Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[N:4][CH:5]=[C:6]([CH:8]=[CH2:9])[CH:7]=1.Br[CH:23]([C:28]1[CH:29]=[C:30]([Cl:36])[C:31]([Cl:35])=[C:32]([Cl:34])[CH:33]=1)[C:24]([F:27])([F:26])[F:25].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:1][C:2]1[C:3]([CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:23]([C:28]2[CH:29]=[C:30]([Cl:36])[C:31]([Cl:35])=[C:32]([Cl:34])[CH:33]=2)[C:24]([F:26])([F:25])[F:27])[CH:7]=1
Reactant: FC(F)(F)C(Br)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: C=Cc1cnc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 180 °C
Yield: 61 %

Procedure:
To a stirred solution of 2-((3-chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (0.35 g, 1.17 mmol) in 1,2-dichlorobenzene (10 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.8 g, 2.3 mmol), CuCl (23 mg, 0.12 mmol), 2,2-bipyridyl (0.073 g, 0.234 mmol), and the reaction mixture was heated at 180° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a liquid (0.4 g, 50%): mp 79-82° C.; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.36 (s, 2H), 6.51 (d, J=15.6 Hz, 1H), 6.32 (dd, J=15.6, 8.0 Hz, 1H), 5.30 (s, 2H), 4.13 (m, 1H); ESIMS m/z 559 ([M+H]+).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=O)C>O.NN>[CH3:16][O:15][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([NH2:4])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(C(=O)O)c1ccc(NC(C)=O)cc1
Agent: NN
Solvent: O
Product: COC(C(=O)O)c1ccc(N)cc1
Yield: 45.1 %

Procedure:
2-(4-Acetamidophenyl)-2-methoxyacetic acid (7.1 g, 31.8 mmol) was heated with hydrazine monohydrate (40 ml) for 16 hr, cooled and concentrated in vacuo. The resulting residual oil was purified by silica gel column chromatography (eluent 20-40% methanol in CH2Cl2) to give 2.6 g (45%) of (±)-2-methoxy-2-(4′-aminophenyl)-acetic acid
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15]Cl.[OH-].[Na+]>C(#N)C>[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15][O:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2cccc(O)c2[nH]1
Reactant: Cc1cccc(C)c1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1nc2cccc(OCc3c(C)cccc3C)c2[nH]1
Yield: 16.9 %

Procedure:
4-hydroxy-2-methylbenzimidazole (0.59 g, 4 mmol) was dissolved in acetonitrile (15 ml). To the solution were added 2,6-dimethylbenzylchloride (0.52 g, 4 mmol) and sodium hydroxide (0.16 g, 4 mmol) (dissolved in 1 ml water) and the reaction mixture was refluxed for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and was washed with 2 M NaOH. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The oily residue was purified by column chromatography on silica gel. The product was eluted with methylene chloride containing 5% methanol. Crystallization from acetonitrile gave 0.18 g (18%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=O)[CH3:11])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:11])=[N:9][CH:8]=2)[CH:7]=1
Reactant: CC(=O)NCc1ccc(F)cn1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ncc2ccc(F)cn12
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
In a round-bottomed flask, N-(5-fluoro-pyridin-2-ylmethyl)-acetamide (653 mg, 3.88 mmol) was dissolved in toluene (19 ml) and phosphorus oxychloride (0.66 ml, 7.1 mmol) was added. The reaction mixture was stirred at 100° C. in an oil bath overnight then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-70% EtOAc) to give 255 mg (44%) of 6-fluoro-3-methyl-imidazo[1,5-a]pyridine as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.61 (d, J=5.3 Hz, 1H), 7.38-7.50 (m, 2H), 6.67 (ddd, J=9.7, 7.6, 1.9 Hz, 1H), 2.66 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10](=[O:29])[CH:11]=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][C:15]([C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[CH:14]2>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10](=[O:29])[CH:11]=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][C:15](/[CH:19]=[CH:20]\[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[CH:14]2
Reactant: O=c1ccn2cc(C#Cc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: O=c1ccn2cc(/C=C\c3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F

Procedure:
A solution of 1-(2,6-difluorophenyl)-7-[(2,4-difluorophenyl)ethynyl]-2H-quinolizin-2-one in methanol was added a catalytic amount of Lindlar catalyst under hydrogen atmosphere (1 atm) for 1 hour. The mixture was filtered through celite and the filtrate was concentrated. The crude material was purified by silica gel (100% ethyl acetate) to give the title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:25]([C:27]4[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:34])=[O:35])=[CH:29][CH:28]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(S(N)(=O)=O)cc3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 4-hydrazino-benzenesulfonamide according to example 43 gave the desired product. MS: M=471.9 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]([N:11]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[O:12]2)=[O:10])=[CH:4][CH:3]=1.[CH:21](OC(OC(C)C)OC(C)C)([CH3:23])[CH3:22]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]([N:11]2[C:15](=[O:16])[N:14]([CH:21]([CH3:23])[CH3:22])[C:13](=[O:17])[O:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)N(C(=O)n1oc(=O)[nH]c1=O)c1ccc(F)cc1
Reactant: CC(C)OC(OC(C)C)OC(C)C
Product: CC(C)N(C(=O)n1oc(=O)n(C(C)C)c1=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of the compound of Step A (1.0 g, 3.6 mmol) in 20 mL of triisopropylorthoformate was heated at 145° C. for 2 h and then allowed to stir at ambient temperature overnight. The volatiles were removed under reduced pressure, and the residue recrystallized from methanol to give 0.99 g (86%) of the title compound, a compound of this invention, as a solid melting at 78-80° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:6][C:5]=1[OH:17])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:6][C:5]=1[OH:17]
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2Cl)cc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2ccccc2Cl)cc1O

Procedure:
9.9 g (40 mmol) of 4-nitro-2′[1,1′-biphenyl]-3-ol from step A was dissolved in 120 mL of ethanol and hydrogenated in the presence of 0.8 g of a palladium-activated carbon catalyst (10%) at 25° C. After the required amount of hydrogen had been absorbed, the catalyst was filtered off, and the solvent was distilled off in a rotary evaporator. This gave 8.1 g of 4-amino-2′-chloro[1,1′-biphenyl]-3-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)C(Cl)=O)([O-])=O.[CH2:13]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])N)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21](=[O:25])[C@H:22]([C:11]1[CH:10]=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=1)[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: C[C@H](C(=O)OCc1ccccc1)c1cccc(N)c1

Procedure:
3-Nitrobenzoyl chloride was reacted with L-alanine benzyl ester, then reduced with aluminium amalgam to produce (S)-2-(3-amino-phenyl)-propionic acid benzyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 11.96 (1H, br s), 9.46 (1H, br s), 8.57 (1H, br d), 8.16 (1H, s), 7.95 (1H, m), 7.54 (1H, d), 7.40-7.35 (1H, m), 4.40 (1H, m), 2.87 (2H, m), 2.63 (1H, m), 1.94-1.32 (30H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 58.89; H, 8.28; N, 8.97%. C39H59N4O9.3.0 mols H2O requires: C, 58.85; H, 8.23; N, 8.86%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][N:6]=[CH:5]2.C(N(CC)C(C)C)(C)C.[CH2:22]([SH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH2:22]([S:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][N:6]=[CH:5]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: SCc1ccccc1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nncc2cc(SCc3ccccc3)ccc12
Reaction time: 0.08 h
Yield: 76 %

Procedure:
A two-neck round-bottom flask was charged with 6-bromo-1-chlorophthalazine (Pharmablock, Nanjing Hi-Tech Zone, China, 4.44 g, 18.24 mmol), Xantphos (0.528 g, 0.912 mmol), and Pd2(dba)3 (0.417 g, 0.456 mmol). 1,4-dioxane (36.5 ml) and N,N-diisopropylethylamine (6.37 ml, 36.5 mmol) were added. The flask was fitted with a reflux condenser and placed in an 80° C. heating bath. After 5 min, benzyl mercaptan (2.265 ml, 19.15 mmol) was added drop wise. After 20 min. the mixture was cooled, then concentrated under a vacuum. EtOAc (about 25 mL) was added to the residue, and the flask was rotated on the rotovap in a 40° C. bath for 1.5 h. This removed most of the solid from the sides of the flask. The flask was sonicated for 30 s, then the mixture was concentrated under a vacuum. The residue was taken up in EtOAc to form a thick slurry. The flask was sonicated for 30 s, then the mixture was filtered. The collected solid was washed with several large volumes of EtOAc (until the filtrates were essentially colorless). The filtrate was concentrated, and the residue was purified by chromatography on silica gel (80-g column with a 25-g silica gel loading column, 0 to 50% EtOAc/Heptane, then 50 to 100% EtOAc/Heptane). The resulting solid was taken up in heptane, sonicated for 30 s, then filtered. The collected solid was washed with heptane (3×, which removed some of the yellow color), and dried under a stream of N2 (g) for 20 min to give 6-(benzylthio)-1-chlorophthalazine (3.975 g, 13.86 mmol, 76% yield) as a light-orange powder: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=9.28 (d, J=0.7 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.82 (dd, J=1.9, 8.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.45-7.28 (m, 5H), 4.35 (s, 2H); m/z (ESI) 287.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][N:12]=3)[S:10][C:3]=12.[CH2:19](O)[CH2:20][OH:21].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[O:16]1[CH2:19][CH2:20][O:21][CH:15]1[C:14]1[CH:17]=[CH:18][C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[N:12][CH:13]=1
Reactant: O=Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Reactant: OCCO
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A suspension of 136 (2.69 g, 9.79 mmol), ethylene glycol (2.184 mL, 39.2 mmol), and (1R)-(−)-10-camphorsulfonic acid (0.227 g, 0.979 mmol) in toluene (150 mL) was heated to reflux with a Dean-Stark trap. After 3 h, the mixture was cooled down and filtered through celite (while still warm). The filtrate was washed with water, NaHCO3 (aq., sat.), NaOH (aq) and brine. The solution was then dried over MgSO4 and concentrated to afford compound 137 (2.77 g, 89% yield) as an off-white solid. MS (m/z): 319.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:26]([Cu])#[N:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:26]#[N:27])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2-c1ccc(F)cc1
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2-c1ccc(F)cc1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-4-hydroxy-1-(4-fluoro-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 482 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH3:39])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-].[CH2:43]1COCC1>>[CH3:6][CH:5]([CH3:7])[C@H:4]([NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH2:39][CH3:43])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:11])[C:3]([OH:2])=[O:40]
Reactant: CCOc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Product: CCCOc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 86 %

Procedure:
To 100 mg of (S)-2-{4′-[(4-ethoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester dissolved in 1 mL of THF was added 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 84 mg (86% yield) of (S)-3-methyl-2-{4′-[(3-methyl-4-propoxy-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid, obtained as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.9, 6.8 Hz, 6 H) 1.1 (t, J=7.3 Hz, 3 H) 1.8 (m, 2 H) 2.0 (m, 1 H) 2.8 (s, 3 H) 3.6 (dd, J=9.1, 6.1 Hz, 1 H) 4.1 (t, J=6.2 Hz, 2 H) 6.8 (d, J=8.1 Hz, 1 H) 7.2 (d, J=8.1 Hz, 1 H) 7.4 (t, J=8.2 Hz, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.3 Hz, 1 H) 10.5 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[C:18]1([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][NH:30][CH2:31]3)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH3:9][C:6]1[N:5]=[C:4]([NH2:10])[C:3]([CH2:2][N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:25][CH:26]=3)[CH2:31]2)=[CH:8][N:7]=1
Reactant: c1ccc(-c2ccc3c(c2)CNCC3)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3ccc(-c4ccccc4)cc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A suspension of 0.17 g (0.00088 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 10 ml of dimethylformamide was treated with 0.30 ml (0.0021 mol) of triethylamine and 0.184 g (0.00088 mol) of 7-phenyl-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed over silica gel with ethyl acetate as the eluent. 0.22 g (76%) of 2-methyl-5-(7-phenyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-pyrimidin-4-ylamine was obtained as a light yellowish solid; m.p. 147°-149°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[I-].[NH2:23][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]3[N:23]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccccn2)c(OC)c1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(-c3ccccn3)c(OC)c2)nn2ccccc12

Procedure:
A solution of ethyl(2E)-3-(3-methoxy-4-pyridin-2-ylphenyl)prop-2-enoate (55 mg, 0.2 mmol) and 1-aminopyridinium iodide (86 mg, 0.4 mmol) in DMF (1 mL) was stirred at rt for 2 days open to the atmosphere. The deep purple reaction mixture was diluted with CH2Cl2 (25 mL) and washed with a saturated solution of sodium thiosulfate (25 mL) and brine (25 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 3:2) to afford the desired ethyl 2-(3-methoxy-4-pyridin-2-ylphenyl)pyrazolo[1,5-a]pyridin-3-carboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][C:16](OCC)=[O:17])[N:10]=[C:9]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[N:8]=[C:7]2[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[C:42](=[O:43])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:44])[CH:40]=3)[N:35]([CH3:45])[C:34]2=[O:46])[CH2:29][CH2:28]1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][OH:17])[N:10]=[C:9]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[N:8]=[C:7]2[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[C:42](=[O:43])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:44])[CH:40]=3)[N:35]([CH3:45])[C:34]2=[O:46])[CH2:29][CH2:28]1)[CH3:2]
Reactant: CCOC(=O)COc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCCO
Yield: 65.8 %

Procedure:
In 20 ml of ethanol was dissolved 2.10 g (3.32 mmol) of Compound 54 obtained in Example 54, excess sodium borohydride was added, and the mixture was stirred under heating at reflux for 1 hour. After cooling, the solvent was removed, water was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with sodium chloride solution, dried and concentrated to give residue. The residue was purified by silica gel column chromatography(eluent: chloroform/methanol=100/1) and recrystallized from ethanol to give 1.29 g (yield: 66%) of Compound 55 as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][C:8](=[O:21])[C:9]3[CH:15]=[C:14]([CH:16]([CH3:20])[C:17](N)=[O:18])[CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1.C([OH:26])C.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][C:8](=[O:21])[C:9]3[CH:15]=[C:14]([CH:16]([CH3:20])[C:17]([OH:26])=[O:18])[CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Sc1ccc(C(C)C(N)=O)cc1C(=O)C2
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)Sc1ccc(C(C)C(=O)O)cc1C(=O)C2
Reaction time: 7.5 h
Yield: 33 %

Procedure:
To a mixture of 393 mg of 2-(10,11-dihydro-7-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 12 ml of ethanol was added 1.2 g of potassium hydroxide in 3 ml of water, and the mixture was refluxed with stirring for 7.5 hours. The solvent or ethanol was removed by distillation to obtain a mixture, to which was added water, and the resulting mixture was washed with benzene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain an orange oil, which was chromatographed over 10 g of silica gel and eluted with chloroform, thereby obtaining 138 mg (yield: 33%) of 2-(10,11-dihydro-7-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a light yellow oil.
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].O.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])S[CH:16]1[CH3:23]>C(O)C>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[S:1](=[O:6])(=[O:2])[CH:16]1[CH3:23]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC1SC(C)(C)C(=O)N1CCCCCl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1N(CCCCCl)C(=O)C(C)(C)S1(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 62.4 %

Procedure:
A suspension of potassium peroxymonosulfate (32.0 g) and water (120 mL) was added to a 2° C. solution of 3-(4-chlorobutyl)-2,5,5-trimethyl-4-thiazolidinone (8.0 g) and ethanol (80 mL) over a period of 30 minutes. The cold bath was removed an the resulting mixture was stirred at room temperature for 22 hours, after which ethyl acetate (200 mL) was added. The mixture was filtered, the insolubles washed with ethyl acetate (3×30 mL), and the combined filtrates were diluted with water (200 mL). The organic layer was separated, and the aqueous layer extacted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (200 mL), water (200 mL), and brine (200 mL), dried (Na2 SO4), and concentrated in vacuo to 8.62 g of an off-white solid. The sulfone was recrystallized from ether to give 5.67 g (62.4%) of a white crystalline solid, m.p. 71°-73° C.