Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[N:24]1([CH2:29][C:30](O)=[O:31])[CH:28]=[CH:27][N:26]=[CH:25]1>>[N:24]1([CH2:29][C:30]([NH:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([NH:12][CH:10]2[C:11]4[C:7](=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])[CH2:8][CH2:9]2)[CH:22]=[CH:21]3)=[O:31])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: O=C(O)Cn1ccnc1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)Cn4ccnc4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 6 from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine and imidazol-1-yl-acetic acid; MS: m/e=414.3 (M+H+).
Reaction SMILES: [Br-:1].ClC[CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:9])[CH3:8].[Br-].[Cl:23]CCCCCC[N+](CCCCCCCCCCCC)(C)C.C(N(C)C)CCCCCCCCCCC>>[Br-:1].[Cl:23][CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:9])[CH3:8]
Reactant: CCCCCCCCCCCC[N+](C)(C)CCCCCl
Reactant: CCCCCCCCCCCC[N+](C)(C)CCCCCCCl
Agent: CCCCCCCCCCCCN(C)C
Agent: [Br-]
Product: CCCCCCCCCCCC[N+](C)(C)CCCCl

Procedure:
(4-Chlorobutyl)dodecyldimethylammonium bromide and (6-chlorohexyl)dodecyldimethylammonium bromide can be prepared by a similar process using the appropriate bromochloroalkane and dodecyldimethylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1O
Product: CC(=O)Oc1c(C)cccc1C
Yield: 102.5 %

Procedure:
100 g (0.82 mole) of 2,6-dimethylphenol and 167.4 g (1.64 mole) of acetic anhydride were refluxed for 4 h. The reaction mixture was poured onto ice and extracted with methylene chloride. The organic phase was washed with dilute sodium hydroxide solution, dried and concentrated under reduced pressure. 138 g of 2,6-dimethylphenyl acetate were obtained. To this product were added 120.2 g (0.9 mole) of anhydrous aluminum chloride in portions, during which the temperature rose to 85° C. The mixture was then heated at 110° C. for 30 min and left to cool. The viscous paste was poured onto ice/hydrochloric acid, and the precipitated product was filtered off. Recrystallization from 1/1 methanol/water resulted in 103.6 g of 3,5-dimethyl-4-hydroxyacetophenone.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1OB(O)O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:18][O:19][C:20]([C:22]1[CH2:26][O:25][CH2:24][C:23]=1OS(C(F)(F)F)(=O)=O)=[O:21].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[CH3:18][O:19][C:20]([C:22]1[CH2:26][O:25][CH2:24][C:23]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:21]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)COC1
Reactant: CC(C)(C)C(=O)Nc1ccccc1OB(O)O
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: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(c2ccccc2NC(=O)C(C)(C)C)COC1
Yield: 87 %

Procedure:
2-(Pivaloylamino)phenylboric acid (F. Guiller, F. Nivoliers, A. Godard, F. Marsais, G. Quéguiner, M. A. Siddiqui, V. Snieckus, J. Org. Chem. 1995, 60, 292) (0.66 g, 3.0 mmol), 3-(trifluoromethylsulfonyloxy)-2,5-dihydrofuran-4-carboxylic acid-methyl ester (0.69 g, 2.5 mmol), tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) and a 2M aqueous Na2CO3 solution (1.26 ml, 2.52 mmol) are refluxed in DME (40 ml) for 2.5 hours. The batch is diluted with ethyl acetate, washed with water and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with ethyl acetate-hexane yields 0.65 g (87%) of 4-(2-(pivaloylamino)phenyl)-2,5-dihydrofuran-3-carboxylic acid-methyl ester (flash point 105-6° C.). 0.59 g (1.94 mmol) of it is then refluxed in concentrated hydrochloric acid for 2 hours. The batch is poured onto ice and extracted with ethyl acetate and dichloromethane. After drying (Na2SO4) and concentration by evaporation, the residue is heated for two more hours with concentrated HCl and worked up as described: 0.22 g (58%) of product.
Reaction SMILES: Cl.C(O[C:5](=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.C(N(CC)CC)C.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[C:21]1([CH2:20][NH:27][C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[NH:12])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: N=C(NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.8 %

Procedure:
To a stirred solution of ethylbenzimidate hydrochloride (3.0 g, 16.2 mmol) in N,N-dimethylformamide (10 mL) was added triethylamine (1.60 g, 16.2 mmol). The reaction mixture was allowed to stir at room temperature for 1 h and then filtered to remove triethylamine salts, which were rinsed with N,N-dimethylformamide (5 mL). Benzylamine (1.23 g, 11.5 mmol) was added to the filtrate, and the mixture was heated to 65° C. for 24 h. To the cooled mixture was added water (80 mL) and ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4) and concentrated under reduced pressure to afford the title product as a clear oil (2.80 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:38]I>C(#N)C.CCOCC>[I:38][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1
Reactant: II
Reactant: OCCc1cccc(C(F)(F)F)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: FC(F)(F)c1cccc(CCI)c1
Reaction time: 4 h

Procedure:
3-(Trifluoromethyl)phenethyl alcohol (10.0 g, 52.6 mmol), triphenylphosphine (17.9 g, 68.4 mmol), and imidazole (5.00 g, 73.6 mmol) were dissolved in acetonitrile (42 mL) and ether (70 mL), then the mixture was cooled to 0° C. Iodine (18.7 g, 73.6 mmol) was added in portions, then the mixture was stirred for 4 h. The reaction mixture was diluted with ether (1 L), washed with saturated Na2S2O3 (3×300 mL), aqueous CuSO4 (2×300 mL), and brine (2×300 mL), dried over Na2SO4, filtered, and concentrated to a volume of 200 mL. The precipitate of triphenylphosphineoxide was removed by filtration and the filtrate was triturated with ether/hexanes (2:1, 300 mL). Additional triphenylphosphine-oxide was removed by filtration, and the filtrate was concentrated to dryness to provide 1-(2-iodoethyl)-3-trifluoromethylbenzene as a yellow oil (16.5 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 7.54–7.35 (m, 4H), 3.37 (t, J=8.3 Hz, 2H), 3.24 (t, J=8.3 Hz, 2H); 19F NMR (282 MHz, CDCl3) δ −63.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH3:16])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C([O-])(O)=O.[Na+].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].C(Cl)Cl>[Cl:17][C:18]1[C:19]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3([CH3:16])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: CC1(CNc2cccc(Br)n2)CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Temperature: 103 °C
Reaction time: 0.3 h

Procedure:
A mixture of 6-bromo-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (750 mg, 2.63 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (830 mg, 4.73 mmol), PdCl2(dppf)-CH2Cl2 Adduct (215 mg, 0.263 mmol) in DME (12 mL) and 2M aqueous Na2CO3 (4 mL, 8.00 mmol) in a sealed tube was heated at 103° C. for 4 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc (˜50 mL) and saturated aqueous NaHCO3 solution. The separated organic layer was washed with saturated aqueous NaHCO3 solution (2×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, 20 min, EtOAc/heptane= 0/100 for 2 min, then EtOAc/heptane= 5/95 to 50/50 over 18 min, then EtOAc/heptane= 50/50] providing 5′-chloro-2′-fluoro-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine as a colorless oil. Yield: 691 mg. LCMS (m/z): 336.2 [M+H]+; Retention time=0.66 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][C:43](=[O:53])[C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:41][O:42][C:43](=[O:53])[C:44]1[CH:52]=[CH:51][C:47]([C:48]([N:15]2[CH2:14][C@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:40])[CH3:8])[CH3:10])[C:19](=[O:20])[N:18]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:23]=3[O:33][CH3:34])[C:17]3[CH:35]=[CH:36][CH:37]=[CH:38][C:16]2=3)=[O:49])=[CH:46][CH:45]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(=O)N2C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc3c(OC)ccc4cc(Br)ccc34)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of {(S)-1-[(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 11) (1.5 g, 2.455 mmol) in pyridine (20 mL) at 0° C. was added terephthalic acid monomethyl ester (884 mg, 4.91 mmol). The mixture was stirred for 10 min at 0° C. and POCl3 (0.472 mL, 5.155 mmol) was slowly added, the cooling bath removed and the mixture stirred at RT. After 16 h the mixture was evaporated and the residue diluted with ice water and extracted with ethyl acetate. The combined extracts were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound. The sequence was repeated to provide a total of 4.2 g of the title compound from as an off white solid. LC-MS: 773 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1OS(C(F)(F)F)(=O)=O)=[O:2].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.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>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[C:4]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[CH:5]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C=O)c(-c2cccs2)c1
Temperature: 95 °C
Yield: 89.5 %

Procedure:
Ex-34B: A solution of trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester (Ex-34A, 1.6 g, 5.63 mmol) in 1,4-dioxane (15 mL) was stirred at room temperature under nitrogen for 5 min. Thiophene-2-boronic acid (1.08 g, 8.44 mmol), tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.56 mmol) and a potassium phosphate (2.2 g, 10.36 mmol) were then added and the resulting mixture was heated to 95° C. under nitrogen overnight. Upon cooling to room temperature the reaction was diluted with EtOAc (25 mL) and water (25 mL) and the layers were cut. The organic phase was concentrated under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 4:1) gave 1.1 g (90%) of the desired 4-methoxy-2-thiophen-2-yl-benzaldehyde product. 1H-NMR (300 MHz, CDCl3): 10.06 (s, 1H), 8.03 (m, 1H), 7.45 (m, 1H), 7.14 (m, 1H), 7.09 (m, 1H), 7.00 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C[O-].[Na+].Cl[CH2:16][C:17]#[N:18]>CO>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[S:4][CH2:16][C:17]#[N:18])([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1S
Reactant: N#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccccc1SCC#N
Temperature: 0 °C
Yield: 69.8 %

Procedure:
A solution of methyl thiosalicylate (164 g, 0.975 mol) in methanol (1.1 L) was added in one portion to a cold solution of freshly prepared sodium methoxide (from 25.5 g, 1.1 mol Na-metal in methanol, 1.1 L). The salt solution was cooled to 0° C. and a cold (0° C.) solution of chloroacetonitrile (83.7 g, 1.1 mol) in methanol (0.5 L) was added in one portion with stirring. After several minutes a strong precipitate appeared. After standing for several days at room temperature, the precipitate was collected, washed with ice-cold methanol, then washed well with water and dried to give 141.0 g of 2-(2-carbomethoxyphenylthio)acetonitrile, mp 120°-122° C. [described by K. Gorlitzer, Arch. Pharmaz., 308, 700 (1975)].
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]23[CH2:16][CH:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:4]2=[CH:3]1)[C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]3=1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][N:2]1[CH2:6][C:5]23[CH2:16][CH:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:4]2[CH2:3]1)[C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]3=1
Reactant: [H][H]
Reactant: CN1C=C2c3ccccc3C3CC2(C1)c1ccccc13
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1CC2c3ccccc3C3CC2(C1)c1ccccc13
Yield: 100 %

Procedure:
A mixture of 13.6 g of 2-methyl-2,3-dihydro-8H-3a, 8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole, 100 ml of acetic acid and 2 g of 10% palladium-on-charcoal catalyst is shaken under 40 psi hydrogen pressure at room temperature until the pressure remains constant. The filtered mixture is concentrated, the residue is made basic and extracted several times with methylene chloride. Removal of the solvent from the dried extracts gives 13.7 g of 2-methyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4;6,7]-cyclohepta[1,2-c]pyrrole (1c) identical by nmr spectroscopy with the product obtained in Example 1.
Reaction SMILES: Cl[C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[NH4+:23].[OH-]>O1CCOCC1>[NH2:23][C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: C[C@]12C=CC(=O)C(Cl)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 90 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
A mixture of 4-chloroandrosta-1,4,6-triene-3,17-dione (1.585 g, 5 mmole), dioxane (50 ml) and 30% NH4OH aqueous solution (100 ml) is stirred at 90° C. in a pressure vessel during 24 hours. After cooling to room temperature, the reaction mixture is worked up as described in the Example I. There are obtained 370 mg (1.24 mmole, 24% yield ) of the title compound or a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:18]=[C:17]([C:7]2[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:11]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2ccc(N)c(F)c2)c1
Yield: 44.2 %

Procedure:
The title compound (1.34 g) was prepared from 2-fluoro-4-bromo aniline (2.5 g, 13.1 mmol) and 3-ethoxyphenylboronic acid (2.8 g, 17.0 T mmol) as a pale-yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.38-7.20 (m, 3H), 7.10 (d, J 7.9, 1H), 7.07-7.05 (m, 1H), 6.83-6.76 (m, 2H), 5.24 (s, 2H), 4.06 (q, J 7, 2H), 1.32 (t, J 7, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16]>O>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Product: COc1cc(C(C)=O)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 40 ml of nitric acid (d=1.41) and 40 ml of water was gradually added while cooling (below 7° C.) and stirring 25.0 g of 4'-hydroxy-3'-methoxyacetophenone. After stirring for 0.5 h at 0° C. the product was filtered, washed first with diluted nitric acid (1:1) and then with water. Yield 24.0 g (75%). The 1H-NMR-spectrum of the product was in accordance with the structure alleged.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[CH3:21][O:22][C:23](Cl)=[O:24].COC(=O)NC1C2C=CN(C(=O)C3C(Cl)=CC=CC=3Cl)C=2C=CN=1>>[CH3:21][O:22][C:23](=[O:24])[NH:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Agent: COC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Product: COC(=O)Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
Methyl[3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]carbamate (Compound No. 79) was prepared by treating (4-amino-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone with methylchloroformate following a procedure similar to the one used for methyl[1-(2,6-dichlorobenzoyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]carbamate (Compound No. 74).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])[S:15][CH:16]=2)[N:9]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.C(O)(=O)C.[C].[Pd]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[S:15][CH:16]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)/C=C/c1cc(C=Cc2csc(NC(C)=O)n2)cs1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)CCc1cc(CCc2csc(NC(C)=O)n2)cs1
Yield: 83 %

Procedure:
Methyl (2E)-3-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}thiophen-2-yl)acrylate (3.000 g, 8.971 mmol) was dissolved in ethyl acetate (400 ml) and acetic acid (100 ml). 20% Palladium carbon was added, and the mixture was hydrogenated at room temperature under an atmospheric pressure. After the completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP, 100 g, ethyl acetate:hexane=2:3) to give methyl 3-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}thiophen-2-yl)propionate (2.521 g, 7.449 mmol, yield 83.0%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[F:44][C@@H:45]1[CH2:49][CH2:48][NH:47][CH2:46]1>C(#N)C.C(OCC)(=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:47]3[CH2:48][CH2:49][C@@H:45]([F:44])[CH2:46]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: F[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2

Procedure:
A solution of (R)-6-(6-chloropyridine-3-sulfonyl)-4a-methoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene (0.098 g), diisopropylethylamine (0.194 g) and (R)-3-fluoropyrrolidine hydrochloride in acetonitrile was heated at 130° C. in a microwave reactor for 45 minutes. The solution was diluted with ethyl acetate, washed with water followed by brine, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (0 to 3:2 by volume), to afford the title compound as a white solid (0.089 g). LCMS (Method F): 542 (M+H)+, Retention time 5.0 minutes
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:33][CH2:34][CH3:35])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:23]=O)[CH3:18]>>[CH2:34]([O:33][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH2:17][CH3:18])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:35]
Reactant: CCOC(=O)c1c(OCC)cc(C=O)cc1OCC
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Product: CCOC(=O)c1c(OCC)cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)cc1OCC
Yield: 32 %

Procedure:
The title (15 mg, 32%) compound was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3,5-diethoxy-4-ethoxycarbonyl-benzaldehyde. MS: 470.5 (MH+)
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.C(O)(=O)C.[C:14]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:16][CH2:17][CH3:18])=[O:15]>ClCCCl>[CH2:17]([O:16][C:14]([N:19]1[CH2:24][CH2:23][CH:22]([N:1]2[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]2)[CH2:21][CH2:20]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: O=C(O)C1CCNCC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)N1CCC(N2CCC(C(=O)O)CC2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of Isonipecotic acid (8.0 g, 61.0 mmol) in DCE (80 mL) was treated with acetic acid (10.7 mL, 185 mmol) and 1-carbethoxy-4-piperidone (12.7 g, 74.3 mmol). The reaction mixture was stirred for 1 hr at 40° C. Then STAB (29.2 g, 92.8 mmol) was added, the reaction mixture was stirred at 70° C. for 6 h, cooled to rt and the solvent was removed in vacuo. The residue was purified by column chromatography (gradient 0% to 50% MeOH in CHCl3) to give 1′-(ethoxycarbonyI)-1,4′-bipiperidine-4-carboxylic acid (16.0 g, 92.2%), Intermediate 1, as an off white solid.