl
Agent: N
Solvent: CC(C)=O
Solvent: CO
Product: Nc1nc(Cl)cc(NCC2(CO)CC(=O)C2)n1
Yield: 70.1 %

Procedure:
To 2-amino-6-chloro-4-[[(1-hydroxymethyl-3,3-dimethoxy-1-cyclobutyl)methyl]amino]pyrimidine (0.61 g, 2.0 mmol) were added acetone (50 ml) and 20% hydrochloric acid (0.5 ml), and the mixture was refluxed for 30 minutes. The mixture was neutralized with 10% ammonia-methanol under ice-cooling. The solvent was distilled away under reduced pressure and the residue was recrystallized from acetone to give colorless prism crystals (0.36 g, 70.1%), m.p. 171-173° C. (acetone).
Reaction SMILES: [CH3:1]/[C:2](=[CH:12]\[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.S(Cl)(Cl)=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCCCSC(=Nc1ccccc1)C(C)=CSc1ccccc1
Reaction time: 0.08 h
Yield: 12 %

Procedure:
A suspension of 1.0 g (3.71 mmol) of (E)-2-methyl-N-phenyl-3-(phenylthio)-2-propenamide, 0.81 ml of thionyl chloride, and 10 mg of DMF in 10 ml of toluene was refluxed for 1 hour and then concentrated under vacuum. The residue was dissolved in 5 ml of DMF and cooled in ice bath. To a solution of 241 mg of n-hexylthiol in 5 ml of DMF was added 90 mg of sodium hydride (60% in oil) under ice cooling and stirred for 5 minutes. The mixture was added portionwise to the above-described DMF solution of the residue under ice cooling and then stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with tert-butyl methyl ether (three times). The combined organic layer was washed sequentially with water and a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 82 mg of n-hexyl 2-methyl-N-phenyl-3-(phenylthio)-2-propenimidothioate (hereinafter referred to as the present compound 47) and 114 mg of n-hexyl 3-(hexylthio)-2-methyl-N-phenyl-2-propenimidothioate (hereinafter referred to as the present compound 48).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]=[C:25]=[S:26]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:25]([NH:24][CH3:23])=[S:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN=C=S
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2N)CC1
Solvent: C1CCOC1
Product: CNC(=S)Nc1ccccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 108.4 %

Procedure:
After dissolving 400 mg of 1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml of tetrahydrofuran, 124 mg of methyl isothiocyanate was added and the mixture was heated to reflux for 3.5 hours. The reaction solution was filtered with NH silica gel and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (537 mg, 100% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:23])[Cl:24])[CH:16]=[C:15]([Cl:25])[C:14]=1[O:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(CCO)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(CCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.8 %

Procedure:
To a mixture of 3.88 g of 4-(2-hydroxyethyl)benzaldehyde, 6.7 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 100 ml of tetrahydrofuran, and 6.0 g of triphenylphosphine was added dropwise a solution of 4.7 g of diisopropyl azodicarboxylate dissolved in 20 ml of tetrahydrofuran at the ice temperature over 1 hour. After completion of the addition, the reaction mixture was stirred at room temperature for 24 hours, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 6.63 g (yield, 69%) of 4-(2-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)ethyl)benzaldehyde, m.p., 54.2° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[CH3:19])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:20]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:20][C:9]1[S:8][C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[CH3:19])=[N:6][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)cs1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(Br)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
4-(4-tert-Butylthiazol-2-yl)-3-methylbenzoic acid (Step B, 7.0 g, 25.4 mmol) was dissolved in 30 mL of acetic acid, and bromine (8.1 g, 50.8 mmol) was added. The red mixture was stirred at room temperature for 20 minutes to see complete conversion by LCMS. Excess sodium bisulfite was added until the reaction mixture became colorless. The mixture was concentrated to dryness, dry-loaded to a silica gel column, and purified, eluting with 10% methanol in methylene chloride, to get 4-(5-bromo-4-tert-butylthiazol-2-yl)-3-methylbenzoic acid as a white solid (8.5 g, 94% yield over 2 steps). LCMS (M+H)+: 355.9; 353.9. 1H NMR (CDCl3, 500 MHz): 7.92 (s, 1H), 7.84 (m, 2H), 2.60 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]([C:16]1[CH:17]=[N:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:20][CH:21]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CN=C1.O>C(#N)C>[Cl:3][C:6]([C:16]1[CH:17]=[N:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:20][CH:21]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(Cl)(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Temperature: 0 °C
Yield: 70.6 %

Procedure:
Thionyl chloride (0.57 g) was added dropwise to a solution of ethyl (RS)-2-hydroxy-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (0.2 g) and imidazole (0.32 g) in dry acetonitile (7 cm3), whilst the reaction temperature was maintained at 0° C. The mixture was allowed to warm to the ambient temperature and stirred for a period of sixteen hours, after which time it was poured into water, and extracted into dichloromethane. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate, passed through a short plug of silica, and concentrated by evaporation of the solvent under reduced pressure to give ethyl (RS)-2-chloro-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate as a yellow oil (0.15 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH:13]=O.[N:15]1[C:24]2[CH:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CC(O)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[C:3]1[CH2:13][N:25]([CH:23]1[C:24]2[N:15]=[CH:16][CH:17]=[CH:18][C:19]=2[CH2:20][CH2:21][CH2:22]1)[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: Cn1c(C=O)nnc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1c(CN(CCCCNC(=O)OC(C)(C)C)C2CCCc3cccnc32)nnc1-c1ccccc1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of 4-methyl-5-phenyl-4H-1,2,4-triazole-3-carbaldehyde, 36, (0.41 g, 2.20 mmol) in 1,2-dichloroethane (4 mL) was added tert-butyl 4-(5,6,7,8-tetrahydroquinolin-8-ylamino)butylcarbamate, 3, (0.76 g, 2.40 mmol), sodium triacetoxyborohydride (0.84 g, 3.95 mmol), and AcOH (10 drops). The reaction mixture was heated to 65° C. and stirred for 18 h. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO3 (15 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine then dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-5% methanol/dichloromethane) to yield 37: 1H NMR (400 MHz, CDCl3) δ 8.40, (d, J=5.2 Hz, 1H), 7.60-7.57 (m, 2H), 7.48-7.44, (m, 3H), 7.31, (d, J=7.2 Hz, 1H), 7.0, (dd, J=8.0, 5.2 Hz, 1H), 5.01, (bs, 1H), 4.20-3.92, (m, 3H), 3.20-2.60, (m, 6H), 2.20-1.85, (m, 4H), 1.75-1.30 (m, 13H); ESI+ MS: m/z (rel intensity) 491 (100, M+H). Step g: Preparation of N-(4-aminobutyl)-N-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine tetrahydrochloride (BQ). Through a methanol (2 mL) solution of 37 (0.16 g, 0.32 mmol) was bubbled HCl(g) generated by the addition of sulfuric acid to dry NaCl. Upon total conversion of the reaction as monitored by LC-MS, the reaction mixture was concentrated in vacuo to yield BQ: ESI+ MS: m/z (rel intensity) 391 (100, M+H).