Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.[OH-].[Na+]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Nc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(-c2nc3ccccc3o2)c1
Temperature: 200 °C

Procedure:
3-Aminobenzoic acid (500 mg, 3.65 mmol) and 2-aminophenol (398 mg, 3.65 mmol) were mixed with polyphosphoric acid (5 ml). The reaction was heated to 200° C. for 4 h. The reaction mixture was slowly poured into ice water (100 ml) and the resulting mixture basified with solid sodium hydroxide. At pH5–6 the precipitate was filtered, washed with water and dried to give the subtitle compound, 625 mg (82%). 1H NMR (CDCl3) δ 7.78(m, 1H), 7.65(d, J=7.5 Hz, 1H) 7.59(m, 2H), 7.36(m, 3H), 6.86(dd, J=2.2, 7.9 Hz, 1H). MS 211 m/z (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]2[C:21](Cl)=[N:22][CH:23]=[C:24]([F:26])[CH:25]=2)=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]2[C:21]([O:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([S:29][CH3:28])[CH:31]=3)=[N:22][CH:23]=[C:24]([F:26])[CH:25]=2)=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1cccc(O)c1
Reactant: O=C(N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)c1
Temperature: 65 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
cis-4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid benzyl ester (2.14 g, 5.5 mmol), 3-methylsulfanylphenol (844 mg, 6.02 mmol) and caesium carbonate (2.67 g, 8.21 mmol) were suspended in dimethylformamide (50 ml) and the reaction was heated to 65° C. and stirred at this temperature under nitrogen for 18 h. The reaction was cooled to room temperature, concentrated under reduced pressure and the residue was diluted with water (50 ml). It was then extracted with ethyl acetate (3×40 ml) and the combined organic extracts were washed with water (2×10 ml), brine (10 ml), dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of pentane:ethyl acetate (2:8 changing to 1:3 then 3:7, by volume) to give cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid benzyl ester (2.0 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)[CH:16]=[CH:17][N:18](C)C)=[N:9]1.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]2[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[N:9]1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccccc2Cl)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccccc2Cl)nc1-c1ccnn1-c1ccccc1
Yield: 8.2 %

Procedure:
To a solution of 1-(2-chlorophenyl)-3-[3-(dimethylamino)prop-2-enoyl]pyridazin-4(1H)-one (crude, 636 mg, 2.10 mmol) in 20 mL of methanol was added phenylhydrazine (907 mg, 8.40 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(2-chlorophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (60 mg, 8% for two steps) as a red gel.
Reaction SMILES: [CH:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>[Zn]>[OH:13][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CCCCCCCCCCCC=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Zn]
Product: CCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Yield: 80.7 %

Procedure:
The reaction of dodecanal (0.92 g) and tert-butyl bromoacetate (1.56 g) was carried out under the presence of zinc (0.59 g) according to similar manner to that of Preparation 1-(1) to afford an oil of tert-butyl 3-hydroxytetradecanoate (1.21 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[CH2:23]([O:30][CH:31](O)[C:32]#[C:33][CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][CH2:31][C:32]#[C:33][CH2:34][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:6]2[CH2:7][CH2:8][S:9][C:10]([CH3:12])([CH3:11])[CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: CC#CC(O)OCc1ccccc1
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCOCc3ccccc3)cc2)CCSC1(C)C
Yield: 42 %

Procedure:
According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 0.345 g (1.0 mmol) of 4-(4-hydroxy-benzenesulfonyl}2,2-dimethyl-thiomorpholine3-carboxylic acid methyl ester and 0.211 g (1.2 mmol) of -(benzyloxy)-2-butyn-1-ol provided 0.211 g (42%) of methyl 4-[(4-{[(benzyloxy)-2-butynyl]oxy)phenyl}-sulfonyl]-2,2-dimethyl-3- thiomorpholine carboxylate as a pale yellow oil. Electrospray Mass Spec: 504.2 (M+H)+
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][NH:11][CH:12]=[O:13].[H-].[Na+]>>[CH3:10][N:11]([CH:12]=[O:13])[CH2:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1
Reactant: ClCc1ccncc1
Reactant: CNC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C=O)Cc1ccncc1
Yield: 76.5 %

Procedure:
To a stirring, argon-purged solution of 4-picolyl chloride-HCl (15 g, 91.4 mmol) and N-methylformamide (53.4 ml, 914 mmol) in 300 ml of TBF at room temperature was added portionwise over a 20 minute period a suspension of 80% NaH (5.48 g, 183 mmol). The reaction was quenched 18 h later by the addition of ice, partitioned between methylene chloride and water, washed with water and brine, dried over MgSO4, and evaporated to dryness to afford a dark oil. Flash chromatography on silica gel provided 10.5 g (76%) of the titled compounds a pale yellow oil. TLC; silica gel (9:1 CHCl/MeOH) Rf=0.54.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]1)#[N:24]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(CCO)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(CCO)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Yield: 9.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1 g) and 5-amino-2-[4-(2-hydroxyethyl)piperidin-1-yl]benzonitrile (1.6 g), the title compound (0.2 g) was obtained, melting point: 186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(Cl)ccc1C#N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(Cl)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of 4-chloro-2-methylbenzonitrile (10 g, 66 mmol) in conc. H2SO4 was added KNO3 (7.0 g, 69.3 mmol) at 0° C. in small portions, and then the reaction mixture was stirred overnight at ambient temperature. It was then poured into ice and extracted with AcOEt. The combined extracts were washed by sat. NaHCO3 aq., dried over MgSO4 and concentrated. The resulting precipitates were collected by filtration, washed with ether, and dried under reduced pressure to give 5.5 g (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.Cl.Cl.[NH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:1].[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([N:23]3[CH2:24][CH2:25][CH2:26][CH:21]([NH2:20])[CH2:22]3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: NC1CCCNC1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC1CCCN(c2ccc(-c3ccc(C(F)(F)F)cc3)nn2)C1
Temperature: 120 °C
Yield: 27.5 %

Procedure:
3-Chloro-6-(4-trifluoromethylphenyl)pyridazine (0.2 g, 0.77 mmol), 3-aminopiperidine dihydrochloride (0.27 g, 1.54 mmol) and potassium carbonate (0.53 g, 3.87 mmol) were mixed in acetone (4 mL) in a 20 mL microwave vessel. The reaction mixture was heated in a microwave oven for 2 h at 120° C. The reaction mixture was filtered and the precipitate was washed with MeOH. The combined organic phases were evaporated. The crude oil was purified on a silicagel column (0.04-0.063 mesh) using dichloromethane/MeOH (9:1) as eluent. This afforded 110 mg of a oil that was dissolved in MeOH and acidified with concentrated HCl (5 mL). The mixture was evaporated and the residue was dissolved in MeOH (1 mL) and ether (100 mL) was added with stirring. The mixture was evaporated to give 76 mg (25%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][CH2:15][OH:16].Cl.[O-:18][C:19]#N.[K+]>O>[OH:16][CH2:15][CH2:14][CH2:13][N:12]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[NH:1][C:19]1=[O:18]
Reactant: N#C[O-]
Reactant: Nc1cc(C(F)(F)F)ccc1NCCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1CCCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a stirred mixture of 21 parts of 3-{[2-amino-4-(trifluoromethyl)phenyl]amino}-1-propanol and 100 parts of water are added 14.4 parts of hydrochloric acid solution. The whole is stirred for 10 minutes at room temperature. After cooling to 0°-10° C., there is added dropwise a solution of 18 parts of potassium cyanate in 50 parts of water. Upon completion, stirring is continued for 2 hours. The precipitated product is filtered off and dried. Then it is melted and the melt is stirred for 10 minutes. After cooling, it is dissolved in trichloromethane while heating. The solution is filtered and the product is allowed to crystallize from the filtrate. It is filtered off and dried, yielding 8 parts (34%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:29])[NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][C:17]([N:26]([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=CC=1)([O-])=O.[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>O1CCOCC1>[CH3:28][N:26]([CH3:27])[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:11]([N:42]2[CH2:43][CH2:44][CH2:45][CH:40]([C:34]3[C:33]4[C:37](=[CH:38][CH:39]=[C:31]([F:30])[CH:32]=4)[NH:36][CH:35]=3)[CH2:41]2)=[O:29])[CH2:15][CH2:16]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Fc1ccc2[nH]cc(C3CCCNC3)c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCCC(c3c[nH]c4ccc(F)cc34)C2)CC1
Yield: 24.8 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid 4-nitrophenyl ester (400 mg, 1 mmole) was added to a solution of 5-fluoro-3-piperidine-3-yl-1H-indole (220 mg, 1 mmole) in dioxane (8 ml). The reaction mixture was then boiled under reflux for 8 hours. The reaction mixture was worked up by distilling off the solvent. The residue contained, apart from nitrophenol, also the two diastereoisomers of 3-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (30 g). Methanol/EE (1:1; 850 ml) was used as eluent. The non-polar diastereoisomer of 3-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (143 mg, m.p. 110°-115° C., 30%) and the polar diastereoisomer of 3-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (118 mg, m.p. 98°-101° C., 25%) were thereby obtained in pure form.
Reaction SMILES: Br[C:2]1[C:14]([CH2:15][O:16]C2CCCCO2)=[CH:13][C:5]([O:6]C2CCCCO2)=[CH:4][C:3]=1[F:23].C([Li])CCC.[B:29](OC(C)C)(OC(C)C)[O:30]C(C)C.Cl>O>[F:23][C:3]1[C:2]2[B:29]([OH:30])[O:16][CH2:15][C:14]=2[CH:13]=[C:5]([OH:6])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc(OC2CCCCO2)cc(COC2CCCCO2)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Product: OB1OCc2cc(O)cc(F)c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.7 %

Procedure:
To a solution of 2-(4-bromo-3-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (9.13 g, 23.5 mmol) was added n-butyllithium (1.6 M in hexanes, 16 mL, 26 mmol) dropwise at −78° C. After stirring 5 min, triisopropyl borate (8.7 mL, 38 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 2 h. 6 M HCl (10 mL) was added, and the mixture was stirred for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (1:1 hexane/ethyl acetate) to give 7-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol (3.54 g, 90%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 4.86 (s, 2H), 6.40 (dd, J=9.9, 1.5 Hz, 1H), 6.59 (s, 1H), 8.92 (br s, 1H), 10.2 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:29][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: COc1ccc(CN)cc1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ncc3c(C)c(Br)c(=O)n(C4CCCC4)c3n2)cc1
Yield: 86.9 %

Procedure:
A suspension of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 2.70 mmol) and 4-methoxybenzylamine (0.39 mL, 4.0 mmol) in toluene (15 mL) was heated under reflux for 2 hours. The solution was cooled, and the resulting solid was collected by filtration to give 6-bromo-8-cyclopentyl-2-(4-methoxy-benzylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.04 g, 86.4%). 1H NMR δ(400 MHz, CDCl3) 1.6 (m, 2H), 1.8 (m, 2H), 2.0 (m, 2H), 2.2 (m, 2H), 2.53 (s, 3H), 3.79 (s, 3H), 4.59 (m, 2H), 5.96 (m, 1H), 6.1 (m, 1H), 6.86 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 8.5 (br s, 1H). MS (APCl) (C21H23Br1N4O2): Calc for M+H, 443. 1; Found, 443.1
Reaction SMILES: CN(C=[O:5])C.[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:26][CH:27]=[CH2:28])[C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>[Pd](Cl)Cl.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:26][C:27](=[O:5])[CH3:28])[C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CCn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Product: CC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
Palladium chloride (100 mg) and cupric chloride dihydrate (50 mg) were added to DMF solution (30 ml) of 2-t-butoxycarbonyl-9-allyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.90 g, 6.1 mmol) and stirred at room temperature for 18 hours. The reaction solution was mixed with ethyl acetate, washed with water and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure, the thus obtained residue was mixed with diisopropyl ether (20 ml) and the thus precipitated crystals were collected by filtration to obtain 1.17 g of the title compound (59% in yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1.C(#N)C>O>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:8]2[NH:9][C:19]1=[O:20]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)[nH]c2cc(C(F)(F)F)cnc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of 1.91 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 3.24 g of carbodiimidazole and 10 ml of acetonitrile was stirred at 50° C. for 1 hour and at 80° C. for 2 hours. Water was poured into the cooled reaction mixture, and the precipitated crystal was obtained by filtration and dried to obtain 2.0 g of 3-methyl-6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.
Reaction SMILES: [OH:1][C:2]([C:15]1[CH:16]2[C:21](=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]([CH:20]=1)[CH:18]1[C:35]([N:37]([CH2:40][CH2:41]OC(=O)C=CC3C=CC(C(C)C)=CC=3)[C:38](=[O:39])[CH:17]21)=[O:36])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:56]([NH:59][C:60]1[CH:70]=[CH:69][C:63]([CH:64]=[CH:65][C:66]([OH:68])=[O:67])=[CH:62][CH:61]=1)(=[O:58])[CH3:57].C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:56]([NH:59][C:60]1[CH:70]=[CH:69][C:63]([CH:64]=[CH:65][C:66]([O:68][CH2:41][CH2:40][N:37]2[C:38](=[O:39])[CH:17]3[CH:18]([CH:19]4[C:21](=[C:22]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:16]3[C:15]([C:2]([OH:1])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:20]4)[C:35]2=[O:36])=[O:67])=[CH:62][CH:61]=1)(=[O:58])[CH3:57]
Reactant: CC(=O)Nc1ccc(C=CC(=O)O)cc1
Reactant: CC(C)c1ccc(C=CC(=O)OCCN2C(=O)C3C4C=C(C(O)(c5ccccc5)c5ccccn5)C(C4=C(c4ccccc4)c4ccccn4)C3C2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C=CC(=O)OCCN2C(=O)C3C4C=C(C(O)(c5ccccc5)c5ccccn5)C(C4=C(c4ccccc4)c4ccccn4)C3C2=O)cc1
Reaction time: 72 h
Yield: 99 %

Procedure:
A similar procedure (Schwartz, E. et al. Macromolecules 2011, 44, 4735-4741) to that previously described for the preparation of 347 was followed using 2 (1.50 g, 2.70 mmol), 4-acetamidocinnamic acid (0.50 g, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.04 g, 5.60 mmol), triethylamine (1.24 mL, 8.91 mmol) and dimethylaminopyridine (60 mg, 0.49 mmol) in dichloromethane (25 mL), at room temperature for 72 h. Purification by flash chromatography (hexane/ethyl acetate 1:4) afforded 337 as a white solid (2.0 g, 2.69 mmol, 99%). mp 125-130° C.; 1H NMR (300 MHz, CDCl3) δ 2.17 (3H, s, NHAc), 3.35-3.90 (4.16H, m, NCH2CH2O, H-2, H-3, W/H-4), 3.83-3.95 (0.84H, m, U/H-1, V/H-1, Y/H-4), 4.14 (0.14H, m, U/H-4), 4.28-4.38 (2.32H, m, NCH2CH2O, V/H-4), 4.43-4.47 (0.54H, m, W/H-1, Y/H-1), 5.53 (0.32H, dd, J=3.4 and 1.2 Hz, V/H-6), 5.55 (0.38H, dd, J=3.4 and 1.2 Hz, Y/H-6), 5.59 (s, OH), 5.60 (s, OH), 5.63 (s, OH), 5.69 (s, OH), 6.06 (0.14H, dd, J=3.4 and 1.2 Hz, U/H-6), 6.06 (0.16H, dd, J=3.4 and 1.2 Hz, W/H-6), 6.17 (0.30H, d, J=15.8 Hz, COCH═CH), 6.26 (0.70H, d, J=15.8 Hz, COCH═CH), 6.74-7.61 (21H, m, Ar and COCH═CH), 8.40-8.63 (2H, m, αPyr); m/z (ESI, 70 eV) 765 (MNa+, 100%); (Found MNa+ 765.2684, C46H38N4NaO6 requires 765.2687).
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH3:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([OH:19])=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:19][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH3:20])[C:4]([CH:1]([CH3:3])[CH3:2])=[C:12]2[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)c1c(-c2ccncc2)c2cc(O)ccc2n1C
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c(C(C)C)n2C

Procedure:
The above compound was prepared from 2-isopropyl-1-methyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:28](I)([CH3:30])[CH3:29]>CC(C)=O>[F:21][C:2]([F:20])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH:28]([CH3:30])[CH3:29])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1OC(C)C
Yield: 21 %

Procedure:
A mixture of 15.1 g (0.209 mol) of product of Example 35, 6.6 g (0.2 mol) of potassium carbonate, 32 g of isopropyl iodide and 50 ml of acetone was held at reflux for 18 hours and concentrated. The residue was treated with water and filtered. The solid was dissolved in ether (100 ml) and the ether solution was washed with 50 ml of 10% NaOH, dried, and concentrated. The residue was recrystallized from hexane to give 14.2 g (83%) of product; mp 53°-55° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][N:9]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1Cl)[CH3:10]>CS(C)=O>[CH3:10][N:9]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])[CH3:8]
Reactant: OCCNCCO
Reactant: CN(C)CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CS(C)=O
Product: CN(C)CCNC(=O)c1cc([N+](=O)[O-])ccc1N(CCO)CCO
Temperature: 150 °C
Reaction time: 3.5 h
Yield: 41.5 %

Procedure:
Diethanolamine (5 g; 48.6 mmol) was added to a solution of 5 g (18.4 mmol) of N-[(N,N-dimethylamino)ethyl]-2-chloro-5-nitrobenzamide in 10 ml of DMSO, followed by stirring at 150° C. for 3.5 hours. After the resulting mixture was cooled to room temperature, it was extracted with ethyl acetate. Magnesium sulfate was added to the extract to dry the same, and the solvent was then distilled out under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate/methanol=1/0→1/1), whereby 2.6 g of the title compound were obtained as a colorless oil (yield: 38%).