Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:27]=[CH:26][C:25](OS(C(F)(F)F)(=O)=O)=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37](C=O)C>C(OCC)C.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:27]=[CH:26][C:25]([C:36]#[N:37])=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: COc1cccc(C2(c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CCN(Cc3ccccc3)CC2)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: COc1cccc(C2(c3ccc(C#N)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl ester (2.2 g, 4.34 mmol) in DMF (8 mL) was added zinc cyanide (0.61 g, 5.22 mmol) and tetrakis triphenylphosphine palladium (0.7 g, 0.63 mmol). The reaction was stirred under a nitrogen atmosphere at 90° C. for 5 hours. The mixture was cooled to room temperature and it was diluted with diethyl ether (100 mL). The organic layer was washed with brine (5×10 mL), dried (MgSO4) and concentrated. Purification with hexanes/EtOAc (2:1) afforded 1.52 g (92% yield) of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzonitrile. 1HNMR (400 MHz, CDCl3) δ 7.51 (d, 2H), 7.34 (d, 2H), 7.28-7.18 (comp, 6H), 6.80 (d, 1H), 6.77 (s, 1H), 6.70(d, 1H), 3.75 (s, 3H), 3.39 (s, 2H), 2.63-2.39 (comp, 8H); MS (M+1) 383.2.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1>CC(N(C)C)=O.CO.[Cu]>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc(C)nc2)cc1

Procedure:
4 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 10 ml of dimethylacetamide, and 5.1 g of p-methoxybromobenzene and 450 mg of a copper powder were added to the suspension, followed by allowing the mixture to react in a nitrogen stream at 140° C. for 14 hours. The reaction mixture was diluted with 50 ml of methanol and filtered, and the filtrate was immediately dried to a solid. 100 ml of ethyl acetate was added to the residue, and the mixture was washed with 50 ml of an aqueous sodium hydroxide solution at pH 9. The ethyl acetate layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 3.9 g of oily 5-(p-methoxyphenoxy)-2-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([F:32])=[CH:27][N:26]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(CCc2cccc(N)c2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)ccn1
Yield: 41.1 %

Procedure:
To a solution of tert-butyl {4-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (160 mg, 0.51 mmol) (prepared in Example C15, step C) and 2,4-dichloro-5-fluoropyrimidine (89.5 mg, 0.54 mmol) in N,N-dimethylformamide (2.3 mL) was added potassium carbonate (212 mg, 1.53 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3, followed by quenching with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as an off-white solid (93 mg, 41%). LCMS for C22H24ClFN5O2 (M+H)+: m/z=444.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6]1)[CH3:4].[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[S:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[C:26]=3[C:34]([C:36]3[CH:41]=[CH:40][C:39](F)=[CH:38][CH:37]=3)=[O:35])=[CH:21][CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C=O)C.[Cl-].[Na+].O>[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[S:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[C:26]=3[C:34]([C:36]3[CH:41]=[CH:40][C:39]([O:10][CH:7]4[CH2:8][CH2:9][N:5]([CH2:3][CH3:4])[CH2:6]4)=[CH:38][CH:37]=3)=[O:35])=[CH:23][CH:24]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCN1CCC(O)C1
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(OCCN5CCCC5)cc4)sc4ccccc34)cc2)C1
Reaction time: 0.25 h
Yield: 63 %

Procedure:
Sodium hydride (60% oil dispersion, 38 mg) was suspended in DMF (1 mL) and stirred at ambient temperature for 15 min under argon before 1-ethyl-3-pyrrolidinol (92 μL) was added. After stirring for 15 min, 4-fluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (223 mg) in 1 mL of DMF was introduced and the resulting solution was stirred at ambient temperature for 4 h. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the product as a colorless oil (171 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:15])C2C=CC=CC=2)=[N:6][CH:7]=1.Cl[C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:15][C:17]2[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=2)=[N:6][CH:7]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OC(c1ccccc1)c1ccc(Cl)cn1
Product: [O-][n+]1ccc(OCc2ccc(Cl)cn2)cc1
Yield: 41 %

Procedure:
5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and 4-chloropyridine-N-oxide (2.94 g, 22.7 mmol) were reacted according to Example 34 (step a) to provide the title compound (2.2 g, 40%) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=2.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 2H), 7.74 (dd, J=8.4, 2.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C.O>[OH:14][N:13]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=N[O-]
Reactant: CCOC(=O)Cc1ccccn1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)c1ccccn1
Yield: 95.2 %

Procedure:
To a stirring solution of ethyl pyridine-2-acetate (12.6 g, 76.3 mmol) in acetic acid (19 mL) at 5° C. was added a solution of sodium nitrite (6.05 g, 87.7 mmol) in water (12 mL) at a rate sufficient to maintain the internal temperature below 15° C. After complete addition and an additional 30 min, an additional 30 mL of water was added. The resulting white precipitate was filtered, washed with water, saturated aqueous NaHCO3, and again with water. The solid was then dried under vacuum to give 14.1 g (95%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[S:19][C:18]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:17]=3[C:16]=2[CH3:25])(=[O:14])=[O:13])=[C:7]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:6]=1)=O.O1CCOCC1.C(=O)([O-])O.[Na+].[C:41]([NH2:44])(=[S:43])[CH3:42]>C(O)C>[F:24][C:22]1[CH:21]=[CH:20][C:18]2[S:19][C:15]([S:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]4[N:44]=[C:41]([CH3:42])[S:43][CH:2]=4)=[CH:6][C:7]=3[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:13])=[O:14])=[C:16]([CH3:25])[C:17]=2[CH:23]=1
Reactant: CC(N)=S
Reactant: Cc1c(S(=O)(=O)Nc2ccc(C(=O)CBr)cc2S(C)(=O)=O)sc2ccc(F)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1nc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)cs1
Reaction time: 2 h
Yield: 42.6 %

Procedure:
Into 4.0 mL of chloroform was dissolved 200 mg of Compound 19, and 194 mg of benzyltrimethylammonium tribromide was added, followed by 1 hour of stirring at room temperature. The reaction was terminated by adding water to the reaction solution and then the solvent was once removed by evaporation. The residue was adjusted to pH 2 to 3 by adding 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was washed with methanol to obtain 201 mg of N-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide as a colorless solid. The thus obtained N-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide (150 mg) was dissolved into a mixed solution of 1.5 mL of dioxane and 1.5 mL of ethanol, and 53 mg of sodium hydrogen carbonate and 26 mg of thioacetamide were successively added, followed by 2 hours of stirring under heating and refluxing. The reaction was terminated by adding water to the reaction solution and then the solvent was removed by evaporation under reduced pressure. The residue was adjusted to pH 2 to 3 by adding 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain 61 mg of the title compound as light yellow powder.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[CH3:6][CH2:7][C:8]([O:10]O)=[O:9]>>[C:1]([O:5][O:10][C:8](=[O:9])[CH2:7][CH3:6])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OO
Reactant: CCC(=O)O
Product: CCC(=O)OOC(=O)CC

Procedure:
Two side reactions could in theory occur in the extraction column, namely the reaction of hydrogen peroxide with sulphuric acid to form Caro's acid and the reaction of propionic acid with perpropionic acid to give propionyl peroxide. However the simultaneous extraction into the organic phase constituted by the propylene dichloride has the general effect of minimising these side reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[O:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[S:10][C:11]=1[O:12][CH3:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylic acid (85 mg, 0.31 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (119 mg, 0.31 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (180 mg, 0.384 mmol) in chloroform (3.5 mL). DIEA (270 μL, 1.54 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (94 mg, 0.14 mmol, 45%): LC-MS (ES) m/z=603 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]([CH2:19][C:20]#[N:21])[CH3:18])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-:27].[K+].[K+].OO.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]([CH3:18])[CH2:19][C:20]([NH2:21])=[O:27])=[CH:10][CH:9]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: CN(CC#N)C/C=C/COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C/C=C/COc1ccc(C(=O)c2ccc(Br)cc2)cc1)CC(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 314.6 %

Procedure:
A suspension of 0.4 g of (E)-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-acetonitrile (Ex. 2j) and 0.04 g of potassium carbonate in 3 ml of dimethyl sulphoxide is cooled to 0° C. and treated with 1 ml of 30% hydrogen peroxide solution. The reaction mixture is warmed to room temperature and stirred overnight. For the working up, the mixture is treated with 10 ml of water and the separated crystals are filtered off and washed with water. There is obtained 0.38 g of (E)-2-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-acetamide, MS: m/e 372 (M+ -H2NCO, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:56][CH:57]4[CH2:62][CH2:61][O:60][CH2:59][CH2:58]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) and TBTU (90 mg, 0.28 mmol) in DMF (3.0 mL) was added DIPEA (217 μL, 1.26 mmol). Then 4-aminotetrahydropyran (28 mg, 0.28 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (100 mg, 96%) as a white solid. MS: m/e=412.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.CS(C)=O.[CH:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:22])[CH3:21].[ClH:29]>O>[ClH:1].[ClH:29].[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:26]3[CH2:27][CH2:28][N:23]([CH:20]([CH3:22])[CH3:21])[CH2:24][CH2:25]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: CC(C)N1CCNCC1
Reactant: COc1ccc(-c2ccc(Cl)nc2)cc1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-c2ccc(N3CCN(C(C)C)CC3)nc2)cc1
Temperature: 130 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A mixture of 2-chloro-5-(4-methoxyphenyl)pyridine (200 mg, 0.91 mmol), dry DMSO (2.0 mL) and 1-isopropylpiperazine (500 mg, 3.9 mmol) was stirred and heated on a 130° C. oil-bath overnight, then at 150° C. for 4 h, left 2 days at rt and finally heated at 140° C. overnight. The reaction mixture was allowed to cool and then poured into water (100 mL). The mixture was extracted with ethyl acetate (100 mL), and the organic extract was washed with water and dried (MgSO4). The solvent was evaporated to give a solid residue which was dissolved into 0.5 N hydrochloric acid (20 mL). A small insoluble solid was removed by filtration, and the aqueous solution was evaporated to give a residue which was re-evaporated with absolute ethanol. The resulting solid was re-crystallised from absolute ethanol to give 210 mg (60%) of 1-[5-(4-methoxyphenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride.
Reaction SMILES: CO[C:3]([C:5]1([CH3:28])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH3:20])[CH:14]=3)[NH:9][C:8]=2[CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)[NH:6]1)=[O:4].[Br:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34]>CC(=O)CC>[Br:29][CH2:30][CH2:31][N:32]1[C:33](=[O:34])[N:6]2[CH:7]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH2:17][C:5]2([CH3:28])[C:3]1=[O:4])=[CH:14][C:13]([O:18][CH2:19][CH3:20])=[CH:12][CH:11]=4
Reactant: CCOc1ccc2[nH]c3c(c2c1)CC(C)(C(=O)OC)NC3c1cccc(O)c1
Reactant: O=C=NCCBr
Solvent: CCC(C)=O
Product: CCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Yield: 39.8 %

Procedure:
To a solution of 500 mg (1.31 mmol) (1RS,3SR)-6-Ethoxy-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester in 25 ml 2-butanon are added 120 μl (1.31 mmol) bromoethyl isocyanate. The mixture is heated to reflux for 24 h. The solvent is removed under reduced pressure. The crude product is purified by column chromatography (silica gel; toluene, ethyl acetate 6:1). 260 mg (40%) of the title compound are obtained as a colorless solid. m.p.: 250-252° C., MS: m/z (MH+)=498.1/500.0
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]([F:47])([F:46])C1C=CC(C2CCC3C(=CC=C(O)C=3)O2)=CC=1>>[F:27][C:28]([F:47])([F:46])[C:24]1[CH:23]=[CH:22][C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)=[CH:26][CH:25]=1
Reactant: Oc1ccc2c(c1)CCC(c1ccc(C(F)(F)F)cc1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccc(C(F)(F)F)cc2)O3)nc1

Procedure:
2-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 605 mg of 2-(4-trifluoromethylphenyl)chroman-6-ol. The product was purified column chromatography using 1.5% ethyl acetate in toluene as an eluant and then crystallised from a mixture of 2-propanol and acetone. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.79 (d, 2H, J 8.2 Hz), 7.70 (d, 1H, J 8.2 Hz), 7.21 (d, 1H, J 9.1 Hz), 7.01 (dd, 1H, J 8.7, 2.7 Hz), 6.98 (d, 1H, J 2.7 Hz), 6.95 (d, 1H, 8.7 Hz), 5.29 (dd, 1H, J 10.1, 2.0 Hz), 3.00 (ddd, 1H, J −16.9, 10.1, 5.8 Hz), 2.4 (ddd, 1H, J −16.9, 8.4, 4.5 Hz), 2.24 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[CH:25]=[CH:26][CH:27]=[C:18]([C:19]=45)[S:17]3(=[O:29])=[O:28])[CH2:9][CH2:8]2)[C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[NH:3]1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[H-].[Na+]>CN(C)C=O.O1CCCC1>[C:34]([N:3]1[C:4]2[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=2[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[CH:25]=[CH:26][CH:27]=[C:18]([C:19]=45)[S:17]3(=[O:29])=[O:28])[CH2:11][CH2:12]2)[C:2]1=[O:1])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(CCCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)n1c(=O)n(C2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 15 h
Yield: 51.5 %

Procedure:
The experiment is carried out as in Example 44, starting with 2-{3-[4-(2-oxo-1-benzimidazolinyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.6 g) in dimethylformamide (20 cc) and benzoyl chloride (1.4 g) in tetrahydrofuran (20 cc) and sodium hydride (0.48 g) as a 50% dispersion in vaseline oil. The mixture is stirred for 15 hours at a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a dichloromethanemethanol (90-10 vol) mixture as eluant, and then recrystallization from a boiling acetone/ethanol (90-10 vol) mixture (60 cc), 2-{3-[4-(3-benzoyl-2-oxo-1-benzimidazolinyl)piperidino]propyl}naphto [1,8-cd]isothiazole 1,1-dioxide (2.9 g) is obtained, m.p. 133° C.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][CH2:20][CH2:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=O)[NH2:2].O.[ClH:38]>O1CCCC1.B#B>[ClH:38].[ClH:38].[NH2:2][CH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][CH2:20][CH2:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:18])=[CH:12][CH:11]=2)=[CH:35][CH:36]=1
Reactant: CC(Cc1ccc(OCc2ccc(C(N)=O)cc2)cc1)NCCC(c1ccccc1)c1ccccc1
Agent: B#B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1ccc(OCc2ccc(CN)cc2)cc1)NCCC(c1ccccc1)c1ccccc1

Procedure:
To the suspension of 5.0 g of racemic 1-[4-(4-carbamoylbenzyloxy)-phenyl]-2-(3,3-diphenylpropylamino)-propane (Example 10/7) in 75 ml of tetrahydrofuran, 70 ml of 1-molar diborane in tetrahydrofuran are added dropwise while stirring under nitrogen at 0°. It is refluxed for 18 hours, cooled to 0° again and 30 ml of water are added dropwise, followed by 15 ml of concentrated hydrochloric acid. The mixture is evaporated, warmed with 50 ml of methanol, evaporated again and the residue is recrystallized from ethanol, to yield the 1-(4-(4-aminomethylbenzyloxy)-phenyl]-2-(3,3-diphenylpropylamino)-propane dihydrochloride melting at 259°-262°.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].Br[CH2:7][C:8]([O:10][CH3:11])=[O:9].C(OCC)(=O)C>C(N(CC)CC)C>[C:1]([O:5][CH2:7][C:8]([O:10][CH3:11])=[O:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC(=O)OCC(=O)OC
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Into a five-liter, three-necked, round-bottom flash (equipped with a mechanical stirrer, a thermometer and a one-liter dropping funnel topped with a drying tube) were placed 527.9 mls. of acrylic acid, 662.7 mls. of methyl bromoacetate and 1750 mls. of ethyl acetate. The resulting solution was cooled to about 15° C. and 1073.2 mls. of triethylamine were added over a period of about one hour. An exotherm was noted and reaction temperature was maintained between 15° and 25° C. with an ice/salt cooling bath. Upon completion of the triethylamine addition, the cooling bath was removed and the reaction mixture was stirred at room temperature (25° to 30° C.) overnight. The resulting thick slurry was poured into 1750 mls. of distilled water and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (two times, 500 mls. each) and the combined organic portions were washed successively with 500 mls. of 0.5N hydrochloric acid, 500 mls. of saturated aqueous sodium bicarbonate and, then, with 500 mls. of saturated aqueous sodium chloride. The organic solution (about 3.5 to 3.75 liters) was then dried (magnesium sulfate) and evaporated in vacuo (water aspirator) at ≤30° C. to provide a very pale-yellow product. The product was purified by addition of one gram of 2,6-di-tert-butyl-p-cresol as a free radical inhibitor and vacuum distilling through a distillation column. The purified product exhibited a boiling point of 50° C. (1.2 mm.) to 56° C. (1.9 mm.).