Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][NH2:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1nc(-c2ccc(F)cc2)n[nH]1
Product: O=C(NCCc1nc(-c2ccc(F)cc2)n[nH]1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 13 %

Procedure:
This compound was synthesized from 2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (11 mg, yield 13%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.26-8.24 (d, J=7.8 Hz, 1H), 8.07-8.03 (m, 3H), 7.67-7.59 (m, 2H), 7.13-7.09 (t, J=8.7 Hz, 2H), 4.01-3.96 (q, J=5.9 Hz, 2H), 3.24-3.21 (d, J=6.1 Hz, 2H). MS (ESI) m/z: Calculated for C20H14F4N6O2: 446.11. found: 447.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1>CN1C(=O)CCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9](=[O:11])[N:10]([CH2:22][CH:19]3[CH2:21][CH2:20]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c2ccc(Cl)nc21
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cn1c(=O)n(CC2CC2)c2ccc(Cl)nc21
Temperature: 90 °C

Procedure:
5-chloro-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-3) (2.97 g, 16.2 mmol) and cesium carbonate (15.8 g, 48.6 mmol) were added to a round bottom flask and suspended in NMP (25 mL) under nitrogen. Cyclopropylmethyl Bromide (4.4, 32.4 mmol) was added to the suspension and then refluxed at 90° C. overnight. The reaction was then cooled to room temperature and suspended in ethyl acetate and sodium bicarbonate. The suspension was washed with sodium bicarbonate, brine (×5), dried over sodium sulfate, filtered, and concentrated. The mixture was purified using normal phase chromatography (0-60% Ethyl Acetate/Hexanes), and the desired fractions were collected to produce the tan solid 5-chloro-1-(cyclopropylmethyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-4). MS (M+H)+: observed=237.7, calculated=238.1.
Reaction SMILES: [C:1]12([C:11](=O)[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8]1)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.C(O)C.Cl.[NH2:21][OH:22].Cl>N1C=CC=CC=1>[C:1]12([O:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3/[C:11]/1=[N:21]/[OH:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: O=C1c2ccccc2OC12CCCCCC2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O/N=C1/c2ccccc2OC12CCCCCC2
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of 10.81 g of spiro[benzofuran-2(3H),1'-cycloheptane]-3-one, 100 ml of absolute ethanol, 34.75 g of hydroxylamine hydrochloride and 100 ml of pyridine was heated at reflux overnight under nitrogen and thereafter cooled to room temperature. The mixture was poured into 500 ml of 2N aqueous hydrochloric acid and extracted with hexane (2×200 ml). The combined hexane extracts were washed with 2N hydrochloric acid (100 ml), distilled water (100 ml) and saturated sodium chloride solution (100 ml). After the last wash, the oxime began to crystallize out of the hexane extracts; dichloromethane was added to redissolve any crystallized solid and the solution was dried overnight over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded a gum which was triturated to solid with hexane. This material was filtered off and recrystallized from 60 ml of boiling hexane to afford 7.28 g of needles, m.p. 98.5°-103.5° C. Recrystallization twice more from 60 ml portions of hexane afforded 5.01 g of pure major (Z) isomer as needles, m.p. 104°-106.5° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[N:7]3[CH2:18][CH2:19][NH:20][C:21](=[O:22])[C:6]3=[CH:5][C:4]=2[CH:3]=1.CN(C)CCN(C)C.[F:31][C:32]([F:35])([F:34])I.O>C(#N)C.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[N:7]3[CH2:18][CH2:19][NH:20][C:21](=[O:22])[C:6]3=[C:5]([C:32]([F:35])([F:34])[F:31])[C:4]=2[CH:3]=1
Reactant: FC(F)(F)I
Reactant: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(F)cc3)c12
Agent: CN(C)CCN(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCn2c1c(C(F)(F)F)c1cc(F)cc(-c3ccc(F)cc3)c12
Temperature: -78 °C
Reaction time: 40 h
Yield: 34 %

Procedure:
To a solution of 8-fluoro-6-(4-fluoro-phenyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 18) (0.1 g, 0.335 mmol) in acetonitrile (1 ml) and DMF (1 ml), N,N,N′,N′-tetra-methylethylenediamine (77.9 mg, 101 μl, 670 μmol) and tris(2,2′-biryridyl)ruthenium(II)-chloride hexahydrate (5.02 mg, 6.7 μmol) were added at room temperature. The vial was sealed, cooled to −78° C., and with the help of a needle trifluoroiodomethane (˜0.5 ml) was condensed into the reaction tube. A high lumen (6500K) cool daylight lamp was positioned in front of the reaction vial and the reaction was allowed to stir for 40 h at room temperature. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate 20-80%) and trituration (diethyl ether/heptane) to yield the title compound as a white solid (42 mg, 34%), MS (ISP) m/z=367.4 [(M+H)+], mp 193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[S:29]
Reactant: COC(=O)c1cccc(OCc2cccc(Cl)c2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: COC(=S)c1cccc(OCc2cccc(Cl)c2)c1
Yield: 145.9 %

Procedure:
In an analogous manner to that described in Example 1(B). 36.5 g (131.9 mmol) of methyl 3-[(3-chlorobenzyl)oxy]benzoate were heated at reflux for 16 hours with 26.7 g (66 mmol) of Lawesson reagent in xylene and thereafter chromatographed on silica gel. Elution with hexane/toluene (2%, 5% and 10%) yielded 28.2 g (73%) of O-methyl 3-[(3-chlorobenzyl)oxy]thiobenzoate as an orange, crystallizing oil.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added TEA (0.06 mL, 0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyl triflluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a brown solid (0.05 g, 44%).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([O:20][CH3:21])=[O:19])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:24]=[CH:23][S:22][C:7]=12.[Br:25]Br>C(Cl)(Cl)Cl>[Br:25][C:23]1[S:22][C:7]2[C:8]3[N:3]([CH2:4][CH2:5][C:6]=2[CH:24]=1)[C:2](=[O:1])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:10][C:9]=3[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sc(Br)cc1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.8 g of methyl 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate are dissolved in 32 ml of chloroform, whereupon the solution was treated at 0° with 0.55 ml of bromine in 1 ml of chloroform and stirred at room temperature overnight. After washing with 2N sodium hydroxide solution and saturated sodium chloride solution, drying over magnesium sulfate and evaporation, the residue in toluene/ethyl acetate (4:1) was chromatographed on silica gel. There was obtained pure methyl 2-bromo-4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 170.5°-171° (from isopropanol).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1)=[CH:3][CH3:4]>C(O)C.[Pd]>[CH:2]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: CC=C(C)c1ccc(N)nc1
Agent: [Pd]
Solvent: CCO
Product: CCC(C)c1ccc(N)nc1
Yield: 68.9 %

Procedure:
A solution of 130 mg (0.87 mmol) of 5-(1-methyl-propenyl)-pyridin-2-ylamine in ethanol (5 mL) was reduced over palladium on charcoal (10 wt %, 13 mg) under a hydrogen atmosphere at room temperature for 18 h. The catalyst was separated by filtration through Celite® and washed with ethanol (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, eluent ethyl acetate) to afford 90 mg of 5-sec-butyl-pyridin-2-ylamine. ES−MS: m/z 151 [M+H+];
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[CH3:33])[NH2:29])(=[O:24])[CH3:23]>CC(O)C>[C:22]([O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[CH3:33])[NH:29][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Oc1cc(N)ccc1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 7-benzyloxy-4-chloro-6methoxyquinazoline (2.18 g, 7.25 mmol), 3-acetoxy-4-methylaniline (1.32 g, 8 mmol) and 2-propanol (50 ml) was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature. The precipitate was collected by filtration, washed with 2-propanol and ether to give 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline. A mixture of 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline (2.68 g, 5.75 mmol), 10% palladium-on-charcoal catalyst (0.27 g) in methanol (50 ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at ambient temperature under 1.5 atmospheres of hydrogen for 30 minutes The catalyst was removed by filtration and the filtrate evaporated. The residual solid was triturated in ether, collected by filtration and dried under vacuum at 50° C. to give 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (2.1 g, 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:24]([CH3:32])([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:10]=[CH:11][C:12]=1[O:13][Si](C(C)C)(C(C)C)C(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[OH:13][C:12]1[CH:11]=[CH:10][C:9]([C:24]([CH3:32])([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:8][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: CCOC(=O)CC(C)(C)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(OCCCOC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)c1ccc(O)c(OCCCOC)c1
Temperature: 0 °C
Yield: 97.8 %

Procedure:
In a round bottom flask, was introduced ethyl 3-{3-(3-methoxypropoxy)-4-[(triisopropylsilyl)oxy]phenyl}-3-methylbutanoate (2.60 g, 5.6 mmol) and tetrahydrofuran (18 mL). The mixture was cooled to 0° C. and tetrabutylammonium fluoride (1N in THF, 8.4 mL) was added. The solution was stirred for 2 hrs and hydrolyzed with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2) to yield 1.7 g (99%) of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH:15]=[O:16])[CH2:12][CH2:13]Br)=[CH:6][CH:5]=1.Cl.[NH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:20].C(=O)(O)[O-].[Na+].O>C(#N)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][N:19]([CH3:20])[CH2:13][CH2:12][CH:11]([CH:15]=[O:16])[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:17])=[CH:5][CH:6]=1)[CH3:26]
Reactant: COC(=O)c1ccc(CC(C=O)CCBr)cc1
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN(C)CCC(C=O)Cc1ccc(C(=O)OC)cc1

Procedure:
0.500 g (1.67 mmol) of methyl-4-(4-bromo-2-formylbutyl)benzoate from Ex. VIII, 0.257 g (1.67 mmol) of ethyl sarcosinate hydrochloride and 0.309 g (3.68 mmol) of sodium bicarbonate in 10 ml of acetonitrile are heated at reflux for 1 hour. The reaction mixture is cooled, 50 ml of water are added and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The crude product is purified by chromatography on silica gel (0.04-0.063 nm) using methylene chloride/methanol 100:3 as mobile phase.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][N:20]([CH2:28][C@@H:29]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=3)[O:30][Si](C(C)(C)C)(C)C)C(OC(C)(C)C)=O)[CH:12]=2)[CH:10]=1)=[O:4].Cl.O.[OH-].[Li+].O1CCCC1.O>O1CCOCC1>[Cl:44][C:40]1[CH:39]=[C:38]([C@@H:29]([OH:30])[CH2:28][NH:20][CH2:19][CH2:18][NH:17][C:13]2[CH:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7][CH:8]=3)[CH:16]=[CH:15][CH:14]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: COC(=O)c1cncc(-c2cccc(NCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OC(C)(C)C)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cncc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1

Procedure:
n.m.r. (CD3OD) δ values include 3.11-3.29 (m, 1 H), 3.58 (t, 2 H), 4.97 (dd, 1 H), 6.76 (d, 1 H), 6.97 (s, 1 H), 6.99 (d, 1 H), 7.26-7.35 (m, 4 H), 7.46 (s, 1 H), 8.51 (s, 1 H), 8.76 (s, 1 H), 9.00 (s, 1 H); from (R)-5-[3-[[2-[[2-(3-chlorophenyl)-2-[[(tert-butyl)dimethylsilyl]oxy]ethyl][(tert-butoxy)carbonyl]amino]ethyl]amino]phenyl]-3-pyridinecarboxylic acid methyl ester (251 mg), 4 N hydrochloric acid in 1,4-dioxane (10 mL) and lithium hydroxide monohydrate (96 mg) in 3:1 tetrahydrofuran-water (20 mL).
Reaction SMILES: CCCCCC.C([Li])CCC.C([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)C1C=CC=CC=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[Cl-].[NH4+].Cl>C1COCC1.CO.[OH-].[Pd+2].[OH-]>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[OH:19])=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: Oc1ccccc1Cc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 76.4 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 4.9 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.04 g, 7.75 mmol) in THF (60 mL) at −78° C. and the mixture was stirred at the same temperature for 20 minutes. To this solution, a solution of 4-fluorobenzaldehyde (801 mg, 6.45 mmol) in THF (10 mL) was added dropwise at −78° C. The mixture was stirred at the same temperature for 1.5 hours, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure to obtain a crude product (2.35 g) of the title compound. To a solution of the obtained crude product in methanol (15 mL), a 20% palladium hydroxide catalyst (186 mg) was added and furthermore 2N—HCl (400 μL) was added thereto. The mixture was stirred under a hydrogen atmosphere for three hours, and then the catalyst was filtered. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (996 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:56][O:57][CH2:58][C@H:59]1[CH2:63][CH2:62][CH2:61][NH:60]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:60]2[CH2:61][CH2:62][CH2:63][C@H:59]2[CH2:58][O:57][CH3:56])=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: COC[C@H]1CCCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC[C@@H]1CCCN1C(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) in DMF (5 mL) was added HOBt (32 mg, 1.2 eq.), EDAC.HCl (46 mg, 1.2 eq.) and TEA (50 mg, 2.5 eq.). After stirring at rt for 30 mins, to the mixture was added (R)-(-)-2-(methoxymethyl)pyrrolidine (46 mg, 2 eq.). After stirring at rt for overnight, the reaction was concentrated and the residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:3]1.[C:20](O)(=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[N+:23]([O-:27])[CH:22]=1>C(#N)C>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:20]([C:21]2[CH:22]=[N+:23]([O-:27])[CH:24]=[CH:25][CH:26]=2)=[O:28])[CH2:3]1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: CC1CCCN(Cc2cccc(OCCCN)c2)C1
Solvent: CC#N
Product: CC1CCCN(Cc2cccc(OCCCNC(=O)c3ccc[n+]([O-])c3)c2)C1
Reaction time: 2 h

Procedure:
To a solution of 0.04 mol of 3-[3-(3-methylpiperidinomethyl)phenoxy]propylamine in 40 ml of acetonitrile, 0.04 mol of the anhydride of the nicotinic acid 1-oxide is added (Synthesis, 1981, 618), then the reaction mixture is stirred for two hours at 50°-60° C. and evaporated to dryness under reduced pressure. The residue is taken up with 20 ml of concentrated sodium hydroxide and extracted 4 times with 30 ml of ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, the solvent is evaporated under reduced pressure and the product thus obtained is purified by chromatography on silica as described in Example 7. Thus, the N-[3-[3-(3-methylpiperidinomethyl)phenoxy]propyl]-3-pyridinecarboxamide 1-oxide, identical to the product of Example 8 is obtained; m.p. 108°-110° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>CS(C)=O.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)c[nH]2)CC1
Reactant: BrCCOC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCOC2CCCCO2)CC1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Dissolve 4-[4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (5.29 g; 13.93 mmol); powdered KOH (111.46 mmol; 6.95 g) in DMSO (69 mL) and heat to 40° C. for 10 min. Add 2-(2-bromoethoxy)tetrahydro-2H-pyran (34.83 mmol; 5.48 mL) dropwise over 45 min, then stir for 30 min. Cool and dilute with EA and wash with 3×300 mL saturated sodium bicarbonate, brine, dry over MgSO4, filter and evaporate. Purify on 400 g silica gel with 0-10% EA/DCM to provide the title compound (6.848 g, 97%). MS (ES): m/z=508 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:11]2([CH3:18])[NH:16][C:15](=S)[CH2:14][O:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(OO)(C)(C)C.[OH-].[NH3:26].[O-]S([O-])(=S)=O.[Na+].[Na+]>N.CO>[Br:1][C:2]1[CH:3]=[C:4]([C@:11]2([CH3:18])[CH2:12][O:13][CH2:14][C:15]([NH2:26])=[N:16]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: N
Reactant: C[C@@]1(c2cc(Br)cc([N+](=O)[O-])c2)COCC(=S)N1
Agent: CC(C)(C)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: C[C@@]1(c2cc(Br)cc([N+](=O)[O-])c2)COCC(N)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-5-(3-Bromo-5-nitro-phenyl)-5-methyl-morpholine-3-thione (2.86 g, 7.77 mmol) was dissolved in 7M NH3 in methanol (50 ml). Tert-Butylhydroperoxide (9.41 ml, 78 mmol) and ammonia hydroxide (25% sol., 21.2 ml, 136 mmol) were added and the reaction was stirred at r.t. for 2 hrs. Upon completion, 50 ml half-saturated Na2S2O3 solution was added to the reaction and the product was extracted with ethyl acetate. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure, yielding the title compound as yellowish solid. 1H-NMR (360 MHz, DMSO-d6): 8.34 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 5.85 (br, 2H), 4.01 (m, 1H), 3.80 (m, 1H), 3.55 (m, 1H), 1.38 (s, 3H); MS: 314 [(M+H)+].