Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:11])[C:9]#[CH:10].Cl[C:13]1[N:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]2[OH:28].CN(C=O)C>CCOCC.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>[OH:28][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:10]#[C:9][CH2:8][OH:11])[N:14]=2)[N:19]=[CH:18][C:17]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: C#CCO
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc(C#CCO)nc2c1O
Reaction time: 0.08 h

Procedure:
Triethylamine (10 mL) is added to dry cuprous iodide (52 mg) under nitrogen. The mixture is stirred for 5 minutes. Propargyl alcohol (50 μL) is added. After stirring another 5 minutes, dichlorobis(triphenylphosphine)palladium(II) (48 mg) is added. The mixture is again stirred for 5 minutes before the addition of ethyl 6-chloro-4-hydroxy[1,5]naphthyridine-3-carboxylate (Preparation 1, 348 mg) and DMF (10 mL). After stirring another 5 minutes, the remaining propargyl alcohol (660 μL) is added, and the reaction is tightly capped and stirred at 70° C. for 11 hours. After cooling, the mixture is diluted with ether (75 mL), sonicated to break up any solids, and filtered. The collected solid is washed with ether, dried under vacuum and recrystallized from ethanol.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:11])C.CC1(C)N([O])C(C)(C)CCC1.[OH-].[Na+]>C(#N)C.O>[CH2:1]([C:3]1([C:7]([OH:11])=[O:8])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CO)COC1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCC1(C(=O)O)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
(3-Ethyloxetan-3-yl)methanol (0.58 g, 5.00 mmol) was dissolved in 10 mL of a 1:1 ACN-water mixture, and bis-acetoxyiodobenzene (BAIB, 3.54 g, 11.0 mmol) was added. The mixture was cooled in an ice bath, and TEMPO (0.156 g, 1.00 mmol) was added under argon flow. The mixture was stirred at room temperature for 1 hr, and then treated with 1 M aqueous sodium hydroxide (20 mL). The solution was washed twice with EtOAc and then acidified to pH 2. The aqueous solution was extract six times with EtOAc and these combined extracts were dried over sodium sulfate and concentrated to afford 0.37 g (57%) of Intermediate 55 as oil, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH:23]1[CH2:28]CCCO1.[OH-].[Na+]>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].O>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH2:23][CH2:28][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: C1CCC(OC2CCCCO2)OC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccccc1)C(CCOC1CCCCO1)c1ccccc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture containing 19.6 g of desoxybenzoin, 20.9 g of tetrahydropyran-2-yl ether-protected bromoethanol, 1.0 g of TEBAC and 50 ml of 48% sodium hydroxide solution is stirred for 2 h at 75° C. Water is added and the product extracted in toluene. The toluene solution is washed with water and dried over sodium sulfate. Finally the solvent is evaporated. The yield is quantitative, but the oily product contains about 20% O-alkylation product.
Reaction SMILES: [OH-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13]C(=O)C)[C:7]=1[NH:17][C:18](=[O:34])[CH2:19][CH:20]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:27][C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH3:5])[CH3:4]>O.CO>[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[C:7]=1[NH:17][C:18](=[O:34])[CH2:19][CH:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[O:27][C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)([CH3:5])[CH3:4]
Reactant: CC(=O)OCc1cccc(C(C)C)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1cccc(CO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 79 mg (1.98 mmol) of sodium hydroxide in 1 ml of water was added to a solution of 567 mg (1.32 mmol) of N-(2-isopropyl-6-acetoxymethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (v) above] in 15 ml of methanol, and the resulting mixture was stirred for 1 hour at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous solution of sodium chloride, and the solvent was removed by distillation under reduced pressure, to give 511 mg (a quantitative yield) of the title compound, melting at 155°-156° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[I-].[Na+].C(O[CH2:25][CH3:26])(=O)C>CN(C=O)C>[C:25]1([CH2:26][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[C:14]2[C:6](=[CH:5][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:12][CH:11]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc3ccccc23)CCCC1=O
Reaction time: 0.08 h
Yield: 41 %

Procedure:
40% Methanolic Triton B (1.6 mL, 3.6 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (870 mg, 3.6 mM) in 30 mL of DMF at 25° C. After 5 minutes, 1-chloromethyl naphthylene (642 mg, 3.6 mM) and sodium iodide (450 mg, 3.0 mM) were added and the resultant mixture stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 560 mg (41%) of the 9-[(1-naphthyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow solid. 1H NMR (CDCl3) δ 8.0 (d, 1H, J=8 Hz), 7.9 (d, 1H, J=8 Hz), 7.7 (d, 1H, J=8 Hz), 7.6 (t, 1H, J=8 Hz), 7.55 (t, 1H, J=8 Hz), 7.35 (d, 1H, J=8 Hz), 7.15-7.05 (m, 3H), 6.4 (d, 1H, J=8 Hz), 5.8 (s, 2H), 4.05 (s, 3H), 2.8 (t, 2H, J=6 Hz), 2.55 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1721, 1646, 1464, 1448, 1438, 1285, 1122, 796, and 761. MS (ES) m/e 382, 384.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[NH2:35][C:33](=[O:34])[CH2:32][CH:29]1[CH2:30][CH2:31][N:26]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:27][CH2:28]1
Reactant: NC(=O)CC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(CC(N)=O)CC3)n2n1
Temperature: 25 °C
Yield: 34 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), 2-(piperidin-4-yl)acetamide hydrochloride (82 mg, 0.58 mmol), and N,N-diisopropylethylamine (112 mg, 0.870 mmol) in DMF (2.0 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (30-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (44.4 mg, 34%). 1H NMR (DMSO-d6) δ: 10.84 (s, 1H), 7.89-8.10 (m, 2H), 7.53-7.66 (m, 2H), 7.33 (br. s., 1H), 7.28 (s, 1H), 6.81 (br. s., 1H), 6.16 (s, 1H), 4.44 (d, J=12.6 Hz, 2H), 3.00-3.12 (m, 2H), 2.37 (s, 3H), 1.94-2.14 (m, 3H), 1.81 (d, J=13.1 Hz, 2H), 1.41-1.53 (m, 6H), 1.30-1.41 (m, 2H); ESI-MS: m/z 451.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C@H:8]2[C@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10][CH2:9]2)[CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Cl>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C@@H:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C@@H:17]2[OH:18]
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1cccnc1)CO2
Reactant: ClCc1ccccn1
Product: O[C@@H]1c2cc(OCc3ccccn3)ccc2OC[C@H]1Cc1cccnc1

Procedure:
By the method of Example 5, 500 mg (1.95 mmol) of trans-3-(3-pyridyl methyl)-4,6-chromandiol and 266 mg (2.09 mmol) of 2-picolyl chloride were converted to present title product, purified by flash chromatography on 100 g silica gel using 1:19 CH3OH:ether as eluant to yield 136 mg (20%) of present title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[H-].[Na+].Br[C:29]1[S:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1>CN(C=O)C>[S:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12
Reactant: Brc1nc2ccccc2s1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc4ccccc4s3)nc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.9 %

Procedure:
To a solution of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 21.2 mg, 0.063 mmol) in DMF (626 μL) was added sodium hydride (10.02 mg, 0.251 mmol) in one portion. After 20 min, 2-bromo-1,3-benzothiazole (53.6 mg, 0.251 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organics were washed with 10% LiCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography using an Isco 4 g column eluting with 0-5% MeOH/CH2Cl2 to yield 4-(benzo[d]thiazol-2-ylamino)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (6.8 mg, 21.87% yield) as an off-white solid.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:27][CH2:28][CH2:29][CH:30]([C:42]1[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=1)[O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=1)(=O)=O>CN(C=O)C>[C:48]([C:45]1[CH:44]=[CH:43][C:42]([CH:30]([O:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=2)[CH2:29][CH2:28][CH2:27][N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:47][CH:46]=1)#[N:49]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: COc1ccc(OC(CCCOS(C)(=O)=O)c2ccc(C#N)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC(CCCN2CC3CCC(C2)N3C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cc1OC
Temperature: 90 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.1 g, 33.4 mmol; from Preparation B above) in DMF (120 mL) was added K2CO3 (5.1 g, 36.8 mmol) and 4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate (13.9 g, 34.4 mmol; see Preparation E, step (c) above). The resulting solution was heated to 90° C., stirred 4 h, cooled and concentrated in vacuo. The residue was suspended in H2O and extracted with CH2Cl2 (3×). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with CH2Cl2:MeOH (98:2) gave 17.3 g (99%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11][CH3:12])[CH:9]=2)[CH:4]=[CH:3]1.[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15]>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11][CH3:12])[CH:9]=2)[C:4]([C:13](=[O:17])[C:14]([Cl:16])=[O:15])=[CH:3]1
Reactant: CSc1ccc2ccn(C)c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CSc1ccc2c(C(=O)C(=O)Cl)cn(C)c2c1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a solution of 1-methyl-6-methylsulfanyl-1H-indole (658 mg, 3.71 mmol) in Et2O(7 ml) at 0° C., was added oxalyl chloride (0.55 ml, 6.31 mmol). After stirring for 3 hours, the orange solid was collected, washed with Et2O, and dried to afford (1-methyl-6-methylsulfanyl-1H-indol-3-yl)-oxo-acetyl chloride (819 mg, 66%).
Reaction SMILES: [Na].[SH:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.Cl[CH2:13][C:14]1[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=1>CO.CN(C=O)C>[F:21][C:20]([F:22])([F:23])[C:16]1[CH:15]=[C:14]([CH2:13][S:2][C:3]2[NH:4][C:5]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Sc1nc2cnccc2[nH]1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(CSc2nc3cnccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.15 g (0.0065 g atom) of sodium in 35 mL of methanol was added 1.0 g (0.0066 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine. After stirring for 15 minutes at room temperature, the methanol was removed in a rotary evaporator. The residue was dissolved in 20 mL of DMF and 1.28 g (0.0066 mol) of α'-chloro-α,α,α-trifluoro-m-xylene in 2 mL of DMF was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature overnight and was then poured into 150 mL of ice water. The product which crystallized was collected and amounted to 1.61 g. An analytical sample (m.p. 148°-150° C.) was obtained by recrystallization from acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[C:14]([O:27]C(=O)C)=[C:15]([CH:24]=[CH:25][CH:26]=2)[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[C:14]([OH:27])=[C:15]([CH:24]=[CH:25][CH:26]=2)[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCCCC3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCCCC3)c2O)=C(C)C1=O
Yield: 37.7 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]piperidine (0.050 g, 0.113 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.017 g, 0.0426 mmol, 38%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[S:18]([NH2:28])(=[O:27])([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)=[O:19].N>C(O)CCC>[S:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])[C:5]([Cl:17])=[CH:4][N:3]=2)=[CH:22][CH:21]=1)(=[O:19])(=[O:27])[NH2:28]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: N#Cc1ccccc1Nc1nc(Cl)ncc1Cl
Agent: N
Solvent: CCCCO
Product: N#Cc1ccccc1Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)ncc1Cl
Temperature: 25 °C
Yield: 10.6 %

Procedure:
2,5-Dichloro4-(2-cyanoanilino)pyrimidine (265 mg, 1.00 mmol) was dissolved in n-butanol (1 ml) and sulphanilamide (207 mg, 1.20 mmol) was added. The resulting suspension was heated at reflux for 2 hours and allowed to cool to ambient temperature. The reaction mixture was then basified using methanolic ammonia and evaporated onto silica. The residue was purified by column chromatography eluting with 0–15% 2.0M methanolic ammonia solution in dichloromethane to afford a solid product (42.6 mg). NMR (303.1K): 7.09 (2H, s), 7.41–7.59 (5H, m), 7.65 (1H, d), 7.74–7.86 (1H, m), 7.94 (1H, d 8.25 (1H, s), 9.46 (1H, s), 9.78 (1H, s); MS (M+H)+: 401, 403.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].O1CCCC1.Cl.[Cl:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH:19]=1)=[O:17]>CO.ClCCl>[ClH:15].[NH:7]([C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([C:37]([F:39])([F:38])[F:40])[CH:28]=2)[CH:19]=1)=[O:17])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2cc(C(F)(F)F)nc3ccccc23)c2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: N=C(N)NC(=O)c1cn(-c2cc(C(F)(F)F)nc3ccccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 cm3 of methanol and 8.4 cm3 (4.2 mmol) of a 0.5N solution of sodium methoxide in methanol are added to 0.401 g (4.2 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm3 of dichloromethane and concentrated to dryness under reduced pressure (2.7 kPa). 40 cm3 of tetrahydrofuran and 0.35 g (0.85 mmol) of 3-chlorocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride, suspended in 20 cm3 of dichloromethane, are then added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.1 g of 3-guanidinocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 216° C. Mass spectrum (EI): m/e 397 (M+.), m/e 339 (base peak).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:21]=[CH:20][C:12]3[C:13]([CH3:19])([CH3:18])[CH:14]=[C:15]([CH3:17])[O:16][C:11]=3[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:24][OH:25]>C1(C)C=CC=CC=1>[CH3:24][O:25][C:15]1([CH3:17])[CH2:14][C:13]([CH3:19])([CH3:18])[C:12]2[CH:20]=[CH:21][C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=3)=[CH:10][C:11]=2[O:16]1
Reactant: CC1=CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Reactant: CO
Solvent: Cc1ccccc1
Product: COC1(C)CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Reaction time: 4.5 h
Yield: 90 %

Procedure:
A mixture of the 7-(4-nitrophenoxy)-2,4,4-trimethyl-4H-1-benzopyran obtained in Referential Example 43, 66 ml of methanol, 0.7 g of Amberlyst-15 and 6 ml of toluene was stirred for 4.5 hours, and Amberlyst-15 was separated by filtration. The filtrate was concentrated, and 30 ml of methanol was added. Crystals that precipitated were collected by filtration, washed with 50 ml of methanol, and dried to give 6.7 g (90%) of the desired product as a white powder (melting point 125° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][C:26]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:27]=1[CH:28]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:28][C:27]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:26]=2[CH3:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: Cc1ccc(C)c(C=O)c1
Product: Cc1ccc(C)c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2,5-dimethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 450.2.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.N([O-])=O.[Na+].[C:14]1(=[O:20])[NH:18][C:17](=[O:19])[CH:16]=[CH:15]1.C([O-])(=O)C.[Na+]>O.CC(C)=O>[Br:2][C:3]1[CH:9]=[CH:8][C:6]([C:16]2[C:17](=[O:19])[NH:18][C:14](=[O:20])[CH:15]=2)=[CH:5][CH:4]=1
Reactant: O=C1C=CC(=O)N1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: CC(C)=O
Solvent: O
Product: O=C1C=C(c2ccc(Br)cc2)C(=O)N1
Temperature: 0 °C
Yield: 52.9 %

Procedure:
A solution of hydrochloric acid (37%, 13 mL) in water (5.5 mL) was added to 4-bromoaniline (7.48 g, 43.52 mmol) at r.t. with vigorous stirring and the formed precipitate was allowed to stir for 30 min. The reaction mixture was cooled to 0° C. and a solution of sodium nitrite (3.30 g, 47.87 mmol) in water (9 mL) was added dropwise. At the end of diazotization, a clear yellow solution was obtained. Maleimide (8.45 g, 87.05 mmol) in acetone (35 mL) was added dropwise at 0° C. and then the pH of the solution was adjusted to 3-3.5 by adding sodium acetate. CuCl2 (0.88 g, 6.57 mmol) was added to the vigorously stirred mixture. The reaction mixture was stirred at 0° C. for 1 h and overnight at r.t. After completion of the reaction as confirmed by TLC, solvents were removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 4:6 EtOAc:Pet. ether) to afford the title compound as a yellow solid (5.8 g, 57%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@H:17]([CH2:28][OH:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([CH2:28][OH:29])[CH2:18][C:19]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: N[C@H](CO)Cc1c[nH]c2ccccc12
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](CO)Cc1c[nH]c2ccccc12
Yield: 73 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with L-tryptophanol to provide the title compound in 73% yield as yellow needles (recrystallization from EtOH).