Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=3)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=4[F:31])[N:24]=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:22]=3[CH3:39])=[CH:11][C:10]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=3)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1cc(C2=CCCCC2)cnc1C1=CCCCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(C2=CCCCC2)cnc1C1=CCCCC1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
A stirred mixture of mostly 2,5-dicyclohexenylpyridin-3-amine (0.047 g, 0.19 mmol), 4-bromo-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.085 g, 0.26 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (0.019 g, 0.039 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.018 g, 0.019 mmol), and sodium tert-butoxide (0.056 g, 0.58 mmol) in dry toluene (2.0 mL) was purged three times with argon and placed under vacuum three times, then the mixture was heated to 100° C. After 2.5 h, the reaction was cooled to rt. After extracting twice with EtOAc, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on silica gel (0-10% of 89:9:1 DCM:MeOH:ammonium hydroxide solution in DCM) to afford an impure light yellow film. The light yellow film was further purified with HPLC 10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution. The desired fractions (Prep. HPLC Retention time was −14.1 min) were concentrated then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as N-(2,5-di-1-cyclohexen-1-yl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (500 MHz, CDCl3) δ ppm 8.74 (1H, ddd, J=4.9, 1.7, 1.0 Hz), 8.23 (1H, d, J=2.0 Hz), 7.91 (1H, m), 7.85 (1H, m), 7.62 (1H, ddd, J=9.7, 2.4, 1.1 Hz), 7.38 (1H, ddd, J=7.4, 4.8, 1.2 Hz), 7.33 (1H, d, J=11.5 Hz), 7.00 (1H, ddd, J=13.6, 8.6, 2.6 Hz), 6.86 (1H, d, J=2.0 Hz), 6.18 (1H, m), 6.14 (1H, m), 2.48 (2H, br. s.), 2.33 (2H, br. s.), 2.29 (2H, m), 2.22 (2H, m), 2.14 (3H, s), 1.88 (2H, m), 1.79 (4H, m), 1.67 (2H, m). Mass Spectrum ESI (pos.) m/e: 509.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH3:24])=[CH:8]2)=[O:4].[CH3:26][Sn](C)(C)C.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[C:13]([CH3:26])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH3:24])=[CH:8]2)=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Br)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(C)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 107.1 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-3-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (162 mg, 0.40 mmol), tetramethyltin (0.3 mL, 2.0 mmol) and PdCl2(PPh3)2 (56 mg, 0.08 mmol) in 5 mL of DMF was heated at 120° C. under nitrogen atmosphere for 1 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (40 mL) was added. 1M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the residue was chromatographed (0-50% EtOAc/hexanes+2% AcOH) to give 145 mg of the title compound as a white solid. MS: (+) m/z 339.11 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CC(N(C)C)=O>[N:13]1([C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Temperature: 140 °C
Yield: 107.8 %

Procedure:
A mixture of 5-chloro-2-nitrobenzonitrile (20.0 g) and imidazole (22.3 g) in DMA (150 ml) was heated at 140° C. for 6 hours. The mixture was evaporated and the residue was triturated with water to give 5-(1-imidazolyl)-2-nitrobenzonitrile (25.3 g); NMR Spectrum: (CD3SOCD3) 7.20 (d, 1H), 8.05 (t, 1H), 8.28 (m, 1H), 8.62 (m, 2H), 8.51 (d, 1H);
Reaction SMILES: Cl.O.C[O:4][C:5]1[CH2:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH2:21][CH:22]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]1=[CH2:23].C(=O)(O)[O-].[Na+]>CO.CC(C)=O>[CH2:23]=[C:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C@@H:20]1[C:7](=[CH:6][C:5](=[O:4])[CH2:22][CH2:21]1)[CH2:8][CH2:9]3
Reactant: C=C1CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: C=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
Con. hydrochloric acid (6.0 mL) and water (6.0 mL) were added to a solution of 17-methylenestra-2,5(10)-dien-3-yl methyl ether (15, 702.8 mg. 2.471 mmol) in methanol (6 mL) and acetone (20 mL). See Example 17. After stirring 1 h, sodium bicarbonate (7.50 g) was added cautiously. The mixture was concentrated under reduced pressure once effervescence had ceased and water (50 mL) was added. The mixture was extracted three times with 25 mL portions of methylene chloride. The combined organic extracts were washed with 50 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 mL of methylene chloride and the combined filtrates were concentrated under reduced pressure. The product was purified by decolorization with charcoal, flash chromatography (20% ethyl acetate/hexanes on silica gel), and recrystallization from aqueous ethanol to give a white powder (302.8 mg. 1.120 mmol, 45%), m.p. 83-89° C. (NA-1994A-271)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:10][N:9]=[C:8]([C@@H:11]([NH:15][C:16]([O:18]C(C)(C)C)=O)[CH:12]([CH3:14])[CH3:13])[CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)CCl.[CH:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][C:43]=1C(O)=O.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:10][N:9]=[C:8]([C@@H:11]([NH:15][C:16]([C:44]2[CH:43]=[CH:42][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)=[O:18])[CH:12]([CH3:13])[CH3:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(COc2ccccc2)CC([C@@H](NC(=O)OC(C)(C)C)C(C)C)=NO1
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(COc2ccccc2)CC([C@@H](NC(=O)c2ccc3ccccc3c2)C(C)C)=NO1
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
A solution of 3-{(1S)-1-(t-butoxycarbonylamino)-2-methyl-propyl}-5-phenoxymethyl-4,5-dihydro-isoxazole-5-carboxylic acid ethyl ester (2.00 g, 4.76 mmol) in dry CH2Cl2 (10 mL) at 0° C. under N2 was treated with TFA (6 mL) and stirred for 1.5 h. After removal of volatiles, the residue was taken up with ethyl acetate (200 mL), washed with sat'd NaHCO3(100 mL×2), dried (anh Na2SO4), filtered and concentrated. To a solution of the crude product, EDC (1.09 g, 1.2 eq), 2-naphthoic acid (983 mg, 1.2 eq) and HOBt (771 mg, 1.2 eq) in DMF (20 mL) at 0° C. was added triethylamine (663 uL, 1.0 eq). The reaction was stirred overnight at room temperature. After removal of volailes in vacuo, the residue was taken up with ethyl acetate (250 mL), washed with water(100 mL), sat'd NaHCO3 (100 mL×2), dried (anh Na2SO4), filtered and concentrated. Flash chromatography with 25-33% ethyl acetate/hexanes gave 2.04 g (90%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)([O-])=O.O.NN>CO.[Pd]>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Nc2ccccc2N)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of methyl 4-[(2-nitrophenyl)amino]benzoate (20 g, 48 mmol) in methanol under nitrogen was treated with 5% Pd/C (1.8 g, 30 w/v) and hydrazine hydrate (11.7 g, 230 mmol), heated at reflux temperature for 2 h, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resultant residue was partitioned between CH2Cl2 and water. The organic phase was separated, dried over Na2SO4 and concentrated under vacuum. The resultant residue was purified with flash column chromatography with (silica, EtOAc:hexanes 4:6) to give 4-(2-aminophenylamino)benzoic acid methyl ester in 80% yield, 1H NMR (400 MHz, CDCl3): 7.87 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.0 Hz, 1H) 7.09 (t, J=8 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.78 (t, J=8 Hz, 1H), 6.67 (d, J=8.0 Hz, 2H), 5.4 (bs, 1H), 3.8 (s, 3H), 3.71 (s, 2H); LCMS (ESI+) 243 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:18])([CH3:17])[O:7]2.[C:19]([O-])([O-])=O.[K+].[K+].CI>>[CH3:19][O:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:18])([CH3:17])[O:7]2
Reactant: O=C([O-])[O-]
Reactant: CC1(C)C=Cc2c(cc([N+](=O)[O-])c(C=O)c2O)O1
Agent: [K+]
Solvent: CI
Product: COc1c2c(cc([N+](=O)[O-])c1C=O)OC(C)(C)C=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-hydroxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde (2.34 g, 10 mmol), K2CO3 (4.12 g, 29.8 mmol) and MeI (2.13 g, 0.94 mL, 15 mmol in Me2CO (40 mL) is refluxed for 4 h and stirred at room temperature overnight. The mixture is concentrated, treated with water (15 mL) and extracted with dichloromethane. The combined organic layers are washed with water, dried over Na2SO4, and the solvent is removed in vacuo to afford an oil, which is chromatographed with 3% Me2CO in hexane to afford 5-methoxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1>C1COCC1>[Cl:1][C:2]1[C:11]([C@H:12]([OH:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)c1cc2cccc(F)c2nc1Cl
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc2cccc(F)c2nc1Cl
Temperature: -55 °C
Reaction time: 1 h

Procedure:
In a round bottomed flask was dissolved (+)-dip-chloride(tm) (4418 mg, 13773 μmol) in anhydrous THF (50 mL) and the solution was cooled to −55° C. (using a dry ice/MeCN bath). To this solution was added 1-(2-chloro-8-fluoroquinolin-3-yl)ethanone (1.4 g, 6.3 mmol) as a solution in THF (10 mL). The reaction was allowed to warm to +10° C. over 5 h. The reaction was quenched with 10 mL acetone and 20 mL of 10% Na2CO3 and allowed to stir for 1 h at rt. Ethyl acetate (200 mL) was added and the layers were separated. The organic phase was washed with three times with a 50% saturated sodium bicarbonate solution and once with brine. The organic layer was dried over MgSO4, filtered, and concentrated to provide 5 g of crude material. The crude material was purified using 7:3 hexanes:ethyl acetate on 120 g silica gel column to afford (R)-1-(2-chloro-8-fluoroquinolin-3-yl)ethanol. Chiral HPLC (10% IPA in hexanes, chiralcel AD) shows product to be 96.0% ee. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s), 7.64 (br d, J=8.2 Hz, 1H), 7.50 (td, J=7.8, 4.7 Hz, 1H), 7.41 (ddd, J=10.2, 7.8, 1.2 Hz, 1H), 5.40 (qd, J=5.9, 0.8 Hz, 1H), 2.22 (br s, 1H), 1.62 (d, J=6.3 Hz, 3H). Mass Spectrum (ESI) m/e=226.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=N[CH2:22][CH2:23][CH2:24][N:25](C)C.C1C=CC2N(O)N=NC=2C=1.C1(N)CC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](=[O:16])[NH:25][CH:24]1[CH2:22][CH2:23]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A mixture of (2S,3S)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (6 g), EDAC (6 g, 1.2 eq.), HOBt (4.2 g, 1.2 eq.), TEA (9 mL, 2.5 eq.) and cyclopropylamine (2.2 mL, 1.2 eq.) in DMF (30 mL) was stirred at rt for over the weekend. The insolubles were filtered off, the filtrate was concentrated, redissolved in ethyl acetate, washed with sodium bicarbonate and brine, dried and concentrated to give 5.6 g of (2S,3S)-2-cyclopropylcarbamoyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17]C(=O)CC)[N:11]=2)[N:9]=1)[NH2:3].[ClH:22]>C(O)C>[ClH:22].[ClH:22].[ClH:22].[NH2:17][CH2:16][C:12]1[N:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Solvent: CCO
Product: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-(6-propionylaminomethylpyridin-2-yl)thiazole (49.0 g) and conc. hydrochloride acid (134 ml) in ethanol (500 ml) was heated under reflux for 7 hours and after the mixture was cooled to ambient temperature. To the mixture was added ethanol (500 ml) with stirring and the isolated precipitate was collected by filtration to give 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (52.36 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].O.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9](=[O:10])[C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[CH:3][C:2]=1[C:26]#[N:27]
Reactant: O=C(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(Br)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 175 °C
Yield: 86 %

Procedure:
A mixture of (3-bromo-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone, prepared as described in Procedure 3 and 62, (2.0 g, 4.84 mmol), zinc cyanide (568 mg, 4.84 mmol) and tetrakis(triphenyphoshine)palladium (559 mg, 0.48 mmol) in DMF was heated at 175° C. under microwave irradiation for 10 minutes. The reaction mixture was allowed to cool to room temperature, poured into H2O and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by ISCO chromatography (12 g column, 0-20% EtOAc/hexane) to yield 2-fluoro-5-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzoyl)benzonitrile as a colorless oil (1.5 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (m, 2H), 7.41 (m, 3H), 7.27 (m, 1H), 5.97 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(I)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(C)cccc1I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
A solution of 2-iodo-6-methylbenzoic acid (I57) (2.50 g, 9.54 mmol) in DCM (30 mL) and methanol (8 mL) under an atmosphere of nitrogen was cooled to 0° C. and trimethylsilyldiazomethane (2.0 M in diethyl ether, 9.54 mL, 19.1 mmol) was added dropwise. The reaction was stirred at 0° C. for 45 minutes and then quenched with 2 M aq. HCl (50 mL). DCM (150 mL) was added to the quenched reaction and the layers were separated. The aqueous layer was extracted with DCM (100 mL), the organics were combined and washed with sat. aq. NaHCO3 (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I58) (2.00 g, 76% yield) as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.65 (ddd, J=7.9, 1.0, 0.5 Hz, 1H), 7.19-7.15 (m, 1H), 6.99 (t, J=7.8 Hz, 1H), 3.95 (s, 3H), 2.33 (s, 3H). LCMS Method C: rt 6.08 min; m/z 277.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][CH:29]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:27])[N:33]=2)=[O:35])[CH2:7]1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(C)n2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-methyl-pyridine-2-carboxylic acid.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7]([CH3:10])=[N:8][CH:9]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>N1C=CC=CC=1>[CH2:12]([NH:14][C:15]([O:11][C:6]1[C:7]([CH3:10])=[N:8][CH:9]=[C:4]([CH2:3][O:2][C:15](=[O:16])[NH:14][CH2:12][CH3:13])[CH:5]=1)=[O:16])[CH3:13]
Reactant: CCN=C=O
Reactant: Cc1ncc(CO)cc1O
Agent: Cl
Solvent: c1ccncc1
Product: CCNC(=O)OCc1cnc(C)c(OC(=O)NCC)c1
Temperature: 0 °C

Procedure:
To a solution of 0.9 g. of 5-hydroxymethyl-2-methyl-3-pyridinol hydrochloride in 10 ml. of pyridine was added 0.8 g. of ethyl isocyanate and the mixture was stirred at 100°C for 2 hours. After cooling, the mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off to give a crystalline product, which was recrystallized from ethyl acetate-n-hexane to give 0.95 g. of the desired product as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:24]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1>[Br-].[Zn+2].[Br-]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:24]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: c1ccc(CCCc2ccc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)cc1

Procedure:
In an analogous manner to that described in Example 125(h), from tert-butyl (3'RS,4'RS)-3'-(naphthalen-2-ylmethoxy)-6-(3-phenyl-propyl)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained (3'RS,4'RS)-3'-(naphthalen-2-ylmethoxy)-6-(3-phenyl-propyl)-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine in the form of an amorphous, colourless foam; MS: 437 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.CC(C)([O-])C.[Na+].[O:32]=[S:33]1(=[O:42])[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][NH2:41])[CH2:35][CH2:34]1>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:41][CH2:40][CH2:39][N:36]3[CH2:37][CH2:38][S:33](=[O:42])(=[O:32])[CH2:34][CH2:35]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCN1CCS(=O)(=O)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN3CCS(=O)(=O)CC3)c2c1
Temperature: 120 °C

Procedure:
To a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) in 1,4-dioxane (4 mL) was added tris(dibenzylideneacetone) dipalladium (0) (40 mg, 0.04 mmol), 1,1′-bis(diphenyphosphino)ferrocene (25 mg, 0.04 mmol), sodium tert-butoxide (77 mg, 0.80 mmol) and 2-(1,1-dioxidothio-morpholin-4-yl)ethanamine (107 mg, 0.60 mmol). The resulting mixture was evacuated and refilled with nitrogen, sealed and heated at 120° C. overnight. After being cooled to room temperature, the mixture was filtered and washed with ethyl acetate, the organic layers were combined and concentrated in vacuo, the residue was purified by flash chromatography (eluenting with 2% methanol in dichloromethane) to afford 67 mg of the title compound as a light solid (yield was 40%). MS obsd. (ESI+) [(M+H)+] 515, 1H NMR (400 MHz, CDCl3) 8.05 (d, J=7.6 Hz, 1 H), 7.66 (d, J=7.2 Hz, 1 H), 7.53-7.48 (m, 2 H), 7.37-7.28 (m, 2 H), 7.21 (s, 1 H), 5.88 (s, 1 H), 5.26 (m, 1 H), 5.12 (s, 1 H), 4.6 (brs, 1 H), 3.56 (m, 1 H), 3.33 (m, 2 H), 3.14 (m, 8 H), 2.99 (t, J=4.8 Hz, 2 H), 2.46 (s, 3 H), 2.0 (d, J=4.5 Hz, 2 H).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6]1[C:13]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O)[CH3:4].[BH4-].[Na+]>CO>[CH2:3]([O:5][C:6]1[C:13]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][CH2:1][NH2:2])[CH3:4]
Reactant: CCOc1c(C=O)cccc1OC(F)(F)F
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1c(CCN)cccc1OC(F)(F)F
Reaction time: 18 h
Yield: 58 %

Procedure:
A solution of methylamine (20 mL of a 2.0 M solution if MeOH, 40 mmol) was added to 2-ethoxy-3-trifluoromethoxybenzaldehyde (1.17 g, 4.95 mmol) under N2 and the solution was stirred for 18 h. The solution was concentrated under reduced pressure. The resulting clear oil was dissolved in EtOH (20 mL) and treated with NaBH4 (0.187 g, 4.95 mmol). After stirring for 5.5 h, the reaction mixture was concentrated under reduced pressure, then dissolved in 1 N NaOH (20 mL) and extracted with Et2O (3×50 mL). The combined organics were collected, washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.72 g, 58%) as a clear oil: 1H NMR (500 MHz, DMSO-d6) δ 7.40 (dd, J=7.7, 1.55 Hz, 1H), 7.25 (d, J=9.5 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 3.97 (t, J=7.0 Hz, 2H), 3.68 (s, 2H), 2.28 (s, 3H), 2.02 (br s, 1H), 1.35-1.30 (m, 3H).