Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([C:33](OC)=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1>C(OCC)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([C:33](=[O:34])[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: Brc1ccccn1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2ccccn2)C1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
Alternative Procedure: 2-Bromopyridine (110.0 g, 690 mmole) as a solution in diethyl ether (200 mL) was added to a cooled (−65° C.) solution of 2.5 M n-BuLi (275 mL, 690 mmol) in diethyl ether (200 mL). The mixture was stirred for 1 h at −70° C. to −65° C. To this solution was then added a suspension of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (100.0 g, 230 mmol) in diethyl ether (1.0 L), keeping the temperature below −65° C. The resulting solution was stirred for 2 hours at −70° C. to −65° C. The reaction mixture was quenched with glacial acetic acid (50 mL) and diluted with water (200 mL). The organic layer was washed with 20% aqueous sodium chloride solution (250 mL), dried over magnesium sulphate and concentrated to give a yellow foam. The crude product was purified over silica gel (350 g, 240-400 mesh) by elution with heptane/ethyl acetate (8:1 to 2:1) to give (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (109.5 g) as a yellow foam.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:18][C:19]([OH:21])=[O:20])[CH:12]=[C:13]([O:16][CH3:17])[C:14]=1[OH:15].[C:22](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:22][O:20][C:19](=[O:21])[CH2:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[C:14]([OH:15])=[C:9]([Br:8])[CH:10]=1
Reactant: COc1cc(CC(=O)O)cc(Br)c1O
Reactant: CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(Br)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.409 mL, 0.818 mmol) was added to a solution of (3-bromo-4-hydroxy-5-methoxy-phenyl)-acetic acid (150 mg, 0.575 mmol) in methanol (1 mL) and toluene (4 mL), and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (158 mg, 99%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([NH:24][C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1sc(NCc2ccccc2)nc1Cl
Temperature: 25 °C
Yield: 95.7 %

Procedure:
7.0 g (0.051 mol) of anhydrous potassium carbonate are added to a solution of 12.0 g (0.06 mol) of 2,4-dichloro-5-nitrothiazole in 50 ml of acetonitrile. A mixture of 5.35 g (0.05 mol) of benzylamine and 50 ml of acetonitrile is then added dropwise at 15° C. to 20° C. in the course of about half an hour and the mixture is subsequently stirred at room temperature for a further hour. It is then heated at the reflux temperature for 15 minutes, cooled to room temperature and stirred into about 500 ml of ice-water and the precipitate is filtered off, washed with water and dried. To remove excess 2,4-dichloro-5-nitrothiazole, the product is stirred into 80 ml of petroleum ether at room temperature, filtered off, washed with petroleum ether and dried. 12.9 g (95.7% of theory) of 2-benzylamino-4-chloro-5-nitrothiazole of melting point 195° C. to 196° C. (decomposition) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Cl[C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>[Cu].O>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:12]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Sc1cccc(Br)c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Sc1cccc(Br)c1

Procedure:
A mixture of 205 g. 3-bromothiophenol, 188 g. potassium hydroxide in 2 l. water, 205 g. 2-chloro-5-nitrobenzoic acid and 6.5 g. copper powder is refluxed for two hours, filtered while hot, acidified with hydrochloric acid and the solid filtered, washed with water and dried to yield 301 g. of the desired white solid, m.p. 202°-206° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=O)=[O:13])=[CH:2]1.[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Na]>CN(C)C=O.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:33][CH2:32][CH2:31][CH2:30][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:20])=[O:13])=[CH:2]1
Reactant: NCCCN1CCOCC1
Reactant: O=C(C=Cc1c[nH]c2ccccc12)Nc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C=Cc1c[nH]c2ccccc12)Nc1cccc(C(=O)NCCCN2CCOCC2)c1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
In 5.0 mL of dimethylformamide were dissolved 3-(3-1H-indol-3-yl-acryloylamino)-benzoic acid (150 mg, 0.49 mmol), prepared in Example 3, and 3-morpholin-4-yl-propylamine (0.11 mL, 0.73 mmol), followed by the addition of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (277.6 mg, 0.73 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.73 mmol). The resulting solution was stirred at room temperature and mixed with ethyl acetate and an aqueous sodium salt solution. The organic layer was dried over anhydrous magnesium sulfate. After the filtration and concentration of the residue, the concentrate was purified using Prep-TLC (methylene chloride:methanol=10:1) to produce the subject compound as a yellow solid (8) (92.6 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:6][CH:5]([CH3:7])[C:4](=[O:8])[N:3]1[CH2:9][C:10]([NH2:12])=[O:11].[CH2:14]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:24][CH2:25][C:26]([N:6]1[CH:5]([CH3:7])[C:4](=[O:8])[N:3]([CH2:9][C:10]([NH2:12])=[O:11])[C:2]1([CH3:1])[CH3:13])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC1NC(C)(C)N(CC(N)=O)C1=O
Product: CC1C(=O)N(CC(N)=O)C(C)(C)N1C(=O)CNC(=O)OCc1ccccc1

Procedure:
The same procedure of Example 2, starting from 2,2,4- trimethyl-5-oxo-1-imidazolidineacetamide and N-benzyloxycarbonylglycine, afforded 3-(2-benzyloxycarbonylaminoacetyl)-2,2,4-trimethyl-5-oxo-1-imidazolidineacetamide, as an oil, then the title compound, m.p. 118° C. Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=212 (M.+ --CH4N), 184 (M.+ --C2H4NO).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10]([OH:12])=O)[C:6]=1[CH3:7].[CH3:44][CH:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48][CH2:47][NH:46]1>>[CH2:39]([N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[C:33]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:46]2[CH2:47][CH2:48][C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:45]2[CH3:44])=[O:12])[N:4]=1)=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: CC1NCCc2ccccc21
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2C)c(C)c1Cl
Yield: 31.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 93B, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 32 mg, 0.051 mmol) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (Parkway Scientific, 8 mg, 0.056 mmol) were converted to the title compound (12 mg, 31%) following purification by preparative HPLC. 1H NMR (DMSO-d6, mixture of amide rotamers) δ 8.65 (s, 1H), 8.21 (d, J=8.1 Hz, 2H), 8.16-8.03 (m, 4H), 8.01-7.94 (m, 1.5H), 7.91 (br s, 0.5H), 7.77-7.61 (m, 3H), 7.27-6.93 (m, 2H), 5.48-5.31 (m, 0.5H), 3.68-3.55 (m, 1H), 3.17-2.57 (m, 4.5H), 2.55 (t, J=5.5 Hz, 3H), 2.20 (s, 3H), 1.53-1.36 (3.5H), 1.29-1.23 (m, 2.5H), 1.21-1.12 (m, 4H), 0.95-0.82 (m, 3.5H), 0.66 (d, J=7.3 Hz, 3H), 0.56 (br s, 0.5H); MS(ESI+) m/z 754.3 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH:15]1([CH:18]=[O:19])[CH2:17][CH2:16]1>C1COCC1>[CH3:8][C:7]1[C:2]([CH:18]([CH:15]2[CH2:17][CH2:16]2)[OH:19])=[N:3][CH:4]=[CH:5][C:6]=1[Cl:9]
Reactant: O=CC1CC1
Reactant: Cc1c(Cl)ccnc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(Cl)ccnc1C(O)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A solution of 2-bromo-3-methyl-4-chloro-pyridine (10.6 g, 57.1 mmol) in freshly distilled THF (120 mL) was cooled down to 0° C. and treated with isopropyl magnesium chloride (45.7 mL, 2.0 M in THF, 91.5 mmol). The resulting mixture was stirred at room temperature for 3 h then cooled to −5° C. Cyclopropane carboxaldehyde (6.83 mL, 91.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and quenched by adding water (100 mL), and extracted with ethyl acetate (2×150 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 3:1) to afford the title compound as a yellow oil (7.01 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]NC(=O)CCC(N)=O>CC(O)=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([Br:26])=[CH:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:20][CH:21]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1ccc(-n2ccc(=O)c(OCc3ccccc3)c2)cc1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC(=O)O
Product: CCCCc1ccc(-n2cc(Br)c(=O)c(OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(benzyloxy)-1-(4-butylphenyl)pyridin-4(1H)-one (705 mg, 2.1 mmol) in AcOH (21 mL) was added N-bromosuccinamide (414 mg, 2.3 mmol) and the reaction mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and purified by flash chromatography (50 g SiO2, 0-70% ethyl acetate/hexanes) to provide 3-(benzyloxy)-5-bromo-1-(4-butylphenyl)pyridin-4(1H)-one. LC/MS (M+H)+ 412/414.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([S:44]([CH3:47])(=[O:46])=[O:45])[CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:42][C:39]([F:40])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:31]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:20]=[C:15]([CH2:14][N:13]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[N:16]=[CH:17][N:18]=4)=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[O:43])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)S(C)(=O)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1)C1CCNC1

Procedure:
(±)-3-(Methanesulfonyl-{6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (12 mg, 0.018 mmol) is stirred in a solution of DCM (2 mL) and TFA (0.5 mL) overnight. After removal of solvents, the residue is quenched with saturated aqueous sodium bicarbonate. The mixture is extracted with EtOAc (3×). The combined organic layers are washed with water and brine and the organic layer is dried with Na2SO4, filtered, and condensed. The residue is then separated by FCC (0-10%, 2 M NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 574.8 (M+1).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.P([O-])([O-])([O-])=O.[OH:17][NH3+:18].O[NH3+].O[NH3+]>O>[OH:17][N:18]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:6]
Reactant: [NH3+]O
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1O
Temperature: 130 °C

Procedure:
1.48 g (10.0 mmol) of phthalic anhydride and 0.723 g (3.67 mmol) of hydroxylammonium phosphate were pulverized, mixed and, following the addition of 2 ml of water, heated at a bath temperature of 130° C. for about 1½ hours. The cooled lemon-yellow reaction mixture was diluted with water, and the solid was filtered off with suction, washed with water and dried at 50° C. The yield was 1.39 g (86%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:4]([C:5](=[O:29])[O:6][C:7]3[C@H:8]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]4)[CH2:3]1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([O:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:4]([C:5](=[O:29])[O:6][C:7]3[C@H:8]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]4)[CH2:3]1)=[O:36]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1C(=O)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](OC(=O)c2ccco2)C[C@@H]1C(=O)O3
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
Compound 2 (51 mg, 0.13 mmol) obtained in Example 2 was dissolved in dichloromethane (0.65 mL), and furan-2-carboxylic acid chloride (0.025 mL, 0.26 mmol) and pyridine (0.041 mL, 0.51 mmol) were added thereto, followed by stirring at 0° C. for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A residue obtained by concentrating the organic layer under reduced pressure was purified by preparative thin layer chromatography to obtain the title compound (65 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([Cl:28])=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)s1
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: NC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 38 %

Procedure:
The titled compound was prepared in 38% yield from (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (75 mg, 0.237 mmol) and 2-bromomethyl-5-chloro-thiophene (83 mg, 0.498 mmol) according to the procedure described in Example 3: 1H NMR (400 Mz, CDCl3) δ 7.72 (d, 2 H, J=6.6), 7.59 (d, 2 H, J=8.9), 7.39 (br s, 1 H), 6.88 (d, 1 H, J=3.7), 6.79 (br s, 1 H), 4.69 (s, 2 H), 3.83 (dt, 1 H, Jd=12.7, J=3.7), 2.71 (m, 1 H), 2.52 (m, 1 H), 1.79–1.69 (m, 2 H), 1.61 (m, 1 H), 1.49–1.22 (m, 3 H), 1.11 (m, 1 H); MS m/e 469.1 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16](C)([CH3:18])[CH3:17]>ClCCl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:15](=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
EX-5A) A solution of 2-amino pyridine (20.42 , 217.0 mmol) in dichloromethane 500 mL was cooled to 0° C. and treated with triethyl amine (36.29 mL, 260.4 mmol) and pivaloyl chloride (28.06 mL, 227.8 mmol). After 15 minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was poured onto ice, and the organic layer was washed with saturated NaHCO3 (aq), and dried over Na2SO4. The volatile components were removed, and a brown oil was isolated. Crystallization with hexanes afforded 31 g of N-(pyrid-2-yl)-2,2-dimethylacetamide (EX-5A) as white crystals in 80% yield. Reference: Turner, J. A. J. Org. Chem, 1983, 48, 3401.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([O-])=[C:6]([OH:15])[C:5]1=[O:16])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:15])[C:5]1=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)c(O)[n+]([O-])c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)c(=O)[nH]c2ccccc21

Procedure:
A solution of 3,4-dihydro-4-isopropyl-2-hydroxy-3-oxo-quinoxaline-1-oxid (15.5 g, 0.07 mole) and triphenylphosphine (26.2 g, 0.1 mole) in dimethylformamide (DMF) (100 ml) was stirred at 120° C. for 12 hours, whereafter the solvent was evaporated in vacuo. The residue was stirred in methylene chloride (150 ml) whereby the formed triphenyl phosphine oxid was dissolved. The product was then collected as pale crystals by filtration followed by wash with methylene chloride M.p. 227°-228° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.[CH2:13]=O.[OH-].[Na+]>C(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH3:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1
Reactant: C=O
Reactant: Cc1ccc(C2CCCN2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: Cc1ccc(C2CCCN2C)cn1
Yield: 92 %

Procedure:
Into a round bottom flask was placed XVI (2.0 g), and formaldehyde (37% w/v in water, 20 mL) and formic acid (95-97% w/v, 45 mL), both a 0° C., were added. The mixture then was refluxed under nitrogen for 8 hr. The cooled reaction mixture was basified with aqueous sodium hydroxide (50% w/v) to pH 8-9, and the solution extracted with chloroform (5×25 mL). The combined organic liquors were dried over anhydrous sodium sulfate, filtered and evaporated; and the resulting oil distilled under reduced pressure to afford XVII as a clear odorless oil (b.p. 107° C. at 3 mm Hg, 92% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:26](C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[N:8]([CH3:26])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc(CNC(c2ccccn2)c2ccccn2)nc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(Cc1ccccn1)C(c1ccccn1)c1ccccn1
Yield: 93 %

Procedure:
To a solution of N-[di(2-pyridinyl)methyl]-N-(2-pyridinylmethyl)amine (1.262 g, 4.59 mmol) in 1,2-dichloroethane (35 ml) was added formaldehyde (37% solution in water, 0.45 ml, 6.0 mmol). NaBH(OAc)3 (3.92 g, 18.5 mmol) was added in small portions. After stirring for 7 h at room temperature saturated NaHCO3(aq) (35 ml) was added and the 1,2-dichloroethane layer was separated. The aqueous layer is extracted with CH2Cl2 (3×20 ml). The combined organic layers were washed with 1N NaOH (20 ml) and brine (20 ml), dried (Na2SO4) and the solvent removed in vacuo to give N-[di(2-pyridinyl)methyl]-N-methyl-N-(2-pyridinylmethyl)amine (1.235 g, 4.27 mmol, 93%) as a slightly yellow oil. 1H NMR (CDCl3, 300 MHz) δ 2.19 (s, 3H), 3.72 (s, 2H), 4.96 (s, 1H), 7.14 (m, 3H), 7.71 (m, 6H), 8.56 (m, 3H); 13C NMR (CDCl3, 50 MHz) δ 40.32 (q), 61.04 (t), 77.87 (d), 121.76 (d), 122.10 (d), 122.92 (d), 123.21 (d), 136.29 (d), 136.43 (d), 148.86 (d), 149.22 (d), 159.37 (s), 160.59 (s), MS (CI): m/z 291 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25].O>O1CCCC1>[CH3:27][O:26][C:24](=[O:25])[N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCNCCc1ccccc1Br
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCN(CCc1ccccc1Br)C(=O)OC
Reaction time: 20 h

Procedure:
4.51 g of N-[2-(2-bromophenyl)ethyl]pentan-1-amine in suspension in 120 cm3 of anhydrous tetrahydrofuran are stirred under an inert atmosphere at 5° C. 2.33 cm3 of triethylamine, then 1.3 cm3 of methyl chloroformate are added to the reaction mixture. This mixture is then stirred for 20 h at a temperature close to 20° C. before being poured over a mixture of water and ice. The phases are stirred for 5 min, then separated. The aqueous phase is extracted 3 times with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 6.33 g of oil obtained are purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 20% heptane/80% ethyl acetate). After concentrating the fractions under reduced pressure, 5.45 g of methyl[2-(2-bromophenyl)ethyl]pentylcarbamate are obtained in the form of a colorless oil
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:16]([CH3:17])=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[CH2:18][CH3:19])[CH2:4][O:3]1.C([O-])(O)=O.[Na+].Cl.[NH2:27][OH:28]>CO>[CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:16]([CH3:17])=[CH:15][C:12]([C:13]([NH:27][OH:28])=[NH:14])=[CH:11][C:10]=2[CH2:18][CH3:19])[CH2:4][O:3]1
Reactant: NO
Reactant: CCc1cc(C#N)cc(C)c1OC[C@@H]1COC(C)(C)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1
Temperature: 60 °C
Reaction time: 18 h
Yield: 107.7 %

Procedure:
To a mixture of (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-benzonitrile (4.45 g, 16.2 mmol) and NaHCO3 (4.75 g, 56.6 mmol) in methanol (30 mL), hydroxylamine hydrochloride (3.37 g, 48.5 mmol) is added. The mixture is stirred at 60° C. for 18 h before it is filtered and the solvent of the filtrate is removed in vacuo. The residue is dissolved in EA and washed with a small amount of water and brine. The org. phase is separated, dried over MgSO4, filtered, concentrated and dried to give the title compound (5.38 g) as a white solid; LC-MS**: tR=0.46 min, [M+1]+=309.23; 1H NMR (D6-DMSO): δ 1.17 (t, J=7.5 Hz, 3H), 1.33 (s, 3H), 1.38 (s, 3H), 2.25 (s, 3H), 2.57-2.69 (m, 2H), 3.73-3.84 (m, 3H), 4.12 (t, J=7.0 Hz, 1H), 4.39-4.45 (m, 1H), 5.76 (s br, 2H), 7.34 (s, 1H), 7.36 (s, 1H), 9.47 (s, 1H).