Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22]([C@@H:24]([NH:28][C:29]([C:31]3[O:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[CH:35]=3)=[O:30])[CH2:25][CH2:26][CH3:27])=[O:23])[C:16](=[O:40])[CH2:15]2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.COC1C=C(S(Cl)(=O)=O)C=CC=1OC.CO>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22]([C@@H:24]([NH:28][C:29]([C:31]3[O:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[CH:35]=3)=[O:30])[CH2:25][CH2:26][CH3:27])=[O:23])[CH:16]([OH:40])[CH2:15]2)(=[O:12])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(S(=O)(=O)c2ccc(OC)c(OC)c2)CC1=O
Agent: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(S(=O)(=O)c2ccc(OC)c(OC)c2)CC1O
Yield: 119.6 %

Procedure:
To a solution of benzofuran-2-carboxylic acid {(S)-1-[1-(3,4-dimethoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide of Example 78c (0.175 g) in dichloromethane was added triethylamine (0.1 mL) and 3,4-dimethoxy-benzenesulfonyl chloride (0.12 g). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dicloromethane) provided the title compound (0.21 g): MS(EI) 587 (M+).
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl-].[NH4+:5].[N:6]1[CH:11]=[C:10]([CH:12]=O)[CH:9]=[N:8][CH:7]=1>O.CO>[NH2:5][CH:12]([C:10]1[CH:11]=[N:6][CH:7]=[N:8][CH:9]=1)[C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=Cc1cncnc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CC(N)c1cncnc1
Yield: 82 %

Procedure:
Potassium cyanide (651 mg, 10 mmol) and ammonium chloride (588 mg, 11 mmol) are dissolved in water (2.6 mL) with stirring. Pyrimidine-5-carboxaldehyde (1.08 g, 10 mmol) in methanol (2.6 mL) is added to the clear solution rapidly, giving first a yellow, then a dark red solution, and mildly exothermic reaction. The water is evaporated after three hours stirring, and the reddish residue is chromatographed (silica, chloroform/methanol) to give a yellow solid 1.1 g (82%) identified as product ms m/z=134.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24]1[CH:39]=[CH:38][C:27]([CH2:28][NH:29][C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:28][C:27]3[CH:38]=[CH:39][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[O:17])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccc(OC)cc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 82.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (140 mg, 0.48 mmol, 1.0 eq), L-isoleucine 4-methoxybenzylamide (238 mg, 0.95 mmol) and dichloromethane (2 mL), was treated with triethylamine (400 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (610 uL, 2.0 eq), to provide 207 mg (82%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] 4-methoxybenzylamide.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[F:11][C:12]([F:35])([F:34])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:20]2)=[CH:15][CH:14]=1.[OH-].[Na+]>CCOCC.O>[CH:1]([N:31]1[CH2:32][CH2:33][CH:28]([C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:12]([F:35])([F:34])[F:11])=[CH:14][CH:15]=3)[N:20]=2)[CH2:29][CH2:30]1)=[O:3]
Reactant: O=CO
Reactant: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: O=CN1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 69.2 %

Procedure:
A stirred mixture of 4-[1-(4-trifluoromethylphenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 101 (15 g, 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated which yielded 13 g (93%) of 1-[4(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. A mixture of formic acid (1 ml, 0.027 moles) and acetic anhydride (2.4 ml, 0.025 moles) was warmed at 55° C. for 1.5 hours. The solution was cooled to 30° C. and a suspension of the indazole (4.0 g, 0.012 moles) in ether (10 ml) was added. The mixture was stirred at ambient temperature for 3.5 hours and then poured into H2O and basified with a 5% NaOH solution. The product was of an oil. The oil was purified on the high pressure liquid chromatograph (silica gel, 100% ethyl acetate) to yield 3.1 g (72%) of 1-formyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine, m.p. 109°-111° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([OH:15])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:28][C:29]([NH2:31])=[NH:30].C1COCC1>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([NH:30][C:29]([NH2:31])=[NH:28])=[O:15]
Reactant: Cc1nc2c(cc1C(=O)O)CCCCC2
Reactant: N=C(N)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nc2c(cc1C(=O)NC(=N)N)CCCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
In an atmosphere of argon, metallic sodium (446.6 mg, 0.019 g atom) was dissolved in anhydrous methanol (15.0 ml) at room temperature, and the solution was mixed with guanidine hydrochloride (1.89 g, 19.7 mmol) at 0° C. After 30 minutes of stirring at room temperature, the thus precipitated sodium chloride was removed by filtration using a glass filter and the resulting filtrate was evaporated under reduced pressure to obtain free guanidine. In an atmosphere of argon, 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylic acid (406.3 mg, 1.98 mmol) was suspended in THF (8.0 ml) and mixed with CDI (491.5 mg, 2.97 mmol) at room temperature. This was stirred at room temperature for 2 hours and then at 50° C. for 1 hour, mixed with the previously obtained guanidine THF suspension (6.0 ml) by its dropwise addition and then stirred at room temperature for 18 hours After evaporation of the solvent under reduced pressure, the thus obtained residue was mixed with waterandextractedwith ethyl acetate. The thus obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the thus formed crystals were washed with ether to obtain the title compound (192.5 mg, 39.5%) as white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.CN.C[CH2:15][N:16]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:8]([NH:16][CH3:15])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1nccnc1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-aminopyrazine-2-carboxylic acid (965 mg, 6.94 mmol), methylamine hydrochloride (697 mg, 10.3 mmol), EDCI (1.61 g, 8.4 mmol), HOBt (1.136 g, 8.4 mmol) and DIEA (2.42 mL, 13.9 mmol) in DMF (24 mL) was stirred at room temperature for 48 h. It was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel chromatography (combiflash-companion; DCM/MeOH gradient) to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:8]1([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1ccccc1
Reactant: C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: c1ccc(N2CCCCC2)cc1
Temperature: 110 °C

Procedure:
224 mg (2 mmoles) of potassium tert.-butoxide, 70 mg (2.5 mole % calculated for the bromobenzene substrate) of the catalyst of formula (I), 105 μl (1 mmole) of bromobenzene, 198 μl (2 mmoles) of piperidine and 5 ml of solvent were charged into an oven-dried Schlenk tube. The reaction mixture was heated on an oil bath at 110° C. for 24 hours, allowed then to cool to room temperature, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluant: hexane/ethyl acetate) to give the desired product; 1H NMR (300 MHz, CDCl3) δ 7.31-7.26 (m, 2H), 7.00-6.97 (m, 2H), 6.89-6.84 (m, 1H), 3.19 (t, J=5.6 Hz, 4H), 1.79-1.72 (m, 4H), 1.64-1.59 (m, 2H).
Reaction SMILES: C([S:9][CH:10]([CH:21]([O:23][CH3:24])[CH3:22])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=O)C1C=CC=CC=1.C(SCC(CSC)C(N1CCC[C@H]1C(O)=O)=O)(=O)C>>[SH:9][CH:10]([CH:21]([O:23][CH3:24])[CH3:22])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: COC(C)C(SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CSCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Product: COC(C)C(S)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-[2-benzoylthio-3-methoxybutanoyl]-L-proline for the 1-[3-acetylthio-2-(methylthiomethyl)propanoyl]-L-proline in the procedure of Example 17, 1-[2-mercapto-3-methoxybutanoyl]-L-proline is obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([NH2:13])[CH2:7]2.[N:14]#[C:15][SH:16].[OH:17][CH:18](O)[C:19](=O)[CH3:20]>>[OH:17][CH2:18][C:19]1[N:13]([CH:6]2[CH2:5][CH2:4][C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[CH2:7]2)[C:15](=[S:16])[NH:14][CH:20]=1
Reactant: N#CS
Reactant: CC(=O)C(O)O
Reactant: NC1CCc2c(F)cc(F)cc2C1
Product: OCc1c[nH]c(=S)n1C1CCc2c(F)cc(F)cc2C1

Procedure:
reacting 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine with thiocyanic acid and dihydroxyacetone to give 5-hydroxymethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione;
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3O[C:36]([CH3:42])=[C:37]([CH:39]([CH3:41])[CH3:40])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:43]([NH:45]C=O)[CH3:44].C(N)C>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:45]([CH2:43][CH3:44])[C:36]([CH3:42])=[C:37]([CH:39]([CH3:41])[CH3:40])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc(C(C)C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCNC=O
Agent: CCN
Product: CCCc1nc2c(C)cc(-c3nc(C(C)C)c(C)n3CC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 146 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-ethylformamide/ethylamine.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](N(CCO)CCO)=[O:9].[C]=O>>[CH:1]1([NH:7][CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=CN(CCO)CCO
Agent: [C]=O
Product: O=CNC1CCCCC1
Yield: 100 %

Procedure:
To 198 grams of cyclohexylamine (2.0 grams), 399 grams of formyldiethanolamine (3.0 mole) were added, and the mixture was placed in a stirred autoclave maintained at a temperature of 150° to 155° C. and a carbon monoxide pressure of 1260 psig. After the reaction was stopped, the contents of the autoclave were removed and distilled at 15 mm Hg. The 256 grams of overhead fraction (B.P. 155°-161° C.) was shown by proton NMR analysis to be cyclohexylformamide. This corresponds to yield of 100%.
Reaction SMILES: N[CH2:2]C(C1(O)CCCCC1)C1C=CC=CC=1.[NH2:17][CH2:18][CH:19]([C:28]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.Cl.C1(O)CCCCC1>>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH:19]([C:28]2([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:18][NH:17][CH3:2])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(CN)C2(O)CCCCC2)cc1
Reactant: NCC(c1ccccc1)C1(O)CCCCC1
Agent: Cl
Solvent: OC1CCCCC1
Product: CNCC(c1ccc(OC)cc1)C1(O)CCCCC1

Procedure:
By replacing 1-[α-(aminomethyl)benzyl]cyclohexanol with a molar equivalent amount of 1-[2-amino-1(p-methoxyphenyl)ethyl]cyclohexanol in Example 7, 1-[1-(4-methoxyphenyl)-2-methylamino)-ethyl]cyclohexanol hydrochloride (m.p. 164°-166° C.) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7]2=[N:9][C:10]([CH2:12][CH3:13])=[CH:11][C:6]2=[C:5]([Cl:14])[N:4]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>O1CCCC1>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:14])[C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[N:8]=1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
A solution of 5.30 g (23.2 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine in 160 mL of tetrahydrofuran (THF) was added to a 0° C. slurry of 7.96 g (46.5 mmol) of benzylbromide and 1.12 g (46.5 mmol) of sodium hydride in 40 mL of THF. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was quenched by the addition of 70 mL of brine. The organic phase was dried with sodium sulfate and concentrated to 12.0 g of brown oil. The oil was purified by flash chromatography using 1 Kg of silica gel and methylene chloride as an eluent to provide 6.40 g (87%) of 2-(methylthio)-4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine as a light yellow solid. nmr (500 MHz, CDCl3) δ1.29 (t, J=7.5 Hz, 3H), 2.60 (s, 3H), 2.61 (q, J=7.5 Hz, 2H), 5.41 (s, 2H), 6.28 (s, 1H), 7.07 (d, J=6.8 Hz, 2H), 7.28 (m, 3H)
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[C:6]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:7]=1[NH2:8])#[N:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[C:1]([C:3]1[S:4][CH:5]=[C:6]([C:9]2[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH3:15])[C:7]=1[NH:8][C:18](=[O:20])[CH3:19])#[N:2]
Reactant: Cc1cc(C)c(-c2csc(C#N)c2N)c(C)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(-c2c(C)cc(C)cc2C)csc1C#N
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of intermediate 3 (6.0 g) in acetic acid (6 ml) was added acetic anhydride (5 g). The reaction mixture was stirred for 1 hour at 110° C. After cooling, the crude mixture was poured into a mixture of ethyl acetate (400 ml), water (600 ml) and saturated NaHCO3 (200 ml). The organic layer was rinsed with water and concentrated. The residue was purified by column chromatography on SiO2 (gradient; hexane:diethyl ether=2:1 to hexane:ethyl acetate=1:1) to give N-[2-cyano-4-(2,4,6-trimethylphenyl)-thiophen-3-yl]-acetamide (intermediate 4).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34]>CN(C=O)C>[Cl-:1].[CH3:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][N+:28]=1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1ccccn1
Reactant: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Solvent: CN(C)C=O
Product: Cc1cccc[n+]1Cc1ccc(NC(=O)C2=Cc3cc(-c4ccccc4)ccc3CC2)cc1
Product: [Cl-]
Temperature: 70 °C
Reaction time: 63 h

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg), and to the mixture was added 2-picoline (126 μl). The mixture was stirred at 70° C. for 63 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 2-methyl 1-[4—(7-phenyl-3,4-dihydronaphthalene-2-carboxamido)benzyl]-pyridinium chloride (Compound 28) (140 mg) as pale brown crystals.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[NH2:8][C:9](=[N:11][C:12]([C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[C:16]=2[CH:15]=1)=[O:13])[NH2:10]>C(O)C>[ClH:1].[ClH:1].[NH2:10][C:9]([NH2:8])=[N:11][C:12]([C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[C:16]=2[CH:15]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c3ccccc3c3ccc(C(=O)N=C(N)N)cc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(N)=NC(=O)c1ccc2c3ccccc3n(C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 0.6 ml portion of 4 M hydrogen chloride/ethyl acetate was added to 4.4 ml ethanol solution of 201 mg tert-butyl 4-(2-{[(diaminomethylene)amino]carbonyl}-9H-carbazol-9-yl)piperidine-1-carboxylate which had been synthesized in the same manner as in Example 1, followed by stirring overnight at room temperature. The thus precipitated-solid was collected by filtration and washed with EtOH to obtain 125 mg of N-(diaminomethylene)-9-piperidin-4-yl-9H-carbazole-2-carboxamide dihydrochloride as pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][CH:22]([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[F:23][CH:22]([F:24])[CH2:21][O:20][C:16]1[N:15]=[CH:14][C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[C:7]=3[CH2:8]2)=[CH:18][C:17]=1[CH3:19]
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)F
Yield: 87 %

Procedure:
The title compound is prepared in 87% yield (300 mg, brown solid) from 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (280 mg, 0.79 mmol, Intermediate-4) and phenyl formate (190 mg, 1.5 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:19][CH3:20])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:21].[CH3:22]O>>[CH3:22][O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[C:12]([Cl:21])[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:8][C:9]=1[O:19][CH3:20]
Reactant: COc1cc(C2CCCCC2)ccc1CCCC(=O)O
Reactant: Cl
Reactant: CO
Product: COC(=O)CCCc1cc(Cl)c(C2CCCCC2)cc1OC
Reaction time: 48 h

Procedure:
7.8 g of 4-(4-cyclohexyl-2-methoxyphenyl)-butyric acid are dissolved in 700 ml of anhydrous methanol and saturated whilst cooling with HCl gas. After 48 hours and with the exclusion of moisture, the mixture is evaporated under vacuum and the residue dissolved in 400 ml of methylene chloride. 2.4 ml of sulphuryl chloride and 500 ml of silica gel are added whilst cooling and stirring. After stirring for 18 hours at 20°, the mixture is filtered and the residue is concentrated until dry.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([F:16])[CH:6]=2.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[F:16][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)[CH:3]=[N:4]2)=[CH:9][C:8]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)Cc1cc2cc(Br)cnc2cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3cc(F)c(CC(=O)O)cc3c2)cn1
Yield: 83.1 %

Procedure:
Nitrogen gas was bubbled through a suspension of (3-bromo-7-fluoro-quinolin-6-yl)-acetic acid (5 g, 17.7 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (3.86 g, 18.6 mmol), potassium carbonate (7.3 g, 53 mmol) in 1,4-dioxane (50 mL) and water (20 mL) for 10 minutes. After such time dichlorobis(triphenylphosphine)palladium (II) (248 mg, 0.35 mmol) was added and the mixture heated to reflux for 3 hours. The aqueous phase was removed via pipette, diluted with 2N aqueous potassium carbonate (15 mL) and washed with ethyl acetate (2×30 mL). The aqueous phase was then acidified to pH 3 with concentrated hydrochloric acid. The formed precipitate was collected via filtration and washed with water and dried to return the title compound as a white solid (4.2 g, 14.7 mmol, 83% yield). 1H NMR 500 MHz (DMSO-d6): δ 3.84 (2H, s), 3.92 (3H, s), 7.71 (1H, d), 7.90 (1H, d), 8.10 (1H, s), 8.39 (1H, s), 8.47 (1H, d), 9.18 (1H, d). ES-MS m/z: 286 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=O.C(Cl)(=O)OCC.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([NH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27])=[O:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: Nc1cccc(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)Nc2cccc(C(=O)O)c2)cc1OC
Reaction time: 2 h
Yield: 50 %

Procedure:
2 Grams of 3,4-dimethoxycinnamic acid were dissolved in a mixture of 20 ml of dry dimethylformamide and 1.5 g of triethylamine. To this solution was added under ice cooling and agitation 1.1 g of ethyl chlorocarbonate and the mixture was then reacted for one hour. To this mixture were added 10 ml of dimethylformamide containing 1.5 g of 3-aminobenzoic acid and the mixture was stirred for 2 hours. After completion of the reaction, the reaction liquid was concentrated approximately to 1/2 volume and poured into an aqueous solution of hydrochloric acid. The precipitated crystals were separated by filtration, washed with water and recrystallized from an equivolume mixture of ethanol and water to obtain a yield of 50 % 3-(3', 4'-dimethoxycinnamoylamino)-benzoic acid having a melting point of 225°-226° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[N+:8]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)=CCCBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]

Procedure:
5-Bromo-2-methyl-2-pentene (15 g, 0.092 mol) was added to a slurry of 2-nitroimidazole (10.4 g, 0.092 mol) and potassium carbonate (12.7 g, 0.092 mol) and refluxed for 24 hrs. Acetone was removed on a rotary evaporator and the residue was purified by column chromatography.