Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[N:23]=[C:22]([C:24]([O:26]C)=O)[CH:21]=[CH:20][N:19]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[CH3:30][NH2:31].Cl>CC(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[N:23]=[C:22]([C:24]([NH:31][CH3:30])=[O:26])[CH:21]=[CH:20][N:19]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccnc(NCCCN2CCN(c3cccc(Cl)c3)CC2)n1
Reactant: CN
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CNC(=O)c1ccnc(NCCCN2CCN(c3cccc(Cl)c3)CC2)n1
Temperature: 25 °C

Procedure:
4.5 g (11.5 mmols) of methyl 2-[[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]amino]pyrimidine-4-carboxylate and 200 ml of methanol are introduced into a 0.5 l, round bottomed flask and then the solution is saturated with gaseous methylamine. The reaction mixture is stirred at room temperature while saturating several times with gaseous methylamine. The solvent is evaporated under reduced pressure. 4.05 g (10.4 mmols) of base are obtained to which 104 ml of 0.1N hydrochloric acid in 2-propanol are added. The solvent is evaporated and the product is recrystallised from 2-butanone. 3.8 g of compound are obtained.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH2:5])=[S:4].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[C:36](Cl)=[O:37]>CCOC(C)=O>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[C:3]1[S:4][C:35](=[O:39])[C:36](=[O:37])[N:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C(N)=S)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C1=NC(=O)C(=O)S1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
To a flask containing EtOAc (30 mL) was added 1-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)thiourea (0.600 g, 1.52 mmol) and triethylamine (510 μl, 3.66 mmol). A solution of oxalyl chloride (467 mL, 5.34 mmol) in EtOAc (24 mL) was added and the solution was stirred at ambient temperature for 15 min Evaporation of solvent in vacuo left a white-yellow solid which was dissolved in 50 mL of dichloromethane and washed with water (3×25 mL). The organic layer was dried (MgSO4) and concentrated to furnish 2-(methyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)thiazole-4,5-dione as an orange solid (632 mg, 92%): mp 114-118° C.; 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.36 (d, J=8.7 Hz, 2H), 7.82 (d, J=9.1 Hz, 2H), 7.50-7.34 (m, 4H), 3.82 (s, 3H); ESIMS m/z 448 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:11]([CH:12]=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[C:14]=2[CH2:18][CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:40]([O:42][CH3:43])=[O:41])#[C:35][C:36]([O:38][CH3:39])=[O:37].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]3[C:12]([C:13]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:24][CH:25]=4)=[C:14]([CH2:18][CH3:19])[C:15]3=[CH:16][CH:17]=1)=[C:34]([C:40]([O:42][CH3:43])=[O:41])[C:35]=2[C:36]([O:38][CH3:39])=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cc(OCc3ccccc3)ccc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)OC)c(C(=O)OC)c3c(OCc4ccccc4)ccc1n32
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
6-Benzyloxy-2-(4-benzyloxyphenyl)-1-ethylindolizine (50.0 g, 115 mmol) and dimethyl acetylene dicarboxylate (18.5 ml, 150 mmol) was dissolved in 1100 ml of dry toluene at 0° C. The reaction was slowly heated to room temperature and stirred for 3 hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (26 g, 115 mmol) was added and stirring was continued for 1/2 hour. The mixture was filtered through celite and the solvent removed. The crude product was crystallised from methanol to afford 47.4 g (71%) of dimethyl 7-benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate as yellow crystals. M.p. 115-120° C. 1H-NMR (DMSO-d6, 300 MHz) δ: 1.32 (t, 3H); 3.01 (q, 2H); 3.56 (s, 3H); 3.72 (s, 3H); 5.21 (s, 2H); 5.50 (s, 2H); 7.17 (d, 2H; 7.32-7.53 (m, 10H); 7.60 (d, 2H); 7.67 (d, 1H); 8.22 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13](=[O:15])[CH3:14].[Br-:16].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(OCC)C.C(=O)([O-])O.[Na+]>[Br:16][CH2:14][C:13]([C:4]1[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:15]
Reactant: COc1ccc(C(F)(F)F)cc1C(C)=O
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(C(F)(F)F)cc1C(=O)CBr
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 1-[2-methoxy-5-(trifluoromethyl)phenyl]ethanone (1.00 g, 4.60 mmol) in diethyl ether (15 mL) was added phenyltrimethylammonium tribromide (1.78 g, 4.60 mmol), and the mixture was stirred overnight. The reaction mixture was diluted with diluted aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (1.35 g, 98%) as a colorless solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[O:18]1[CH:22]=[C:21]([C:23](OC)=[O:24])[C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]1=2>O1CCCC1>[OH:24][CH2:23][C:21]1[C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[O:18][CH:22]=1
Reactant: COC(=O)c1coc2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1coc2ccccc12
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Diisobutylaluminium hydride in toluene (1.5M, 16.8 ml, 25.2 mmol) was added dropwise to a solution of methyl benzo[b]furan-3-carboxylate (2.02 g, 11.5 mmol) in tetrahydrofuran (50 ml) at -75° C. The resulting solution was stirred at -75° C. for 30 minutes, the cooling bath removed and the mixture allowed to warm to room temperature. The reaction mixture was recooled to -40° C. and quenched by sequential addition of methanol (3 ml), water (1.5 ml) and 2M sodium hydroxide (1.5 ml). The mixture was allowed to warm up to produce a gel, which was filtered off and washed with dichloromethane (6×50 ml). The filtrate was evaporated to dryness, the residue redissolved in ether and the solution dried over magnesium sulfate. The solution was evaporated to afford the title compound (1.66 g, 98%) as an oil which crystallised on standing; δH (CDCl3) 1.61 (1H, br s, OH), 4.85 (2H, s, CH2OH), 7.25-7.35 (2H, m, ArH), 7.49 (1H, dd, J 7.8, 1.0Hz, ArH), 7.61 (1H, s, 2-H), 7.67 (1H, m, ArH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(OCCCCl)cc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Product: N#Cc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 30 %

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 4-(3-chloropropoxy)benzonitrile were reacted using potassium iodide as catalyst to give the white title compound (recrystallizing from isopropyl alcohol-isopropyl ether) in 30% yield, m.p. 107°-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=2)[C:5](=O)[NH:4][CH:3]=1.O.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=2)[C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: CCOC(=O)c1ccc2c(Cl)c[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reaction time: 18 h

Procedure:
Anal. Found: C, 57.02; H, 3.99; N, 5.53. Calc for C12H10ClNO3 : C, 57.27; H, 4.01; N, 5.57. ##STR168## Ethyl 4-chloro-1-oxo-1,2-dihydro-7-isoquinolinecarboxylate (500 mg, 1.99 mmol) was warmed in POCl3 (3 mL) until a clear solution formed, and was then allowed to stand at 23° C. for 18 h. The reaction mixture was poured into warm water, extracted with EtOAc (3×20 mL), and the combined organic extracts washed with water and saturated brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexane-EtOAc (90:10) as eluant followed by crystallisation from i-Pr2O to give ethyl 1,4-dichloro-7-isoquinolinecarboxylate (377 mg, 1.40 mmol) as a pale pink solid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][NH2:36]>>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:36]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=465.1 (M+H)+
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[N:27]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[N:26]=[N:25][N:24]=1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([N:27]3[C:23]([CH3:22])=[N:24][N:25]=[N:26]3)=[CH:29][CH:30]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Reactant: Cc1nnnn1-c1ccc(C(=O)O)cc1
Product: Cc1nnnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 4-(5-methyl-tetrazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.41 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
22.4 g of 1-[2-(4-chlorophenyl)-ethyl]piperazine and 12.1 g of triethylamine are dissolved in 200 ml of dichloromethane, and a solution of 20.4 g of 4-methoxybenzoyl chloride in 30 ml of dichloromethane is added dropwise, while stirring, at 25°-30°. Stirring is continued overnight at room temperature and then the whole is washed in succession with 150 ml of 2N sodium hydroxide solution and with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is crystallised from ethanol. 1-[2-(4-chlorophenyl)-ethyl]-4-(4-methoxybenzoyl)piperazine having a melting point of 105°-106° is obtained.
Reaction SMILES: O1CCC[CH2:2]1.[F:6][C:7]([F:16])([F:15])[C:8]1[S:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=1.C[Mg]Br>C(O)(=O)C>[F:16][C:7]([F:15])([F:6])[C:8]1[S:12][C:11]([CH:13]([OH:14])[CH3:2])=[CH:10][CH:9]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccc(C(F)(F)F)s1
Agent: C[Mg]Br
Solvent: CC(=O)O
Product: CC(O)c1ccc(C(F)(F)F)s1

Procedure:
To a tetrahydrofuran solution (2.0 mL) of 5-(trifluoromethyl)thiophene-2-carbaldehyde (80.0 mg, 0.444 mmol), methylmagnesium bromide (533 μL, 0.444 mmol) was added at 0° C. and the resultant mixture was stirred at room temperature for 5 minutes. After completion of the reaction, acetic acid was added to the reaction solution and the resultant mixture was concentrated under reduced pressure. To the obtained residue, water was added and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([N+]([O-])=O)=[CH:7][CH:6]=1)(O)(=O)=O.[O:14]=[C:15]([N:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]1([CH2:25][O:26][CH3:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH3:17].COC(C)(C)C>C(N(CC)CC)C>[CH3:17][CH2:16][C:15]([N:18]([C:19]1([CH2:25][O:26][CH3:27])[CH2:20][CH2:21][N:22]([CH2:7][CH2:6][C:5]2[S:1][CH:8]=[CH:12][CH:13]=2)[CH2:23][CH2:24]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2cccs2)CC1
Yield: 84.2 %

Procedure:
To a suitably sized reaction flask (e.g., a jacketed glass reactor with stirring, nitrogen blanket, internal temperature recorder, and reflux capabilities) is charged 4-[(1-oxopropyl)phenylamino]-4-methoxymethyl piperidine nosylate (100.0 g), 2-(2-thiophenylethyl) 4-nitro-benzene sulfonate (79.2 g), tert-butyl methyl ether (MTBE, 333 mL), and triethylamine (TEA, 666 mL). The reaction mixture is warmed to 55°±5° C. and allowed to react at that temperature for not less than 24 hours. As the reaction progresses, a slurry is formed. The extent of the reaction can be followed by HPLC until most of the initial reactants are consumed. At that point, the reaction mixture is cooled to 20°±5° C. and charged with MTBE (400 mL) and water (400 mL). The diluted slurry is mixed for at least 10 minutes and then aqueous and organic phases are allowed to separate in a separatory funnel. The aqueous phase is discarded and then the organic phase is washed with water two additional times. Carbon (20 g) is then added to the resultant organic phase, mixed for at least 10 minutes and the carbon is filtered from the organic phase through a CELITE® diatomaceous earth bed. The CELITE® diatomaceous earth bed is washed with 200 ml of MTBE, the organic phases are combined and then solvent exchanged with ethanol under vacuum distillation conditions (by concentrating the organic phase to minimum stir volume three times and thereafter adding 400 mL of ethanol following each step of concentrating). The final volume should be about 600 mL. The solution is warmed to 45°±5° C. and then water (834 mL) is added slowly to give a turbid system. The hazy slurry is cooled slowly to 5°±5° C., and held at that temperature for at least 16 hours. The resultant slurry is filtered, washed with 30% aqueous ethanol and then dried in a vacuum oven at 50° C. to yield 67.9 g of the desired sufentanil product (expected yield 84%; expected purity 99.7%).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:14]([N:5]1[CH2:6][CH2:7][C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:1])[CH2:3][CH2:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 62.8 %

Procedure:
4-Hydroxy-4-phenylpiperidine (0.5 g, 2.8 mmol), benzylbromide (0.5 g, 3 mmol) and potassium carbonate (0.8 g, 6 mmol) were dissolved in DMF (5 mL) and stirred for 2 hours. The mixture was diluted with ethyl acetate and washed with a solution of saturated aqueous sodium carbonate solution then dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The resulting solid was recrystallised from pentane to give the title compound as a white solid (0.47 g). LCMS m/z 268.3 [M+H]+. R.T.=2.37 min (Analytical Method 4).
Reaction SMILES: [OH:1][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=O)[C:3]=1[C:11]([C:13]1[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12].CN(C)C=O.C(Cl)(=O)C([Cl:32])=O>>[Cl:32][C:4]1[CH:5]2[CH2:9][CH:8]([CH2:7][CH2:6]2)[C:2](=[O:1])[C:3]=1[C:11]([C:13]1[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C2CCC(C2)C1=O
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Cl)C2CCC(C2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
20.15 g (0.062 mo l) of 4-hydroxy-3-(2-methyl-6-trifluoromethyipyridine-3carbonyl)-bicyclo[3.2.1]oct-3-en-2-one are suspended in 50 ml of oxalyl chloride, and 0.1 ml of dimethylformamide are added dropwise. After the intensive evolution of gas has ceased, the mixture is kept at a bath temperature of 45° C. for another 1.5 hours and then evaporated, and the residue is suspended in a little ethyl acetate and admixed with stirring at 0° C. with hexane. Filtration gives 19.19 g (90% of theory) of 4-chloro-3-(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one of m.p. 137-138° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])[CH2:31][CH2:30]1>C(#N)C.O>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[CH2:33][CH2:34]2)[CH2:22][CH2:21]1
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1N1CCN(CCN2CCC(Cc3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 79.9 %

Procedure:
Pulverized potassium carbonate (0.76 g, 5.5 mmole) and potassium iodide (0.97 g, 5.5 mmole) was added to a mixture of 4-(5-fluoro-1H-indol-3-ylmethyl)piperidine (1.16 g, 5.0 mmole) and 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (1.27 g, 5.0 mmole) in 25 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen for 5 hours. After cooling, it was diluted with water (150 ml) and the product extracted into ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a white solid (1.8 g, 80%). Treatment with an excess of 1M etheral hydrochloric acid gave the acid addition salt, which was recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 77 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (1.202 g) and 2-bromo-4'-chloroacetophenone (2.114 g) in triethylamine (2 ml) and ethanol (20 ml) was stirred at ambient temperature for 75 mins. The resulting suspension was filtered, the solid was washed with water then crystallised from acetone to give the title pyrimidinone (1.973 g,); m.p. 216°-218°; λmaxEtOH 252 nm (ε 22360), 233 nm (ε 2080), λinf 288 nm (ε 1530).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O.[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:17]1([C@@H:15]2[CH2:16][C@H:14]2[NH:5][CH2:6][CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([CH2:25][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)[CH2:12][CH2:13]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(N(CCC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)c1ccc(CN2CCC(CCN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(2-(piperidin-4-yl)ethyl)acetamide (126 mg, 0.370 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added 4-formylbenzoic acid (66.7 mg, 0.444 mmol) and sodium triacetoxyborohydride (157 mg, 0.740 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved into methanol (2 ml) and 1N NaOH aqueous solution (2 mL) was added. The mixture was stirred at room temperature for 1 h and concentrated. The residue was treated with MeOH (3 mL) and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions. The resulting TFA salt of the product was treated with 1N HCl and concentrated. The residue was further dried under vacuum to give 87 mg of product as white solid (HCl salt). MS: (M+H)+=379.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (q, 1H), 1.46-1.67 (m, 5H), 1.82 (br. s., 2H), 2.87 (br. s., 3H), 3.05 (br. s., 2H), 3.30 (br. s., 2H), 4.34 (d, J=3.79 Hz, 2H), 7.10-7.40 (m, 5H), 7.74 (d, J=8.08 Hz, 2H), 8.00 (d, J=7.83 Hz, 2H), 9.53 (br. s., 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:27])=[N:5][O:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][CH2:24][CH2:25][N:26]=2)=[CH:18][CH:17]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O>[O:23]1[CH2:24][CH2:25][N:26]=[C:22]1[C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[O:6][N:5]=[C:4]([CH3:27])[C:3]=2[CH2:2][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:17][CH:18]=1
Reactant: C1CCNC1
Reactant: Cc1noc(CCCCCCCOc2ccc(C3=NCCO3)cc2)c1CCl
Solvent: CN(C)C=O
Product: Cc1noc(CCCCCCCOc2ccc(C3=NCCO3)cc2)c1CN1CCCC1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A solution of 2.8 g of 4-chloromethyl-5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole (Example 35) and 1.3 g of pyrrolidine in 50 ml of dimethylformamide was heated on a steam bath for six hours and then kept overnight at room temperature. The solvent was removed in vacuo, and the residue was dissolved in water and made basic with sodium bicarbonate solution. The solid product which separated was collected and dried to give 1.3 g of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methyl-4-(1-pyrrolidylmethyl)isoxazole, m.p. 98°-99° C.