Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:70]([NH2:74])([CH2:72][CH3:73])[CH3:71]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[N:7]=[C:6]([NH:74][C@H:70]([CH2:72][CH3:73])[CH3:71])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(S(=O)(=O)N(C)C)c1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(S(=O)(=O)N(C)C)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
Add toluene (20 mL), 2-chloro-6-dimethylsulfamoyl-isonicotinic acid methyl ester (2.49 g, 8.93 mmol), palladium acetate (0.201 g, 0.893 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.556 g, 0.893 mmol) and cesium carbonate (4.36 g, 13.4 mmol) to a sealed vessel flushed with nitrogen. Slowly add (S)-sec-butylamine (1.36 mL, 13.4 mmol) to the mixture. Heat and stir the sealed vessel at 90° C. overnight. Cool to room temperature, filter through a pad of filtering agent, concentrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title compound (1.43 g, 51%).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:38]([CH3:40])[CH3:39])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C(OC1C(=O)N=C(CC2(C3C=C(Cl)C=CC=3Cl)CCCC2)N2CCN(C(C)C)C(=O)C=12)C1C=CC=CC=1>C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:38]([CH3:39])[CH3:40])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N1CCn2c(CC3(c4cc(Cl)ccc4Cl)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Solvent: CCOC(C)=O
Product: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 46.3 %

Procedure:
9-Benzyloxy-2-isopropyl-6-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (247) (40 mg, 45.93%) as a white sticky solid was synthesized from 5-benzyloxy-6-hydroxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (246) (90 mg, 0.16 mmol) following the procedure as described for 9-benzyloxy-6-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (208). Silica thin layer chromatography was performed (ethyl acetate, Rf=0.3).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[Br:12])C=C.[C:13]1(C)[CH:18]=C(C)C=C(C)[CH:14]=1>>[CH2:18]([C:10]1[CH:9]=[C:8]([F:11])[CH:7]=[C:6]([Br:12])[C:5]=1[OH:4])[CH:13]=[CH2:14]
Reactant: C=CCOc1ccc(F)cc1Br
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1cc(F)cc(Br)c1O
Yield: 99 %

Procedure:
Treatment of 1-(allyloxy)-2-bromo-4-fluorobenzene (23.90 g, 0.103 mol) in refluxing mesitylene (50 mL) generally according to the procedure described for Intermediate 8 provided 23.44 g (99%) 2-allyl-6-bromo-4-fluorophenol as a brown oil. Rf=0.64 (silica, ethyl acetate:hexanes 1:19); Anal. calcd. for C9H8BrFO: C, 46.78; H, 3.49. Found: C, 49.19; H, 3.59.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(OC3CCOCC3)nc(Cl)nc21
Temperature: 75 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-5-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), pyridin-4-ylboronic acid (1.1 equiv), tetrakis(triphenylphosphine)palladium(0) (0.1 equiv) in a 5:1 mixture of 1,4-dioxane and water (0.17 M) was added sodium carbonate (2.1 equiv). The reaction was stirred at 75° C. for 3 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90%) ethyl acetate (with 10% 1N ammonia in methanol) in hexane) to give the title compound (50.5% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.06 (s, 9 H) 0.82-0.91 (m, 2 H) 1.74 (dtd, J=12.74, 8.37, 8.37, 3.71 Hz, 2 H) 2.01-2.16 (m, 2 H) 3.50-3.63 (m, 4 H) 3.69-3.83 (m, 2 H) 5.50 (tt, J=7.91, 3.81 Hz, 1 H) 5.59 (s, 2 H) 7.72 (d, J=6.25 Hz, 2 H) 8.12 (s, 1 H) 8.60 (d, J=6.25 Hz, 2 H); MS (ESI) m/z 461.0 [M+1]+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:17](F)=[C:16]3[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]3[CH2:19][CH3:20])=[CH:10][C:9]=2[F:25])[N:7]=1.[CH3:26][NH2:27]>>[NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:17]([NH:27][CH3:26])=[C:16]3[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]3[CH2:19][CH3:20])=[CH:10][C:9]=2[F:25])[N:7]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3csc(CN)n3)c(F)c21
Reactant: CN
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3csc(CN)n3)c(NC)c21
Temperature: 50 °C

Procedure:
To 500 mg (1.37 mmol) of the 7-[2-(aminomethyl)-4-thiazolyl]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added 15 ml of 40% aqueous methylamine. The mixture was heated at 50° C. for 72 hours. The solution was taken to pH 6.5 and was filtered to give 350 mg of 7-[2-(aminomethyl)-4-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-8-methylamino-4-oxo-3-quinolinecarboxylic acid, mp 194°-195° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][NH:18][CH2:19][C@H:20]([OH:39])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29]CC4C=CC=CC=4)=[CH:25][C:24]=3[O:37][CH3:38])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([C@@H:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][NH:18][CH2:19][C@H:20]([OH:39])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=3[O:37][CH3:38])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1COc2cc(CCNC[C@H](O)COc3ccc(OCc4ccccc4)cc3OC)ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1COc2cc(CCNC[C@H](O)COc3ccc(O)cc3OC)ccc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.6 %

Procedure:
To a solution of 6-[2-[3-(4-benzyloxy-2-methoxyphenoxy)-2-(S)-hydroxypropylamino]ethyl]-2,3-dihydro-1,4-benzodioxine-2-(R)-carboxylic acid ethyl ester obtained in Example 17 (240 mg) in ethanol (10 mL) was added 10% palladium-carbon (24 mg). This solution was stirred under hydrogen atmosphere at room temperature for 6 hours. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and the title compound (129 mg) was obtained from the effluent with chloroform/methanol/aqueous ammonia=85/15/0.1 (v/v). Yield: 64%
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.Cl[CH2:12]/[CH:13]=[C:14](\[CH3:21])/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>>[CH3:21]/[C:14](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:13]\[CH2:12][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)=CCC/C(C)=C/CCl
Product: CCOP(=O)(C/C=C(\C)CCC=C(C)C)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a four-neck 1000 mL reaction flask with mechanical stirrer and thermometer 250 g of triethyl phosphite was added and heated to 150° C.-155° C., then a mixture of 172.7 g (E)-1-Chloro-3,7-dimethyl-2,6-octadiene and 160 g triethyl phosphite was added drop wise. The resulting mixture was stirred at 150° C.-155° C. for an additional 2 h to complete the reaction according to GC. Then cooling the mixture to room temperature, the excessive triethyl phosphite was recycled by vacuum distillation, and 272.8 g of distillate (105-109° C./1 mmHg) was collected as a light yellow transparent liquid with the content of 98.8% according to GC and the yield of 92.1%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH3:22]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][CH3:22])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: CCI
Reactant: COCOc1c(Br)ccc(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(Br)c(OCOC)c1OC
Temperature: 70 °C
Yield: 79.1 %

Procedure:
To a stirring solution of 4-bromo-2-methoxy-3-(methoxymethoxy)phenol (600 mg, 2.28 mmol) in acetonitrile (20 mL) was added potassium carbonate (944 mg, 6.84 mmol) and ethyl iodide (711 mg, 4.56 mmol) and the resultant reaction mixture was heated to 70° C. for 3 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-7% ethyl acetate in pet ether) to afford 1-Bromo-4-ethoxy-3-methoxy-2-(methoxymethoxy)benzene as a solid (525 mg, 79%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])([CH3:4])[CH3:3]>[Pd].CO>[CH3:4][C:2]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[C:9]([CH2:10][NH2:11])[CH:12]=[CH:13][CH:14]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C#N)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Under an atmosphere of nitrogen, 10% palladium on carbon (250 mg) was added to a solution of 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzonitrile (1 g, 4.3 mmol) in methanol (25 mL) at 25° C. The reaction mixture was hydrogenated at 50 psi in a Parr shaker for 3 h. The reaction mixture was then filtered through Celite and the filter cake was washed well with methanol (50 mL). The solvents were concentrated under reduced pressure and the residue was dried under vacuum for 1 h to give 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-benzenemethanamine (950 mg, 95%) as an oil.
Reaction SMILES: C(NC(=O)NC1C=CC(C2N=C(N3CCOC[C@@H]3C)C3CCN(C(OC(C)(C)C)=O)CC=3N=2)=CC=1)C.Cl[C:38]1[N:39]=[C:40]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][C@@H:53]2[CH3:58])[C:41]2[CH2:46][N:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][C:42]=2[N:43]=1.[OH:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([NH:67][C:68]([NH:70][C:71]2[CH:76]=[CH:75][C:74](B3OC(C)(C)C(C)(C)O3)=[CH:73][CH:72]=2)=[O:69])=[CH:63][CH:62]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:59][CH2:60][C:61]1[CH:62]=[CH:63][C:64]([NH:67][C:68](=[O:69])[NH:70][C:71]2[CH:72]=[CH:73][C:74]([C:38]3[N:39]=[C:40]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][C@@H:53]4[CH3:58])[C:41]4[CH2:46][N:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][C:42]=4[N:43]=3)=[CH:75][CH:76]=2)=[CH:65][CH:66]=1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccc(CO)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)Nc4ccc(CO)cc4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 41 %

Procedure:
Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 1-(4-(hydroxymethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst. The reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified first by prep HPLC (low pH) yielding the title compound (34 mg, 0.06 mmol, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7](C(=O)C(F)(F)F)[C:8]2[C:13]([C:14]=1[NH2:15])=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=2)[NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1c(N)c2cc(Cl)ccc2n1C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1N
Temperature: 70 °C
Reaction time: 1.75 h
Yield: 71.2 %

Procedure:
Heat at 70° C. and stir a mixture of 3-amino-5-chloro-1-(2,2,2-trifluoro-ethanoyl)-1H-indole-2-carboxylic acid ethyl ester (3.34 g, 10 mmol), ethanol (50 mL), and potassium carbonate (1.50 g, 10.85 mmol). After 1.75 h, add water (20 mL), and after another hour add additional potassium carbonate (0.58 g, 4.20 mmol). Cool the reaction mixture to ambient temperature and partition between water/ethyl acetate. Separate the organic layer, dry over MgSO4, filter and concentrate to afford 1.70 g of the title compound as a solid. MS 239(M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:13][O-].[Na+].O>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 6.43 g (0.039 mole) 4-acetamidobenzaldehyde (14) (Aldrich, A180-0) in 55 mL of glacial acetic acid, was added 100 mL of 5.25% solution of sodium hypochlorite (Clorox, Pathmark brand) and the reaction mixture was stirred at room temperature for 48 hours. A white precipitate developed in the reaction mixture when a sample of the reaction mixture was taken off for TLC. The mixture was poured into 100 mL water and filtered to give 2.5 g (32%) of 24 as white powder, mp 110-113°. Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:19]=[C:18]([C:20]4[C:30]([CH3:31])=[CH:29][C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][C:21]=4[CH3:32])[NH:17][C:16]=3[CH:33]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:19]=[C:18]([C:20]4[C:21]([CH3:32])=[CH:22][C:23]([O:24][CH2:25][C:26]([N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[O:27])=[CH:29][C:30]=4[CH3:31])[NH:17][C:16]=3[CH:33]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OCC(=O)O)cc4C)[nH]c3c2)cc1C
Reactant: CN1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OCC(=O)N5CCN(C)CC5)cc4C)[nH]c3c2)cc1C

Procedure:
A solution of {4-[6-(3,4-dimethyl-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethyl-phenoxy}-acetic acid (53.2 mg), 1-methylpiperazine (12 mg), BOP (62 mg) and DIEA (0.031 mL) in DMF (0.5 mL) was stirred at room temperature for 16 h. Then 1N NaOH aqueous solution was added. The aqueous layer was extracted with EtOAc, and the organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=20:80 to 80:10) and prep-HPLC to give 2-{2,6-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethoxy]-phenyl}-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 526 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[N:5][CH:4]=1.[ClH:30].C(O)C>C(O)C>[ClH:30].[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:20][CH2:19]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCO
Product: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 0.23 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 5 mL of ethanol, 5 mL of a 6.0 mol/L hydrogen chloride/ethanol solution was added at room temperature and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, diethyl ether was added to the resultant residue, and the solid was filtered off to obtain 0.22 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([OH:45])=[O:44])[CH2:10]2)=[CH:5][CH:4]=1.[N+](=[CH2:48])=[N-].S([O-])([O-])(=O)=O.[Mg+2]>CO.CCOCC>[CH3:48][O:44][C:43](=[O:45])[CH2:42][C@H:11]1[CH2:10][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:33])=[O:34]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: C=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOCC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)OC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
To a solution of 2.03 g of [(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (from example 25f) in 50 ml of methanol at 0° C. is added a 0.1M solution of diazomethane in ether until the conversion to the methyl ester is complete. The reaction mixture is treated with magnesium sulfate to destroy the excess of diazomethane. The solids are removed by filtration and the organic layer is concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.24 (EtOAc-heptane 1:1); Rt=5.24.
Reaction SMILES: C(O[CH:5]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C>C(O)C.[Pd]>[NH:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1=[O:18]
Reactant: CC(=O)OC1CCCCC(=O)Nc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCCCc2ccccc2N1

Procedure:
A solution of 7-acetoxy-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (7.4 g) in ethanol (250 ml) is hydrogenated at 45 psi at 70° C. using 10% palladium on charcoal (1.5 g) as catalyst. The catalyst is filtered off and the solvent removed under reduced pressure. The residue is recrystallized to give 1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2[C:13](=[O:15])[O:12][CH2:11][C:10]3[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([O:20][CH3:21])[C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26].[CH3:29][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[OH:28][C:23]([C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:9]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[CH:16][C:10]=3[CH2:11][O:12][C:13](=[O:15])[C:14]=2[C:3]=1[O:2][CH3:1])([CH3:29])[CH2:24][CH:25]([CH3:26])[CH3:27]
Reactant: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(OC)c1C(=O)OC2
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C)cc2c1Oc1ccc(C(C)(O)CC(C)C)c(OC)c1C(=O)OC2
Reaction time: 4 h

Procedure:
100 mg (0.26 mmol) of 4,11-dimethoxy-9-methyl-3-(3-methylbutan-1-onyl)-7H-dibenzo[b,g][1,5]dioxocin-5-one are dissolved in 5 ml of absolute tetrahydrofuran under argon and 0.2 ml (0.6 mmol) of a 3M methylmagnesium bromide solution in diethyl ether are added at room temperature. After 4 h, the reaction is discontinued by addition of 0.2 ml of ammonium chloride solution. The mixture is concentrated in vacuo, the residue is taken up in dichloromethane and the solution is washed with water. After drying the organic phase over magnesium sulphate, it is concentrated and the residue is purified by column chromatography on silica gel using petroleum ether/ethyl acetate 10:1.
Reaction SMILES: [CH3:1][C:2]1[N:23]([CH3:24])[C:5]2[CH:6]=[C:7]([C:20]([OH:22])=O)[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1.C[N:26](C)C=O>O1CCCC1>[CH3:1][C:2]1[N:23]([CH3:24])[C:5]2[CH:6]=[C:7]([C:20]([NH2:26])=[O:22])[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)N3
Solvent: C1CCOC1
Product: Cc1nc2c3c(c(C(N)=O)cc2n1C)CCC(c1ccccc1)N3
Reaction time: 4 h
Yield: 71 %

Procedure:
To a suspension of 0.9 g (2.8 mmol) 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]quinoline-5-carboxylic acid in 10 ml tetrahydrofuran and 8 ml N,N-dimethylformamide were added 0.5 g (3.1 mmol) N,N′-carbonyldiimidazole. After 4 h at 60° C., the solution was cooled down and ammonia was bubbled through the flask for 4 h. The mixture was allowed to stand 60 h and then poured into 100 ml water. The precipitate was collected, washed with water and dried at 50° C. to yield 0.64 g (71%) of the title compound. m.p. 311-319° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([Cl:21])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].N1C(C)=CC=CC=1C>CC#N>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[C:12]([Cl:21])[CH:11]=1)[CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)CCNc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 115 °C
Yield: 64.1 %

Procedure:
A neat solution of 8.50 g (22.5 mmol) of 3-(3-chloro-4-trifluoromethoxy-phenylamino)-propionic acid tert-butyl ester, 10.71 ml (112.6 mmol) of methyl bromoacetate and 13.07 ml (112.6 mmol) of 2,6-lutidine was stirred 14 h at 60° C., diluted with 30 ml of CH3CN and heated at 115° C. for 20 h. The reaction was then partitioned between aqueous 10% KHSO4 solution and EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 95:5 to 85:1) to yield 5.94 g (64%) of the title compound as light yellow oil. MS: 412.11 (MH+, Cl).