Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[OH:10])=[C:5]([CH2:18][OH:19])[CH:4]=1)#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[OH:10])=[C:5]([CH:4]=1)[CH2:18][O:19][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])#[N:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1ccc(C(O)c2ccc(F)cc2)c(CO)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCc1cc(C#N)ccc1C(O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of (4-cyano-2-hydroxymethylphenyl)(4-fluorophenyl)methanol (9.2 g, 0.037 mol) and triethylamine (4.0 g, 0.04 mol) was added pivaloyl chloride (4.2 g, 0.39 mol). After stirring for 60 minutes the reaction mixture was poured onto ice, extracted with diethyl ether (2×75 mL), dried (MgSO4), and concentrated under reduced pressure to give a colourless oil (12.0 g). The compound was purified by chromatography (eluent hexane/ethyl acetate 1:9 to give the title compound (8.2 g, 70%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH2:30])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:43][CH3:44]>C1COCC1>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:43][CH3:44])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCI
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
To a solution of compound 1 (500 mg, 1.10 mmol) in dry THF (20 mL) was added LiHMDS (1.0 mL, 1.0 mmol) at −10° C. under N2. After stirring for 30 min, iodoethane (312 mg, 2.0 mmol) was added. The solution was stirred for another 3 h at 35° C., then quenched with water and extracted with EA twice. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (EA/PE=1/5) to give compound 2 (50 mg, 10%) as a solid. 1H-NMR (400 MHz, CDCl3) δ: 0.63-0.65 (m, 2H), 0.97-1.03 (m, 3H), 1.13-1.17 (m, 3H), 1.34 (s, 18H), 1.32-1.35 (m, 3H), 1.50-1.55 (m, 3H), 2.52 (s, 3H), 3.04-3.07 (m, 2H), 3.72 (d, J=6.8 Hz, 2H), 4.12 (m, 1H), 6.41 (s, 1H), 7.15 (s, 2H), 7.40 (s, 1H). MS Calcd.: 472; MS Found: 473 (M+1).
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:21]([C@@:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2[C@]2(C(=O)c3ccccc3)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 100 mL flask was added guanosine (2.0 g, 7.06 mmol) and N,N-dimethyl-4-aminopyridine (0.017 g, 0.14 mmol). N,N-dimethylformamide (30 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (16 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and benzoyl chloride (1.2 mL, 8.5 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 72 h, the mixture was poured into 300 mL of 0.1 M sodium bicarbonate solution (warmed to 60° C.) giving a white solid which was isolated by suction filtration (using a medium glass frit), washed with 3×100 mL cold water, and air dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=[CH:38]2>CN(C=O)C>[CH3:45][N:41]1[C:42]2[C:37](=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][N:13]([CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])=[CH:44][CH:43]=2)[CH:38]=[CH:39][C:40]1=[O:46]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1cccnc1
Reactant: Cn1c(=O)ccc2cc(OCCCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
2-Nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide (308 mg), and potassium carbonate (276 mg) were added to a DMF solution (5 ml) of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one (348 mg). The mixture was stirred at room temperature for 2 hours. Ice water was poured to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give 5 the title compound (535 mg) as a yellow amorphous solid.
Reaction SMILES: [CH:1]1([NH:8][CH:9]([P:18](=[O:25])([O:22]CC)[O:19]CC)[P:10](=[O:17])([O:14]CC)[O:11]CC)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.CC(C)=O>Cl>[CH:1]1([NH:8][CH:9]([P:18](=[O:19])([OH:22])[OH:25])[P:10](=[O:11])([OH:14])[OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOP(=O)(OCC)C(NC1CCCCCC1)P(=O)(OCC)OCC
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: O=P(O)(O)C(NC1CCCCCC1)P(=O)(O)O
Yield: 86.9 %

Procedure:
4.0 g of tetraethyl (cycloheptylamino)methylenebis(phosphonate) was dissolved in 40 ml of concentrated hydrochloric acid and heated under reflux for 2.5 hours. After cooling, the reaction solution was concentrated under reduced pressure to eliminate hydrochloric acid. Then, 30 ml of purified water was added to the residue and the mixture was again concentrated under reduced pressure. The oily product thus obtained was solidified by methanol and acetone and subject to the filtration. The residue was washed with acetone to give 2.5 g of (cycloheptylamino)methylenebis(phosphonic acid) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:33]([OH:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)=[O:10].Cl.[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41]Cl)[CH3:38].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:37]([N:39]([CH2:43][CH2:44][O:34][C:33](=[O:35])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:28])([F:29])[F:27])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH2:40][CH3:41])[CH3:38]
Reactant: CCN(CC)CCCl
Reactant: Cc1cc(C(F)(F)F)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.8 %

Procedure:
To a mixture of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (145 mg, 0.275 mmol), 2-diethylaminoethyl chloride hydrochloride (487 mg, 2.75 mmol) and potassium carbonate (380 mg, 2.7 mmol) was added ethyl acetate (3 mL) and water (3 mL) at room temperature. The mixture was stirred for 72 h at room temperature. Then, the reaction mixture was poured into a mixture of water (30 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (60 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product, which was purified by silica gel chromatography using a Biotage (40 s) column afforded 122 mg (71% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine 2-[(N,N-diethyl)amino]ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C30H32Cl2F3N3O4 (M+H) 626.1796. found 626.1802.
Reaction SMILES: C(OC([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]1OCC)=O)C.Cl.Cl.N[C@@H](CC(C)C)[C@H:23](C1C=CC=CN=1)[OH:24].C(N(CC)CC)C>ClCCl>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:15]=1[CH:14]([CH2:13][CH2:12][CH3:11])[CH2:23][OH:24]
Reactant: CC(C)C[C@H](N)[C@@H](O)c1ccccn1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CO)c1ccccn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 3.32 g sample of (S) 2-tert-butoxycarbonyl-amino-4-methyl-(R)1-(2-pyridinyl)pentan-1-ol, 0-acetate was dissolved in a mixture of 3 ml of methanol and 8 ml of 5N sodium hydroxide. The solution was stirred at 10° C. for 2 hours and then extracted with dichloromethane. The extract was dried (Na2SO4) and the solvent removed under vacuum to give 2.69 g of (S) 2-tert-butoxycarbonylamino-4-methyl-(R)1-(2-pyridinyl)-pentan-1-ol as an oil. To the preceding compound (2.69 g) was added 15 ml of 2N anhydrous hydrochloric acid in ethyl acetate. After stirring at room temperature, the solvent was removed under vacuum to give 2.46 g of (S) 2-amino-4-methyl-(R)1-(2-pyridinyl)-pentan-1-ol, dihydrochloride as tan crystals, mp 152°-154° C. To a solution of N-[(phenylmethoxy)carbonyl]-L-phenylalanyl-D,L-2-ethoxyglycine (2.0 g; 5 mmol) (Reference Example 12) and 5 mmol of 2-ethoxy- 1(2H)-quinolinecarboxylic acid ethyl ester in 50 ml of dichloromethane is added 5 mmol of (S)-2-amino-4-methyl-(R)1-(2-pyridinyl)pentan-1-ol, dihydrochlorde and 4 ml of triethylamine in 25 ml of dichloromethane. The mixture is stirred at room temperature for 20 hours and worked-up as described for Reference Example 8 to give N-[N-[(phenylmethoxy)carbonyl)-L-phenylalanyl-D,L-2-ethoxyglycyl]-(S)2-amino-4-methyl-(R)1-(2-pyridinyl pentan-1-ol as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[C:21]([NH:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
30 mg of 3-amino-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 1 ml of methylene chloride and 1 ml of pyridine, to which 19 mg of benzoyl chloride was added with cooling with ice, and the mixture was stirred at room temperature for a night. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried by magnesium sulfate, and refined by NH silica gel chromatography (ethyl acetate). The solvent was concentrated, and the resultant crude crystal was washed with ethyl acetate/hexane, to obtain 35 mg of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=O)[NH:8][C:5]2=[CH:6][N:7]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:1].[ClH:24].[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: O=C(c1ccccc1)c1cc2cc(Cl)ncc2[nH]1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=C(c1ccccc1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 161.8 %

Procedure:
To a solution of (5-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanone (Example 73) (65 mg, 0.25 mmol) in ethanol (5 mL) was added aminoguanidine hydrochloride (55 mg, 0.85 mmol) and 6 N HCl (0.2 mL). The reaction mixture was heated to reflux under N2. After 2 h, heating was terminated and the reaction mixture was cooled to room temperature forming a white precipitate. The precipitate was collected by filtration and dried under vacuum to provide [[(5-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methylene]amino]guanidine dihydrochloride (78 mg, 100%) as a white solid: mp 274-278° C.; 1H NMR (300 MHz, CD3OD) δ 6.62 (1H, s), 7.49-7.58 (2H, m), 7.68-7.79 (4H, m), 8.04 (1H, s), 8.98 (1H, s); ESI MS m/z 313 [C15H13ClN6+H]+; HPLC (Method A) >99% (AUC) tR=16.5 min.
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28](O)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=CC=1)CCC.C[N:33](C=O)C.S(Cl)(Cl)=O>C1COCC1>[CH2:25]([N:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:31][C:19]=2[CH:20]=[C:21]([C:28]([NH2:33])=[O:29])[CH2:22][CH2:23]1)[CH2:26][CH3:27]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCC)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCN1CCC(C(N)=O)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.80 g) was dissolved in THF (8.0 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (16 ml) was added dropwise to a solution of 4-[3-(imidazol-1-yl)propyl]aniline (0.42 g) and triethylamine (2.1 ml) in THF (12.6 ml) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[imidazol-1-yl]propyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 287) (0.80 g).
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:26]([O-:28])=[O:27])[CH2:19]C1C=CC=CC=1.C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH3:19])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)[O-]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CC#N
Product: C[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. Next, 813 mg (2 mmol) of tetrabutylammonium phenylalanine salt and 15 mL of acetonitrile were dropped to the solution, and then the mixture was stirred for 15 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-alanine was obtained. An isolation amount and an isolation yield were 445.0 mg and 78%, respectively.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([C@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.C(O)(=O)C>[Zn].C1C=CC=CC=1>[CH3:1][C@H:2]1[C@@:19]2([CH3:20])[C:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:22])[CH2:3]1
Reactant: C[C@@]12C(=CC(=O)[C@H]3C[C@H]31)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C

Procedure:
A mixture of 1β,2β-methylene-4-androstene-3,17-dione, zinc powder, and acetic acid is refluxed for one hour. Benzene is added and the suspension filtered. The filtrate is taken to dryness under vacuum. The residue which remains is chromatographed on silica gel and eluted with methylenechloride. Recrystallization of the residue obtained from the eluate from an acetone-hexane solution yields 1β-methyl-4-androstene-3,17-dione.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2].[CH3:33][O:34][CH2:35][C:36]#[CH:37]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:37]#[C:36][CH2:35][O:34][CH3:33])[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2]
Reactant: C#CCOC
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCCN3CCOCC3)c2)cc1Cl
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCOC)cc(OCCCN3CCOCC3)c2)cc1Cl

Procedure:
{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (0.2 g; 0.37 mmol), 3-methoxy-propyne (0.10 g; 1.47 mmol), bis(triphenylphosphine) palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150° C. for 1 h. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 160 mg. HPLC-MS: m/z: 534.1 (M+); Rt: 1.79 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.[NH4+:15].[OH-]>C1COCC1>[NH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([NH2:15])=[O:9]
Reactant: [NH4+]
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methoxy-1H-benzo[d][1.3]oxazine-2,4-dione (7.0 g, 36.2 mmol) in THF (50 mL) was added NH4OH (20 mL) and the reaction was stirred at rt for 1 h. The solution was concentrated under reduced pressure and dried to give 5.0 g of 2-amino-5-methoxy-benzamide as a dark brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.[Rh]>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)cc2)CC1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)CC1
Yield: 546.6 %

Procedure:
To a solution of tert-butyl 4-(4-bromophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.30 mmol) in EtOAc was added Rh/C (8 mg, 0.03 mmol). The resulting reaction mixture was stirred at rt in a hydrogen atmosphere for 17 h. The mixture was filtered through a cake of Celite and the filtrate was concentrated to give the title compound as a colourless oil (558 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.3 Hz, 2H), 4.27-4.23 (m, 2H), 2.79 (t, J=12.9 Hz, 2H), 2.65-2.58 (m, 1H), 1.82-1.79 (m, 2H), 1.64-1.56 (m, 2H), 1.49 (s, 9H); MS ESI 361.9 [M+Na]+, calcd for [C16H22BrNO2+Na]+ 362.07.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:6].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]23[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][CH2:20][N:19]2[CH2:18][CH2:17][C:16](=O)[CH2:15]3)=[CH:10][CH:9]=1.[BH3-]C#N.[Na+]>CO>[ClH:6].[ClH:6].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]23[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][CH2:20][N:19]2[CH2:18][CH2:17][CH:16]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:15]3)=[CH:12][CH:13]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(C23CC(=O)CCN2CCc2ccccc23)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C23CC(N4CCCC4)CCN2CCc2ccccc23)cc1

Procedure:
A solution of 14 ml of pyrrolidine (168 mmoles) in 75 ml of methanol is neutralized with HCl gas while the solution is cooled in an ice bath. 13 ml more (156 mmoles) of yrrolidine is added along with 100 ml of methanol. Thereafter is added 16.0 g (54.9 mmoles) of 11b-(4-methylphenyl)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-one, 3.47 g (55.2 mmoles) of NaBH3CN and molecular sieves. A drying tube is attached and the reaction conditions of EXAMPLE 7 are employed. The work-up procedures of EXAMPLE 8 are used to obtain 11b-(4-methylphenyl)-1,3,4,6,7,11b-hexahydro-2-pyrrolidin-1-yl-2H-benzo[a]quinolizine dihydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].[C:25]([C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[N:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:26]#[C:25][C:27]4[CH:28]=[N:29][C:30]([CH3:33])=[N:31][CH:32]=4)=[CH:11][CH:10]=3)[C:5](=[O:24])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: C#Cc1cnc(C)nc1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#Cc3cnc(C)nc3)cc2c1=O
Temperature: 150 °C
Yield: 54 %

Procedure:
Compound D (50 mg, 0.13 mmol, 1.0 eq), 5-ethynyl-2-methyl-pyrimidine (30 mg, 0.26 mmol, 2.0 eq), copper(I) iodide (2.5 mg, 0.013 mmol, 0.010 eq), bis(triphenylphosphine)palladium(II) dichloride (4.5 mg, 0.0064 mmol, 0.050 eq) and triethylamine (53.6 μL, 0.38 mmol, 3.0 eq) were dissolved in DMF (1.3 mL) in a microwave vial and heated in a microwave reactor at 150° C. for 15 minutes. The reaction was purified directly using reverse phase chromatography to afford 30 mg (55%) of the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 8.47 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.81-7.76 (m, 3H), 7.53 (t, J=8.7 Hz, 2H), 7.02 (d, J=8.80 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 2.66 (s, 3H), 1.25 (t, J=7.1 Hz, 3H); ES-MS [M+1]+: 428.2.