Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:55])([CH3:54])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[C:38]2[N:37]=[CH:36][N:35]=[C:33]([NH2:34])[C:32]=2[N:31]=[C:30]1[NH:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][C:42]=1[OH:53])([CH3:4])([CH3:3])[CH3:2].O[CH2:57][CH2:58][NH:59][C:60](=[O:69])[O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:62]([O:61][C:60]([NH:59][CH2:58][CH2:57][O:53][C:42]1[CH:43]=[C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:46][C:41]=1[CH2:40][NH:39][C:30]1[N:29]([C:38]2[N:37]=[CH:36][N:35]=[C:33]([NH2:34])[C:32]=2[N:31]=1)[C@@H:8]1[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@H:7]1[O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:55])[CH3:54])=[O:69])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)cc3O)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)cc3OCCNC(=O)OCc3ccccc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A mixture of 2′,3′,5′-tris-O-(tert-butyldimethyl-silyl)-8-(3-hydroxybiphenyl-4-ylmethylamino)adenosine (0.175 g), benzyl N-(2-hydroxyethyl)carbamate (0.065 g), triphenylphosphine (0.074 g) in tetrahydrofuran (1.1 mL) was stirred at 50° C. for 30 minutes. Diisopropyl azodicarboxylate (40% toluene solution, 0.143 g) was added dropwise, and the resulting mixture was stirred at 50° C. for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2 to 1/1) to give 8-[3-(2-benzyloxycarbonylaminoethoxy)biphenyl-4-ylmethyl-amino]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)adenosine (0.146 g). To a solution of 8-[3-(2-benzyloxycarbonyl-aminoethoxy)biphenyl-4-ylmethylamino]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)adenosine (0.143 g) in methanol (1.5 mL) was added ammonium fluoride (0.323 g), and the resulting mixture was stirred at 60° C. for 13.5 hours. The reaction mixture was cooled to room temperature. Dichloromethane (7.5 mL) was added, and the insoluble material was filtered out. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol=15/1) to give the title compound (0.077 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH:12]([CH3:14])[CH3:13])[C:7]([CH2:16][C:17](O)=[O:18])([OH:15])[CH2:6][CH2:5]2.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][CH2:31][NH:32][CH3:33]>>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][CH2:31][N:32]([CH3:33])[C:17](=[O:18])[CH2:16][C@@:7]1([OH:15])[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C@@H:8]1[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C1c2ccc(F)cc2CCC1(O)CC(=O)O
Reactant: CNCCCc1nc2ccccc2[nH]1
Product: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CC(=O)N(C)CCCc1nc2ccccc2[nH]1

Procedure:
An "activated derivative" of (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl) acetic acid is a derivative that renders the acid more active in the reaction with [3-(1H-benzimidazol-2-yl)propyl]methylamine to form (1S,2S)-N-[3-(1H-benzimidazol-2-yl) propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide. Typical such derivatives include the corresponding acyl halides and anhydrides, and a preferred activated derivative is the mixed anhydride of(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetic acid with trimethylacetic acid.
Reaction SMILES: N1C=CC=CC=1C1C=CC=CN=1.Cl[C:14]1[C:15]([C:23]([OH:25])=[O:24])=[N:16][C:17]([Cl:22])=[C:18]([Cl:21])[C:19]=1[Cl:20]>O.Cl[Ni]Cl.[Zn]>[Cl:20][C:19]1[C:18]([Cl:21])=[C:17]([Cl:22])[N:16]=[C:15]([C:23]([OH:25])=[O:24])[CH:14]=1
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl[Ni]Cl
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reaction time: 24 h
Yield: 33.7 %

Procedure:
A 25 mL scintillation vial was charged with NiCl2 (76.2 mg, 0.586 mmol) and 2,2′-bipyridine (188.4 mg, 1.20 mmol). The vial was sealed and purged with nitrogen for 20 min. The inert reactor was charged with DMF (9 mL) and water (1 mL). The resulting mixture was allowed to stir for 24 h, and then solid 3,4,5,6-tetrachloropicolinic acid (1.54 g, 5.9 mmol) and zinc powder (3.33 g, 50.9 mmol) were added through the top of the reactor. The reaction mixture was allowed to stir at ambient temperature for 3 h and was diluted to 20 mL with water. The resulting heterogeneous mixture was filtered to remove the solids, and the resulting clear, aqueous filtrate was made acidic (pH˜1) with concentrated HCl. Upon standing, a fine white solid formed and was collected via vacuum filtration to give the title compound (0.45 g, 33.6%) that was 86% pure as analyzed by calibrated HPLC. The residual material was 9% unreacted starting material and 2 unknown impurities.
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=O)[CH2:4][CH2:5][CH3:6].[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12].C(O)=O>CO>[CH3:1][C:2]([C:3]([CH2:4][CH2:5][CH3:6])=[N:12][C:11]1[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:10]=1[CH3:9])=[N:12][C:11]1[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:10]=1[CH3:9]
Reactant: Cc1cccc(C)c1N
Reactant: CCCC(=O)C(C)=O
Solvent: CO
Solvent: O=CO
Product: CCCC(=Nc1c(C)cccc1C)C(C)=Nc1c(C)cccc1C
Reaction time: 6 h

Procedure:
2,3-Hexanedione (4.0 mL, 33 mmol) was slowly added to the mixture of 2,6-dimethylaniline (10 g, 80 mmol) and 0.2 mL formic acid in 25 mL of methanol. The mixture was stirred for 6 hours. After this time period, the solvent and excess of aniline were removed under vacuum. The residual viscous oil was dissolved in n-pentane and cooled to give a yellow solid which was recrystallized from n-pentane. The product, 2-methyl-3-propyl-1,4-bis(2,6-dimethylphenyl)-1,4-diaza-1,3-butadiene was isolated as yellow crystals (1.9 g, 18%). 1H NMR (200 MHz, CDCl3, δ, ppm): 0.84 t (3H, J=7.28 Hz, (CH2)2CH3); 1.52 m (2H, CH2CH2CH3); 2.03 s (3H, N═CCH3); 2.05 s and 2.06 s (6H and 6H, 2,6- and 2′,6′-CH3); 2.50 m (2H, CH2CH2CH3); 6.89-7.15 m (6H, 2×C6H3). 13C NMR (50.3 MHz, CDCl3, δ, ppm): 14.59 (CH2CH2CH3); 16.38 (N═CCH3); 17.96 and 18.03 (0.2,6- and 2′, 6′-CCH3); 20.28 (CH2CH2CH3); 31.24 (CH2CH2CH3); 123.13 and 123.18 (4- and 4′-CH); 124.67 and 124.75 (2,6 and 2′,6′-C); 127.94 and 127.98 (3,5- and 3′,5′-CH); 147.99 (140 -C); 148.51 (1-C); 167.61 (N═CMe); 171.52 (N═CPr).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:6][C:5]=1[CH:24]=[C:25]1[NH:29][C:28](=[O:30])[NH:27][C:26]1=O)([O-])=O.II>CN(C)C=O.[Pd].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>[C:18]1([S:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:1]=[C:26]4[NH:27][C:28](=[O:30])[NH:29][C:25]4=[CH:24][C:5]=3[CH:6]=2)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1NC(=O)C(=Cc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2[N+](=O)[O-])N1
Agent: [Pd]
Agent: II
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc3cc(OCCCCS(=O)(=O)c4ccccc4)ccc3nc2[nH]1
Reaction time: 18 h

Procedure:
A solution of 5-[[2-nitro-5-[4-(phenylsulfonyl)butoxy]phenyl]methylene]-2,4-imidazolidinedione (4.12 g, 9.1 mmol) in dimethylformamide (125 mL) was hydrogenated at 60 p.s.i. over 10% palladium on charcoal (1.25 g) in a low pressure hydrogenation apparatus. After 18 hours, the mixture was filtered through kieselguhr, the solvent evaporated and the residue dissolved in dimethylformamide (125 mL) and resubjected to hydrogenation over 10% palladium on charcoal (1.2 g). After 4 hours, the mixture was filtered through kieselguhr, concentrated in vacuo and the residue dissolved in refluxing methanol (150 mL). Iodine (2.35 g, 9 mmol) was added and the mixture refluxed for 1 hour, cooled and diluted with 10% sodium thiosulfate solution and 10% potassium carbonate solution. The mixture was stirred for 10 minutes, filtered and the solid washed with water and dried at 90° C. in vacuo. Crystallization from acetonitrile/dimethylformamide/water afforded 7-[4-(phenylsulfonyl)butoxy]-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one as a partial hydrate (1.90 g, 51%), m.p. 258° C. (dec.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:12][C:11]([CH:13]([C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[N:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:12][C:11]([CH:13]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:32][CH:33]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[N:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
To a solution of tert-butyl 4-[1-{5-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-pyrrol-2-yl}-2-(tetrahydro-2H-pyran-4-yl)ethyl]benzoate (200 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated and subjected to preparative HPLC to give the title compound (60.0 mg, yield 34%) as a pale-yellow solid. MS: 413 (MH+).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1C=O.Cl>N1C=CC=CC=1>[CH:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:15]=1[CH:1]=[CH:2][C:3]([OH:5])=[O:4]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 82 %

Procedure:
Malonic acid (7.5 g, 72.1 mmole) and 2-naphthaldehyde (5.0 g, 32.0 mmole) were dissolved in pyridine (20 mL) and refluxed for 1 hour. After cooling to room temperature, the reaction mixture was poured into 2N HCl solution (200 mL). The product precipitated immediately. It was collected by filtration and recrystallized from aqueous ethanol (200 mL ethanol/50 mL water) to give colorless needles (5.2 g, 82%).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])C.[OH-].[Na+].CCCCCC>C(O)C>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:25])=[O:3])=[CH:17][CH:16]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Product: CCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)O

Procedure:
Analogously to the process described in Example 2, 13 g of α-[p-(1-cycloheptenyl)-phenoxy]-heptanoic acid ethyl ester and 29 ml of 2 N sodium hydroxide solution in 130 ml of ethanol give α-[p-(1-cycloheptenyl)-phenoxy]-heptanoic acid of melting point 69°-71° C (from cold hexane).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.C([O-])([O-])=O.[K+].[K+].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-n2ccnc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 60 °C
Yield: 80.2 %

Procedure:
To a degassed solution of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.21 mmol) and K2CO3 (43 mg, 0.31 mmol) in DMF (1 mL) was added 1H-imidazole (14 mg, 0.21 mmol) under N2 at 0° C. The mixture was heated at 60° C. for 10 hours. The reaction mixture was concentrated and it was extracted with EtOAc. The residue was washed with H2O, brine, dried over Na2SO4. After being concentrated, the crude product was purified by column (PE:EA=1:1) to give of 5-bromo-2-(1H-imidazol-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (72 mg, yield: 83%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.40 (d, J=4.4 Hz, 1H), 8.36 (s, 1H), 8.10 (s, 2H), 7.80 (s, 1H), 7.19 (s, 1H), 3.21 (s, 3H), 3.20 (s, 3H), 2.81 (d, J=4.4 Hz, 3H). MS (M+H)+: 427/429.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][C@@H:12]([O:14][Si](C)(C)C)[CH:11]=[C:10]1[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].Cl>O1CCCC1.[Pd].C(OCC)(=O)C.O>[CH2:1]([O:8][C@@H:9]1[C@H:10]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:11][C@H:12]([OH:14])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)O[C@H]1C=C(COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O[C@H]1C[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a solution of ((1R,4S)-4-(benzyloxy)-3-(benzyloxymethyl)cyclopent-2-enyloxy)trimethylsilane (22) (478.00 g, 1.2494 mol) in tetrahydrofuran (9.6 L), Pd, 5 wt % on barium sulfate (265.9 g, 0.1249 mol) was added and the mixture was stirred under 100 psi of hydrogen at ambient temperature for 18 hours, stirring at 200 rpm. HPLC analysis after 18 hours indicated consumption of starting material. The reaction mixture was filtered through a medium frit funnel and the bed was washed with tetrahydrofuran (2000 mL). The filtrate was concentrated, yielding a yellow oil. The resulting oil was taken up in ethyl acetate (2000 mL) to which 2.0 M of hydrochloric acid in water (2000 mL) was added, and the biphasic mixture was stirred for 1 hour. The organic layer was separated and extracted once with saturated sodium bicarbonate in water (2000 mL), twice with 2.0 M of sodium hydroxide in water (2000 mL) and finally with saturated sodium chloride in water (2000 mL). The organic layer was concentrated to give a brown oil (344 g, 88%) which was used without further purification. 1H NMR (300 MHz, CD3OD, δ): 7.18 (m, 10H), 4.38 (m, 4H), 4.12 (m, 1H), 3.85 (t, 1H), 3.68 (m, 1H), 3.44 (m, 1H), 2.00 (m, 3H), 1.75 (m, 1H) and 1.42 (m, 1H).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][C:11]2[C:6]3=[C:7]([C:13]([C:15]4[C:16](=[O:30])[NH:17][C:18](=[O:29])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH:21]=4)=[CH:14][N:5]3[CH2:4]1)[CH:8]=[CH:9][CH:10]=2.CS(OS(C)(=O)=O)(=O)=O.N1C=CC=CC=1.[CH3:46][NH:47][CH3:48]>O1CCCC1.C(OCC)(=O)C>[CH3:46][N:47]([CH2:2][CH:3]1[CH2:12][C:11]2[C:6]3=[C:7]([C:13]([C:15]4[C:16](=[O:30])[NH:17][C:18](=[O:29])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH:21]=4)=[CH:14][N:5]3[CH2:4]1)[CH:8]=[CH:9][CH:10]=2)[CH3:48]
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CO)C3)=C1c1c[nH]c2ccccc12
Reactant: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)CC1Cc2cccc3c(C4=C(c5c[nH]c6ccccc56)C(=O)NC4=O)cn(c23)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 106.6 %

Procedure:
To a mixture of 3-(5-hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrole-2,5-dione (0.335 g, 0.84 mmol) and methylsulfonic acid anhydride (0.3 g, 1.7 mmol) in tetrahydrofuran was added pyridine (0.245 mL, 3.4 mmol). The mixture was heated to reflux for 4.5 h, cooled to room temperature, diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated to give an oil, which was used in the next step without further purification. The crude mesylate was dissolved in tetrahydrofuran (9 mL), then dimethylamine aqueous solution (40%, 4.22 ml, 33.6 mmol) was added. After stirring for 24 hours at room temperature, additional dimethylamine aqueous solution (40%,4.22 mL, 33.6 mmol) was added, and the mixture stirred for an additional 48 hours. The mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to provide 0.38 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C=O)C.O>[O:20]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:25])[N:19]1[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(CBr)c2ccccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 85 °C
Yield: 99.7 %

Procedure:
To a stirred solution of 4-(bromomethyl)-1-naphthaldehyde (7 g, 28 mmol) in DMF (100 mL) was added potassium phthalimide (7.3 g, 39.5 mmol), and the mixture was heated at 85° C. for 2 h. The reaction mixture was cooled to ambient temperature and diluted with H2O (100 mL). The obtained solid was separated by filtration and dried under vacuum to afford the title compound as a white solid (8.8 g, 98%): mp 190-192° C.; 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.25 (m, 1H), 8.41 (m, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39 (s, 2H); ESIMS m/z 316.09 ([M+H]+); IR (thin film) 1708 cm−1.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].N.[C:5]1([P:11]([CH:13]([CH3:15])[CH3:14])Cl)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH:13]([P:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:3][CH2:1][CH3:2])([CH3:15])[CH3:14]
Reactant: CCO
Reactant: CC(C)P(Cl)c1ccccc1
Agent: N
Product: CCOP(c1ccccc1)C(C)C
Reaction time: 0.5 h
Yield: 10.8 %

Procedure:
50 g (1.09 mol) of absolute ethanol are cooled to -15° C. under a nitrogen atmosphere. 3 g (1.76 mol) of ammonia gas are then introduced at this temperature with constant stirring. 26 g (1.39 mol) of phenyl(isopropyl)chloro-phosphine are then added dropwise at this temperature in 30 minutes. The mixture is then stirred for a further 30 minutes at this temperature and then refluxed for a further 12 hours. The mixture is then cooled, filtered by suction and rinsed out with ethanol. The filtrate is freed from ethanol in vacuo and the remaining residue is distilled. 23 g of ethyl isopropyl(phenyl)phosphinite are obtained at 0.07 mbar and an overhead temperature of 50° C. This corresponds to a yield of 85% of theory.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[O:34])[NH:19][C:20]2([C:29]([O:31]CC)=[O:30])[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[O:34])[NH:19][C:20]2([C:29]([OH:31])=[O:30])[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCN(C(=O)OC(C)(C)C)C3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)NC2(C(=O)O)Cc3ccccc3C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
The mixture of 5-(2-ethoxycarbonyl-indan-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (71) (882 mg, 1.78 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (15 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (50 mL) and acidified with conc. HCl until no more white precipitate came out of the water. After the filtration, the solid is purified by HPLC to give a pure product (72) as white solid (680 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16]C)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][CH:3]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:18][C:19]([CH3:25])([CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2ccc(OC)cc2n1Cc1ccc(Br)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1nc2ccc(O)cc2n1Cc1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 3-(1-(4-bromobenzyl)-6-methoxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (12 g, 27 mmol) in DCM (200 mL) was added BBr3 (20 g, 81 mmol) in DCM (100 mL) drop wise at −78° Celsius. The solution was gradually warmed to 5° Celsius and stirred for 3 h. The reaction mixture was slowly added to saturated NaHCO3 with rapid stirring for 1 h. The organic phase was separated and aqueous phase was extracted with DCM (200 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated to dryness and purified by FCC to provide the title compound. MS (ESI): mass calcd. for C21H23BrN2O3, 430.09; m/z found, 438 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](/[CH:11]=[CH:12]/[C:19]2[CH:22]=[CH:23][C:16]([Br:15])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)c1ccc(Cl)cc1
Yield: 80 %

Procedure:
A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and 4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 80% yield.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:34][CH2:35][CH3:36])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:27]([N:17]([C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:37])=[O:5])[C:9]([CH2:34][CH2:35][CH3:36])=[N:10][C:11]=2[CH:16]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccc(F)c3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccc(F)c3)ccc2n1CC(=O)O

Procedure:
{5-[Benzyl-(3-fluoro-benzoyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.79 (m, 1H), 7.68 (m, 1H), 7.55 (m, 2H), 7.21 (m, 6H), 7.02 (m, 1H), 6.92 (m, 1H), 5.11 (s, 2H), 4.99 (s, 2H), 2.68 (t, 2H), 1.71 (m, 2H), 0.95 (t, 3H). MS calculated for C26H24FN3O3+H: 446, observed: 446.