Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:24]([NH2:25])=[CH:23][N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:31](=[O:32])[NH:25][C:24]3[C:19]2=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:14][CH:13]=1
Reactant: Cn1c(Oc2ccc(Nc3ncncc3N)cc2)nc2ccccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1c(Oc2ccc(-n3c(=O)[nH]c4cncnc43)cc2)nc2ccccc21
Yield: 65 %

Procedure:
A solution of N4-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}pyrimidine-4,5-diamine (80 mg) and CDI (39 mg) in THF (20 mL) was refluxed for 3 h. CDI (39 mg) was added to the mixture. After refluxing overnight, the mixture was concentrated in vacuo. The residual solid was washed with AcOEt to give 9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one (56 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:31])=[CH:4][N:3]=1.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[C:36]([O:43][CH3:44])[CH:35]=1)#[N:33]>>[C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[C:5]([F:31])=[CH:4][N:3]=2)=[C:36]([O:43][CH3:44])[CH:35]=1)#[N:33]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)cc1
Reactant: COc1cc(C#N)ccc1B(O)O
Product: COc1cc(C#N)ccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ccncn3)ccc12

Procedure:
Example 218 was synthesized in a similar manner to Example 212, except that 1-chloro-4-fluoro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate QQQ) and (4-cyano-2-methoxyphenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 25 to 100% EtOAc:Heptane) to afford 1-(4-cyano-2-methoxyphenyl)-4-fluoro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.74 (s, 1H), 8.59 (d, J=15.7 Hz, 2H), 8.37-8.14 (m, 1H), 8.05 (d, J=7.4 Hz, 1H), 7.75 (d, J=1.3 Hz, 2H), 7.66-7.60 (m, 1H), 7.57-7.50 (m, 1H), 3.72 (s, 3H). m/z (ESI) 436.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[C:25]1(B(O)O)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:33]5[C:34]6[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=6)[CH:30]=[CH:31][CH:32]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: OB(O)c1cccc2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3cccc4ccccc34)cc2)C1
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.256 mmol) in dioxane (1.5 mL) was treated with 1-naphthalenylboronic acid (0.281 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.767 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave (Biotage Initiator) at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was treated with Si-Thiol (Silicycle, 20 mg), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (30-60% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions from the HPLC were combined, adjusted to pH˜5 with the addition of saturated aq sodium bicarbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as an amorphous white solid (56%). MS(ES)+ m/e 439.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:13]([F:16])([F:15])[F:14])=[CH:5][C:6](=[O:12])[NH:7]2.C(NC(C)C)(C)C.[Br:24]N1C(=O)CCC1=O.Cl>CCOC(C)=O>[Br:24][C:11]1[C:2]([OH:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:12])[CH:5]=[C:4]2[C:13]([F:16])([F:14])[F:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(C(F)(F)F)c2c(O)cccc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: O=c1cc(C(F)(F)F)c2c(O)c(Br)ccc2[nH]1
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 5-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one (4.38 g, 19.1 mmol) and diisopropylamine (14 mL, 100 mmol) in 100 mL EtOAc was added a solution of N-bromosuccinimide (3.74 g, 21.0 mmol) in 70 mL EtOAc at −10° C. over 30 min. The reaction mixture was stirred for 1 h, then acidified to pH 1 by the addition of 6M HCl. The mixture was extracted with EtOAc (3×150 mL) and the combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Recrystallization from chloroform:hexanes afforded 4.5 g (77%) of 6-bromo-5-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one, an off-white solid. Rf0.4 (1:1 EtOAc:hexanes); 1H NMR (400 MHz, acetone-d6) δ 11.1 (broad s, 1H), 8.75 (broad s, 1H), 7.76 (d, 1H, J=8.8), 7.04 (d, 1H, J=8.8), 6.98 (s, 1H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C)cc1
Yield: 96.6 %

Procedure:
In 70 ml of acetone were suspended 5.00 g of p-cresol, 7.72 g of ethyl bromoacetate and 6.39 g of potassium carbonate, and the resulting mixture was refluxed for 12 hours. After the solvent was distilled off under reduced pressure, water was added to the mixture, followed by extraction with methylene chloride. The organic phase was washed with in aqueous 2N sodium hydroxide solution and then with saturated sodium chloride solution, which was then dried over magnesium sulfate. On evaporation of the solvent under reduced pressure, 8.67 g of ethyl 4-methylphenoxyacetate was produced.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].ClC1C=CC(C2N(CCN(C)C)N=C3C=2CCNCC3)=CC=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CN(C)CCCl
Agent: CN(C)CCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Agent: Cl
Product: CN(C)CCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.33 mmol) using (2-chloro-ethyl)-dimethyl-amine hydrogen chloride (0.66 mmol) in place of chloro-cyclobutane. The title compound was obtained as a 2:1 mixture (10 mg) with {2-[3-(4-chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-ethyl}-dimethyl-amine. Data for the mixture: MS (ESI): exact mass calculated for C17H23ClN4, 318.16. found, m/z 319.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.45 (m, 2H), 7.37-7.33 (m, 2H), 4.51-4.49 (m, 1.3H), 4.27-4.26 (m, 0.7H), 3.63-3.61 (m, 1.3H), 3.48-3.42 (m, 2H), 3.33-3.29 (m, 2H), 3.24-3.23 (m, 2H), 3.14-3.12 (m, 0.7H), 3.00-2.98 (m, 1.3H), 2.91 (s, 4H), 2.84 (s, 2H), 2.75-2.73 (m, 0.7H).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH2:19]([O:27][C:28](Cl)=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:28]([O:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])[N+:7]([O-:8])=[C:6]([NH:9][C:28]([O:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reactant: CCCCCCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OCCCCCCCC)[n+]1[O-]
Temperature: 5 °C

Procedure:
10 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide are suspended in 150 ml. of methylene chloride and 20 ml. of triethylamine. The suspension is cooled to 5° C. and 28 g. of chloroformic acid octyl ester are added dropwise while stirring. The mixture is cooled for 30 minutes and then stirred at room temperature for 1 hour. The mixture is extracted with methylene chloride, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride/ethanol, there being obtained dioctyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 64° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[NH:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.CN(C=O)C>CS(C)=O>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=2)=[CH:6]3)[CH:32]=[CH:31][CH:30]=[CH:29]1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: c1cc[nH]c1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(Cn4cccc4)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester prepared in Preparation 41 and pyrrole were reacted according to the same procedure as Preparation 92 except that DMF was used as the solvent instead of DMSO to give the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:31])([F:30])[C:10]1[C:11]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[F:30][C:9]([F:8])([F:31])[C:10]1[C:11]([N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2ncccc2C(F)(F)F)CC1
Reaction time: 1 h
Yield: 58.1 %

Procedure:
A solution of TFA (10 mL) and CH2Cl2 (10 mL) was added to a flask containing the tert-butyl carbamate from Step 17A (1.39 g, 4.0 mmol). After 1 h, the mixture was concentrated, diluted with CH2Cl2 (100 mL), washed with 1N NaOH (100 mL), H2O (100 mL) and brine (100 mL), dried (MgSO4), and concentrated to afford the amine (0.57 g, 57%), a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.38-1.70 (m, 2H), 1.75-2.08 (m, 2H), 2.44 (br s, 2H), 2.71-3.21 (m, 3H), 3.59 (d, J=13.4 Hz, 2H), 6.76-7.13 (m, 1H), 7.85 (dd, J=7.7, 1.9 Hz, 1H), 8.41 (dd, J=4.8, 1.3 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[Br:21])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:23][OH:24].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[Br:21])=[N:23][OH:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2sccc2Br)CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C(=NO)c2sccc2Br)CC1
Reaction time: 3 h
Yield: 58.4 %

Procedure:
Stir a mixture of 4-(3-bromo-thiophene-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (Example 3a) (41.5 g, 0.11 mol), hydroxylamine hydrochloride (15.4 g, 0.23 mol) and pyridine (190 mL) at ambient temperature overnight. Pour the reaction into water (500 mL) and extract with dichloromethane (3×). Wash the combined extracts with saturated CuSO4 solution (2×), dry (MgSO4) and concentrate to a green solid. Dissolve the solid in toluene (175 mL) and let stand at ambient temperature for 3 h. Collect the resulting crystals that form and wash with toluene (60 mL). Concentrate the filtrate and again dissolve the residue in toluene and proceed to collect additional crystals to obtain a total yield of 25 g (58%) of the title compound as a light, green solid.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[N:4]2[C:15]([CH2:18][CH2:19][CH3:20])=[N:16][N:17]=[C:3]12.Cl.Cl.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH:25]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>[Cl-].[Na+].O.CN(C)C=O.C(N(CC)CC)C>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]2[C:15]([CH2:18][CH2:19][CH3:20])=[N:16][N:17]=[C:3]2[C:2](=[O:1])[NH:11]3)=[O:14])[CH2:26][CH:25]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCCc1nnc2c(=O)[nH]c3cc(C(=O)O)ccc3n12
Reactant: CN1CCNCC1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCc1nnc2c(=O)[nH]c3cc(C(=O)N4CCN(C)C(c5ccccc5)C4)ccc3n12
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a mixture of 150 mg of 4-oxo-1-propyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid, 165 mg of 1-methyl-2-phenyl piperazine dihydrochloride, 0.24 mL of triethylamine, 112 mg of 1-hydroxybenzotriazole, and 2.25 mL of N,N-dimethylformamide was added 158 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, followed by stirring at room temperature for 1 day. To the reaction liquid were added a saturated aqueous sodium hydrogen carbonate solution and saturated brine, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=95/5 to 90/10). The obtained solid was triturated with a mixture of ethanol and diisopropyl ether to give a powder. The precipitate was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain 197 mg of 7-[(4-methyl-3-phenyl piperazin-1-yl)carbonyl]-1-propyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one as a white powder.
Reaction SMILES: [OH-].[Na+:2].[C:3]([OH:12])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].NC1C=CC=CC=1.[Na]>O.[N+]([O-])([O-])=O.[Ag+]>[C:3]([O-:12])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[Na+:2]
Reactant: O=C(O)c1ccccc1O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: O
Product: O=C([O-])c1ccccc1O

Procedure:
An aqueous solution of sodium salicylate was prepared by adding 43.2 g of 2N sodium hydroxide to 12 g of salicylic acid in 240 g of demineralized water. This aqueous solution was simultaneously added with 120 mL of a 0.588 M aqueous solution of silver nitrate over a period of 10 s to 280 mL of a stirred aqueous solution containing 160 mL of a 5% aqueous solution of GAFAC ™ RM710 (an alkylphenyl- polyethene oxide-phosphate from GENERAL ANILINE), 80 mL of a 2% aqueous solution of NATRASOL™ 250L (a hydroxyethylcellulose from AQUALON) and 40 mL of demineralized water. 160 mL of a 5% aqueous solution of PIGMENTVERTEILER™ N (a sodium salt of polyacrylic acid from BASF) was then added to the resulting dispersion.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22]C)=[O:20].O>CC(C)=O.C(Cl)Cl>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 5-hydroxyindole (5.00 g; 37.6 mmol), caesium carbonate (26.9 g, 82.6 mmol) and ethyl bromoacetate (4.60 g, 30.0 mmol) in 100 ml acetone is stirred for 18 hours at ambient temperature. Then the reaction mixture is combined with water and DCM. The phases are separated and the aqueous phase is extracted with DCM. The combined phases are dried on sodium sulphate and freed from the solvent in vacuo.
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][CH2:6][OH:7].Cl[CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CO>[CH2:6]([OH:7])[CH2:5][S:4][CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: OCCS
Reactant: CCCCCCCCC#CCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCC#CCC#CCSCCO
Reaction time: 0.5 h
Yield: 61 %

Procedure:
1.06 ml of a 30% solution of sodium methoxide in methanol were added dropwise, at room temperature, to a solution of 374 μl of 2-mercaptoethanol in 5 ml of anhydrous methanol, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then added to a solution of 1.2 g of 1-chloro-2,5-tetradecadiyne in 6 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 15 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oil thus obtained crystallized on cooling. It was purified by recrystallization from a heptane/pentane mixture and then from a heptane/pentane/diisopropyl ether mixture. 3-Thia-5,8-heptadecadiyn-1-ol was thus isolated in the form of pale yellow flakes with a yield of 61%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:24])[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(=O)[CH2:2][CH3:3].CC(C)([O-])C.[K+]>C(O)C>[CH2:2]([C:1]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:11]=[C:12]([OH:24])[C:13]=1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:3]
Reactant: CCC(=O)c1ccccc1NC(=O)CC(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCc1c(C(=O)OCc2ccccc2)c(O)nc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
Benzyl N-(2-propionylphenyl)malonamate (1.8 g) was dissolved in ethanol (20 mL), followed by addition of potassium t-butoxide (0.65 g), and the mixture was stirred at room temperature for 3 h. The precipitated solids were collected by filtration and washed with water to obtain benzyl 4-ethyl-2-hydroxyquinoline-3-carboxylate (1.4 g).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[N:10]([C:18]([NH:20][C:21]3[S:22][C:23]([S:26][CH2:27][CH2:28][CH2:29][N:30]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:24][N:25]=3)=[O:19])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].O.NN>C(O)C>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[N:10]([C:18]([NH:20][C:21]3[S:22][C:23]([S:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:24][N:25]=3)=[O:19])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN3C(=O)c4ccccc4C3=O)s1)c1ccc(Cl)cc12
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN)s1)c1ccc(Cl)cc12
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 76.5 %

Procedure:
1′-Acetyl-5-chloro-N-(5-((3-(1,3-dioxoisoindolin-2-yl)propyl)thio)thiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (0.93 g, 1.57 mmol) was dissolved in ethanol (30 mL). Thereafter, a hydrazine hydrate (0.12 g, 2.36 mmol) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred at 90° C. for 3.5 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (chloroform:methanol=4:1) to obtain the captioned compound (0.56 g, 77%) in the form of a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1>C(O)(=O)C.[Pt](=O)=O>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(N)ncnn23)CC1
Reaction time: 16 h
Yield: 103.3 %

Procedure:
To a dry flask purged with N2 was added platinum(IV) oxide (127 mg, 0.56 mmol) followed by tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (587 mg, 1.86 mmol) as a solution in acetic acid (19 mL). The mixture was stirred under an H2 atmosphere for 16 h. The mixture was filtered through a pad of Celite® rinsing with acetic acid and ethanol. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The organic was washed with saturated aqueous NaHCO3 (2×75 mL) and the aqueous mixture was back extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to dryness to afford 610 mg (100%) of the desired product as a gray solid. 1H NMR (300 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.57 (br s, 2H), 6.78 (d, 1H), 6.42 (d, 1H), 4.08-3.97 (m, 2H), 3.28-3.18 (m, 1H), 1.94 (d, 2H), 1.55-1.42 (m, 2H), 1.41 (s, 9H); ES-MS m/z 318.1 [M+H]+, HPLC RT (min) 2.21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[N:9][C:8]1[C:7]([C:6]=2[NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:19][CH3:20])[CH2:22][CH2:23]2)=[N:15][C:14]([O:16][CH3:17])=[CH:13][CH:12]=1
Reactant: CCN1CCC(N)CC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Product: CCN1CCC(Nc2c3ccc(Cl)cc3nc3ccc(OC)nc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 7,10-dichloro-2-methoxypyrido[3,2-b]quinoline and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=371). 1H NMR (DMSO-d6, 400 Hz): 8.43-8.42 (d, 1H, J=9.2 Hz), 8.11-8.10 (d, 1H, J=9.2 Hz), 7.84 (s, 1H), 7.37-7.35 (d, 1H, J=9.2 Hz) 7.25-7.23 (d, 1H, J=9.2 Hz), 6.95 (b, 1H), 4.98 (b, 1H), 4.00 (s, 3H), 2.85 (b, 2H), 2.30 (b, 2H), 2.02-1.99 (m 4H), 1.00-1.97 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2>CN(C=O)C>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:30]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Fc1cccc2c1CNC2
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4cccc(F)c4C3)c(F)cc2c1=O
Yield: 82.9 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 210 mg of 4-fluoroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 190 mg of the target compound.