Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:24]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[O:13][CH3:24])[C:6]=2[N:7]=1
Reactant: CI
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound from Step B (1.0 g, 3.3 mmol) in dry DMF (100 mL) at 15° C. was treated with 60% NaH (0.14 g, 3.5 mmol). After 30 min., iodomethane (47 g, 3.3 mmol) was added portionwise to the stirred solution. The reaction was stirred at room temperature for 16 hrs. and then evaporated at a temperature below 40° C. The resulting solid was chromatographed on silica gel to afford the product as a white solid; yield 0.81 g.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:28])[C:10]([N:16]1[CH2:18][CH:17]1[C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1)=[CH:11][C:12]([O:14][CH3:15])=[O:13]>O1CCOCC1>[CH3:7][O:8][C:9]([C:10]1[NH:16][CH:18]=[C:17]([C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)[C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:28]
Reactant: COC(=O)C=C(C(=O)OC)N1CC1c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1[nH]cc(-c2ccc3c(c2)OCO3)c1C(=O)OC
Temperature: 100 °C
Yield: 92.5 %

Procedure:
Cesium carbonate (110 mg, 0.30 mmol, 4.0 equiv) was added to a stirred solution of aziridine 26 (25 mg, 82 μmol, 1.0 equiv) in 1,4-dioxane (12 mL) at 25° C. The reaction vessel was sealed under argon and heated to 100° C. via oil bath for 20 h. The reaction mixture was cooled to 25° C., gravity filtered, and concentrated by rotary evaporation to afford 27 (23 mg, 92% yield) as a dark orange film. 1H NMR (500 MHz, CDCl3) δ 10.22 (br d, 1H, J=11 Hz, NH), 7.43 (dd, 1H, J=14, 11 Hz, pyrrole H), 6.80 (d, 1H, J=1.5 Hz, ArH), 6.72 (d, 1H, J=8 Hz, ArH), 6.69 (dd, 1H, J=8, 1.5 Hz, ArH), 5.93 (s, 2H, OCH2O), 3.89 (s, 3H, OCH3), 3.73 (s, 3H, OCH3); IR (neat film) 3348 (w, br), 2944 (w), 2890 (w), 1731 (m), 1651 (s), 1608 (s), 1503 (m), 1484 (m), 1444 (m) cm−1; HRMS (ESI) m/z: Calcd for C15H14NO6 (MH+) 304.0821, observed 304.0815.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH2:11][C:12]#[N:13])[C:7]=2[CH:14]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH2:11][C:12](=[N:16][OH:17])[NH2:13])[C:7]=2[CH:14]=1
Reactant: COc1ccc2onc(CC#N)c2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2onc(CC(N)=NO)c2c1
Yield: 76.6 %

Procedure:
In ethanol (20 ml) was dissolved 5-methoxy-1,2-benzisoxazole-3-acetonitrile (2.0 g) and thereto was added a solution of hydroxylamine hydrochloride (0.88 g) and sodium carbonate (1.34 g) in water (10 ml). After heating the mixture on water bath at 70° to 80°C for 3 hours, ethanol was distilled off under a reduced pressure. To the residue was added water and the precipitated crystallines were separated by filtration, washed with water and dried to give the desired compound (1.8 g), which was recrystallized from ethanol. m.p. 180° to 183°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)CC)C.Cl.[OH:28][CH2:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[NH2:36].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:36][C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]1[CH2:29][OH:28])=[O:9]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@@H]1CCCC[C@@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCCC[C@@H]2CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.716 mmol) was dissolved in dimethylformamide (3 ml) and triethylamine (300 μl, 2.14 mmol) was added followed by cis-2-hydroxymethyl-1-cyclohexylamine hydrochloride (125 mg, 0.755 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151 mg, 0.788 mmol) and 1-hydroxybenzotriazole(106 mg, 0.785 mmol). The reaction was stirred at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (30 ml) and ethyl acetate (30 ml). The organic phase dried over Na2SO4, the solvent removed under reduced pressure, and the residue purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluent to afford an oil which crystallized from n-pentane to give the title compound as a white solid (136 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>CC(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:27])=[CH:21][CH:20]=1
Reactant: CCN(CC)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCN(CC)c1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
This benzenesulfonamide (0.99 g, 4.3 mmoles) was dissolved in acetone (4.3 ml) to which was then added 1.0N sodium hydroxide (4.4 ml). To this mixture was added 4-chlorophenylisocyanate (0.68 g, 4.4 mmoles), dissolved in 4.3 ml of acetone. This mixture was allowed to stir at room temperature for about 15 minutes. A solid was then removed from the reaction mixture by filtration. To the filtrate was added 1.0N hydrochloric acid (4.4 ml), causing separation of a brown oil. Water (5 ml) was then added and the mixture stirred until the oil had converted to a solid. The solid was collected and washed three times with water.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[C:8]1([C:14](Cl)=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(N(CC)CC)C>[O:5]([C:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:15])[C:3]([C:2]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC(=O)c1ccccc1)c1ccccc1

Procedure:
For the preparation of compounds of formula I, (Q1 is R1CO or PhCO), an intermediate VIII (Q1 is t-butoxycarbonyl) is treated with trifluoroacetic acid (TFA) as in the conversion of VII to VIII. The resulting TFA salt of the corresponding amino compound is then treated with an acid chloride of the formula R1COCl or PhCOCl or an anhydride of the formula (R1CO)2O or (PhCO)2O in the presence of a tertiary amine such as triethylamine to give VIII (Q1 is R1CO or PhCO). This is subsequently transformed into IX (Q1 is R1CO or PhCO) by the same procedure as for the conversion of VIII (Q1 is t-butoxycarbonyl or benzyloxycarbonyl) to IX (Q1 is t-butoxycarbonyl or benzyloxycarbonyl).
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[S:15])[NH:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1.[H-].[Na+].IC.[CH2:25](O)C>CN(C)C=O>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([S:15][CH3:25])=[N:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: Cc1ccnc2c1NC(=S)c1cccnc1N2C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSC1=Nc2c(C)ccnc2N(C2CC2)c2ncccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a warm (40° C.) solution of 1.0 g (3.54 mmol) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-thione in 25 mL of dry dimethylformamide under argon was added 200 mg (4.43 mmol) of a 60% sodium hydride on mineral oil dispersion. The suspension was heated at 60° for 30 min., cooled to 40° C., and 0.3 mL (4.43 mmol) of iodomethane was added in one portion. After stirring the mixture for 1 hr at room temperature, ethanol was added dropwise until bubbling ceased. The mixture was then poured over 200 mL of water, and the product was extracted with 2×200 mL of ethyl ether. The combined organics were washed with 300 mL of water, dried (Na2SO4), and concentrated. The resulting reddish solid was flash chromatographed over silica gel (eluted with 83% methylene chloride/ethyl acetate) to give a yellow solid. Recrystallization from ethyl ether/petroleum ether gave 350 mg of the title compound, m.p. 173°-177° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])[CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])[CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Temperature: 78 °C
Yield: 50.9 %

Procedure:
2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (1.12 g, 2.89 mmol) and ethyl formate (0.700 mL, 8.67 mmol) were dissolved in anhydrous ethanol (5.78 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (5.40 mL, 14.50 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure product (0.609 g, 1.47 mmol, 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[N:6][CH:7]=1
Reactant: Oc1cncc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ncc(F)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice cooling, 5 g of 5-fluoropyridin-3-ol (44 mmol, 1 equivalent) were dissolved in 43 ml of concentrated sulphuric acid, and, at 0° C., 2.8 ml of concentrated nitric acid were added over a period of 5 min. The reaction was warmed to RT, and stirring was continued overnight. The mixture was added to 100 g of ice and stirred for 30 min. The solid obtained was filtered off and dried under reduced pressure. This gave 5.6 g (81% of theory) of the title compound, which were used without further purification for the next reaction.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)O1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.13) (0.31 g, 0.8 mmol) and commercially available 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.16 g, 0.8 mmol) according to the general procedure VI. Obtained as an off-white solid (0.012 g, 4%). MS (ISP) 382.3 [(M+H)+]; mp 208-210° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])C>Cl>[C:7]1(=[O:16])[N:6]([CH2:5][CH:4]=[O:3])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Agent: Cl
Product: O=CCN1C(=O)c2ccccc2C1=O
Yield: 88.1 %

Procedure:
Phthalimidoacetaldehyde diethyl acetal (100 g, 0.38 mol) and 1 N hydrochloric acid (600 ml) was mixture was stirred at reflux temperature for 5 min. or until a homogeneous solution is obtained. The reaction mixture was cooled and the precipitate was filtered off and dried in vacuo at 50° C. for 16 h which afforded 63.3 g (88%) of phthalimido-acetaldehyde as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1.[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(O)C.C(OCC)(=O)C>[CH3:17][C:14]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)cnc1NCc1ccc(C(C)(C)C)cc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A solution of ethyl 2-chloro-5-fluoro-3-pyridinecarboxylate (0.490 g, 2.41 mmol) in ethanol (10.0 mL) was treated with 4-tert-butylbenzylamine (0.450 mL, 2.55 mmol). The mixture was heated to 150° C. for 0.5 h and then to 160° C. for 20 min. in a Biotage Initiator microwave synthesizer. The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (20-40% ethyl acetate in hexanes) afforded a mixture of the title compound and starting material as a clear yellow oil (0.326 g, 41%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.39 (d, J=3.0 Hz, 1H), 8.20 (d, J=3.3 Hz, 1H), 8.14 (t, J=5.1 Hz, 1H), 7.91 (dd, J=6.9, 3.2 Hz, 2H), 7.89 (dd, J=8.1, 3.0 Hz, 2H), 4.69 (d, J=5.3 Hz, 2H), 4.44 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.32 (s, 9H). MS(ES+) m/e 331 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([Cl:33])=[O:32]>N1C=CC=CC=1>[ClH:33].[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:32]
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1)c1cccc(F)c1

Procedure:
A solution of 50 mg (0.13 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 40.2 mg (0.25 mmol) of 3-fluorobenzoyl chloride in 1.0 ml of pyridine is stirred at room temperature for 3 h. The reaction mixture is concentrated in vacuo, and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 48 mg (73.4% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH2:14]O)=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:28]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH2:14][N:28]3[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]3)=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCc1ncc(-c2ccc(Cl)c(Cl)c2)s1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2ncc(-c3ccc(Cl)c(Cl)c3)s2)c1
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of the compound (260 mg, 1.00 mmol) obtained in Example 22a and triethylamine (0.21 mL, 1.50 mmol) in tetrahydrofuran (4 ml) was added methanesulfonyl chloride (0.093 mL, 1.20 mmol), and the mixture was stirred for 30 min. The reaction mixture was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL), ethyl 1H-pyrazole-4-carboxylate (140 mg, 1.00 mmol) and potassium carbonate (207 mg, 1.50 mmol) were added, and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (85 mg, 22%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:22])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:7]2=1.C[C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[Cl:22][C:4]1[CH:5]=[C:6]2[C:14](=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[N:32][CH:24]=3)[CH:3]=1)[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:7]2=1
Reactant: Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
N-(8-amino-6-chloro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide (90 mg, 0.274 mmol, 1 equiv.) and 2-methylnicotinic acid (40 mg, 0.329 mmol, 1.2 equiv.) were dissolved in 1.5 ml of anhydrous pyridine under N2. EDCI (84 mg, 0.438 mmol, 1.6 equiv.) was added in one portion and the reaction mixture was stirred at room temperature 2 hours. The reaction was quenched and treated following the preceding protocol to obtain 38 mg (32%) of N-[6-chloro-4-(2,2,2-trifluoro-acetylamino)-9H-β-carbolin-8-yl]-nicotinamide. 1H-NMR (300 MHz, DMSO-d6): δ 11.89 (br, 1H), 10.73 (s, 1), 9.28 (s, 1), 8.97 (s, 1), 8.84 (d, 1), 8.43 (d, 1), 8.37 (s, 1), 7.85 (s, 1), 7.76 (s, 1), 7.67 (m, 1). Formic acid standard conditions. DAD RT=1.94 min. M+H=434.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](C(N)CCBr)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:21]([O:20][C:18](=[O:19])[NH:10][CH2:9][CH2:8][CH2:7][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)C(N)CCBr
Reactant: c1ccc(C2(c3cccs3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccc2)(c2cccs2)CC1
Yield: 20 %

Procedure:
A solution of 4-phenyl-4-(thiophen-2-yl)piperidine and 3-Boc-aminopropylbromide (1.0 g, 4.4 mmol) with 1 g of K2CO3 in 20 ml of dioxane was stirred at reflux for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solution was dried over Na2SO4 and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.43 g (1.1 mmol, 20% for two steps) of 3-(4-phenyl-4-(thiophene-2-yl)piperidin-1-yl)-propylcarbamic acid tert-butyl ester as colorless oil. The ester in 5 ml of CH2Cl2 was added with 1 ml of CF3CO2H and resulting solution was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo to yield oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO3. Concentration of the reaction mixture provided the desired product as an oil (0.29 g, 0.96 mmol, 88%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:4][C:3]=1[C:18]1[S:19][C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=1.C([O-])(=O)C.[NH4+:29]>C(OCC)(=O)C>[NH2:29][C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:18]2[S:19][C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:4]=1)=[O:17]
Reactant: [NH4+]
Reactant: Cc1nc(-c2cc(NC(=O)CC(=O)C(F)(F)F)ccc2Cl)sc1C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cc(NC(=O)C=C(N)C(F)(F)F)ccc2Cl)sc1C
Temperature: 25 °C

Procedure:
A mixture of N-[4-chloro-3-(4,5-dimethyl-1,3-thiazol-2-yl)phenyl]-4,4,4-trifluoro-3-oxobutaneamide (3.80 g) and ammonium acetate (6.22 g) in 35 ml of ethyl acetate is refluxed for 7 hours, then cooled to room temperature and diluted with ethyl acetate (70 ml). The mixture is washed once with water and once with brine, then dried over sodium sulphate and concentrated under vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[C:10](=[O:12])=[O:11]>C1COCC1.[Li]C(C)(C)C>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: Cc1c(Br)cccc1Br
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 1,3-dibromo-2-methylbenzene (6.57 g) in dry THF (100 mL), t-BuLi solution (1.5 M in pentane, 17 mL) was added dropwise at −80° C. Then reaction mixture was stirred between −76˜−78° C. for 2 h. Then the mixture was cooled to below −80° C. and dry ice was added after which the mixture was warmed to room temperature naturally. Solvent was removed, 5% NaOH solution (40 mL) added and the aqueous solution was washed with CH2Cl2 (10 mL×2). Then the aqueous layer was acidified with concentrated HCl to pH=1 and extracted with EtOAc (100 mL×2). The combined organic extracts were dried over anhydrous Na2SO4. After removing the solvent, the residue was purified by silica column chomatography, (eluted with petrol. ether: EtOAc=8:1 to 1:1), to obtain 3.58 g of the product. Yield: 63.4%. 1H NMR (400 MHz, CDCl3) δ 2.73 (s, 3H), 7.15 (t, J=8.0 Hz, 1H), 7.77 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.94 (dd, J=8.0 Hz, J=1.2 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:29]=[C:24]1[NH:25][C:26](=[O:28])/[C:27](=[CH:1]\[C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][O:10][C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:5][CH:4]=2)/[S:23]1
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)c1ccc(OCCOc2ccc(C=O)cc2)cc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(OCCOc2ccc(/C=C3/SC(=O)NC3=O)cc2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of 355 (1.59 g, 3.86 mmol) in toluene (10 mL) was added thiazolidine-2,4-dione (542 mg, 4.63 mmol), benzoic acid (61.3 mg, 0.50 mmol) and piperidine (57 μL, 0.58 mmol). The resultant mixture was refluxed with the Dean-Stark adapter for ½ h and cooled to the room temperature. A precipitate formed which was collected by filtration to afford the title compound (1.41 g, 92%). 1H NMR: (DMSO-d6) δ (ppm): 7.90 (d, J=8.8 Hz, 2H), 7.73 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.8 Hz, 2H), 7.08 (d J=8.8 Hz, 2H), 4.42 (bs, 4H), 3.80 (s, 3H). LRMS (ESI): (calc.) 399.1; (found) 400.0 (MH)+.