Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([CH:19](OS(C(F)(F)F)(=O)=O)[CH3:20])[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[CH2:13][O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>ClCCl>[CH2:1]([O:8][C:9]([C:11]1([CH:19]=[CH2:20])[CH2:16][O:15][C:14]([CH3:17])([CH3:18])[CH2:13][O:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(OS(=O)(=O)C(F)(F)F)C1(C(=O)OCc2ccccc2)COC(C)(C)CO1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: ClCCl
Product: C=CC1(C(=O)OCc2ccccc2)COC(C)(C)CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.6 %

Procedure:
A suspension of sodium hydride (80 mg, 2 mmol, 60% dispersion in mineral oil) in anhydrous tetrahydrofuran (3 mL) was stirred at −78° C. under nitrogen. A solution of 2-(1-hydroxy-ethyl)-5,5-dimethyl-[1,4]dioxane-2-carboxylic acid benzyl ester (400 mg, 1.36 mmol) in tetrahydrofuran (3 mL) was added and the reaction mixture was stirred at −78° C. for 15 min. A solution of N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (1.06 g, 2.7 mmol) in tetrahydrofuran (5 mL) was added and the reaction mixture was stirred at −78° C. for 30 min. The reaction mixture was warmed to room temperature and then stirred at room temperature for 5 h. The reaction mixture was cooled to 5° C., saturated ammonium chloride solution was cautiously added and the mixture was extracted with ethyl acetate. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 9:1 to 4:1 to afford crude 5,5-dimethyl-2-(1-trifluoromethanesulfonyloxy-ethyl)-[1,4]dioxane-2-carboxylic acid benzyl ester (833 mg, 1.3 mmol) as a yellow oil which darkened upon standing and as a 2:1 mixture of diastereoisomers which was used immediately in the next step. LCMS (m/z) 449.0 [M+H], Tr=3.29 min. A solution of 5,5-dimethyl-2-(1-trifluoromethanesulfonyloxy-ethyl)-[1,4]dioxane-2-carboxylic acid benzyl ester (833 mg, 1.3 mmol) in dichloromethane (5 mL) was stirred at room temperature under nitrogen. 1,8-Diazabicycloundec-7-ene (790 mg, 0.8 mL, 5.2 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was cooled to 0° C. and acidified to pH 2 with ice cold hydrochloric acid (2 M). The mixture was extracted with dichloromethane. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/diethyl ether 9:1 to 3:1 to afford the title compound (189 mg, 52% over two steps) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.13 (s, 3H), 1.32 (s, 3H), 3.53 (d, J=11.8 Hz, 1H), 3.66 (d, J=11.8 Hz, 1H), 3.72 (d, J=12.1 Hz, 1H), 4.24 (d, J=12.1 Hz, 1H), 5.19-5.35 (m, 3H), 5.51 (dd, J=17.4, 0.9 Hz, 1H), 5.80 (dd, J=17.4, 10.7 Hz, 1H), 7.35-7.40 (m, 5H). LCMS (m/z) 277.1 [M+H], Tr=2.81 min.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:8]=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH2:2][CH2:3][CH3:4].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([N:5]([C:6]1[N:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:8]=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)[C:29]([NH:28][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: O=C=NC1CCCCC1
Product: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, butyl-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) to give the title compound as yellow solid. MS: m/e=425.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17]Cl)=[O:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6]>O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[N:11]=[C:12]1[N:14]([CH2:15][CH2:16][CH2:17][O:13]1)[C:5]2=[O:6]
Reactant: O=C(NCCCCl)Nc1c(Cl)cccc1C(=O)O
Solvent: O
Product: O=c1c2cccc(Cl)c2nc2n1CCCO2
Temperature: 25 °C
Yield: 40 %

Procedure:
A 250 mL round bottom flask is charged with 3-chloro-2-[3-(3-chloro-propyl)-ureido]-benzoic acid (3.40 g, 11.7 mmol) and 50 mL of 10% aqueous KHCO3, and warmed to reflux for 1 hour. 50 mL of H2O is added and the solution is allowed to cool to room temperature, then to 0° C. The resulting yellow solid is collected by filtration to provide 2.32 g of crude product, which is recrystallized from CH2Cl2-isopropyl ether to provide the product as a white solid: 1.10 g (4.6 mmol, 40% yield). M.p. 206.7-207.9° C. 1H NMR (CDCl3): 8.09 (d, J 8, 1H), 7.77 (d, J=8, 1H), 7.24 (t, J=8, 1H), 4.54 (t, J=5, 2H), 4.14 (t, J=6, 2H), 2.32 (m, 2H). MS (CI): 237 (M+H, 100).
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].[O-]Cl.[Na+].[OH:21]S([O-])(=O)=O.[Na+]>C(Cl)Cl>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[C:6](=[O:21])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: O=S(=O)([O-])O
Reactant: N#CN1c2ccccc2CCc2ccccc21
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: N#CN1c2ccccc2CC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
20 g (85 mmols) of (I) are dissolved in 120 ml of CH2Cl2. The solution is cooled to 0° C. and added with 0.24 g of 2,2,6,6-tetramethylpiperidine nitroxide, then with 180 ml of 1.4M NaClO, adjusted to pH 8.3 with a NaHSO4 saturated solution. The mixture is left for 1 hour at 0° C., then warmed to 20° C. for 4 hours. The organic phase is separated and washed with 50 ml of water, dried with 2 g of Na2SO4 and solvent is evaporated off. The residue is taken up with 50 ml of acetone and kept at 0° C. for 2 hours. The mixture is filtered, washed with 50 ml of cold acetone, dried at 60° C. for 4 hours to obtain 17 g of 5-cyano-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine (VII), m.p. 153-4° C., with 98.5% purity by HPLC (85% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3]1.[C:17](OC=C)(=[O:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(CC(C)C)=O>[C:17]([O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3]1)(=[O:19])[CH3:18]
Reactant: C=COC(C)=O
Reactant: COc1cccc(CC2=CC(O)CC2=O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)O
Product: COc1cccc(CC2=C[C@H](OC(C)=O)CC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-Hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone (9 g, 41.26 mmol) was dissolved in isobutyl methyl ketone (90 mL), and vinyl acetate (8.4 g, 97.57 mmol) and Lipase derived from Pseudomonas cepacia (0.9 g) were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove the Lipase and the filtrate was evaporated. The resulting residue was dissolved in PhCH3 (150 ml), and triphenylphosphine (6.5 g; 24.78 mmol) and AcOH (1.61 g, 26.81 mmol) were added to the solution. Then diisopropylazodicarboxylate (5 g, 24.72 mmol) was added to the mixture at 5° C. After the reaction was completed, the reaction mixture was filtered to remove the precipitate and the filtrate was evaporated. The residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-3-(3-methoxybenzyl)-4-oxocyclopent-2-enyl acetate as yellow oil: 10 g (yield: 93%, 95% ee by HPLC using a chiral column)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:13]([CH3:12])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: CNc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1ccc(N(C)c2ccccc2)cc1
Yield: 99.5 %

Procedure:
According to the general procedure B, methyl 4-chlorobenzoate (172 mg, 1.00 mmol) reacted with N-methylaniline (130 mg, 1.20 mmol) using 1 mol % of Pd(OAc)2, 2 mol % of Ph5FcP(t-Bu)2, and K3PO4 (640 mg, 3.02 mmol) in DME at 100° C for 20 h to give the title compound (240 mg, 97%) as a solid: 1H-NMR (500 MHz, CDCl3): δ 7.89 (d, 2H, J=9.05 Hz), 7.41 (t, 2H, J=7.68 and 8.17 Hz), 7.24-7.21 (m, 3H), 6.79 (d, 2H, J=9.06 Hz), 3.88 (s, 3H), 3.37 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 167.09, 152.44, 147.41, 130.91, 129.70, 125.50, 125.24, 119.08, 113.70, 51.47, 40.09. GC/MS(EI): m/z 241 (M+). Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.74; H, 6.34; N, 5.80.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:19][C@H:16]2[CH2:15][CH2:14][C@@H:13]([NH:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine (20 mg, 0.07 mmol) in chloroform (0.5 mL) at 20° C. was treated with 4-chlorophenyl isocyanate (11 mg,0.07 mmol). The mixture was shaken at room temperature for 18 hours then concentrated under reduced pressure. The compound was purified by reverse phase HPLC to provide the desired compound. MS (ESI (+)) m/e 429 (M+H)+; 1H NMR (500 MHz, DMSO) δ ppm 8.55 (s, 1 H), 8.52 (d, 1 H), 8.45 (d, 1 H), 7.83 (s, 1 H), 7.57 (d, 1 H), 7.41 (d, 2 H), 7.26 (d, 2 H), 6.70 (s, 1 H), 6.31 (d, 1 H), 3.78 (s, 1 H), 3.71 (s, 1 H), 1.63-1.93 (m, 8 H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2.[CH3:32][NH:33][C:34]([C:36]1[CH:46]=[CH:45][C:39]([CH:40]=[CH:41][C:42](O)=[O:43])=[CH:38][CH:37]=1)=[O:35].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:42](=[O:43])[CH:41]=[CH:40][C:39]3[CH:45]=[CH:46][C:36]([C:34](=[O:35])[NH:33][CH3:32])=[CH:37][CH:38]=3)[CH2:29][CH2:30]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N4CCNCC4)c3Cl)c2n1
Reactant: CNC(=O)c1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)N2CCN(C(=O)c3ccc(Cl)c(COc4cccc5ccc(C)nc45)c3Cl)CC2)cc1
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of 8-[2,6-dichloro-3-(piperazine-1-carbonyl)benzyloxy]-2-methylquinoline dihydrochloride (60 mg), 4-(methylcarbamoyl)cinnamic acid (26.9 mg) and 1-hydroxybenzotriazole (22.6 mg) in N,N-dimethylformamide (0.6 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (27.4 mg) at ambient temperature, and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[4-[4-(methylcarbamoyl)cinnamoyl]piperazine-1-carbonyl]benzyloxy]-2-methylquinoline (73 mg) as colorless amorphous.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)#[N:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([C:27]#[N:28])=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, yellow solid (54 mg, 47%), MS (ISP) m/z=456.5 [(M+H)+], mp 195° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-cyano-benzoic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(Cl)(Cl)Cl.Cl[C:20]([O:22][C:23]1([CH3:27])[CH2:26][CH2:25][CH2:24]1)=[O:21]>C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:20]([O:22][C:23]1([CH3:27])[CH2:26][CH2:25][CH2:24]1)=[O:21]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC1(OC(=O)Cl)CCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC1(C)CCC1
Reaction time: 8 h

Procedure:
A suspension of 171 mg. (0.74 mM) of phenylalanine methyl ester hydrochloride in 10 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 1.5 mM is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-phenylalanine methyl ester. Saponification of the above ester is carried out by dissolving the residue in 10 ml. of methanol, water (10 ml.) is added and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2 N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and trituration with pet ether affords N-(1-methylcyclobutyl-oxycarbonyl)-phenylalanine, which is isolated by filtration.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.NC1CCN(CCN2C3C(=CC(C#N)=CC=3)N=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(C#N)cc32)CC1
Agent: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1

Procedure:
tert-Butyl{1-[2-(7-cyano-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 199) was deprotected with TFA as described for Intermediate 197 to give the crude free base of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:13][CH2:12][CH2:11][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CCCO)c(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCBr)c(OC)c1
Yield: 76.6 %

Procedure:
Compound 19-1 (2.68 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (3.99 g) and N-bromosuccinimide (2.69 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to give the object product (2.71 g) as a pale-brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([NH2:8])[N:7]=1.[FH:13]>>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([F:13])=[C:6]([NH2:8])[N:7]=1
Reactant: COC(=O)c1ncc(N)nc1N
Reactant: F
Product: COC(=O)c1nc(F)c(N)nc1N
Temperature: -78 °C

Procedure:
In a reactor cooled to -78° C. in an acetone-dry ice bath is placed methyl 3,5-diaminopyrazinoate (6 g.) and liquid hydrogen fluoride (70 ml.). A stream of fluorinehelium mixture (1:4 v /v) is passed through the solution for 51/2 hours at <78° C. followed by a vigorous stream of nitrogen to remove the solvent. The reaction residue is treated with conc. hydrochloric acid (60 ml.) evaporated to dryness, dissolved in water (75 ml.) and neutralized with aqueous sodium hydroxide to give methyl 3,5-diamino-6-fluoropyrazinoate (5 g.) which is purified by sublimation (140°-50° C, 0.05 mm Hg) and recrystalliation from 2-propanol.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(OCC)(=O)C>[OH-].[Na+]>[CH2:11]([O:10][C:8]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(NCCCBr)OCc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
3-Bromopropylamine hydrobromide (5.0 g, 22.8 mmol) was dissolved in an aqueous NaOH solution (15 wt %, 80 ml) and cooled to 0° C. under nitrogen before benzyl chloroformate was added dropwise. The reaction was left to stir overnight then ethyl acetate (100 ml) was added and the phases were separated. The organic phase was further washed with a HCl solution (2 M, 100 ml), a NaOH solution (2 M, 100 ml), brine (100 ml), dried over Na2SO4, and evaporated to yield 12 as a clear oil (6.22 g, 22.8 mmol, 100%). Rf=0.31 (8:2 Hexane/Ethyl acetate); 1H NMR (300 MHz, CDCl3) δ=7.40-7.33 (m, 5H, ArCH), 5.11 (s, 2H, CH2Ph), 4.94 (bs, 1H, NHCbz), 3.45 (t, 3J(H,H)=6.4 Hz, 2H, CH2Br), 3.36 (q, 3J(H,H)=6.4 Hz, 2H, CH2NHCbz), 2.08 (q, 3J(H,H)=6.4 Hz, 2H, CH2CH2CH2); 13C NMR (75 MHz, CDCl3) δ=156.4 (CO), 136.4 (ArCCH2), 128.5 (ArCH), 128.2 (ArCH), 127.0 (ArCH), 66.8 (CH2Ph), 39.4 (CH2NHCbz), 32.4 (CH2CH2CH2), 30.6 (CH2Br); HRMS (ESI+): m/z calculated for C11H14BrNO2Na [M+Na]+: 294.0106, found 294.0099.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[C:35](Cl)([Cl:37])=[O:36]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:35]([Cl:37])=[O:36])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:26]2[CH2:30][S:29]C(=S)[S:27]2)[CH:17]=[C:18]([O:24][CH3:25])[C:19]=1[O:20][CH2:21][O:22][CH3:23]>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:26]([SH:27])[CH2:30][SH:29])[CH:17]=[C:18]([O:24][CH3:25])[C:19]=1[O:20][CH2:21][O:22][CH3:23]
Reactant: COCOc1c(OC)cc(C2CSC(=S)S2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1c(OC)cc(C(S)CS)cc1OC
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (0.622 g, 16.38 mmole) is added to 60 ml dry diethyl ether. To this slurry is added dropwise 4-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1,3-dithiolane-2-thione (33) (3.40 g, 10.24 mmole) predissolved in 35 ml dry THF. The reaction is stirred under an N2 atmosphere until the solution becomes colorless (4 hours). The reaction is cooled to 0° C. and the excess hydride destroyed with H2O. The reaction mixture is acidified with 10% HCl and immediately extracted with diethyl ether. The organic layer is washed with H2O, dried over MgSO4, filtered and evaporated to a white solid (2.47 g, 84%). NMR: (CDCl3) 2.33,d,1H;2.90,m,1H;3.10,m,1H; 3.59,s,3H;3.85,s,6H;4.03,m,1H;5.10,s,2H;6.53,s,2H Melting Point: 84°-85° C. C,H,S analysis: (theoretical, actual) C (49.63,49.52); H (6.25,6.28); S (22.08,22.16).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1CCC2C(=CC(O)=CC=2)C1CC1C=CC(Cl)=C(Cl)C=1)(C)(C)C.[OH-].[K+].Cl[C:59]([F:69])([F:68])C(C1C=CC=CC=1)=O>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH:59]([F:69])[F:68])=[CH:13][CH:14]=2)[CH:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCc2ccc(OC(F)F)cc2C1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Tert-butyl[1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (180 mg, 0.464 mmol, prepared analogously to tert-butyl[1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate, cf. Example 34.2 and potassium hydroxide (1.4 g, 25 mmol) were suspended in acetonitrile (4 mL). After stirring the two phase system for 45 min at room temperature the reaction mixture was cooled to −15° C. and a solution of 2-chloro-2,2-difluoro-1-phenylethanone (442 mg, 2.32 mmol) in acetonitrile (1 mL) was added dropwise over 30 min. The reaction mixture was warmed to room temperature and then heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane, silica gel). Yield: 30 mg (0.069 mmol, 15%).