Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:22][CH2:23][O:24][C:25]([CH2:27][CH:28]1[C:33](=O)[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26]>>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:29]3[CH:28]([CH2:27][C:25]([O:24][CH2:23][CH3:22])=[O:26])[CH2:33][CH2:32][CH2:31][C:30]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-trifluoromethylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared as a mixture of ethyl and isopropyl esters.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CCOC(C)=O>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([CH2:12][OH:13])=[CH:10]2
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Product: Cc1cccc2cc(CO)c(N3CCCC3)nc12
Yield: 88 %

Procedure:
(2-Chloro-8-methylquinolin-3-yl)methanol (200 mg, 0.97 mmol) and pyrrolidine (2 mL) were stirred in a sealed tube at 100° C. for 4 h. After cooling, the solution was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgSO4), filtered and the solvent was removed in vacuo. Purification by column chromatography on silica, eluting with 20% EtOAc in isohexane, gave the title compound (206 mg, 88%). δH (CDCl3) 7.86 (1H, s), 7.46 (1H, d, J=8.01 Hz), 7.40 (1H, d, J=7.04 Hz), 7.13 (1H, t, J=7.50 Hz), 4.85 (2H, s), 3.72 (4H, t, J=6.36 Hz), 2.65 (3H, s), 2.12 (1H, s), 2.03-1.96 (4H, m).
Reaction SMILES: [NH2:1]/[C:2](=[N:4]\[O:5][C:6](=O)[C@@H:7]([NH:12][C:13]([C:15]1[N:16]=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:19]=12)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])/[CH3:3]>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>[CH3:10][C:8]([CH3:9])([CH3:11])[C@H:7]([NH:12][C:13]([C:15]1[N:16]=[C:17]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][C:19]=12)=[O:14])[C:6]1[O:5][N:4]=[C:2]([CH3:3])[N:1]=1
Reactant: C/C(N)=N/OC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CN(C(=O)OC(C)(C)C)CC3)C(C)(C)C)n1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
Intermediate 22C (0.20 g, 0.39 mmol) was dissolved in a 1N solution of TBAF in THF (0.55 mL). The resulting mixture was stirred overnight, concentrated, diluted with EtOAc and washed successively with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative flash chromatography on silica, eluting with a 20-70% ethyl acetate/hexanes gradient to provide Intermediate 22D (0.17 g, 88%). 1H-NMR (400 MHz, CDCl3-d) δ: 1.09 (s, 9H), 1.51 (s, 9H), 2.40 (s, 3H), 3.78 (m, 2H), 4.11 (m, 2H), 5.01 (m, 2H), 5.37 (d, 1H), 7.35 (m, 3H), 7.64 (m, 2H), 7.78 (d, 1H); LCMS (+ESI) m/z 495.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH2:8][C:9]([NH:11][C:12]2([C:20](OC)=[O:21])[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14][CH2:13]2)=[O:10])[CH:7]=1.CN(C)C(=O)C.CC(C)([O-])C.[K+].Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[C:9](=[O:10])[NH:11][C:12]3([CH2:13][CH2:14][C:15]([F:19])([F:18])[CH2:16][CH2:17]3)[C:20]=2[OH:21])[CH:7]=1
Reactant: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC(F)(F)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Br)cc1C1=C(O)C2(CCC(F)(F)CC2)NC1=O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
11.0 g (27.2 mmol) of the compound from Example 10A were initially charged in a solution of 22 ml of DMA (N,N-dimethylacetamide), a solution of 10 ml of DMA and 3.54 g (1.1 eq.) of potassium tert-butoxide was added dropwise at 20-30° C. and the mixture was stirred at 30° C. for a further 1 h. The mixture was poured into 200 ml of water and the mixture was adjusted to pH 2 using aqueous 1N hydrochloric acid, the resulting precipitate was filtered off with suction, washed with water and dried in a vacuum drying cabinet at 50° C. The product was suspended in hot methyl tert-butyl ether, n-hexane was added and the mixture was filtered off with suction and dried. This gave 11.0 g (97% of theory) of the title compound in a purity of 89%.
Reaction SMILES: [NH2:1][C:2]1[C:19]([C:20]#[N:21])=[CH:18][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:16][CH3:17])=[O:15])[CH2:9][CH2:8]2)=[C:4]([O:22][CH3:23])[CH:3]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>CC1CCCO1.C(O)(=O)C>[C:20]([C:19]1[C:2]([N:1]=[CH:26][N:27]([CH3:29])[CH3:28])=[CH:3][C:4]([O:22][CH3:23])=[C:5]([CH:18]=1)[O:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]([NH:16][CH3:17])=[O:15])[CH2:11][CH2:12]1)#[N:21]
Reactant: COC(OC)N(C)C
Reactant: CNC(=O)CN1CCC(Oc2cc(C#N)c(N)cc2OC)CC1
Solvent: CC1CCCO1
Solvent: CC(=O)O
Product: CNC(=O)CN1CCC(Oc2cc(C#N)c(N=CN(C)C)cc2OC)CC1
Temperature: 76 °C
Yield: 100.5 %

Procedure:
2-[4-(4-Amino-5-cyano-2-methoxyphenoxy)piperidin-1-yl]-N-methylacetamide (6, 18.21 g, 52.05 mmoles) was suspended in 2-methyltetrahydrofuran (99.62 g). To this was added acetic acid (162.79 mg), and N,N-dimethylformamide dimethyl acetal (DMF-DMA) (8.63 g, 70.27 mmoles) and the resulting reaction mixture was heated at 76° C. for 16 hrs. Additional N,N-dimethylformamide dimethyl acetal (639.41 mg, 5.20 mmoles) was added to the reaction mixture to ensure the reaction completed. The reaction mixture was cooled to 30° C. during which time crystallisation occurred. The resulting solid was isolated by filtration, washed with 2-methyltetrahydrofuran (14.23 g) and dried to afford the title compound (19.53 g, 97% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65 (m, 2H) 1.86 (m, 2H) 2.24 (m, 2H) 2.60 (d, J=4.7 Hz, 3H) 2.66 (m, 2H) 2.87 (s, 2H) 2.95 (s, 3H) 3.04 (s, 3H) 3.81 (s, 3H) 4.19 (tt, J=8.2, 3.8 Hz, 1H) 6.72 (s, 1H) 7.15 (s, 1H) 7.67 (q, J=4.7 Hz, 1H) 7.90 (s, 1H); Mass Spectrum: m/z (M+H)+ 374.2.
Reaction SMILES: Cl.N1C=C(C[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:18][C:13]=3[CH2:12][N:11](C(C3C4C(=CC=CC=4)C=CC=3)=O)[CH2:10][CH2:9]2)N=C1.C([O-])([O-])=O.[K+].[K+].Br[CH:44]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:45]([O:47][CH3:48])=[O:46]>CO>[C:49]1([CH:44]([N:11]2[CH2:12][C:13]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:14]=3[NH:8][CH2:9][CH2:10]2)[C:45]([O:47][CH3:48])=[O:46])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccc3)cc2C1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C(c1ccccc1)N1CCNc2ccc(-c3ccccc3)cc2C1
Reaction time: 18 h
Yield: 59.1 %

Procedure:
To a stirred suspension of Compound B of Example 12 (220 mg, 1.0 mmol) in MeOH in the presence of solid K2CO3 at room temperature under argon was added methyl bromophenylacetate (0.18 mL, 1.1 mmol). The mixture was stirred for 18 h, the solvent was removed, and the residue was purified by flash column chromatography (3:2, hexanes and ethyl acetate) to give 1,2,3,5-tetrahydro-a,7-diphenyl-4H-1,4-benzodiazepine-4-acetic acid, methyl ester as an oil (220 mg, 63%). This material was reacted as described for Compound D of Example 1 to afford Example 222 as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[CH3:10][C@H:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[NH:12]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:12]2[C@@H:13]([CH3:17])[CH2:14][CH2:15][CH2:16][C@H:11]2[CH3:10])[CH:7]=1
Reactant: ClCc1cncc(Br)c1
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCC[C@H](C)N1Cc1cncc(Br)c1
Yield: 53.5 %

Procedure:
To a solution of 3-bromo-5-(chloromethyl)pyridine (XLVI) (1.17 g, 4.8 mmol) in MeCN (0.2 mL) and (2S,6R)-2,6-dimethylpiperidine (2.6 mL, 19.3 mmol) was added K2CO3 (667 mg, 4.8 mmol). The reaction was refluxed for 5 hrs. TLC showed the presence of starting material so additional (2S,6R)-2,6-dimethylpiperidine (2.0 mL, 14.8 mmol) was added and the reaction was refluxed for an additional 5 hrs. The solvent was removed and the residue was partitioned between EtOAc/water. The EtOAc was separated and washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% hexanes→6:94 EtOAc:hexanes) to afford 3-bromo-5-(((2R,6S)-2,6-dimethylpiperidin-1-yl)methyl)pyridine (XLVII) as a clear oil (728 mg, 2.57 mmol, 53% yield). 1H NMR (DMSO-d6) δ ppm 0.92 (d, J=8 Hz, 6H), 1.21-1.32 (m, 3H), 1.52-1.55 (m, 2H), 1.59-1.63 (m, 1H), 2.42-2.46 (m, 2H), 3.73 (s, 2H), 7.97-7.98 (m, 1H), 8.50 (d, J=3 Hz, 1H), 8.55-8.56 (m, 1H); ESIMS found for C13H19BrN2 m/z 283 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]1[S:34](=[O:36])(=[O:35])[N:33](CC[Si](C)(C)C)[C:32](=[O:43])[CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]1[S:34](=[O:35])(=[O:36])[NH:33][C:32](=[O:43])[CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3cccc(OCc4ccccc4)n3)cc2OCc2ccccc2)S1(=O)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: O=C1CN(c2ccc(Cc3cccc(OCc4ccccc4)n3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[2-benzyloxy-4-(6-benzyloxypyridin-2-ylmethyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (213 mg, 0.35 mmol) in DMF (3 mL) is added CsF (265 mg, 1.75 mmol). The reaction is stirred at 60° C. for 2 h. The reaction is allowed to cool to RT and the solvent is removed under reduced pressure. The crude cesium salt of the title compound is used in the next step without further purification: (M+H)+=516.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=1[Cl:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[Cl:14][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[C:10]([F:11])[C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: COc1cc(F)c(C(=O)CBr)c(Cl)c1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1cc(F)c(-c2csc(N)n2)c(Cl)c1
Yield: 42.2 %

Procedure:
To a solution of 2-bromo-1-(2-chloro-6-fluoro-4-methoxyphenyl)ethanone (13-4, 0.80 g) and thiourea (0.27 g, 3.6 mmol) in 95% EtOH (8.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure, and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2-chloro-6-fluoro-4-methoxyphenyl)thiazol-2-ylamine (13-5, 0.30 g, 1.2 mmol) as yellow solids in 39% yield: 1H NMR (500 MHz, CDCl3) δ 6.84 (s, 1 H), 6.65 (m, 1 H), 6.57 (s, 1 H), 3.83 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C@H:12]2[CH2:17][C@@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][N:13]2C(OC)=O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br>>[CH3:1][C:2]1[CH:3]=[C:4]([C@H:12]2[CH2:17][C@@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)c(C)c1
Agent: Br
Product: Cc1cc([C@H]2C[C@@H](c3cc(=O)[nH]o3)CCN2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
(2R,4S)-Methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.177 g, 0.46 mmol) was dissolved in HBr (33% in acetic acid, 5.6 g, 22.84 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3-methyl-4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (0.082 g, 55%). 1H NMR (600 MHz, dmso) δ 1.31-1.39 (m, 1H), 1.41-1.50 (m, 1H), 1.84-1.90 (m, 1H), 1.95-2.00 (m, 1H), 2.40 (d, 3H), 2.57-2.59 (m, 1H), 2.83-2.90 (m, 1H), 3.08-3.13 (m, 1H), 3.68 (d, 1H), 5.72 (s, 1H), 7.35 (d, 1H), 7.43 (s, 1H), 7.57 (d, 1H). HRMS Calcd for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1311.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)Nc1ccccc1-c1ccccc1F)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=S)Nc1ccccc1-c1ccccc1F

Procedure:
A mixture of N-benzoyl-N'-(2'-fluoro-2-biphenylyl)thiourea (9.5 g), sodium hydroxide (1.14 g) and water (80 ml) was heated at 90°-95° C. for 8 hours to give N-(2'-fluoro-2-biphenylyl)thiourea as a colourless solid (m.p. 175°-177° C.).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.Br[CH2:35][C:36]#[N:37].[OH-].[Na+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:14]1([S:11]([N:7]2[C:8]3[C:4](=[C:3]([CH2:20][N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)[C:2]([O:1][CH2:35][C:36]#[N:37])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:12])=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: N#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN1CCNCC1
Temperature: 25 °C
Yield: 7 %

Procedure:
To a solution of tert-Butyl 4-{[5-hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (45 mg, 0.10 mmol; Intermediate 64) in dry DCM (2 mL) was added bromoacetonitrile, 57 mg (0.48 mmol), tetrabutylammonium hydrogensulphate, 8 mg (0.02 mmol), 2M NaOH (1 mL) and the two phase system was vigorously stirred at room temperature over night. The organic phase was separated and the aqueous phase was washed once with water. The solvent from the combined organic phases was removed at reduced pressure and the residue was purified on a on a preparative HPLC, method B, to yield 2.9 mg (7%) of the target compound as a light brown oil. MS (ESI+) for C21H22N4O3S m/z 411 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]([CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[N:1]1([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]([CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCN4CCCC4CN4CCCC4)cccc32)CC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OCc2nc3c(OCCCN4CCCC4CN4CCCC4)cccc3n2CCCC2CCNCC2)cc1

Procedure:
The title compound was prepared from (RS) 4-[3-[2-(pyrroldin-1-ylmethyl)pyrrolidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole using trifluoroacetic acid deprotection as described supra.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.II.Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC1(c2ccc(Cl)cc2)CCNCC1
Agent: II
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: COC1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
4-(4-Chloro-phenyl)-4-methoxy-piperidine (0.072 g, 0.319 mmol) was dissolved in isopropanol (5 mL) and 2,6-lutidine (0.034 g, 37 uL, 0.319 mmol) was added. Catalytic iodine was also added. The resulting suspension was warmed to 80° C. Solid 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.060 g, 0.160 mmol) was added in approximately equal portions over 2 h. Stirring was continued an additional 20 h at 80° C. The mixture was concentrated and the resulting residue purified by silica gel chromatography (ethyl acetate to 87/10/3 ethyl acetate/methanol/triethylamine gradient) to afford the title compound (70 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][C@@H:12]([CH:14]([CH2:16][CH3:17])[CH3:15])[CH2:11][S:10]2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:12]([CH:14]([CH2:16][CH3:17])[CH3:15])[CH2:11][S:10]2)=[CH:4][C:3]=1[C:18]([F:19])([F:21])[F:20]
Reactant: CCC(C)[C@H]1CSC(=Nc2ccc(Cl)c(C(F)(F)F)c2)N1
Reactant: CC(C)CBr
Product: CCC(C)[C@H]1CSC(=Nc2ccc(Cl)c(C(F)(F)F)c2)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Chloro-3-(trifluoromethyl)aniline was converted to 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate according to Method A2a, Step 3 4-Chloro-3-(trifluoromethyl)phenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-chloro-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-chloro-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=1[NH2:10].[CH2:21]([N:25]1[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=[C:26]1S(C)(=O)=O)[CH:22]([CH3:24])[CH3:23].[Cl-].[NH4+]>CCOCC.[H-].[Na+]>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:9]=1[NH:10][C:26]1[N:25]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[N:27]=1
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CC(C)Cn1c(S(C)(=O)=O)nc(C(F)(F)F)cc1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Cn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
Sodium hydride (60% in oil, 1.01 g, 15.2 mmol) was added to DMF (30 ml) solution of 2,5-bis(trifluoromethyl)aniline (3.2 g, 14.1 mmol), followed by stirring at room temperature for 30 minutes. Then, 3-isobutyl-2-methylsulfonyl-6-trifluoromethyl-4(3H)-pyrimidinone (3.0 g, 11.7 mmol) was added, followed by further stirring for 4 hours. After completion of the reaction, the reaction solution was diluted with ether (20 ml), excess sodium hydride was neutralized with saturated ammonium chloride aqueous solution (20 ml), and then the aqueous layer was separated. After extraction of the aqueous layer with ether (20 ml×2), the organic layers were combined, washed with saturated brine (10 ml), and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated from the resulting filtrate under a reduced pressure. By purifying the thus obtained crude product by a silica gel column chromatography (hexane:ethyl acetate=20:1), 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-isobutyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 56] was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)Cc1cccc(Cl)c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNS(=O)(=O)Cc2cccc(Cl)c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
At room temperature, 1.06 g of 3-chlorophenylmethanesulfonyl chloride were initially charged in 30 ml of dichloromethane, and 1.42 ml of 2,4-dimethoxybenzylamine were added dropwise. The reaction mixture was stirred for 30 minutes. Then the mixture was admixed with 50 ml of water and 50 ml of water, and then the aqueous phase was washed once more with 30 ml of ethyl acetate. The combined organic phases were washed with 1 N aqueous hydrochloric acid, dried over MgSO4 and concentrated by rotary evaporation. The residue (1.65 g) was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18](OCC)=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([CH2:18][OH:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1
Reactant: CCOC(=O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of ethyl 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carboxylate is reduced with lithium aluminum hydride in refluxing tetrahydrofuran to give the product of the example.