Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:24]=[C:23]2[C:18]([C@@H:19]([NH2:25])[CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.[N-:37]=[C:38]=[O:39].[Cl:40][C:41]1[CH:58]=[CH:57][C:44]([CH2:45][N:46]2[C:50]([C@H:51]3[CH2:55][CH2:54][CH2:53]N3)=[N:49][C:48]([CH3:56])=[N:47]2)=[CH:43][CH:42]=1>ClCCl>[Cl:40][C:41]1[CH:58]=[CH:57][C:44]([CH2:45][N:46]2[C:50]([C@H:51]3[CH2:55][CH2:54][CH2:53][N:37]3[C:38]([NH:25][C@@H:19]3[C:18]4[C:23](=[CH:24][C:15]([C:14]([F:13])([F:26])[F:27])=[CH:16][CH:17]=4)[O:22][CH2:21][CH2:20]3)=[O:39])=[N:49][C:48]([CH3:56])=[N:47]2)=[CH:43][CH:42]=1
Reactant: Cc1nc([C@H]2CCCN2)n(Cc2ccc(Cl)cc2)n1
Reactant: [N-]=C=O
Reactant: N[C@H]1CCOc2cc(C(F)(F)F)ccc21
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc([C@H]2CCCN2C(=O)N[C@H]2CCOc3cc(C(F)(F)F)ccc32)n(Cc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a stirring solution of triphosgene (18 mg, 0.06 mmol) in dichloromethane (3 ml) was slowly added dropwise via syringe a premixed solution of (S)-7-(trifluoromethyl)chroman-4-amine (39 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.069 ml) dissolved in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 30 minutes. The isocyanate thereby generated was then treated dropwise with a solution of (R)-1-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-1H-1,2,4-triazole (52 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.067 ml, 0.4 mmol) dissolved in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC yielded a clear oil (14 mg, 15%)
Reaction SMILES: [NH2:1][CH:2]([CH:14]([CH3:17])[CH2:15][CH3:16])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:4].C(O)C.[S:21](=[O:25])(=[O:24])([OH:23])[OH:22]>C(O)(C)C>[S:21]([O:23][S:21]([OH:24])(=[O:23])=[O:22])([OH:22])(=[O:25])=[O:24].[NH2:1][CH:2]([CH:14]([CH3:17])[CH2:15][CH3:16])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:4]
Reactant: O=S(=O)(O)O
Agent: CCC(C)C(N)C(=O)NCCN1CCOCC1
Solvent: CC(C)O
Solvent: CCO
Product: O=S(=O)(O)OS(=O)(=O)O

Procedure:
To a solution of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide free base (25 g, 0.103 mol) dissolved in absolute, anhydrous ethanol (250 mL, 10 vol) cooled in an ice-water bath was slowly added concentrated sulfuric acid (4 mL, 75 mmol) by dropwise addition. Precipitation immediately occurred causing stirring to stop. The ice-water bath was removed and the addition of ethanol (200 mL) and isopropanol (225 mL) was necessary to restart stirring. The remaining required sulfuric acid (7 mL, 131 mmol) was slowly added in an ethanol:isopropanol solution (2:1, 75 mL). An exotherm (20.8° C.-24.0° C.) was observed. The white slurry was allowed to stir overnight under positive nitrogen pressure. The mixture was then filtered washing with isopropanol (150 mL) and dried under high vacuum (35° C.-40° C.) to afford 33.6 g (75% yield) of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide Disulfate as a white solid. 1H NMR, LC-MS confirmed the identity and XRD pattern matches the small scale screen sample pattern.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CN)C(N)=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Boc-Gly-Pro-Nleu-NH2 (3.5 g, 0.0089 mol.) was dissolved in a solution of 30% TFA in DCM (50 ml). The solution was stirred for 40 minutes. The DCM and TFA were removed under reduced pressure, and 3×50 ml benzene were added and distilled under reduced pressure to remove trace TFA. The resulting mixture was dissolved in 30 ml methanol and the solution was chilled to 0° C. HCl/dioxane (4N, 10 ml) was added to the solution to transfer the product from TFA salt to HCl salt. Ethyl ether (200 ml) was added to the solution and a precipitation formed. The ether was removed by filtration and a white solid product was obtained (2.9 g, 87%). Analytical RP-HPLC chromatogram, single peak, RT=15.7 min. (5-15% B in 30 min.). FAB-MS, observed (M+H)+=285. 1H-NMR (500 MHz, DMSO-d6, 25° C., assignment by TOCSY) δ8.03 (m, 3H, Gly-NH3), 7.65 (s, C-terminal NH2), 7.46 (s, C-terminal NH2), 7.34 (s, C-terminal NH2), 7.24 (d, C-terminal NH2), 7.08 (s, C-terminal NH2), 6.92 (s, C-terminal NH2), 4.94 (d, Pro-α), 4.76 (m, Pro-α), 4.59 (m, Pro-α), 4.25-3.52 (sets of bands, Nleu-α, Gly-α), 3.52-3.44 (m, Pro-δ), 3.42-2.70 (sets of bands, Gly-α, Nleu-β), 2.36-1.65 (sets of bands, Pro-β, Pro-γ, Nleu-γ), 0.90 (m, Nleu-δ), 0.79 (m, Nleu-δ).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][N:56]([C:59](=[O:71])[C:60]2[CH:65]=[C:64]([F:66])[CH:63]=[CH:62][C:61]=2[C:67]([F:70])([F:69])[F:68])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.O>[F:66][C:64]1[CH:63]=[CH:62][C:61]([C:67]([F:69])([F:68])[F:70])=[C:60]([CH:65]=1)[C:59]([N:56]1[CH2:57][CH2:58][N:53]([C:51](=[O:52])[CH2:50][NH:49][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:26][CH:25]=2)[CH2:54][CH2:55]1)=[O:71]
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)NCC(=O)N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 41.5 %

Procedure:
DIPEA (350 mg, 0.5 mL, 2.7 mmol) was added to a stirred solution of 4-(4-methyl-piperazin-1-yl)-benzoic acid hydrochloride salt (116 mg, 0.45 mmol) in DMF (5 mL). HOBT (67 mg, 0.5 mmol) and EDCI (216 mg, 1.12 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (184 mg, 0.5 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid residue. The obtained residue was purified by preparative HPLC to afford 100 mg (41.3% yield) N-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(4-methyl-piperazin-1-yl)-benzamide. LCMS Purity: 88.3%. 1H NMR (DMSO-d6): δ 10.4 (s, 1H), 8.4 (s, 1H), 8.0 (t, 1H), 7.86 (d, 2H), 7.64 (m, 2H), 7.1 (d, 2H), 4.2-3.96 (m, 4H), 3.66-3.4 (m, 8H), 3.24-3.0 (m, 6H), 2.9 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[CH2:8][C:9]([NH:11][CH:12]([CH2:15][OH:16])[CH2:13][OH:14])=[O:10].CO.O>C(O)(CC)(C)C>[OH:14][CH2:13][CH:12]1[NH:11][C:9](=[O:10])[CH2:8][O:16][CH2:15]1
Reactant: O=C(CCl)NC(CO)CO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCC(C)(C)O
Solvent: O
Product: O=C1COCC(CO)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
Sodium tert-butoxide (6.70 g, 59.7 mmol) was dissolved in tert-amyl alcohol (40 mL). To this, a tert-amyl alcohol solution (90 mL) of 2-chloro-N-(2-hydroxy-1-hydroxymethylethyl)acetamide (4.00 g, 23.9 mmol) was added dropwise at room temperature over 30 minutes, and the mixture was stirred at room temperature for 2 hours. To this, methanol (25 mL) and water (1.5 mL) were successively added and the mixture was further stirred at room temperature for 30 minutes. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=80/20) to give 5-(hydroxymethyl)morpholin-3-one (Compound EE) (2.00 g, yield: 64%).
Reaction SMILES: [CH3:1][CH:2]([NH2:6])[CH:3]([NH2:5])[CH3:4].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.CS(O)(=O)=O.[CH:43]1[CH:48]=[CH:47][C:46]([CH2:49][O:50][C:51](Cl)=[O:52])=[CH:45][CH:44]=1>O.C(O)C.COCCOC.C(O[K])(C)=O>[NH2:5][CH:3]([CH3:4])[CH:2]([NH:6][C:51](=[O:52])[O:50][CH2:49][C:46]1[CH:47]=[CH:48][CH:43]=[CH:44][CH:45]=1)[CH3:1]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)C(C)N
Agent: CC(=O)O[K]
Agent: CS(=O)(=O)O
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(N)C(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
To a mixture of butane-2,3-diamine (4.8 g, 54.5 mmol) in water (50 mL) containing bromocresol green as indicator was slowly added a solution of methane sulfonic acid (10.46 g) in water (50 mL) until a blue to yellow color transition was observed. The mixture was diluted with ethanol (100 mL) and to it was added a solution of Cbz-Cl (7.61 g, 45.5 mmol) in DME (50 mL) and aqueous AcOK (w/v=50%) to maintain the pale-green color. The reaction mixture was stirred (RT, 1 h), concentrated under reduced pressure, treated with water and filtered. The solution was washed with toluene, basified with 40% aqueous NaOH and extracted with toluene (4×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford benzyl 3-aminobutan-2-ylcarbamate (4.2 g, 35%) as a colorless oil. Mass calculated for C12H18N2O2=222.28; found: [M−H]+=221.2.
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]1[OH:21].Cl.O>CO>[OH:21][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@@H:18]1[C:5](=[CH:4][C:3](=[O:2])[CH2:20][CH2:19]1)[CH2:6][CH2:7]3
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1
Agent: Cl
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 15 h
Yield: 46.5 %

Procedure:
Dissolve dl-3-methoxyestra-2,5(10)-dien-17β-ol (0.84 g) in methanol (18 ml) containing concentrated hydrochloric acid (1.2 ml) and water (0.8 ml) and allow the mixture to stand at room temperature for 15 hours. Add water and extract the mixture with ether. Wash, dry and evaporate the ethanol solution and dissolve the residue in a little benzene. Filter through a column of alumina (25 g) with benzene-ether (7.3). Evaporate the eluates and recrystallize the residue from ether-hexane to obtain the title compound (372 mg), m.p. 123°-124.5° or in an alternate form, m.p. 131°-132°; ultraviolet absorption maximum at 241 mμ (ε16,600); infrared absorption peaks at 6μ, 7.9 μ, 9.4 μ.
Reaction SMILES: [C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15](S)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC2[N:32]=[N:33]C(Cl)=CC=2C1)(=O)C1C=CC=CC=1.NC(N)=S>>[C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15]([NH:32][NH2:33])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: O=C(c1ccccc1)N1CCc2nnc(S)cc2C1
Agent: NC(N)=S
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
The 6-benzoyl-5,6,7,8-tetrahydro-3-mercaptopyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 41 (a), from 27.4 g of 6-benzoyl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 8.4 g of thiourea. After cooling the reaction mixture with ice, the compound precipitates. M.P. 225°-228° (decomp., from glacial acetic acid).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(N2CCOCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.5 %

Procedure:
Part A: A mixture of 2,4-dichloro-6-methylpyrimidine (4 g, 24.54 mmoles), morpholine (2.14 mL, 24.54 mmoles) and N,N-diisopropylethylamine (4.52 mL) in ethanol (60 mL) was stirred at 0° C. for 3 hours, 25° C. for 24 hours, followed by reflux for 1 hour. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (200 mL) and aq. sodium hydroxide (1 M, 50 mL). The organic layer was washed with water and brine and dried and concentrated in vacuo. The residue was recrystallized from ethyl acetate/hexanes to give 2-chloro-4-morpholino-6-methylpyrimidine (3.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][O:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C([Li])CCC.[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:46])=[C:35](OS(C(F)(F)F)(=O)=O)[CH:36]=3)[C:31](=[O:47])[C:30]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:29]2)[CH2:27][CH2:26]1>O1CCCC1.CCCCCC.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:46])=[C:35]([C:2]4[CH:3]=[C:4]([CH:12]5[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][O:13]5)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=4[O:8][CH3:9])[CH:36]=3)[C:31](=[O:47])[C:30]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:29]2)[CH2:26][CH2:27]1
Reactant: COc1cc(C2OCC(C)(C)CO2)cc(Br)c1OC
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(OS(=O)(=O)C(F)(F)F)c(F)cc2c1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C4OCC(C)(C)CO4)cc(OC)c3OC)c(F)cc2c1=O
Temperature: 25 °C
Yield: 68.5 %

Procedure:
A solution of 1.17 g of 2-(3-bromo-4,5-dimethoxy-phenyl)-5,5-dimethyl-1,3-dioxan (Example 6a)) in 10 ml of tetrahydrofuran is treated dropwise at -100° over 20 minutes with 2.2 ml of a 1.6M n-butyllithium solution in n-hexane. The solution is stirred for a further hour at -100° and then treated dropwise at this temperature with 7 ml of a 0.5M zinc chloride solution in tetrahydrofuran within 20 minutes. The reaction mixture is warmed slowly to 0° and stirred at this temperature for a further 1hr. The solution is then slowly added dropwise through a Teflon tube to a boiling mixture of 1 g of ethyl 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[[(trifluoromethyl)sulphonyl]oxy]quinoline-3-carboxylate (J. Heterocyclic Chem., 28, 1581 (1991)) and 20 mg of tetrakis-triphenylphosphine-palladium in 10 ml of tetrahydrofuran. The mixture is stirred at reflux temperature for a further 2 hrs. it is cooled to room temperature, diluted with 50 ml of ethyl acetate and washed with 50 ml of a saturated aqueous ammonium chloride solution, 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and concentrated. The residue is chromatographed on silica gel with ethyl acetate. 850 mg (68%) of ethyl 1-cyclopropyl-7-[5-(5,5-dimethyl-1,3-dioxan-2-yl)-2,3-dimethoxy-phenyl]-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate are isolated as a colourless solid. M.p. 178°-180° after recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH:11]=O)[CH2:7][CH2:6][N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:4][CH2:3]1.[F:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:11][CH2:10][CH2:9][N:8]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:6][CH2:7]2)[CH2:26][CH2:25]1
Reactant: O=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: FC1CCNCC1
Product: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1CCCN1CCC(F)CC1

Procedure:
The title compound was prepared from 3-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-propionaldehyde (Example 34C) and 4-fluoropiperidine in analogy to example 34D. MS: 402.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Li])CCC.CN(CCN(C)C)C.[CH2:22]1[O:32][C:25]2([CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[O:24][CH2:23]1>CCOCC.C1COCC1>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2([OH:31])[CH2:29][CH2:30][C:25]3([O:32][CH2:22][CH2:23][O:24]3)[CH2:26][CH2:27]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc(Br)cn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccc(F)nc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A solution of 5-bromo-2-fluoropyridine (2 g, 0.011 mol) in 50 mL of dry ether under nitrogen was cooled to −78° C. n-butyllithium (7.5 mL, 0.011 mol, 1.6 M solution in hexane) and TMEDA (2.5 g, 0.022 mol) were added dropwise. The orange solution was stirred for an additional 1 h at −78° C. and then treated dropwise over 10 min with a solution of 1,4-cyclohexanedione monoethylene ketal (1.8 g, 0.011 mol) in 20 mL of dry THF. The reaction mixture was stirred for 1 h, allowed to warm to 20° C. and poured into ice water (400 mL). The organic layer was separated, and the aqueous layer was extracted twice with EtOAc (20 mL×2). The combined organic extracts were dried over MgSO4 and evaporated to give 2 g of white solid. Chromatography on silica gel afforded 1.7 g (67% yield) of white crystals: MS: 254 (M+1)+.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C@H:14]([NH:25][C:26](=[O:41])[C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])=[C:29]([CH3:40])[CH:28]=1)[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=2[N:16]=1)=O)C1C=CC=CC=1.I[Si](C)(C)C.ClCCl.C(O)C.ClCl>ClCCl>[NH2:11][CH2:12][CH2:13][C@H:14]([NH:25][C:26](=[O:41])[C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])=[C:29]([CH3:40])[CH:28]=1)[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=2[N:16]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCNC(=O)OCc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: C[Si](C)(C)I
Agent: ClCl
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 94 from N-[(1S)-3-(benzyloxycarbonylamino)-1-(5-chloro-1H-benzimidazol-2-yl)propyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and iodotrimethylsilane in dichloromethane. Yield: quantitative; Rf value: 0.25 (silica gel; dichloromethane/ethanol=4:1); C23H26ClN5O2 (439.94); mass spectrum: (M+H)+=440/442 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:4][C:3]=1[NH:17][C:18](=[O:33])[CH:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1)[CH:20]([CH3:25])[C:21]([F:24])([F:23])[F:22].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:17][C:18](=[O:33])[CH:19]([N:26]1[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]1)[CH:20]([CH3:25])[C:21]([F:24])([F:23])[F:22]
Reactant: CC1CCN(C(C(=O)Nc2cc(CCC(=O)OC(C)(C)C)ccc2Cl)C(C)C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCN(C(C(=O)Nc2cc(CCC(=O)O)ccc2Cl)C(C)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45.0 mg (0.092 mmol) of tert-butyl 3-(4-chloro-3-{[4,4,4-trifluoro-3-methyl-2-(4-methylpiperidin-1-yl)butanoyl]amino}phenyl)propanoate (racemic diastereomer mixture) were dissolved in 0.1 ml of dichloromethane, and 0.35 ml of trifluoroacetic acid was added at RT. The reaction mixture was stirred at RT overnight and then concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 39.0 mg of the target product as a diastereomer mixture (97.9% of theory).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:18])[NH:10][C:11]([O:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]=[C:36](C(Cl)(Cl)Cl)[O:35][N:34]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-:43].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:9](=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][C:36](=[O:43])[O:35][N:34]=3)=[CH:23][CH:22]=2)[C:11]([O:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1nc(C)c(Cc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 12 h
Yield: 20.1 %

Procedure:
To a solution of 5-benzyl-2-ethoxy-6-methylpyrimidin-4(3H)-one (0.27 g) and 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.58 g) in N,N-dimethylformamide (5 mL) was added cesium carbonate (0.44 g), and the mixture was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran-ethanol (1:1, 4 mL), 1 M sodium hydroxide (2 mL) was added and the mixture was stirred for 30 min. The reaction mixture was weakly acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.11 g, 20%) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[S:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([S:17][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)OC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: S=c1[nH]c2ccccc2cc1-c1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(Sc2nc3ccccc3cc2-c2ccccc2)C1
Temperature: 25 °C

Procedure:
3-Phenylquinolin-2-thione (5.2 g.) was added to a suspension of sodium hydride (1.15 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (35 ml.) at 0°-5°. When all the hydrogen had evolved, 1-t-butoxycarbonyl-3-p-toluenesulphonyloxypiperidine (7.8 g.) was added and the mixture was heated at 80° for 2 hr. The mixture was cooled to ambient temperature poured into ice-water (350 ml.) and extracted with ethyl acetate (3×150 ml). The ethyl acetate extract was washed with brine (150 ml.) and then dried (MgSO4). The solvent was evaporated to give 2-(1-t-butoxycarbonyl-3-piperidylthio)--3-phenylquinoline, which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][NH:10][C:11]([NH2:13])=[S:12]>C(O)C>[C:4]([C:3]1[N:13]=[C:11]([NH:10][NH2:9])[S:12][CH:2]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=O)CBr
Reactant: NNC(N)=S
Solvent: CCO
Product: CC(C)(C)c1csc(NN)n1
Yield: 59 %

Procedure:
A mixture of 1-bromo-3,3-dimethyl-butan-2-one (1.35 mL, 10 mmol) and thio-semicarbazide (0.91 g, 10 mmol) in ethanol (35 mL) was refluxed for 1.5 h and evaporated. Purification by flash chromatography (SiO2) provided (4-tert-butyl-thiazol-2-yl)-hydrazine (1.01 g, 59% yield) as an orange solid. 1H-NMR (DMSO-d6, 500 MHz) 9.0 (br, 1H), 7.3 (br, 2H), 6.37 (s, 1H), 1.22 (s, 9H) ppm; MS (LC-MS) 172.1 (M+H); HPLC (method A) 2.520 min.