Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].[O-]CC.[Na+].O>C(O)C>[N+:8]([CH2:11][C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCOCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CCOCC1
Yield: 33.7 %

Procedure:
A solution of tetrahydro-4H-pyran-4-one (45.0 g, 449 mmol) and nitromethane (36.5 mL, 674 mmol) in ethanol (27 mL) was treated with a solution of sodium ethoxide in ethanol (2.67 M, 8.40 mL, 22.5 mmol) using the method described in Part A of Example 9. The reaction mixture was transferred to a separatory funnel and water (450 mL) was added. The mixture was extracted with ethyl acetate (3×900 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to a light brown oil. Ethyl acetate/hexanes was added and pale brown crystals formed that were isolated by filtration and dried to provide 4-(nitromethyl)tetrahydro-2H-pyran-4-ol (24.4 g, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][C:6](=[CH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:15])[CH:4]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH2:7][CH:6]([CH2:8][CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[C:5](=[O:15])[CH:4]=1
Reactant: [H][H]
Reactant: COC1=CC(=O)C(=CC2CCOCC2)C1
Agent: [Pd]
Solvent: CCO
Product: COC1=CC(=O)C(CC2CCOCC2)C1
Yield: 95.8 %

Procedure:
A solution of 3-methoxy-5-[1-(tetrahydro-pyran-4-yl)-methylidene]-cyclopent-2-enone (938 mg, 4.5 mmol) in ethanol (45 ml) was added to 5% palladium on activated charcoal (94 mg) and the reaction stirred for 7.5 hours under 3 bar of hydrogen. The reaction was then filtered through a pad of Celite, washed with ethanol and concentrated in vacuo to give 3-methoxy-5-(tetrahydro-pyran-4-ylmethyl)-cyclopent-2-enone (906 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)c(=O)[nH]c1=O
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)C(=O)Cn1c(=O)c(Br)cn(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-1-methylpyrimidine-2,4(1H,3H)-dione (80 mg, 0.390 mmol), 2-chloro-N,N-dimethylacetamide (47.4 mg, 0.390 mmol), and potassium carbonate (64.7 mg, 0.468 mmol) in DMSO (3 mL) was stirred at room temperature 2 hours. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 5-70% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [O-]CC.[Na+].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1.[N:24]([C:27]1[CH:36]=[C:35]2[C:30]([C:31]([CH3:38])=[CH:32][C:33](=[O:37])[O:34]2)=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C=O)C>[CH3:38][C:31]1[C:30]2[C:35](=[CH:36][C:27]([NH:24][C:25](=[O:26])[O:23][CH2:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:6]4[O:5][C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[CH:7]=4)=[CH:17][CH:18]=3)=[CH:28][CH:29]=2)[O:34][C:33](=[O:37])[CH:32]=1
Reactant: OCc1ccc(OCc2cc3ccccc3o2)cc1
Reactant: Cc1cc(=O)oc2cc(N=C=O)ccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)oc2cc(NC(=O)OCc3ccc(OCc4cc5ccccc5o4)cc3)ccc12
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
Sodium ethoxide (40 mg, 0.59 mmol) was added to DMF at 0° C., and the suspension was stirred for 10 min. (4-(benzofuran-2-ylmethoxy)phenyl)methanol (150 mg, 0.59 mmol), was added and resulting mixture was stirred at this temperature for 0.5 h, then allowed to reach room temperature. To this mixture 76 (130 mg, 0.65 mmol) was added portionwise. Resulting mixture was stirred at room temperature for 2 h. DMF was evaporated off in-vacuo. The crude residue was purified by flash chromatography, eluting with hexane: EtOAc (2:1) to give the target compound (20 mg, 8%) as a white solid. m/z=456.10 (M+H). H1 NMR (500 MHz, DMSO-d6): δ=10.22 (1H, bs, NH), 7.69-7.64 (2H, m, ArH), 7.58 (1H, d, J=8.15 Hz, ArH), 7.55 (1H, s, ArH), 7.42 (2H, d, J=8.00 Hz, ArH), 7.33 (1H, t, J=7.70 Hz, ArH), 7.26 (1H, t, J=7.5 Hz, ArH), 7.11 (2H, d, J=8.28 Hz, ArH), 7.06 (1H, s, ArH), 6.23 (1H, s, ArH), 5.29 (2H, s, CH2), 5.12 (2H, s, CH2), 2.37 (3H, s, CH3).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:25])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:24])[C@H:11]([CH3:23])[NH:12]C(OCC1C=CC=CC=1)=O)[CH3:2].[BrH:26].CCOCC>C(O)(=O)C>[BrH:26].[CH2:1]([NH:3][C:4](=[O:25])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:24])[C@H:11]([CH3:23])[NH2:12])[CH3:2]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Temperature: -60 °C
Yield: 82 %

Procedure:
1.81 g (0.0052 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline ethylamide were stirred for 1 hour in 10 ml of 4-N hydrobromic acid in acetic acid. To the solution were added 150 ml of dry ether and, after stirring for a few minutes, the oil was allowed to settle. The mixture was cooled to -60° C. and the ether decanted from the oil and discarded. The oil was then dissolved in methanol, the product crystallising out on the addition of ethyl acetate. There were obtained 1.25 g (82%) of L-alanyl-L-proline ethylamide hydrobromide of melting point 202°-204° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:36][C:34]([CH3:37])([CH3:35])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: CC(C)(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCC(C)(C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.3 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (300 mg, 0.673 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and 1-amino-2-methyl-2-propanol (150 mg, 1.68 mmol), WSCI.HCl (185 mg, 0.965 mmol) and 4-dimethylaminopyridine (165 mg, 1.35 mmol) were added, followed by stirring at room temperature for 17 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired product (307 mg, yield 88%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][C:6]([N:8]([CH3:24])[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7].C(Cl)(Cl)Cl>CO>[C:18]1([C:9]2([N:8]([CH3:24])[C:6](=[O:7])[CH2:5][N:2]([CH3:3])[CH3:1])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNC
Reactant: CN(C(=O)CCl)C1(c2ccccc2)Cc2ccccc2C1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)CC(=O)N(C)C1(c2ccccc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 96.1 %

Procedure:
To a stirred solution of dimethylamine (30 mL, 0.45 mol) in methanol (150 mL) at 0° C. under nitrogen were added 2-chloro-N-methyl-N-(2,3-dihydro-2-phenyl-1H-inden-2-yl)acetamide (8.0 g, 0.027 mol) and chloroform (110 mL). The mixture was stirred at ambient temperature for 60 hours. The solvents were evaporated, the residue was dissolved in chloroform (250 mL) and 5% NaOH (250 mL), and the phases were separated. The aqueous phase was extracted with chloroform (3×200 mL). The combined chloroform extracts were washed with brine (200 mL), dried over magnesium sulfate and the solvent evaporated. The residual solid (8.1 g) was dissolved in ethanol (175 mL) and acidified with HCl gas. The solid which formed was collected by filtration and vacuum dried at 65° C. for 48 hours to provide 8.0 g of N-(2,3-dihydro-2-phenyl-1H-inden-2-yl)-N-methyl-2(dimethylamino)acetamide, mp 244°-245° C.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH:19]1[NH:23][C:22](=O)[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([CH:19]1[N:23]([C:22]2[CH2:21][CH2:20][CH:19]([CH2:15][CH2:16][CH2:17][CH3:18])[N:23]=2)[C:22]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:21][CH2:20]1)[CH2:16][CH2:17][CH3:18]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CCCCC1CCC(=O)N1
Product: CCCCC1CCC(N2C(N3c4ccccc4Sc4ccccc43)=CCC2CCCC)=N1

Procedure:
reaction of phenothiazine with 5-n-butyl-2-pyrrolidinone according to the procedure of Example 4 provides 10-[5-n-BUTYL-1-(5-n-BUTYL-1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[F:30][C:31]([F:37])([F:36])[O:32][CH2:33][CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[F:30][C:31]([F:37])([F:36])[O:32][CH2:33][CH2:34][NH:35][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCOC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOC(F)(F)F)ccc21
Yield: 68.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-trifluoromethoxy-ethyl)-amide (87 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-(trifluoromethoxy)ethylamine hydrochloride (45 mg), HBTU (112 mg), and DIEA (65 uL). LC/MS: m/z 520.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.41 (bs, 1H), 8.72 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.74 (d, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 4.23 (t, 2H), 3.81-3.55 (m, 5H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:22]=[CH:21][C:20]=2[CH3:31])=[O:17])=[CH:14][N:13]=1.C(OCC)(=O)C>N1C(C)=CC(C)=CC=1C.[Cu]I>[CH:28]1([NH:27][C:25]([C:23]2[CH:22]=[CH:21][C:20]([CH3:31])=[C:19]([NH:18][C:16](=[O:17])[C:15]3[CH:32]=[CH:33][C:12]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:13][CH:14]=3)[CH:24]=2)=[O:26])[CH2:30][CH2:29]1
Reactant: OCc1ccccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(Cl)nc1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
To 2-pyridinylmethanol (1 mL) was added sodium hydride 60% dispersion in oil (122 mg, 3.05 mmol) under inert atmosphere and the resulting mixture was stirred for 10 minutes then added to a mixture of 6-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}nicotinamide (334 mg, 1.02 mmol) and copper (I) iodide in collidine (3 mL). The resulting mixture was stirred at room temperature for 30 minutes then at 100° C. for 4 h. The mixture was cooled to room temperature, ethyl acetate was added and the mixture filtered. The filtrates were concentrated under reduced pressure and purified by silica column chromatography eluting with 0 to 100% ethyl acetate in isohexane. Trituration with diethyl ether gave the title compound as a colourless solid (105.6 mg, 26%); NMR Spectrum: (DMSOd6) 0.59 (m, 2H), 0.67-0.71 (m, 2H), 2.27 (s, 3H), 2.86 (m, 1H), 5.53 (s, 2H), 7.10 (d, 1H), 7.35 (m, 2H), 7.48 (m, 1H), 7.65 (m, 1H), 7.82 (m, 2H), 8.29 (m, 1H), 8.37 (m, 1H), 8.58 (m, 1H), 8.80 (d, 1H), 9.99 (s, 1H); Mass Spectrum: M+H+ 403.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:6][CH2:5]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(N2CCN(CCO)CC2)nc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(C#N)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a solution of 6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-nicotinonitrile (350 mg, 1.51 mmol) and imidazole (236 mg, 3.47 mmol) in anhydrous DMF (3 mL) was added TBDMS chloride (295 mg, 1.96 mmol) in anhydrous DMF (2 mL) and the reaction mixture stirred for 16 h at RT. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was separated, passed through a phase separation cartridge and concentrated in vacuo. The crude residue was purified on silica gel column chromatography eluting with 30% EtOAc/isohexane, and increasing the polarity to 50% EtOAc/isohexane to afford 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-yl}-nicotinonitrile as a pale yellow solid (394 mg, 75%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][CH3:10])=[N:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2].C(O)(=O)C.[BrH:20].Br.[NH+]1C=CC=CC=1>O>[Br:20][CH2:2][C:1]([C:4]1[S:8][C:7]([NH:9][CH3:10])=[N:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3]
Reactant: Br
Reactant: CCOC(=O)c1nc(NC)sc1C(C)=O
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(NC)sc1C(=O)CBr
Reaction time: 2.5 h

Procedure:
To a mixture of ethyl 5-acetyl-2-methylamino-4-thiazolecarboxylate (7.1 g), 30% acetic acid solution of hydrogen bromide (10 ml) and acetic acid (50 ml) was added pyridinium hydrobromide perbromide (9.9 g) at ambient temperature and stirred for 2.5 hours. The reaction mixture was poured into water (300 ml) and the precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and water and the resultant mixture was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with ethyl ether to give ethyl 5-(2-bromoacetyl)-2-methylamino-4-thiazolecarboxylate (6.6 g). mp 130°-131.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH2:20]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH2:20]2
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1OC)CCN(CCc1ccc([N+](=O)[O-])cc1)C2
Yield: 67.7 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (0.3 g), 1,2,3,4-tetrahydro-5,6-dimethoxyisoquinoline [0.25 g; R. D. Haworth, J. Chem. Soc., 2281 (1987); Robin D. Clark, J. Med. Chem., 596-600, 33, (1990)] and potassium carbonate (0.5 g) in DMF (25 ml) was heated at 60° for 3 h. The mixture was then filtered and the filtrate evaporated. The residue was taken up in water, extracted with dichloromethane, dried, evaporated and purified by column chromatography eluting with dichloromethane/methanol (99:1) to give the title compound (0.3 g) as an orange solid, MP:97°. NMR includes signals at d 3.6 (2H,s,N--CH2Ar), 3.75 (6H,s,OCH3).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-trifluoromethylbenzoyl chloride (14 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[OH:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:17]1[CH:18]=[C:14]([CH2:13][OH:12])[N:15]=[CH:16]1
Reactant: OCc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2cnc(CO)c2)c(F)c1
Yield: 75.4 %

Procedure:
3,4-Difluoro-nitrobenzene (23.85 g) was dissolved in acetonitrile (180 ml), followed by 4-hydroxymethylimidazole (14.7 g) and ethyldiisopropylamine (65.2 ml). The mixture was stirred and heated to reflux for 2 days. After cooling, acetonitrile was evaporated and the residue was shaken with a mixture of methyl t-butyl ether (200 ml) and water (100 ml), and the solid filtered. After washing with a mixture of methyl t-butyl ether (50 ml) and water (25 ml), the solid was dried in vacuo at 60° C. overnight, to give product (26.8 g) mp 157-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[C:28]1(=[O:49])[N:32]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[C:31](=[O:44])[C:30]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:29]12.[OH-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:43][C:40]4[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][N:32]5[C:28](=[O:49])[C:29]6=[CH:48][CH:47]=[CH:46][CH:45]=[C:30]6[C:31]5=[O:44])=[CH:42][CH:41]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Reaction time: 5 h
Yield: 6 %

Procedure:
To a stirred solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl) piperazine (24 g) and 14.5 g of 4-(3-phthalimidopropyloxy)phenol in dimethylsulfoxide (500 ml) at 50° under nitrogen was added sodium hydroxide (1.9 g) in water (15 ml), and the solution was stirred for 5 hours 55°-60°. After standing at room temperature overnight, the reaction was poured into water (1 L) and the oil was extracted using ethyl acetate. The extract dried over sodium sulfate was evaporated in vacuo and the residual material was dissolved in acetonitrile. The supernatant was decanted from some insoluble material and then hydrogen chloride was bubbled into the solution to precipitate the product as the dihydrochloride salt. Methanol was added to the mixture to redissolve the salt and the solution was concentrated until a solid started to precipitate. The solid was collected by filtration to give 2 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2 -[4-(3-phthalimidopropyloxy)phenoxy]ethyl]piperazine as its di-hydrochloride salt, mp 233°-246°. The filtrate was evaporated and the resulting oil was crystallized from methanol yielding an additional 8.3 g of the same material, mp 225°-240°
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=O)[CH3:2].[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:15]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:18][CH:17]=1)#[N:14]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOC(C(=O)O)c1ccccc1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
(RS)-Ethoxy-phenyl-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-phenyl-acetamide. Light yellow semisolid. MS 295.3 ([M+H]+)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:22][CH:23]=1)[N:14]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[N:13]=[CH:12]2)C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[N:22][CH:23]=1)[N:14]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[N:13]=[CH:12]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc3c(cnn3C3CCCCO3)cc2OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc3c(cnn3C3CCCCO3)cc2O)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.9 %

Procedure:
To a solution of tert-butyl 5-(5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyridin-2-ylcarbamate (260 mg, 519 μmol) in EtOH (25 mL) and EtOAc (25 mL) is added Pd/C (100 mg, 10% wt) under N2. The resulting mixture is degassed by evacuation and backfilled with nitrogen. Then the reaction mixture is stirred at RT under H2 atmosphere for 6 hours. The reaction mixture is filtered. The filtrate is concentrated to give the product (200 mg, 93.8% yield). MS (m/z): 411.1 (M+H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)[CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[CH3:4]>C1COCC1.CO>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:25][CH2:26]3)[CH2:17][CH2:16]2)[CH:9]=[CH:10][C:11]=1[NH2:12])[CH3:4]
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
Sodium borohydride (0.41 g, 10.9 mmol) was added in portions to a stirring suspension of 1-{1-[3-(ethyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.50 g, 3.64 mmol) and NiCl2.6H2O (0.26 g, 1.1 mmol) in THF (15 mL) and MeOH (30 mL) at rt. The reaction mixture was allowed to stir at rt overnight and then it was concentrated in vacuo. The residue was taken up in DCM and passed through a bed of celite. The resultant filtrate was then concentrated onto silica gel and purified by flash chromatography to afford 2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.40 g, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.42-6.56 (m, 2H), 6.29 (dd, J=8.4, 2.3 Hz, 1H), 4.21 (br. s., 2H), 3.96 (q, J=6.9 Hz, 2H), 3.37-3.48 (m, 2H), 3.05-3.12 (m, 4H), 2.86 (s, 3H), 2.56-2.63 (m, 4H), 2.26-2.37 (m, 1H), 1.75-1.85 (m, 2H), 1.42-1.61 (m, 2H), 1.31 (t, J=7.0 Hz, 3H).