Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][C:18]=2[N:19]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([NH:35][NH:34][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([Cl:27])=[CH:37][CH:36]=3)=[O:26])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)O)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)NNC(=O)c3ccc(Cl)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of the crude 2-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3H-benzoimidazole-5-carboxylic acid in 10 ml of DMF was added 900 mg of 4-chlorobenzoic acid hydrazide, 1.1 g of EDCI and 700 mg of HOBT. The reaction was stirred at room temperature under nitrogen atmosphere for 5 hours. The reaction mixture was diluted with water and the resulting precipitates were collected by filtration and purified by column chromatography (DCM:MeOH=20:1) to give the title compound. LCMS ret T=1.19 min, m/z=504.1, Method 10.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>O1CCCC1>[CH2:9]([O:8][P:6]([CH:11]([CH2:21][CH2:20][CH:19]=[CH2:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:5][CH2:3][CH3:4])=[O:7])[CH3:10]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(C(=O)OCC)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Sodium hydride (60% in oil, 65.0 g) was suspended in tetrahydrofuran (800 mL) under a nitrogen atmosphere, and ethyl (diethoxyphosphoryl)acetate (200 g) was added dropwise at room temperature over 30 min. After the completion of the dropwise addition, the mixture was further stirred by a mechanical stirrer for 30 min. 4-Bromobut-1-ene (217 g) was added dropwise to the reaction mixture over 30 min. The reaction mixture was heated under reflux for 5 hr, allowed to cool to room temperature, and quenched by adding 1M aqueous ammonium chloride solution (300 mL). The mixture was concentrated under reduced pressure, to the residue were added water (500 mL) and diethylether (500 mL), and the mixture was partitioned. The aqueous layer was saturated with sodium chloride, and the mixture was extracted with diethylether (500 mL×2). The combined extracts were washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product (241.6 g) of the title compound as a yellow oil. This was used for the next reaction without further purification.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.Br[C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[CH:23][C:24]([C:25]([O:27]CC)=[O:26])=[C:18]2[CH:17]=1>>[F:9][C:7]1[CH:6]=[C:5]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[C:18]3[CH:17]=2)[CH:4]=[C:3]([F:2])[CH:8]=1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Reactant: Fc1cc(F)cc([C@H]2CCCN2)c1
Agent: Cl
Product: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(F)c3)cc12

Procedure:
The title compound was prepared by a method substantially similar to that mentioned in step-5 and step-6 of example-3 using (R)-2-(3,5-Difluorophenyl)pyrrolidine hydrochloride (step-1) and Ethyl 5-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate to afford the product as white solid. MS (ESI): m/z 344.1 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])(=[O:4])=[O:3].Cl[C:14]1[N:19]=[C:18]([Cl:20])[N:17]=[C:16]2[N:21]([CH3:24])[N:22]=[CH:23][C:15]=12>>[Cl:20][C:18]1[N:17]=[C:16]2[N:21]([CH3:24])[N:22]=[CH:23][C:15]2=[C:14]([NH:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[N:19]=1
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Product: Cn1ncc2c(NCc3cccc(S(C)(=O)=O)c3)nc(Cl)nc21

Procedure:
Reaction of 3-(methylsulfonyl)benzylamine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3-methanesulfonyl-benzyl)-amine.
Reaction SMILES: FC1(F)CC(C([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O)C1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl:24][C:25]1[C:26]([O:39][C:40]2[CH:41]=[N:42][C:43](F)=[C:44]([Cl:46])[CH:45]=2)=[CH:27][C:28]([F:38])=[C:29]([CH:37]=1)[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[O:31]>C1(C)C=CC=CC=1>[C:9]([O:8][C:43]1[N:42]=[CH:41][C:40]([O:39][C:26]2[C:25]([Cl:24])=[CH:37][C:29]([C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[O:31])=[C:28]([F:38])[CH:27]=2)=[CH:45][C:44]=1[Cl:46])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)C1CC(F)(F)C1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ncc(Oc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To a solution of tert-butyl 3,3-difluorocyclobutanecarboxylate (Preparation 227, 126 mg, 0.66 mmol) in toluene (2 mL) was added a solution of sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1M solution in THF, 1.6 mL, 1.6 mmol) at 0° C. The resulting solution was stirred for 10 minutes at the same temperature, then 5-chloro-4-[(5-chloro-6-fluoropyridin-3-yl)oxy]-2-fluoro-N-(methylsulfonyl)benzamide (Example 19, 200 mg, 0.50 mmol) was added. The resulting mixture was warmed up to room temperature and stirred for 36 hours. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with aqueous 1N citric acid solution, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as a yellow oil. The crude product was purified by silica gel column chromatography eluting with 0-100% EtOAc in heptane to give a yellow foam. The foam was triturated with heptane to give the title compound (101 mg, 44%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>N1C=CC=CC=1>[OH:5][C:3]([CH3:6])([CH3:4])[C@H:2]([NH:1][C:15](=[O:16])[C:14]([Cl:19])([Cl:18])[Cl:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(O)[C@H](N)c1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(O)[C@H](NC(=O)C(Cl)(Cl)Cl)c1ccccc1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of (13) (1.413 g, 8.56 mmol) in pyridine (24 ml) at 0° C. was added trichloroacetyl chloride (1.05 ml, 9.41 mmol). After stirring at this temperature for 10 minutes the reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous sodium chloride solution, after which the product was extracted with dichloromethane and the combined organic extracts were washed with hydrochloric acid (1M). Concentration in vacuo and purification by flash column chromatography using 30% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (14) (1.782 g, 65%) as a solid which was recrystallised from ether/40-60 petroleum ether; mp 97° C.; νmax (CHCl3) 1716 cm-1 ; [α]D24 (c 1 in CHCl3)=-55.5; (Found: C, 46.41; H, 4.26; N, 4.49. C12H14Cl3NO2 requires C, 46.40; H, 4.54; N, 4.51%); δH (200 MHz; CDCl3) 1.06 (3H, s, C(CH3)2), 1.39 (3H, s, C(CH3)2), 1.94 (1H, s, OH), 4.70 (1H, d, J=8.5, CHCH), 7.29-7.39 (5H, m, ArCH); δC (125 MHz; CDCl3) 27.70 (CH3), 27.86 (CH3), 63.06 (CH), 75.52 (C), 92.97 (CCl3), 128.13 (ArCH), 128.35 (ArCH), 128.71 (ArCH), 137.88 (C), 161.51 (CO); m/z (CI-, NH3) 310 (M+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[F:14][C:15]1[CH:16]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34](Cl)[O:35][CH:36]=2)=[O:31])[CH3:28])[CH:18]=[C:19]([F:26])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:26][C:19]1[CH:18]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[O:35][CH:36]=2)=[O:31])[CH3:28])[CH:16]=[C:15]([F:14])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc3ccccc3c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 22.8 %

Procedure:
2-Naphthaleneboronic acid (44.7 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (14 mg, 23%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Mg].II.Br[CH2:5][C@@H:6]([CH3:9])[CH2:7][CH3:8].[C:10]1([Si:16](Cl)([Cl:18])[Cl:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.CCCCCC>[CH3:9][C@@H:6]([CH2:7][CH3:8])[CH2:5][Si:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([Cl:18])[Cl:17]
Reactant: CC[C@H](C)CBr
Reactant: Cl[Si](Cl)(Cl)c1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[C@H](C)C[Si](Cl)(Cl)c1ccccc1

Procedure:
Anhydrous tetrahydrofuran (125 mL) was put into a reactor with magnesium (5.7 g, 0.24 mol) and molecular sieves 4A which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. (S)-(+)-1-bromo-2-methylbutane (30 g, 0.20 mol) was added dropwise to the slowly stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing phenyltrichlorosilane (50 g, 0.24 mol) in anhydrous tetrahydrofuran (50 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 40° C.-50° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH2:16][C:17]([CH2:24][CH3:25])([CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>COCCOC.[Cl-].[Na+].O.[Zn]>[CH2:20]([C:17]1([CH2:24][CH3:25])[CH:18]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH2:16]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCC(C=O)(CC)CSc1ccccc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: COCCOC
Solvent: O
Product: CCCCC1(CC)C=C(c2ccccc2)c2ccccc2SC1
Temperature: 5 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl3 and 80 mL of anhydrous ethylene glycol dimethyl ether (DME) was held at reflux for 2 h. The reaction mixture was cooled to 5° C. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in 30 mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g (43%) of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g (3%) of 4b in the later fraction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])=[N:37][CH:38]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:59]C(N1CCCC1C(O)=O)=O)(C)(C)C>>[OH:59][C@@H:42]1[CH2:41][N:40]([C:44](=[O:54])[C@@H:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:47])[CH3:48])[C@H:39]([C:36]2[NH:37][CH:38]=[C:34]([C:31]3[CH:30]=[CH:29][C:28]([C:23]4[CH:24]=[C:25]5[C:20](=[CH:21][CH:22]=4)[CH:19]=[C:18]([C:15]4[NH:14][C:13]([C@@H:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:17][CH:16]=4)[CH:27]=[CH:26]5)=[CH:33][CH:32]=3)[N:35]=2)[CH2:43]1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1nc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)c[nH]1)C(C)C

Procedure:
(S)-tert-butyl 2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate was prepared following the procedure for 2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (Example EQ), substituting 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](Cl)(=O)[CH2:12][CH3:13]>O1CCOCC1.CN(C)C=O>[OH:9][C:6]1[N:7]2[N:8]=[C:11]([CH2:12][CH3:13])[N:1]=[C:2]2[N:3]=[C:4]([CH3:10])[CH:5]=1
Reactant: Cc1cc(=O)n(N)c(N)n1
Reactant: CCC(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCc1nc2nc(C)cc(O)n2n1

Procedure:
Intermediate 1 (0.4 g, 2.85 mmol) was allowed to react with propionyl chloride (ALDRICH, 0.372 mL, 4.28 mmol) in a mixture of 1,4-dioxane (8 mL) and N,N-dimethylformamide (2 mL) overnight under refluxing conditions. The reaction was concentrated under vacuum and the residue was purified (silica gel column, eluting with DCM:MeOH mixtures from 100:0 to 90:10%) to obtain 7-hydroxy-2-ethyl-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 4) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25]CC)=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.[OH-].[Na+]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Reaction time: 28.5 h
Yield: 79.8 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-[3-(2-pyridylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (0.94 g, 2.18 mmole) and 1.0 N NaOH (2.6 mL, 2.62 mmole) in absolute EtOH (19.2 mL) is warmed in an oil bath set at 50° C. After 28.5 hr, the reaction was concentrated on the rotavap and the residue was purified by ODS chromatography (1:1 MeOH/H2O). Concentration left a cloudy, aqueous solution, which was made homogeneous by addition of a little 1.0 N NaOH. The pH was adjusted to 7 with 1.0 N HCl, and the solid precipitate was collected and washed with H2O. The mother liquors were concentrated, and the residue treated similarly to afford a small second crop. The combined materials were dried in high vacuum at 40° C. to afford the title compound (0.70 g, 79%) as a nearly colorless solid: HPLC (Hamilton PRP-1®, 40% CH3CN/H2O containing 0.1% TFA) k'=1.2; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=4.4 Hz, 1 H), 7.32-7.41 (m, 1 H), 7.03-7.22 (m, 4 H), 6.97 (d, J=8.4 Hz, 1 H), 6.83 (d, J=2.4 Hz, 1 H), 6.60-6.74 (m, 2 H), 6.41-6.50 (m, 2 H), 4.20 (d, J=14.7 Hz, 1 H), 4.00 (t, J=6.2 Hz, 2 H), 3.88 (d, J=14.7 Hz, 1 H), 3.60-3.70 (m, 1 H), 3.26-3.40 (m, 2 H, partially obscured by residual solvent signal), 3.20 (dd, J=15.1, 4.3 Hz, 1 H), 2.83 (dd, J=15.1, 10.3 Hz, 1 H), 2.60 (dd, J=15.9, 5.3 Hz, 1 H), 2.50 (dd, 1 H, partially obscured by residual solvent signal), 1.88-2.00 (m, 2 H); MS (ES) m/e 403 (M+H)+. Anal. Calcd for C25H26N2O3 . 0.25 H2O: C, 73.78; H, 6.56; N, 6.88. Found: C, 73.85; H, 6.47;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[CH2:13]([N:20]=[C:21]=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(N(C)C)=O>[CH2:13]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc2c(=O)[nH]ccc2c1
Reactant: O=C=NCc1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(NCc1ccccc1)Nc1ccc2c(=O)[nH]ccc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
6-Amino-2H-isoquinolin-1-one (0.2 mmol, 39 mg) and benzyl isocyanate (0.2 mmol, 27 mg) were dissolved in 1 mL DMA. The mixture was allowed to stir at 60° C. overnight. The product was obtained by HPLC purification. MS (M+1) 294.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1.[O:30]=[C:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1>>[O:30]=[C:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]1[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Br)c2)c1C(=O)OC
Reactant: O=C1CCc2ccccc2N1
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(N3C(=O)CCc4ccccc43)c2)c1C(=O)OC

Procedure:
1-(2-Bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene and 2-oxo-1,2,3,4-tetrahydroquinoline are treated in the same manner as in Example 6-(2) to give 1-[2-(2-oxo-1,2,3,4-tetrahydroquinolin-1-yl)-4-pyridyl]-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.O=S(Cl)[Cl:17].CN(C=O)C>>[Cl:17][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc2nc(S)oc2c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(Cl)oc2c1

Procedure:
To Compound 4 (2 g, 9.5 mmol), SOCl2 (9.8 ml, 134 mmol) and DMF (0.8 mL, 10 mmol) was added at room temperature. The reaction mixture heated to reflux for 15 min. The solvent was removed under reduced pressure. The crude oil was azeotroped with xylene twice.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.N1C=CC=CC=1.[ClH:33]>O>[ClH:33].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O

Procedure:
A mixture of 2.83 g (0.01 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (II), 4.4 g (0.051 mol) of anhydrous piperazine and 30 ml of dry pyridine is refluxed for 6 hours. The solvent is stripped off in vacuo, the residue is taken up in 25 ml of water, the pH is adjusted to 1 with concentrated hydrochloric acid, while cooling with ice and, when the mixture is cold, the precipitate is filtered off under suction and washed with cold 10% strength hydrochloric acid and ethanol. After drying in vacuo at 100° C., 3.05 g of 1-cyclopropyl-6,8-difluoro-7-(piperazin-1-yl)-1,4-di- hydro-4-oxoquinoline-3-carboxylic acid hydrochloride having a decomposition temperature of 354°-355° C. are obtained.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([NH:11][CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:10])[CH2:7][CH2:8][CH3:9]>>[C:6]([NH:11][CH2:12][CH2:13][C:14]1[S:15][C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:17][CH:18]=1)(=[O:10])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(=O)NCCc1cccs1
Reactant: O=S(=O)(O)Cl
Product: CCCC(=O)NCCc1ccc(S(=O)(=O)Cl)s1

Procedure:
6.6 ml (0.100 mol) of chlorosulphonic acid are cooled in an ice bath to 4°C whilst stirring, and 3.35 g (0.017 mol) of 2-(2-butyramido-ethyl)-thiophene are then added over the course of 15 minutes in such a way that the reaction temperature does not rise above 8°C. The ice bath is then removed and the reaction mixture is stirred for 30 minutes at 28°-30°C and then poured, whilst stirring, onto 100 g of ice under which there is a layer of 50 ml of methylene chloride. The methylene chloride phase is separated off and the aqueous phase is extracted with a further 50 ml of methylene chloride. The combined extracts are washed with 50 ml of concentrated sodium chloride solution, dried over sodium sulphate and evaporated at 40°C bath temperature with the aid of a rotary evaporator. The crude 5-(2-butyramido-ethyl)-2-thiophenesulphonyl chloride is obtained.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[CH3:22].O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=2)=[CH:15][C:14]=1[CH3:22]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: FC(F)(F)c1nsc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2nc(C(F)(F)F)ns2)cc1C
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
5-Chloro-3-(trifluoromethyl)-1,2,4-thiadiazole (2.26 g, 12.0 mmol) (synthesis described in DE 3228147) was dissolved in 1,2-dimethoxyethane (50 mL) and 4-methoxy-3-methylphenylboronic acid (2.4 g, 14.4 mmol) and tetrakis(triphenylphosphine)palladium (0.1 g, 0.09 mmol) were added. After 1.5 h at rt, Na2CO3 (19.2 mL, 2M aqueous solution) was added and the mixture was stirred for 4 h at 80° C. and for 14h at rt. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. Due to low conversion the crude product was again reacted with 5-chloro-3-(trifluoromethyl)-1,2,4-thiadiazole (2.4 g, 14.4 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.09 mmol) in DME (50 mL) and Na2CO3 (19.2 mL, 2M aqueous solution). After stirring at 80° C. for 16 h, the reaction mixture was cooled and water was added. The mixture was extracted with ethyl acetate, the organic phase dried over MgSO4, filtered and concentrated under reduced pressure. The crude product (3.2 g) had a purity of ˜90% and was used in the next step without further purification.