Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:118])[C:82]2[CH:81]=[C:80]([C:83]3[N:84]=[C:85]([C@@H:88]([NH:92][C:93](=[O:103])[C@@H:94]([NH:98][C:99](=[O:102])[O:100][CH3:101])[CH:95]([CH3:97])[CH3:96])[CH:89]([CH3:91])[CH3:90])[NH:86][CH:87]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:104]1[CH:105]=[CH:106][C:107]3[N:111]=[C:110]([C@@H:112]4[CH2:116][CH2:115][CH2:114][NH:113]4)[NH:109][C:108]=3[CH:117]=1)=[CH:74][CH:75]=2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:113]1[CH2:114][CH2:115][CH2:116][C@H:112]1[C:110]1[NH:109][C:108]2[CH:117]=[C:104]([C:73]3[CH:74]=[CH:75][C:76]4[C:77]5[C:82](=[CH:81][C:80]([C:83]6[N:84]=[C:85]([C@@H:88]([NH:92][C:93](=[O:103])[C@@H:94]([NH:98][C:99]([O:100][CH3:101])=[O:102])[CH:95]([CH3:97])[CH3:96])[CH:89]([CH3:90])[CH3:91])[NH:86][CH:87]=6)=[CH:79][CH:78]=5)[C:70]([F:69])([F:118])[C:71]=4[CH:72]=3)[CH:105]=[CH:106][C:107]=2[N:111]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](c1nc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6)[nH]c5c4)ccc2-3)c[nH]1)C(C)C)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N[C@H](c1nc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)c[nH]1)C(C)C)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-1-((S)-1-(4-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-2-methylpropylamino)-3-methyl-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 873.92 [M+H]+. (62 mg, 37%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.C([O:43][C:44](=[O:47])[CH2:45]Br)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:45][C:44]([OH:47])=[O:43])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(=O)OC[C@H]1OC(OCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 15.22 g (100 mmol) of DBU in 300 ml of tetrahydrofuran is cooled to 0° C. At 0° C., 34.36 g (150 mmol) of 2-bromoacetic acid benzyl ester, dissolved in 40 ml of tetrahydrofuran, is added in drops over 30 minutes while being stirred vigorously. It is stirred for three hours at 0° C. 300 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of tetrahydrofuran. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until hydrogen absorption is completed. Then, catalyst is filtered out, it is rewashed with a little tetrahydrofuran and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: N1C=CC(C2C=C(C=CC=2)N)=N1.[NH:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20](=[O:28])[C:21](=[O:27])[NH:22]3)=[N:14]1.[CH:29]1[C:34]([NH:35][NH2:36])=[CH:33][CH:32]=[C:31]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:30]=1.Cl>>[NH:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20](=[O:28])[C:21](=[O:27])[NH:22]3)=[N:14]1.[O:27]=[C:21]1[C:20](=[N:36][NH:35][C:34]2[CH:33]=[CH:32][C:31]([S:37]([NH2:40])(=[O:38])=[O:39])=[CH:30][CH:29]=2)[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[C:15]2[CH:16]=[CH:17][NH:13][N:14]=2)[NH:22]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: Nc1cccc(-c2cc[nH]n2)c1
Agent: O=C1Nc2cccc(-c3cc[nH]n3)c2C1=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc(-c4cc[nH]n4)c32)cc1

Procedure:
4-(1H-Pyrazol-3-yl)-1H-indole-2,3-dione was prepared from 3-(1H-pyrazol-3-yl)aniline according to Procedure A. The title compound was prepared from 4-(1H-pyrazol-3-yl)isatin and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: 1H NMR (DMSO-d6): δ 6.72 (s, 1H), 7.22 (s, 2H), 7.39 (s, 1H), 7.48-7.60 (m, 4H), 7.76 (d, J=8.7 Hz, 2H), 7.77 (s, 1H), 11.11 (s, 1H), 12.93 (s, 1H); ESI−MS: m/z 381 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[CH:22]1([C:20]([C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10](=[O:11])[NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[N:5]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2nc(CCNS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.05 g, 0.13 mmol) in 10 mL DCM at 0° C. was added methanesulfonyl chloride (0.02 g, 0.13 mmol) followed by pyridine (0.02 g, 0.21 mmol). The reaction was stirred at ambient temperature overnight, concentrated and purified by flash chromatography on silica gel with 20-50% EtOAc/hexane to obtain the product as white solid in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:15]([NH2:18])[CH:16]=[CH2:17]>CN(C=O)C>[CH2:15]([NH:18][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:16]=[CH2:17]
Reactant: C=CCN
Reactant: CC(C)c1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(C(C)C)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
In 5 ml of DMF, 71 mg (0.29 mmol) of 2,4-dichloro-7-isopropylthieno[3,2-d]pyrimidine was dissolved, and then 36 mg (0.63 mmol) of allylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 73 mg (yield: 94.8%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:3]1([C:6]([O:8]C)=[O:7])[CH2:5][CH2:4]1.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]([S:10]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11])[C:3]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4]1
Reactant: COC(=O)C1(N(C)S(=O)(=O)c2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 81 %

Procedure:
A solution of 14A (1.3 g, 4.52 mmol) in dioxane (40 mL) was added with 10% NaOH aq. solution (20 mL) and the mixture was heated at 50° C. overnight. The organic solvent was removed under reduced pressure and the aqueous phase was acidified with 10% HCl. The solid formed was collected by filtration, washed with water (2×20 mL) and dried to afford 15A as white solid (1.0 g, 81% yield). 1HNMR (DMSO, 200 MHz) δ 1.40 (bs, 4H), 2.91 (s, 3H), 7.42 (m, 2H), 7.80 (m, 2H), 12.60 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1F.[CH3:11][S-:12].[Na+]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:12][CH3:11]
Reactant: C[S-]
Reactant: COc1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(SC)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1,2-Difluoro-4-methoxy-benzene (100 mg, 0.69 mmol) and sodium methanethiolate (148 mg, 2.08 mmol) were dissolved in N,N-dimethylformamide (2 mL) and the reaction mixture stirred at 60° C. for 18 hours. Additional sodium methanethiolate (99 mg, 139 mmol) was added and the reaction mixture heated to 100° C. for 18 hours. The reaction mixture was diluted with water and extracted with ether (×2). The ether extracts were washed with water (×2), dried over magnesium sulphate and concentrated in vacuo. The residue was taken up in pentane:ether 1:1 mixture (2 mL) and filtered through a plug of silica in a pipette, washing through with pentane:ether 1:1 mixture (5 mL). The reaction mixture was concentrated in vacuo to yield the title product as a colourless oil, 135 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:9][CH2:8][CH:7]1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([Cl:29])[CH2:27][CH3:28]>CC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:9][CH2:8][CH:7]1[C:10](=[O:18])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:28][CH2:27][CH2:26][Cl:29])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCC(Cl)Br
Reactant: CCOC(=O)C1CCC1C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCC1C(=O)c1ccc(OCCCCl)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 2-(4-hydroxy-benzoyl)-cyclobutanecarboxylic acid ethyl ester (0.55 g, 2.20 mmol) in acetone (10 mL) was added potassium carbonate (0.91 g, 6.58 mmol) and 1-bromo-chloropropane (0.26 mL, 2.63 mmol). After overnight stirring at 70° C., the reaction was filtered, partitioned between dichloromethane/water, washed with brine, dried over sodium sulfate, and concentrated. The product was purified using a Single Step column (9:1 hexanes:ethyl acetate) to obtain 0.30 g (42%); MS m/z 325 (M+H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:18]([C:21]1[S:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>C(N(CC)CC)C>[CH3:17][O:16][C:14](=[O:15])[CH2:13][CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[S:25][C:21]([C:18](=[O:20])[CH3:19])=[CH:22][CH:23]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: COC(=O)CCNc1ccc2ncc(Br)n2n1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: COC(=O)CCNc1ccc2ncc(-c3ccc(C(C)=O)s3)n2n1
Yield: 79 %

Procedure:
The methyl 3-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)propanoate was then subjected to Suzuki coupling reaction with (5-acetyl-thiophen-2-yl)boronic acid as described in example 5.6.19. However for this reaction, triethylamine was used as the base in place of the regular base (K2CO3). The desired product was obtained in 79% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.62-2.65 (m, 3H) 2.88 (t, J=5.94 Hz, 2H) 3.77 (s, 3H) 3.88 (t, J=5.68 Hz, 2H) 7.06 (d, J=9.85 Hz, 1H) 7.70 (d, J=4.04 Hz, 1H) 7.77 (d, J=4.04 Hz, 1H) 8.15 (s, 1H) 8.33 (d, J=9.85 Hz, 1H); LRMS (ESI) m/e 345.0 [(M+H)+, calcd for C16H16N4O3S 344.0].
Reaction SMILES: [CH2:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:32])[C:18](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])[C:19]([CH3:21])=O>>[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17]([C:18]1[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][N:7]([CH3:11])[C:8]=2[NH:10][C:19]=1[CH3:21])=[O:32]
Reactant: COCCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Reactant: CCCCc1cc(N)n(C)n1
Product: CCCCc1nn(C)c2c1C(c1ccccc1[N+](=O)[O-])C(C(=O)OCCOC)=C(C)N2

Procedure:
Starting from 3-butyl-1-methyl-5-pyrazolamine and (2-methoxyethyl)-2-(2-nitrobenzyliden)acetoacetate.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1>[C:36]1([C:35]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCCCC=C(c1ccccc1)c1ccccc1
Yield: 70.6 %

Procedure:
The reaction was carried out as in Example 87 using the following reagents: sodium hydride (56% dispersion in oil; 8.6 g); dimethylsulfoxide (100 mL), (5-carboxypentyl)triphenylphosphonium bromide (37.64 g); benzophenone (18 g) and tetrahydrofuran (100 mL). The acid, isolated in the normal manner, was crystallized from hexane to give 16.3 g of 7,7-diphenyl-6-heptenoic acid, mp 71.5°-72.5° C. A portion was recrystallized from hexane to give the analytical sample, mp 72.5°-73.5° C. Anal. Calculated for C19H20O2 : C, 81.40; H, 7.19. Found: C, 81.61; H, 7.40.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].IC.[C:15]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 3-hydroxy-4-nitrobenzaldehyde (51.3 g), iodomethane (38.3 ml) and K2CO3 (85 g) in DMF (250 ml) was stirred at 60° C. for 1 h. The reaction mixture was cooled to room temperature and poured into water (600 ml). The solids were collected by filtration and dried in vacuo (50° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[F:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][CH2:23][CH2:22][CH2:21][F:20])=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: NCCCCF
Reactant: CCOC(=O)c1cnc2c(OC)cc(F)cc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cc(F)cc2c1NCCCCF

Procedure:
4-Chloro-6-fluoro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.88 mmol) was treated with 4-fluoro-butylamine following general procedure B to afford 6-fluoro-4-(4-fluoro-butylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (175 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (95 mg) following general procedure E. The above ethylamide (95 mg, 0.28 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-9-fluoro-1-(4-fluoro-butyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (52 mg). LCMS: m/z 364 [M+1]+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:28])=O.C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:28])[C:11]2[C:16]([C:17]=1[OH:18])=[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2cccc(-c3ccccc3)c2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2cccc(-c3ccccc3)c2c1O
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
411 mg of 1,4-Dihydroxy-5-phenyl-isoquinoline-3-carboxylic acid butyl ester, from Example D-39c isomer B, was suspended in 15 ml of anhydrous acetonitrile. 2.0 g of phosphorous oxybromide was added and the reaction mixture was heated to reflux for 3.5 h. The reaction mixture was cooled and poured into 75 ml of 0° C. saturated aqueous sodium bicarbonate solution. The mixture was stirred for 5 min and then extracted with 75 ml portions of ethyl acetate three times. The combined organic fractions were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue (434 mg) was purified by chromatography on silica gel using a gradient of 0 to 25% ethyl acetate in hexanes to elute the product as one major fraction. 480 mg of the desired product was obtained; MS (+): m/z 422.02 (M+23)
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([Br:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([Br:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: NC1CCc2cc(Br)ccc21
Reactant: Clc1nc2ccccc2[nH]1
Product: Brc1ccc2c(c1)CCC2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and racemic 1-amino-5-bromoindane (prepared by Procedure B from 5-bromo-1-indanone) by Procedure A (30 min at 170° C.). The product was isolated by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 242-243° C.). MS(ES+) m/z 328 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.92 (m, 1H), 2.50 (m, 1H), 2.83 (m, 1H), 2.95 (m, 1H), 5.35 (m, 1H), 6.82-7.02 (m, 3H), 7.12-7.35 (m, 4H), 7.46 (s, 1H), 10.7 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([CH3:16])=[CH:11][N:10]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[C:12]([CH3:16])=[CH:11][N:10]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2C)n[nH]1
Temperature: 40 °C

Procedure:
A mixture of 5-methyl-1H-pyrazol-3-amine (3.00 g, 30.9 mmol), 2,4-dichloro-5-methylpyrimidine (5.03 g, 30.9 mmol, 1 equiv.) and Na2CO3 (3.60 g, 34.0 mmol, 1.1 equiv.) in EtOH (100 mL) is heated at 40° C. for 24 h. The solvent is removed in vacuo. The resulting residue is partitioned between EtOAc (350 mL) and water (100 mL). The EtOAc layer is washed with water (3×), saturated aqueous NaCl (1×), dried over Na2SO4, and concentrated in vacuo. The resulting crude product is sonicated in Et2O (200 mL) and the resulting precipitate collected by filtration. This powder is further washed with Et2O, providing the product 2-chloro-5-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMS m/z 224.1 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:17][C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Product: COC(=O)c1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1
Yield: 36 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and methyl 4-(bromomethyl)benzoate instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 36%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8](Br)[S:7][C:6]=1[C:11]([NH2:13])=[O:12])=[O:3].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:15]2[S:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=2)[S:7][C:6]=1[C:11]([NH2:13])=[O:12])=[O:3]
Reactant: NC(=O)Nc1cc(Br)sc1C(N)=O
Reactant: OB(O)c1cc2ccccc2s1
Product: NC(=O)Nc1cc(-c2cc3ccccc3s2)sc1C(N)=O

Procedure:
The title compound was prepared from 3-[(aminocarbonyl)amino-5-bromothiophene-2-carboxamide and 1-benzothien-2-ylboronic acid in a similar manner to Example 11 (g).
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]([CH:18]([NH:20][C:21]3[C:22]4[N:30]=[CH:29][CH:28]=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH3:19])=[CH:16][C:15]3[N:14]=[CH:13][CH:12]=[C:11]([CH3:31])[C:10]=3[C:9]2=[O:32])=CC=1>FC(F)(F)C(O)=O>[CH3:31][C:11]1[C:10]2[C:9](=[O:32])[NH:8][C:17]([CH:18]([NH:20][C:21]3[C:22]4[N:30]=[CH:29][CH:28]=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH3:19])=[CH:16][C:15]=2[N:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(Cn2c(C(C)Nc3ncnc4cccnc34)cc3nccc(C)c3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc2cc(C(C)Nc3ncnc4cccnc34)[nH]c(=O)c12
Temperature: 140 °C
Reaction time: 48 h

Procedure:
6-(4-Methoxybenzyl)-4-methyl-7-(1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)-1,6-naphthyridin-5(6H)-one I-67 (60 mg, 0.13 mmol) was dissolved in trifluoroacetic acid (4 mL) in a sealed tube and the resulting mixture was stirred at 140° C. for 48 h. The mixture was allowed to cool to RT, quenched with water and then neutralized with saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate, washed with brine, dried with Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product, 4-methyl-7-(1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)-1,6-naphthyridin-5(6H)-one I-68. ESI-MS m/z: 333.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.[CH:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[C:18]([C:24]([CH2:26]Br)=[O:25])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:23][C:19]1[CH:20]=[C:21]([Cl:22])[CH:16]=[CH:17][C:18]=1[C:24](=[O:25])[CH2:26][N:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5 g (23.6 mmol) of diethyl 1H-pyrazole-3,5-dicarboxylate were dissolved in 100 ml of acetone, and 6.3 g (23.6 mmol) of 2-bromo-2,4-dichloroacetophenone and 3.6 g (26 mmol) of potassium carbonate were added. The mixture was stirred at RT for 12 h. The reaction mixture was concentrated and the residue was taken up in water and dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was triturated with diethyl ether, and the solid was filtered off with suction. This gave 9.48 g (94% of theory) of the product as a solid.