Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To a solution of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (2.0 g, 7.3 mmol), 4-methoxyphenyl boronic acid (1.13 g, 7.40 mmol) in EtOH (50 mL) and toluene (50 mL) was added 2N aqueous potassium carbonate solution (21.8 mL, 43.6 mmol). The reaction mixture was degassed with N2 for 5 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (296 mg, 0.36 mmol) and degassed with N2 for an additional 5 minutes. The reaction mixture was sealed in a pressure tube and heated to 130° C. for 3 hours. As the reaction progressed, the suspension became clear and turned to orange then dark brown. The reaction mixture was cooled to room temperature, and filtered through Celite®. The filtrate was concentrated in vacuo and the residue was partitioned between EtOAc (150 mL) and water (150 mL). The aqueous layer was acidified to pH 2, and extracted with EtOAc. Silicycle-thiol resin was added to the organic layer and the suspension was stirred for 10 minutes. The suspension was filtered and activated charcoal was added to the filtrate. The suspension was stirred at room temperature for another 20 minutes and filtered. The resulting light yellow solution was concentrated in vacuo and the residue was triturated with CH2Cl2 and MeCN. The solid was filtered to provide the title compound (280 mg, 13% yield) as a light yellow solid. The filtrate was concentrated, diluted with EtOAc (20 mL) and filtered to give another batch of desired product (80 mg). MS (ES+) 303.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.86 (s, 1H), 7.38 (d, J=8.29 Hz, 2H), 7.03 (d, J=8.78 Hz, 2H), 3.82 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:20])=[C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]=2)[C:7](=[O:21])[C:6]([C:22]([O:24]CC)=[O:23])=[CH:5]1>[OH-].[Na+]>[F:20][C:10]1[CH:9]=[C:8]2[C:13](=[N:12][C:11]=1[C:14]1[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=1)[N:4]([CH:3]=[CH2:2])[CH:5]=[C:6]([C:22]([OH:24])=[O:23])[C:7]2=[O:21]
Reactant: CCOC(=O)c1cn(CCCl)c2nc(-c3ccncc3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(-c3ccncc3)nc21
Temperature: 70 °C

Procedure:
Ethyl 1-(2-chloroethyl)-6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylate was suspended in 1N sodium hydroxide and the suspension was heated at 70° C. for 4 hours. The precipitate was collected by filtration, and dissolved in water. Then the pH of the solution was adjusted to about 6 with acetic acid. The resulting solid was collected and recrystallized from ethanol to give 6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid (Compound 2) (0.22 g, m.p. 254°-257° C.).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c([N+](=O)[O-])cn1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)cn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (S)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(4-fluorophenyl)ethyl)-5-nitropyridine-2,4-diamine (Method 89, 0.15 g, 0.40 mmol) and zinc dust (0.13 g, 2.0 mmol) in MeOH-THF (1:1, 16 ml) was slowly added saturated ammonium chloride solution (2 ml). The reaction mixture was stirred at 25° C. for 1 hour, to which was added saturated ammonium acetate solution (5 ml). The resulting mixture was stirred for another 30 min. Zn dust was removed by filtration and washed with EtOAc (20 ml). The organic layer was separated, washed with brine (10 ml), dried over Na2SO4, and concentrated. The crude product was used directly for the next step without further purification. MS: Calcd.: 352; Found: [M+H]+ 353.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[C:12]12[C:29](=O)[O:28][C:26](=[O:27])[C:24]3=[C:25]1[C:16](=[CH:17][C:18]1[C:23]3=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=[CH:14][CH:13]=2>C(O)C>[O:27]=[C:26]1[C:24]2[C:25]3[C:16](=[CH:15][CH:14]=[CH:13][C:12]=3[C:29](=[O:28])[N:11]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH2:1])[CH:17]=[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]1=2
Reactant: O=C1OC(=O)c2c3ccccc3cc3cccc1c23
Reactant: NCCNCCCNCCN
Solvent: CCO
Product: NCCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.3 %

Procedure:
A solution of 5.0 g (31 mmol) of N,N'-bis(2-aminoethyl)-1,3-propanediamine in 200 ml of ethanol 99% is treated with 1,5 g (6 mmol) of anthracene-1,9-dicarboxylic acid anhydride in 100 ml of ethanol and stirred for 24 hours at room temperature. The solid is collected on a filter, washed with ethanol and crystallized from ethanol to give 0.5 g (20%) of N-[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-N'-(2-aminoethyl)-1,3-propanediamine. M.p. 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[C:28]([NH2:29])=[CH:27][C:26]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[CH2:35][OH:36])=[C:25]([Cl:37])[CH:24]=1.C(Cl)CCl>CC#N>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[NH:29][C:28]2[CH:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[CH2:35][OH:36])[C:25]([Cl:37])=[CH:24][C:23]=2[N:22]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: Nc1cc(Cl)c(N2CCC[C@@H]2CO)cc1N
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC[C@@H]4CO)cc3[nH]2)c1)C1(C(F)(F)F)CC1

Procedure:
The title compound was prepared from N-(4-chloro-3-isothiocyanato-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide (85 mg, 0.3 mmol), (R)-1-(4,5-diamino-2-chloro-phenyl)-2-hydroxymethyl-pyrrolidine (62 mg, 0.3 mmol) and EDC (45 μL, 0.3 mmol) in MeCN (5 mL) in analogy with the method described in example 1 step (g).
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12](Cl)=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[Cl:34]C1C=C2C(C=C(OS(C(F)(F)F)(=O)=O)N=C2)=CC=1>>[ClH:4].[ClH:34].[ClH:1].[Cl:34][C:13]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:16]3[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:26]=4)[CH:21]=3)[N:9]=[CH:10]2)=[CH:5][CH:14]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Reactant: O=S(=O)(Oc1cc2ccc(Cl)cc2cn1)C(F)(F)F
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2ccc(Cl)cc2cn1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 7-chloroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.29-2.46 (m, 4H), 3.24-3.31 (m, 2H), 3.59-3.67 (m, 2H), 4.61-4.72 (m, 1H), 7.91 (dd, J=8.8, 2.0 Hz 1H), 8.10 (s, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.43 (s, 1H), 8.73 (s, 1H), 8.90 (d, J=2.3 Hz, 1H), 9.43 (s, 1H). MS (ES+): m/z=405.09/407.03 [MH+]. HPLC: tR=1.95 min (ZQ3, polar—5 min).
Reaction SMILES: C([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[C:14]([C:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]=2)[CH:13]=1)[CH2:7][O:8]C(=O)C)(=O)C.[OH-].[Na+].C(Cl)Cl.O>CC(O)C>[C:36]1([C:14]2[CH:13]=[C:12]([CH:6]([CH2:5][OH:4])[CH2:7][OH:8])[CH:17]=[CH:16][C:15]=2[NH:18][C:19]([C:21]2[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]=1
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CO)CO)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of acetic acid 3-acetoxy-2-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-propyl ester (as prepared in the previous step, 580 mg, 1.00 mmol) in i-PrOH (15 mL), 2N NaOH (1 mL, 2 mmol) was added. The reaction mixture was stirred at RT for 1 h, and DCM (200 mL) and water (200 mL) were added. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified on silica (40% EtOAc-hexane) to obtain the title compound (312 mg, 63%): Mass spectrum (ESI, m/z): Calcd. for C26H36N4O4Si, 497.2 (M+H). found 497.0.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:22][CH:23]1[C:24]([O:69][CH:70]([O:72][CH2:73][CH3:74])[CH3:71])([CH3:68])[CH2:25][CH2:26][CH:27]([O:60][Si](C(C)(C)C)(C)C)[CH2:28][C:29]([O:31][CH:32](/[C:37](/[CH3:59])=[CH:38]/[CH:39]=[CH:40]/[CH:41]([CH3:58])[CH2:42][CH:43]2[O:57][CH:44]2[CH:45]([CH3:56])[CH:46]([O:49][C:50](=[O:55])[CH2:51][O:52][CH2:53][CH3:54])[CH2:47][CH3:48])[CH:33]([CH3:36])[CH:34]=[CH:35]1)=[O:30])(=[O:21])[CH3:20]>O1CCCC1.C(OCC)(=O)C>[C:19]([O:22][CH:23]1[C:24]([O:69][CH:70]([O:72][CH2:73][CH3:74])[CH3:71])([CH3:68])[CH2:25][CH2:26][CH:27]([OH:60])[CH2:28][C:29]([O:31][CH:32](/[C:37](/[CH3:59])=[CH:38]/[CH:39]=[CH:40]/[CH:41]([CH3:58])[CH2:42][CH:43]2[O:57][CH:44]2[CH:45]([CH3:56])[CH:46]([O:49][C:50](=[O:55])[CH2:51][O:52][CH2:53][CH3:54])[CH2:47][CH3:48])[CH:33]([CH3:36])[CH:34]=[CH:35]1)=[O:30])(=[O:21])[CH3:20]
Reactant: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C1C
Agent: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C1C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.037 mL, 0.037 mmol) was added to a solution of (8E,12E,14E)-7-acetoxy-3-t-butyldimethylsiloxy-21-ethoxyacetoxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (15 mg, 0.018 mmol) in tetrahydrofuran (1 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crude product was purified by silica gel column chromatography (Kanto silica gel 60N, spherical, neutral, 40 to 100 μm, eluate; hexane:ethyl acetate=50:50) to obtain the title compound (8.8 mg, 68%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=O)[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.Cl.[NH2:34][OH:35]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[N:34][OH:35])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: NO
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: ON=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3R,3aR,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (88 mg, 0.196 mmol) and hydroxylamine hydrochloride (39.5 mg, 0.568 mmol) in pyridine (0.5 ml) was stirred at room temperature for 2 hours. Then the reaction mixture was evaporated to give a foam, which was dissolved in methanol (2 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water to give the title compound. Major Oxime stereoisomer LC-MS: calculated for C24H19ClN4O4 462.11 observed m/e: 463.18 (M+H)+ (Rt 1.20/2 min); 1H NMR δ (ppm) (CD3OD): 7.94 (s, 1H), 7.76 (ABq, 4H), 7.71 (d, 2H), 7.49 (dd, 2H), 7.39 (dd, 1H), 5.62 (m, 1H), 5.14 (t, 1H), 5.00 (d, 1H), 4.63 (s, 2H), 4.27 (dd, 2H) and 4.08 (dd, 1H). (Contains a small amount of minor oxime stereoisomer).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.N1CCCCC1>C(O)C>[OH:13][C:8]1[N:3]2[N:4]=[C:5]([SH:7])[N:6]=[C:2]2[N:1]=[C:10]([CH3:12])[CH:9]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1n[nH]c(S)n1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(O)n2nc(S)nc2n1
Yield: 37.6 %

Procedure:
A mixture of 3-amino-5-mercapto-s-triazole (10 g), ethyl acetoacetate (34 g), piperidine (10 ml) and ethanol (300 ml) was refluxed for four hours. After removing the solvent by distillation under reduced pressure, 150 ml water was added, the mixture was neutralized to pH 7.0 with hydrochloric acid and cooled, giving 5.9 g of the objective compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][F:21].[Cl-].[Na+]>CN(C=O)C>[F:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: FCCBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCCF
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a solution of 3-hydroxy-4-methoxy-benzaldehyde (10.0 g, 66.0 mmol, 1.0 equiv) in anhydrous DMF (40 mL) was added K2CO3 (13.6 g, 99.0 mmol, 1.5 equiv) and 1-bromo-2-fluoro-ethane (9.2 mg, 72.0 mmol, 1.1 equiv) and the mixture stirred at rt for 48 h. The K2CO3 was removed by filtration and the organic phase concentrated under reduced pressure. To the crude reaction mixture was added a conc. solution of sodium chloride (100 mL) and the solution extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and the product crystallized from a mixture of isopropanol/diethylether to yield 12.69 g (97%) of the title compound. 1H NMR (300 MHz, DMSO): δ 3.89 (1H), 4.24-4.27 (m, 1H), 4.34-4.37 (m, 1H), 4.67-4.70 (m, 1H), 4.83-4.86 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.4 Hz, J=1.9 Hz, 1H), 9.84 (s, 1H). MS (ISP): 198.6 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[N:18][N:19]=2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[CH:30]([CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)=O.C(Cl)Cl.C(OC(=O)C)(=O)C>ClCCCl.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:30][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:34][CH2:33]4)[CH2:26][CH2:27]3)=[O:21])=[N:18][N:19]=2)[CH3:28])(=[O:11])=[O:12])=[C:5]([CH3:29])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCNCC3)o2)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CC4CCN(C(=O)OC(C)(C)C)CC4)CC3)o2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Methoxy-N,2,6-trimethyl-N-{[5-(piperazin-1-ylcarbonyl)-1,3,4-oxadiazol-2-yl]methyl}benzenesulfonamide (0.2 g, 0.44 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (0.14 g, 0.66 mmol) were dissolved in DCE (4 mL) and a few 4 Å molecular sieves added. The reaction was stirred for 30 min at ambient temperature prior to addition of STAB (0.28 g, 1.3 mmol). The reaction was stirred for 18 h, diluted with MeOH (0.5 mL) and concentrated in vacuo. The residue was redissolved in DCM (5 mL) and filtered through Celite, washing with DCM. The DCM solution was treated with acetic anhydride (0.1 mL, 1.0 mmol) and stirred for 30 min at ambient temperature. The solvent was removed in vacuo and the residue redissolved in MeOH (2 mL) and the solution absorbed on to a 2 g SCX cartridge. The sorbent was washed with MeOH (10 mL) and the product eluted with 7 N NH3 in MeOH (10 mL). The solvent was removed in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:27][CH3:28])[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44]>CCN(CC)CC>[CH3:28][O:27][C:4]1[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]2[C:11](=[C:2]([NH:1][CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]3[C:38](=[O:39])[C:37]4=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]4[C:35]3=[O:44])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCCCc1ccccc1
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCCCc1ccccc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(7-phenylheptoxy) quinoline [Example 1c] (9.2 g, 0.024 mol) and 4-bromo-1-phthalimidopentane (BPP) (15 g, 0.05 mol) was heated at 120°-125° C. while Et3N (5 ml) was added in small portions. After 3 h at 120°-125° C., second portions of BPP (7.5 g) and Et3N (2.5 ml) were added and heating was continued for 4 h. Third portions of BPP (3 g) and Et3N (1 ml) were introduced, and heating was continued for 2 h. The reaction was allowed to cool and extracted with Et2O (total, ca. 500 ml). The extract was treated with carbon and then with saturated ethereal hydrogen chloride (300 ml). The resulting dark red semi-solid mass was separated and basified with Et2O--Et3N. Concentration of the ethereal solution left 11.5 g (81 %) of brown oil which was dissolved in CHCl3, placed on a silica gel column (200 g) and eluted with CHCl3. The first six eluates (75 ml each) were combined and concentrated to give 10.9 grams of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-(7-phenylheptoxy) quinoline which was used without further purification.
Reaction SMILES: C(OC([N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]3[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=3[C:12]=2[N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH2:7]1)=O)C.[OH-].[K+]>C(O)CCC.C1C=CC=CC=1>[N:16]1([C:12]2[C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[CH:9]=[C:8]3[C:13]=2[CH2:14][CH2:15][NH:6][CH2:7]3)[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: CCOC(=O)N1CCc2c(cc3ccccc3c2-n2cccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCCCO
Product: c1ccc2c(-n3cccc3)c3c(cc2c1)CNCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.0 g of 5-(1-pyrrolyl)-1,2,3,4-tetrahydrobenzo[g]isoquinolin-2-yl-carboxylic acid ethyl ester and 4.0 g of potassium hydroxide in 20 ml of n-butanol is boiled for 2 hours. After cooling to room temperature, the mixture is diluted with benzene, washed neutral with water and extracted 3 times with a 10% aqueous tartaric acid solution. The acid solution is washed with ether, made alkaline by the addition of 40% caustic soda solution and extracted with benzene. The benzene extract is washed with water and dried over magnesium sulphate. The title compound is obtained by evaporation of the benzene solvent and converted into the hydrochloride salt having a M.Pt. from 240° (decomposition).
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].OCCCCNC(=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([N:4]([CH:31]1[CH2:32][CH2:33][C:34]2[N:9]=[CH:10][S:11][C:35]=2[CH2:36]1)[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH2:14][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]2[CH2:13][CH2:12][C:8]3[N:9]=[CH:10][S:11][C:7]=3[CH2:6]2)=[CH:16][CH:17]=1)[CH2:2][CH3:3]
Reactant: O=C(NCCCCO)c1ccccc1
Reactant: CCCN(Cc1ccc(C(=O)Cl)cc1)C1CCc2ncsc2C1
Product: CCCN(Cc1ccc(C(=O)N(CCC)C2CCc3ncsc3C2)cc1)C1CCc2ncsc2C1
Yield: 74 %

Procedure:
Compound 42 is prepared from 42C and IC-CORRECT? as described for 1D.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.[C:33]1(=[O:38])[CH2:37][CH2:36][CH:35]=[CH:34]1>O1CCOCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:35]2[CH2:36][CH2:37][C:33](=[O:38])[CH2:34]2)=[CH:8][C:7]=1[C:21]([F:22])([F:23])[F:24]
Reactant: COC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Reactant: O=C1C=CCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCc1ccc([C@H]2CCC(=O)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
[Rh(S-BINAP)(nbd)]BF4 (0.03 mmol) and 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenyl]-propionic acid methyl ester (preparation 2) (1.5 mmol) were added to a 25 mL-flask containing a magnetic stirring bar and a septum inlet. The flask was flashed with argon. Triethylamine (1.5 mmol) and 2-cyclopenten-1-one (1.0 mmol) dissolved in aqueous 1,4-dioxane (6/1, 3 mL) were then added. The mixture was stirred for 6 h at 25° C. Brine was added, the mixture was extracted with ethyl acetate, and the solvents were removed in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[C:15]([F:34])[CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:35]1([CH2:40][CH2:41][C:42](Cl)=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:28])([CH3:29])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)[C:42](=[O:43])[CH2:41][CH2:40][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:15]([F:34])[CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)c(F)c2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)C(=O)OC(C)(C)O4)c(F)c2)cc1

Procedure:
The titled compound was prepared following the procedure B using 6-({4-[(4-butylphenyl)ethynyl]-2-fluorobenzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropanoyl chloride as a colorless oil (73%). 1H NMR (CDCl3, 300 MHz) δ 7.69 (m, 1H), 7.43-7.30 (m, 3H), 7.28-7.20 (m, 1H), 7.19-7.03 (m, 4H), 6.92 (d, J=8.7 Hz, 1H), 4.87 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.06 (m, 2H), 1.73 (s, 6H), 7.70-1.26 (m, 13H), 1.00-0.85 (m, 5H). M+ (ESI): 582. HPLC, Rt: 6.63 min (Purity: 100%).