Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][NH:35][C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:35]2[CH2:36][CH2:37][N:33]([C:25]3[S:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:22])[N:24]=3)[C:34]2=[O:38])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Fc1ccc(CBr)cc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 69 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)-4-fluorobenzene to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 69% yield: 1H NMR (300 MHz, CDCl3) δ 7.31-7.28 (m, 2H), 7.07-7.02 (m, 2H), 4.47 (s, 2H), 4.29 (q, J=6.0 Hz, 2H), 4.08 (t, J=9.0 Hz, 2H), 3.46 (t, J=9.0 Hz, 2H), 2.62 (s, 3H), 1.34 (t, J=6.0 Hz, 3H); MS (ES+) m/z 364.1.0 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: COCCCOc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COCCCOc1ccccc1N

Procedure:
A suspension of 2.55 g of 1-(3-methoxypropoxy)-2-nitrobenzene, 3.72 g of ammonium formate in 25 ml of methanol is hydrogenated at reflux in the presence of 0.26 g of 10% Pd/C over 1.5 hours. The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation. The residue is dissolved in diethyl ether, washed with water (2×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a red oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.30 (1:2 EtOAc-heptane); Rt=228.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]([CH3:11])[C:3]21O[CH2:4]2.CC1(C)C(C)CCC(C)C1C=O.CC1(C)C(C)CCC(C)C1=O>>[CH3:10][CH:9]1[CH2:8][CH2:7][CH:6]([CH3:11])[C:3](=[CH2:4])[C:2]1([CH3:12])[CH3:1]
Reactant: CC1CCC(C)C2(CO2)C1(C)C
Agent: CC1CCC(C)C(C)(C)C1=O
Agent: CC1CCC(C)C(C)(C)C1C=O
Product: C=C1C(C)CCC(C)C1(C)C

Procedure:
The present invention provides a process for the preparation of 4,4,5,8-tetramethyl-1-oxaspiro[2.5]octane which compound can then be converted into useful 2,2,3,6-tetramethyl-cyclohexane-carbaldehyde by treating it with a Lewis type acid. The aldehyde thus obtained possesses a high degree of isomeric purity (equal or higher than 90%). The process of the invention consists in the methylenation of 2,2,3,6-tetramethyl-1-cyclohexanone to give 1,2,2,4-tetramethyl-3-methylene-cyclohexane followed by the epoxidation of the obtained compound to give 4,4,5,8-tetramethyl-1-oxaspiro[2.5]octane.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:20])[CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[ClH:1].[O:20]=[C:11]1[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][NH:9][CH2:10]1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCNCC1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
To a suspension of 1.0 g of Pd—C (10 wt. %) was added ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (10.0 g, 33.58 mmol) (Sigma-Aldrich) dissolved in Ethanol (120 mL). The reaction mixture was then heated at 50° C. under a hydrogen atmosphere (balloon) at atmospheric pressure and followed by HPLC and UPLC-MS. After 4 h at 50° C., the analyses revealed full conversion of the reaction. After cooling to room temperature, the crude mixture was filtered through celite. The celite was washed with EtOH and the filtrate was concentrated in vacuo to give the desired ethyl 3-oxopiperidine-4-carboxylate hydrochloride as an off-white solid (5.84 g, 28.12 mmol, 84% yield). 1HNMR (500 MHz, DMSO-d6): 1.25 (t, J 7.3 Hz, 3H); 2.58 (t, J 6.3 Hz, 2H); 3.26 (t, J 6.3 Hz, 2H); 3.67 (s, 2H), 7.22 (q, J 7.3 Hz, 2H); 9.50 (s, br, 1H); 11.90 (s, br, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)=[O:20])[CH3:17].[C:30]([CH:32]1[CH2:34][NH:33]1)#[N:31]>C(OCC)C>[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:33]2[CH2:34][CH:32]2[C:30]#[N:31])=[O:27])=[CH:28][CH:29]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1ccc(C(=O)O)cc1
Reactant: N#CC1CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(C(=O)N2CC2C#N)cc1
Reaction time: 1 h

Procedure:
The same compound is obtained when a solution of 1.1 g. dicyclohexylcarbodiimide in 5 ml. diethyl ether is added at 0° C. to a mixture of 0.97 g. p-ethoxycarbonylbenzoic acid and 0.34 g. 2-cyanoaziridine in 15 ml. diethyl ether, stirred for 2 hours at this temperature and then for 1 hour at ambient temperature, the precipitated dicyclohexylurea is filtered off with suction (1.13 g.), the filtrate evaporated and the evaporation residue is triturated with about 3 ml. diethyl ether. The yield is 0.66 g.; m.p. 92°-94° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O.[H][H]>[Ni].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccccc1C1(O)CCCCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1C1(O)CCCCC1

Procedure:
A suspension of 5.20 g (16.45 mmol) of 1-(2-nitrophenyl)cyclohexanol and 500 mg of Raney nickel in EtOH (70 mL) is hydrogenated at RT and under 3 bar hydrogen pressure for 4 hours. The catalyst is filtered off through CELITE® filter aid and the filtrate is evaporated down in vacuo. The residue is recrystallized from hexane. Yield: 1.53 g (49%); Rf=0.38 (silica gel, hexane/EtOAc 4:1); ESI-MS: [M+H—H2O]+=174.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14].CN1CCOCC1>ClCCl>[CH3:8][C@@H:7]([CH2:9][CH3:10])[C@H:5]([NH:6][C:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:14])[C:4]([O:3][CH3:2])=[O:11]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 64 h
Yield: 98.2 %

Procedure:
A solution of L-iso-leucine methyl ester hydrochloride (2.5 g, 13.75 mmol) in dichloromethane (35 mL) at 0° C. was treated with 4-nitrophenyl chloroformate (3.05, 15.13 mmol) and 4-methylmorpholine (3.2 mL, 29.11 mmol), stirred at 25° C. for 64 hours, and partitioned between dichloromethane and saturated NaHCO3. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (4.19 g, 98% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([CH:12]([CH2:14][CH3:15])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:16]([CH2:18][CH3:19])[CH3:17])[CH:2]1[O:4][CH2:3]1.[NH3:20]>O>[OH:4][CH:2]([CH2:1][O:5][C:6]1[C:11]([CH:12]([CH2:14][CH3:15])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:16]([CH2:18][CH3:19])[CH3:17])[CH2:3][NH2:20]
Reactant: N
Reactant: CCC(C)c1cccc(C(C)CC)c1OCC1CO1
Solvent: O
Product: CCC(C)c1cccc(C(C)CC)c1OCC(O)CN
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A 2.5 liter autoclave is charged, at room temperature and under nitrogen blanketing, with 440 g (1.667 mol) of 2,6-bis(sec-butyl)phenyl glycidyl ether and 30.2 g of water. Then 698.5 g (41.08 mol) of ammonia gas is blown in under pressure over 5 minutes and the reaction mixture is thereafter heated to 80° C. over 2 hours. After 1 hour at 80° C., the reaction mixture is cooled to room temperature, the pressure in the system is removed and the reaction product is concentrated on a rotary evaporator at 80° C./13 mbar. Yield: 436.1 g (93% of theory) of a brownish liquid reaction product which is purified by flash distillation. The boiling point is 170° C./0.13 mbar and the amine content is 3.548 meq/g (=99.1% of theory).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]2[C:22]([CH3:23])=[C:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30](I)[CH:31]=4)[C:26]([CH3:35])([CH3:34])[CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[F:36])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]2[C:22]([CH3:23])=[C:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[CH:31]=4)[C:26]([CH3:35])([CH3:34])[CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[F:36])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1COCCN1
Reactant: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc2cccc(F)c2c1N1CC(C)(C)c2ccc(I)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc2cccc(F)c2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 105 °C
Reaction time: 1 h

Procedure:
Prepared according to procedure N using 2-(3,5-bis(trifluoromethyl)phenyl)-5-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methylquinoline (in a mixture with the 7-F regioisomer; described herein) (160 mg, 0.25 mmol), morpholine (43 μL, 0.50 mmol), Pd2dba3 (34.1 mg, 0.037 mmol), 2-(dicyclohexylphosphino)-2,4,6-tri-i-propyl-1,1-biphenyl (35.5 mg, 0.074 mmol), and sodium tert-butoxide (71.6 mg, 0.745 mmol) in toluene (2.5 mL). The reaction was stirred at 105° C. for 1 h. Purification afforded 2-(3,5-bis(trifluoromethyl)phenyl)-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-5-fluoro-3-methylquinoline as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.15 (2H, s), 8.00 (2H, t), 7.65 (1H, m), 7.28 (1H, m), 7.24 (1H, m), 7.17 (1H, m), 7.07 (1H, m), 3.62-3.95 (6H, m), 2.81-2.31 (4H, m), 2.35 (3H, s), 1.51 (3H, s), 1.45 (3H, s). Mass Spectrum (ESI) m/e=604 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[CH2:37]Cl)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([C:26]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH:35]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1
Product: COc1cc(-c2cccc(CN(c3ccc(Br)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
4-(4-Bromophenyl)amino-1-(tert-butoxycarbonyl)piperidine (711 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][C:19](=O)[CH2:18][N:17]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(=O)(O)[O-].[Na+]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[C:7]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][C:19](=[CH:1][CH3:2])[CH2:18][N:17]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Product: CC=C1C[C@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of ethyltriphenylphosphonium bromide (11 eq) in 14 mL of THF was added potassium tert-butoxide (10 eq) at room temperature. The reaction mixture was stirred at that temperature for 20 minutes. Then the reaction was cooled to 0° C., and (S)-benzyl 3-(tert-butoxycarbonylamino)-5-oxopiperidine-1-carboxylate (1 eq) in 7 mL of THF was added to the reaction mixture. The reaction was allowed to warm up room temperature. After being stirred for 40 minutes, the reaction mixture was poured into aq. sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated and washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=2:1) to yield (S)-benzyl 3-(tert-butoxycarbonylamino)-5-ethylidenepiperidine-1-carboxylate. LC/MS (m/z): 261.2 (MH+-100), Rt: 1.12 min. HPLC: Rt: 4.31 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=O)[CH3:22])=[CH:16][CH:15]=1.[OH:24][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[CH2:26][NH2:27]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:27][CH2:26][CH:25]([OH:24])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=2)[CH3:22])=[CH:16][CH:15]=1
Reactant: CC(=O)Cc1ccc(OCCCCCCCCCCCO)cc1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Product: CC(Cc1ccc(OCCCCCCCCCCCO)cc1)NCC(O)c1cccc(C(F)(F)F)c1

Procedure:
The compound was prepared as in Example 4, from 1-[4-(11-hydroxyundecyloxy)phenyl]propan-2-one (7.3 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)-ethanamine (4.7 g) and purified by chromatography on silica gel in 5% methanol dichloromethane, mp 45°-50° C. as a 50:50 mixture of diastereoisomers.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1.O.NN>C(O)C>[CH3:1][O:2][CH2:3][C:4]1([NH2:13])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1
Reactant: COCC1(N2C(=O)c3ccccc3C2=O)Cc2ccccc2C1
Agent: NN
Solvent: O
Solvent: CCO
Product: COCC1(N)Cc2ccccc2C1

Procedure:
A mixture of 2-(2-methoxymethylindan-2-yl)-isoindole-1,3-dione (0.30 g, 0.976 mmol) and hydrazine hydrate (47 μl, 0.976 mmol) in 95% ethanol (15 ml) is heated to reflux for 45 hours. Further hydrazine hydrate (9.4 μl, 0.976 mmol) is added and the reaction refluxed for an additional 16 hours, followed by addition of a final portion of hydrazine hydrate (9.4 μl, 0.976 mmol) and a further 16 hours reflux. After cooling, the resultant suspension is filtered and the filter cake washed with ethanol. The combined filtrate and washings are evaporated and triturated with ether to afford 2-methoxymethylindan-2-ylamine, MH+178.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:17]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NCCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(Cl)cc1)C1CCCCC1
Reaction time: 1.5 h

Procedure:
[2-(4-chlorophenyl)ethyl]amine (3.5 g) was dissolved in a 1:2 mixed solution (45 mL) of EtOAc-saturated aqueous sodium bicarbonate. A solution of cyclohexanecarbonyl chloride (3.35 mL) in EtOAc (18 mL) was added dropwise to the reaction liquid over 5 minutes. After stirring for 1.5 hours, the reaction liquid was extracted with EtOAc, washed with an aqueous 1 M sodium hydroxide solution and water, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dried to obtain N-[2-(4-chlorophenyl)ethyl]cyclohexanecarboxamide (5.69 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([F:18])[F:17])=[CH:6][CH:5]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC(F)F)cc1
Temperature: 125 °C
Yield: 45.9 %

Procedure:
Under N2 flow, 1.3 g of 4-hydroxy-benzoic acid methyl ester (8.3 mmol, 1.0 eq) and 1.5 g of sodium chlorodifluoroacetate (10.0 mmol, 1.2 eq) were dissolved in DMF (25 mL) in a two neck round bottom flask; potassium carbonate (1.4 g, 10.0 mmol, 1.2 eq) was added and the mixture was heated at 125° C. for 3.5 hours. The mixture was then diluted with water and extracted with DCM; organic phases were dried and evaporated, the crude was purified with Si column (eluent: cycloexane/EtOAc 80/20) to obtain 0.77 g of product (yield 46%) which was used directly for the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: Cn1cnc2cc(C(=O)O)ccc21
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cnc2cc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)ccc21
Yield: 90 %

Procedure:
The title compound is prepared from 1-methyl-1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 90% of theory; LC (method 4): tR=1.62 min; Mass spectrum (ESI+): m/z=332 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH2:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:27][CH:26]=1)[CH3:24]
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: CCc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCc1ccc(CNC2CCN(CCn3c(=O)cnc4ccc(OC)cc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 200 mg of 4-ethylbenzaldehyde, 100 mg of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 15 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.32 g of 1-(2-(4-(4-ethylbenzylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(O)C.O1CCCC1.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: O=C(O)/C=C/C(=O)c1ccc(F)c(Br)c1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCC(=O)c1ccc(F)c(Br)c1

Procedure:
A solution of 6.2 g (0.023 mol) of (E)-4-(3-bromo-4-fluorophenyl)-4-oxo-2-butenoic acid in a mixture of 200 ml ethanol and 25 ml tetrahydrofuran was hydrogenated in the presence of 1.0 g of 10% platinum/charcoal at ambient temperature under a pressure of 50 psi until the uptake of hydrogen was complete. The residue remaining after the catalyst and solvent had been eliminated crystallised spontaneously and after being washed thoroughly with diisopropylether yielded 1.7 g (27% of theoretical) of colourless crystals, m.p. 108–110° C. and Rf 0.73 (El F).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=O>C(O)(=O)C>[F:20][C:19]([F:21])([F:22])[C:15]1[CH:14]=[C:13]([C:11]2[N:3]3[N:4]=[CH:5][N:6]=[C:2]3[N:1]=[CH:9][CH:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc[nH]n1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2ccnc3ncnn23)c1

Procedure:
A mixture of 3.36 g. of 3-amino-1,2,4-triazole and 9.66 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone in 50 ml. of glacial acetic acid is refluxed for 5 hours. The resulting mixture is worked up as described in Example 54 to give the product of the Example, m.p. 158.5°-159.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:30][CH2:17][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:19][CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(CNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Into a 1-neck round-bottom flask were added 3-[3-({5-chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phenyl]propan-1-ol (0.18 g, 0.45 mmol) and DCM (5 mL). To the reaction mixture was added a solution of boron tribromide in methylene chloride (3.0 mL, 3.0 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when NaHCO3 (saturated aqueous solution, 10 mL) was added. The mixture was allowed to warm up to rt and DCM was added. The aqueous layer was extracted with DCM twice. The organic layers were combined, dried, filtered, and concentrated under vacuum to give the desired product as an off-white powder (150 mg, 74%). LCMS for C20H21BrClN4O (M+H)+: m/z=447.0, 449.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)[CH3:2]
Reactant: Sc1ccc(Cl)cc1
Reactant: CCOC(=O)CCCCCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCSc1ccc(Cl)cc1

Procedure:
To a solution of 7-bromoheptanoic acid ethyl ester (2.5 mL, 12.8 mmol) and triethylamine (2 mL, 14.3 mmol) in dichloromethane (10 mL) was added 4-chlorothiophenol (1.86 g, 12.8 mmol) under an atmosphere of argon. The mixture was stirred at reflux for 2 hours after which it was concentrated under reduced pressure. The oil was dissolved in ethyl acetate (50 mL) and then washed successively with saturated aqueous sodium hydrogen carbonate (25 mL), distilled water (25 mL) and brine (25 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an yellow oil that was purified by flash chromatography (1:9 diethyl ether:40-60° C. petroleum ether). The title compound was obtained as a colourless oil (3.3 g, 87%).