Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].CN(C)C=O.[CH3:26][O:27][C:28](=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>CCOCC>[CH3:26][O:27][C:28](=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
As described in example 1(a), the reaction is carried out with 130.7 g (0.5 mol) of 4-chloro-N-(4-methoxyphenyl)-benzamide, 24.5 g (1 mol) sodium hydride, 700 cc. of dimethylformamide and 118.5 g (0.5 mol) of 8-bromocaprylic acid methyl ester. Reaction time and reaction temperature: 5 hours at 80° C., thereafter 12 hours at 100° C. The reaction mixtures are further processed as described in example 1(a). The crude product is dissolved in 300 cc. of ether. After standing for a prolonged period, the unreacted 4-chloro-N-(4-methoxyphenyl)-benzamide separates by crystallisation and is filtered off. The solvent is partly distilled off and the resulting oily crude product (181 g) is separated. 125 g are used in the next step without further purification, the remainder (56 g) is purified chromatographically on silicic acid using chloroform as eluant.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CS(O[C@H:11]1[CH2:15][N:14]([CH3:16])[C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)(=O)=O.C(OCC)(=O)C.[Cl-].[Na+]>C(O)C.O>[C:1]([S:3][C@@H:11]1[CH2:15][N:14]([CH3:16])[C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)(=[O:4])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C
Reactant: CC([O-])=S
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@H](SC(C)=O)CN1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
Potassium thioacetate (677 mg) was added to a solution of methyl (2S,4R)-4-methylsulfonyloxy-1-methyl-2-pyrrolidinecarboxylate (609 mg) obtained from Reference example 4 in ethanol/water (9:1) (6 ml), and the resulting mixture was stirred at 80° C. for 3 hours, and then the mixture was allowed to stand overnight at the same temperature. Ethyl acetate (20 mL) and 10% aqueous sodium chloride solution (10 mL) were added to the reaction mixture, which was then extracted. The organic layer was separated from the aqueous layer, which was washed with water (10 mL). The solvent of the organic layer was removed by distillation under reduced pressure to give the title compound (543 mg, yield 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-:3])=[O:2].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:33][S:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])(=[O:31])=[O:32])=[O:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-:3])=[O:2]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1

Procedure:
The carboxylic acid (Example 2) (6.2 g) was stirred at room temperature in dichloromethane (50 ml) with 2-methylbenzene sulphonamide (3.4 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.6 g) and 4-dimethylaminopyridine (0.25 g) for 72 hours. The reaction mixture was diluted with dichloromethane and washed with 0.5N hydrochloric acid, then water. The organic extract was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with 0-2% ethyl acetate in dichloromethane, afforded N-[1-(3-nitrobenzyl)indol-5-ylcarbonyl]-2-methylbenzene sulphonamide (m.p. 208°-210° C.).
Reaction SMILES: C(OC(=O)[N:7]([CH3:36])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][C:20](NC(NCC(C4C=CC=CC=4)C)=O)=[CH:19][CH:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.F[C:39](F)(F)[C:40](O)=O.[OH2:45]>>[CH3:36][NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:39]([CH3:40])[CH2:36][NH:7][C:8](=[O:45])[NH2:13])=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: O
Reactant: CC(CNC(=O)Nc1ccc(-c2cnc3c(N(C)C(=O)OC(C)(C)C)nccn23)cc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Product: CNc1nccn2c(-c3ccc(C(C)CNC(N)=O)cc3)cnc12
Reaction time: 12 h
Yield: 90 %

Procedure:
To the purified product Y, (68 mg, 0.136 mmol) was added trifluoroacetic acid (2 mL) and water (1 mL). The reaction mixture was then swirled and left to stand for 12 h. The mixture was then concentrated under vacuum and dissolved in dichloromethane (250 mL) dichloromethane (50 mL) and neutralized with saturated bicarbonate solution (150 mL). The organic layer was then dried over sodium sulfate and concentrated under vacuum to provide Example 154 as a white solid. Yield: 90%.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[O:24][C:25]1[CH:26]=[C:27]([NH:28][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: COc1cccc(Oc2cccc(N)c2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cccc(Oc2cccc(NC(=O)c3ccn4c3CSC4c3cccnc3)c2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (9 g) is added, at a temperature between 60° and 65° C., to a solution of 3-(3-methoxyphenoxy)aniline (6.45 g) and triethylamine (6.1 g) in dioxane (200 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 15 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 4 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 65° C. The residue is dissolved in methylene chloride (350 cc). The solution obtained is washed twice with distilled water (200 cc in total), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 5 times with distilled water (750 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (12 g) is thereby obtained, which is dissolved in boiling acetonitrile (50 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 2 hours. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (10 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(3-methoxyphenoxy)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (4.5 g) in the form of cream-coloured crystals, m.p. 130° C., is thereby obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:29]1)=[O:27])C1C=CC=CC=1.Cl.CCOC(C)=O>CC(C)=O>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(O)cc1O

Procedure:
Hydrogenation of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihydro-isoindol-2-yl]-methanone (as described in method A5) followed by treatment with saturated HCl/EtOAc and trituration with hot acetone afforded 890 mg of the title compound (hydrochloride salt) as a cream solid. 1H NMR (DMSO-d6) 10.78 (1H, br s), 10.05 (1H, br s), 9.55 (1H, br s), 7.30 (1H, t), 7.08 (1H, s) 6.98-6.90 (2H, m), 6.45 (1H, s), 4.80 (2H, s), 4.75 (2H, s), 4.15 (2H, t), 3.95 (2H, br m), 2.80 (2H, br, m), 3.50-3.35 (2H, br m), 3.25 (2H, br m,), 3.18-3.02 (3H, br m), 2.20 (2H, br m), 1.15 (6H, d). MS: [M+H]+ 441.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH2:32][C:33]1([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:32][C:33]4([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: NC1(C(=O)O)CC1
Product: O=C(O)C1(NCc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and 1-aminocyclopropanecarboxylic acid (98.1 mg; 0.97 mmol) to give Example 162 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.5, 1.6 Hz), 7.95-7.87 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.7 Hz), 7.56-7.47 (4H, m), 3.95 (2H, s), 1.18-1.14 (2H, m), 0.96-0.92 (2H, m). LC/MS (Method C): 498 (M+H)+. HPLC (Method F) Rt 2.70 min (Purity: 98.6%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)N>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[N:2]=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: N#Cc1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 4-hydrazino-benzonitrile according to example 43 gave the desired product. MS: M=424.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:10]=1/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C:10]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1c(C=CCCCCO[Si](C)(C)C(C)(C)C)cccc1OCCCC(=O)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCO[Si](C)(C)C(C)(C)C)c1CCC(=O)OCC
Yield: 85.8 %

Procedure:
To a solution of 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hex-1-enyl]-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (0.977 mmol, 507 mg) in ethyl acetate (10 mL) was added 10% palladium on carbon (350 mg) at room temperature. The resulting black mixture was stirred in the presence of atmospheric hydrogen gas in a balloon for 36 h at room temperature. Then, the catalyst was removed by filtration using a filter paper and the residue was washed with hot ethyl acetate (˜60 mL). The filtrate was concentrated in vacuo and the resulting residue was dried under high vacuum to obtain 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (438 mg, 86%) as a colorless oil: ES(+)-HRMS m/e calculated for C29H50O6Si (M+Na)+ 545.3269, found 545.3267.
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][N:6]([CH2:19][CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>CO.C1COCC1.C1COCC1>[OH:3][CH2:4][CH2:5][N:6]([CH2:19][CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1
Reactant: CCN(CCO[Si](C)(C)C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: C#Cc1ccc(N(CC)CCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 5.0 g, that is 15 mmole of 4-[(2-trimethylsiloxyethyl)ethylamino]trimethylsilylethynylbenzene, prepared in the previous step, dissolved in 60 mL of methanol-THF (1:1) mixture, 33 ml, that is 33 mmole, of 1M tetrabutylammonium fluoride in THF, from Aldrich Chemical Co. was added dropwise. The solution was stirred at room temperature for 1 hour. Ethyl ether was added and the mixture was extracted with water. The organic layer was separated, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was flash column chromatographed on silica gel with 35% ethyl acetate-hexane to produce 2.5 g of a viscous yellow oil at an 88% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1Br.CC([N:15]([CH2:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C(=O)[O-])(C)C.[NH2:28][CH:29](CC1C=CC=CC=1)[CH2:30][CH2:31][NH:32][C:33](=O)OC(C)(C)C>>[NH2:15][CH2:19][C@@H:20]([NH:27][C:8]([C:4]1[S:5][CH:6]=[C:2]([C:31]2[N:32]([CH3:33])[N:28]=[CH:29][CH:30]=2)[CH:3]=1)=[O:10])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cc(Br)c(Br)s1
Reactant: CC(C)(C)OC(=O)NCCC(N)Cc1ccccc1
Reactant: CC(C)(C)N(C[C@@H](N)c1ccccc1)C(=O)[O-]
Product: Cn1nccc1-c1csc(C(=O)N[C@H](CN)c2ccccc2)c1

Procedure:
The title compound was prepared as a white solid according to the procedure of Example 20, except substituting 4-bromo-2-thiophenecarboxylic acid (83 mg, 0.4 mmol) for 4,5-dibromo-2-thiophenecarboxylic acid and substituting 1,1-dimethylethyl[(2S)-2-amino-2-phenylethyl]carbamate (94 mg, 0.4 mmol) [prepared according to the procedure of Preparation 1] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 327 (M+H)+, 1H NMR (400 MHz, MeOD) δ ppm 3.44 (d, J=2.78 Hz, 1H) 3.60 (br. s., 1H) 4.06 (br. s., 3H) 5.47 (dd, J=10.36, 4.29 Hz, 1H) 6.70 (br. s., 1H) 7.38 (d, J=6.82 Hz, 1H) 7.44 (t, J=7.20 Hz, 2H) 7.53 (d, J=7.58 Hz, 2H) 7.79 (br. s., 1H) 8.04 (br. s., 1H) 8.32 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([CH2:11][C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:6](=[O:17])[C:5]=2[NH:4][N:3]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+].ClC[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([CH2:11][C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:6](=[O:17])[C:5]=2[N:4]([C:18](=[O:21])[CH2:26][CH2:27][N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)[N:3]=1
Reactant: Nc1n[nH]c2c1CCN(Cc1ccco1)C2=O
Reactant: O=C(CCCl)N1CCN(c2ccccc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Nc1nn(C(=O)CCN2CCN(c3ccccc3)CC2)c2c1CCN(Cc1ccco1)C2=O

Procedure:
A target compound (192.8 mg, 0.429 mmol, 96.2%) was yielded as solid in the same manner as Example 1 by reacting 3-amino-6-N-((furan-2-yl)methyl)-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (104 mg, 0.447 mmol) with potassium carbonate (92.6 mg, 0.670 mmol) and 3-chloro-1-(4-phenylpiperazin-1-yl)propan-1-one (124.1 mg, 0.491 mmol).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]([C@@H:9]1[CH2:14][CH2:13][C@@H:12]([NH2:15])[C@H:11]([OH:16])[CH2:10]1)=[O:8].[C:17](=O)([O:23]C(C)(C)C)[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:5][O:6][C:7]([C@@H:9]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[C@H:11]([OH:16])[CH2:10]1)=[O:8]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1CC[C@@H](N)[C@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C1
Temperature: 50 °C
Yield: 102.6 %

Procedure:
The acetate salt (c) (15.6 g, 66 mmol) was suspended in tetrahydrofuran (200 ml) and treated with di-tert-butyl carbonate (16 g, 73 mmol) and diisopropylethylamine (14 ml, 10.4 g, 80 mmol). The mixture was heated at 50° C. for 18 hours then evaporated to dryness. The residue was partitioned between water and ethyl acetate. The aqueous phase was further extracted with ethyl acetate and the combined extracts washed with brine, dried and evaporated to give a solid (18.5 g, 100%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)=[N:6][C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of 7-benzyl-1-(5-fluoro-pyridin-3-yl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (17 mg, 0.042 mmol), β-alanine (374 mg, 4.19 mmol) and NaOMe solution (6.3 mL, 3.15 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/CH2Cl2+1% AcOH) to give 9 mg of the title compound. MS: (+) m/z 463.35 (M+1).
Reaction SMILES: C(O[C:6]([N:8]([CH3:39])[C@H:9]([CH2:23][O:24][C:25](=[O:38])[NH:26][C:27]1[N:28]=[CH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([F:37])=[CH:32][CH:31]=2)[CH2:10][C:11]1[N:12]=[CH:13][N:14](C(OC(C)(C)C)=O)[CH:15]=1)=[O:7])(C)(C)C.Cl.CCN(C(C)C)C(C)C.[Cl:50][C:51]1[C:70]([F:71])=[CH:69][CH:68]=[CH:67][C:52]=1[CH2:53][NH:54]C(=O)OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[F:37][C:33]1[CH:32]=[C:31]2[C:30](=[CH:35][CH:34]=1)[CH:29]=[N:28][C:27]([NH:26][C:25](=[O:38])[O:24][CH2:23][C@@H:9]([N:8]([CH3:39])[C:6]([NH:54][CH2:53][C:52]1[CH:67]=[CH:68][CH:69]=[C:70]([F:71])[C:51]=1[Cl:50])=[O:7])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)=[CH:36]2
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)Cc1cn(C(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of (S)-tert-butyl 4-(2-(tert-butoxycarbonyl(methyl)amino)-3-(6-fluoroisoquinolin-3-ylcarbamoyloxy)propyl)-1H-imidazole-1-carboxylate (280 mg, 0.51 mmol) in THF (10 mL) was added HCl (4 N in 1,4-dioxane, 2.55 mL, 10.2 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to dryness. The residue was suspended in THF (20 mL). To the suspension were added DIEA (0.27 mL, 1.53 mmol) and 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (166 mg, 0.51 mmol). The reaction mixture was stirred at RT for 2 h and concentrated to dryness. The residue was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(1H-imidazol-4-yl)propyl 6-fluoroisoquinolin-3-ylcarbamate (35 mg, 13%). LRMS (M+H+) m/z 529.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20]CC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3[N:46]=2)=C(OCC2CCCC2)C=1.BrCC1C=CC(C#N)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:46])=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Agent: N#Cc1ccc(CBr)cc1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccc(C#N)cc1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 4-bromomethyl-benzonitrile (CAS Reg. No. 17201-43-3). Brown solid (48%). MS (Turbo Spray): m/z=410.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13]OS(C)(=O)=O)[O:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]([CH2:13][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])[O:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC1CN(c2cccc(F)c2)C(=O)O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2cccc(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
A solution of mesylate 109 (2.89 g, 10.0 mmol) in anhydrous DMF (20 mL) was treated with solid potassium phthalimide (2.22 g, 70.0 mmol, 1.2 equiv) at 25° C., and the resulting reaction mixture was warmed to 70° C. for 4 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (60 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0-5° C. for 1 h. The white precipitate was collected by filtration, washed with water (2×40 mL), and dried in vacuo to afford the desired (5R)-2-[3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione 110 (3.12 g, 91.8% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C18H13FN2O4, LCMS (EI) m/e 341 (M++H).