Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH:59][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:56][C:46]=2[C:47]([N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[N:48][CH:49]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:2][C:3]([OH:5])=[O:4])=[CH:13][CH:12]=1)(=[O:10])[CH3:8]
Reactant: O=C(O)CCl
Reactant: CC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1ccc(NCC(=O)O)cc1
Yield: 90 %

Procedure:
Chloroacetic acid (40 mmol) was neutralized with aqueous 2N NaOH (50 mmol), then 4-aminoacetophenone was added (25 mmol) was added to the above solution, and the whole reaction mixture was refluxed for 5 hrs. Cooled the reaction mixture, and the solid separated was filtered and washed with water. The solid was recrystallized from aqueous ethanol to get pure 2-((4-acetylphenyl)amino)acetic acid (4.2 g, 90% yield). To a solution of 1-(4-methoxyphenyl)piperazine (0.6 mmol) and 2-((4-acetylphenyl)amino)acetic acid (0.66 mmol) (obtained from the above reaction step) and DMAP (cat) in dichloromethane was added EDCI (0.8 mmol), and the resulting reaction mixture was stirred for 8 h. The reaction mixture was diluted with ethyl acetate and washed with dilute HCl solution, saturated NaHCO3 solution, water and brine solution. Dried the solution with sodium sulfate and concentrated to give crude mass which on silica gel chromatography eluting with 0.6% methanol in dichloromethane provided TG2-150 (70% yield). Similar synthetic procedures were used for making the compounds listed in Table 1 and Table 2.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[N:11](C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=3)[N:4]2[N:3]=1.Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>>[NH:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:9]1[N:4]2[N:3]=[C:2]([NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=3)[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc2nc(N)nn12
Agent: Cl
Product: O=C(Nc1nc2cccc(-c3ccc[nH]3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 9, but starting from tert-butyl 2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate ((A6), 360 mg; 1.20 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (428 mg; 2.41 mmol; 2.0 eq.) as a brown powder (245 mg, 67%). HPLC, Rt: 2.14 min. (purity 100.0%). LC/MS, M−(ESI): 303.3.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)=[O:2].[H-].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.O>[C:10]([N:5]1[CH:6]=[CH:7][C:3]([CH:1]=[O:2])=[CH:4]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cc[nH]c1
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccn(C(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
500 mg of 3-formyl-pyrrole were dissolved in 10 ml of tetrahydrofuran and then, at +20° C., 227 mg of sodium hydride dispersed at 55% in vaseline oil were added all at once. Gas evolved and after stirring for 15 minutes, a solution of 0.58 ml of benzoyl chloride in 2 ml of tetrahydrofuran was introduced dropwise at +5° C. The mixture was stirred for 2 hours at 20° C. and diluted with water. Extracting with ether, concentrating to dryness by distillation under reduced pressure and chromatographing the residue over silica and eluting with a mixture of hexane and ethyl acetate (7-3) yielded 558 mg of 1-benzoyl-3-formyl-pyrrole.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O.[CH3:27][NH:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH3:27])=[O:26]
Reactant: O=C(O)CCCCCCCBr
Reactant: CCCCNC
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCN(C)C(=O)CCCCCCCBr
Reaction time: 0.5 h

Procedure:
9.1 ml of N-methylmorpholine and then 10.4 ml of isobutyl chloroformate were added dropwise at -10° C. to -15° C. to a solution of 5 g of 8-bromo octanoic acid in 200 ml of methylene chloride. The mixture was stirred for 30 minutes at -10° C. to -15° C. and then at this temperature, 13 ml of N-methylbutylamine were added. The mixture was allowed to rise ambient temperature and stood for 40 minutes. Then, 150 ml of a saturated solution of sodium bicarbonate were added and the mixture was stirred for 10 minutes. After decanting, extraction was done with methylene chloride and the extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue was chromatographed on silica (eluant: methylene chloride-acetone 95-5) to obtain 6.14 g of the expected product.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)[CH3:4].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>O1CCCC1>[CH2:3]([C:5]1[N:6]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[CH:9]2)[CH3:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCc1n[nH]c2cc(C(=O)N(C)OC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1c2ccc(C(=O)N(C)OC)cc2nn1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
NaH (1.3 g, 60% dispersion in mineral oil, 0.033 mol) and tetrahydrofuran (223 mL) were mixed in a 1-necked flask and cooled to 0° C. To this was added dropwise a mixture of 3-ethyl-N-methoxy-N-methyl-1H-indazole-6-carboxamide (2.6 g, 0.011 mol) in tetrahydrofuran (60 mL), and the mixture was stirred at 0° C. for 1 hour. [β-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was then added and the reaction mixture was allowed to warm to room temperature. The resulting mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organics were washed with brine (25 mL), dried (sodium sulfate) and concentrated in vacuo to afford 4.0 g (quantitative yield) of 3-ethyl-N-methoxy-N-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-6-carboxamide, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:11])[CH:9]=[CH2:10].[OH-].[K+].[CH3:14]I>O1CCCC1>[CH3:14][O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)NCCOCCO
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC(=O)NCCOCCOC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
N-[2-(2-hydroxyethoxy)ethyl]acrylamide (35.87 g), potassium hydroxide (15.2 g), tetrahydrofuran (100 g) and methyl iodide (33.58 g) were introduced into a 1 L eggplant type flask equipped with a reflux condenser and a magnetic rotor. A reaction was carried out at 45° C. for 2 hours and then for 2 hours at 60° C. as the mixture was being stirred. The salt that separated out was removed by filtration and the low boiling point components were removed by means of a rotary vacuum evaporator. Purification was performed by distillation under reduced pressure and N-[2-(2-methoxyethoxy)ethyl]acrylamide was obtained as a yellow transparent, viscous liquid.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:14][C:13](=[O:15])[O:12][C:10]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:16]([OH:23])[C:17]([NH2:22])([CH2:20][OH:21])[CH2:18]O.N#N>>[OH:21][CH2:20][C:17]1([CH2:16][OH:23])[CH2:18][O:15][C:13]([CH2:14][CH:9]([C:10]2[O:12][CH2:18][C:17]([CH2:20][OH:21])([CH2:16][OH:23])[N:22]=2)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:22]1
Reactant: NC(CO)(CO)CO
Reactant: CCCCCCCCC1CC(=O)OC1=O
Agent: N#N
Product: CCCCCCCCC(CC1=NC(CO)(CO)CO1)C1=NC(CO)(CO)CO1
Yield: 100 %

Procedure:
10 parts n-octylsuccinic anhydride and 12 parts tris(hydroxymethyl)aminomethane were heated neat 3 hrs. at 180° C. under a rapid flow of N2. The product was obtained as a colorless glass in 100% yield. The following spectral properties confirm the structure shown below: ir (neat) 3300 (OH), 1600 (C=N); nmr (CDCl3) δ 4.40 (broad s, 4.0 H, 2 CH2 's in rings), δ 4.25 (broad s, 3.7 H, 4 OH, addition of D2O eliminates peak), δ 3.55 (broadened 10 Hz AB, 7.2 H, 4 CH2O), δ 2.5 (broad s, 3.0 H, CH--CH), δ 1.4 (broad s with t shoulder at 0.9, 17 H, n-C8H17).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH:20]1[CH2:22][CH2:21]1)[C:17]([OH:19])=[O:18].[CH:23]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:32]=[C:33]([C:34]([O:36][CH3:37])=[O:35])[C:26]=12)=O>C(Cl)Cl>[C:41]([O:40][C:38]([N:31]1[C:27]2=[N:28][CH:29]=[CH:30][C:25]([CH2:23][NH:15][C@H:16]([CH:20]3[CH2:22][CH2:21]3)[C:17]([OH:19])=[O:18])=[C:26]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: N[C@@H](C(=O)O)C1CC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C3CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol), (R)-2-amino-2-cyclopropylacetic acid (37.8 mg, 0.329 mmol), and DCM (2 mL). The reaction mixture was stirred at room temperature in for 30 min, after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture was concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C20H25N3O6, 404; found, 404.3.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl.C(O[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])C>C(#N)C>[N+:43]([C:38]1[CH:39]=[N:40][CH:41]=[CH:42][C:37]=1[NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)([O-:45])=[O:44]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cnccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 38.8 %

Procedure:
To a stirred solution of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (390 mg, 1.2 mmol) in acetonitrile (˜5 mL), was added Hunig's base (230 μL, 1.35 mmol, 1.1 eq.) and 4-ethoxy-3-nitropyridine hydrogen chloride (250 mg, 1.2 mmol, 1 eq.) and the mixture stirred at reflux for 72 hours. To this a further portion of 4-ethoxy-3-nitropyridine hydrogen chloride (50 mg, 0.24 mmol, 0.2 eq.) was added and the mixture stirred at reflux for a further 24 hours. The reaction mixture was then concentrated in vacuo to give a dark yellow oily residue. This was partitioned between 2M NaOH (30 mL) and DCM (2×30 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a dark yellow oil. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:0.2 to 90:10:1, by volume) to provide the title compound (205 mg, 38%). HRMS ESI+ m/z 441.2486 [MH]+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[CH2:38][OH:39])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C>C(Cl)Cl>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[CH:38]=[O:39])=[CH:33][CH:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OCC(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: O=CC(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Yield: 86.2 %

Procedure:
Dess-Martin periodinane (5.38 g, 12.7 mmol) was suspended in CH2Cl2 (70 mL). Compound 3 (3.22 g, 10.0 mmol) dissolved in 20 mL CH2Cl2, was added under stirring. The resulting mixture was stirred overnight at room temperature. Diethyl ether (200 mL) was added and the organic phase was washed with NaOH (2×30 mL, 2M), NaHCO3 (50 mL, saturated aqueous solution), and brine (50 mL) and dried over Na2SO4. Filtration and evaporation of the solvent under reduced pressure gave a crude material which was purified by column chromatography (heptane:ethyl acetate 4:1) to yield 2.76 g, 86% of 4 as a white solid. 1H-NMR (CDCl3) δ; 9.94 (dd, 1H, J=2.0 Hz and 1.5 Hz), 7.45-7.26 (m, 6H), 7.16 (d, 2H, J=8.6 Hz), 7.14-7.08 (m, 3H), 7.0 (d, 2H, J=9.0 Hz), 5.11 (ad, 1H, J=1.2 Hz), 5.07 (s, 2H); 13C-NMR (CDCl3) δ 197.6 (d, J=1.5 Hz), 160.7 (d, J=247 Hz), 158.5, 136.8, 130.5 (d, J=2.0 Hz), 130.5 (d, J=2.0 Hz), 129.3 (d, J=8.1 Hz), 128.6, 128.0, 127.4, 127.1, 124.4 (d, J=3.5 Hz), 115.7 (d, J=22.3 Hz), 115.5 (2C), 70.1, 57.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][C:43]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[F:55])([OH:47])[CH2:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[CH2:48][C:43]1([OH:47])[CH2:44][CH2:45][CH2:46][CH:41]([NH:40][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:42]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NC1CCCC(O)(Cc2ccccc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(O)(Cc5ccccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.05 mmol, 24.8 mg), HCl salt of 3-amino-1-(2-fluorobenzyl)cyclohexanol (0.05 mmol, 11 mg), HATU (0.05 mmol, 19 mg) and DIEA (80 μL) in DMA (300 μL) was stirred at room temperature for overnight. The product, N-(3-(2-fluorobenzyl)-3-hydroxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].C(O)(=O)C.[S:25]1[CH2:29][CH2:28][C:27](=O)[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:27]2[CH2:28][CH2:29][S:25][CH2:26]2)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCN
Reactant: O=C1CCSC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1nc2cnc3ccccc3c2n1CCCCNC1CCSC1
Reaction time: 0.17 h

Procedure:
To a suspension of 4-(2-Ethyl-imidazo[4,5-c]quinolin-1-yl)-butylamine obtained in step VI in tetrahydrofuran was added acetic acid (1 eq.) and dihydrothiophen-3-one (1.1 eq.). Resulting reaction mixture was stirred for 10 min. Sodium triacetoxyborohydride (2.2 eq.) was added to reaction mixture over a period of 1 hrs and resulting suspension was then stirred for 4-5 hrs. Reaction was then quenched with methanol and concentrated to dryness. Reaction mixture was basified using aq.sodium hydroxide solution and extracted with chloroform. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield sticky solid. Product was then purified by silica gel column chromatography to afford [4-(2-Ethyl-imidazo[4,5-c]quinolin-1-yl)-butyl]-(tetrahydro-thiophen-3-yl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.N>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)[CH:20]=2)=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Clc1ccc(-c2cc(-c3cncc(Cl)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-chloro-4-ethynylbenzene (Aldrich, 41 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ7.69 (dt, J=8.9, 2.6, 2.4 Hz, 2H), 7.82 (s, 1H), 7.93 (dt, J=8.9, 2.4, 2.2 Hz, 2H), 8.44 (t, J=2.2 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 9.08 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+, 293 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.S(C1C=CC(C)=CC=1)(O[CH2:14][C@@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][CH:21]=3)[N:17]([CH3:31])[CH2:16]1)(=O)=O.C>C(O)C.CN(C)C=O>[CH3:31][N:17]1[C@H:18]2[C@@H:28]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:30]=3[C:20]([CH2:19]2)=[CH:21][NH:22]4)[CH2:29][C@@H:15]([CH2:14][N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C:3]2=[O:9])[CH2:16]1
Reactant: O=C1CCC(=O)N1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CN1C[C@H](CN2C(=O)CCC2=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
0.8 g of 50% sodium hydride in an oil was added in small portions to a mixture of 3.4 g of succinimide and 50 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 30 minutes. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitated crystals were separated by filtration, and washed with water. The crystals thus obtained were treated with charcoal in ethanol and recrystallized from ethanol to obtain 0.9 g of the titled compound as colorless needles having a melting point of 233°-238° C. (with decomposition).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35]Br>>[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Product: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccc(F)cc3F)c(=O)c2-c2ccc(F)cc2)cc1
Yield: 24 %

Procedure:
2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 68, was N-debenzylated according to the method of Example 11. The intermediate was N-alkylated according to the method of Example 20, substituting 2,4-difluorobenzylbromide in place of 4-fluorobenzyl bromide to provide the title compound (yield: 65 mg, 24%). mp 236-238° C. 1H NMR (300 MHz, CDCl3) δ 4.78 (s, 2H), 5.43 (s, 2H), 6.88 (m, 2H), 6.97 (t, J=9 Hz, 2H), 7.18 (d, J=9 Hz, 6 Hz, 2H), 7.38 (d, J=9 Hz, 2H), 7.55 (m, 1H), 7.85 (s, 1H), 7.86 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 472 (M+H)+. Anal. calc. for C23H16F3N3O3S: C, 58.59; H, 3.42; N, 8.91. Found: C, 58.44; H, 3.47; N, 8.72.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O>CO>[Br:11][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[N:9][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: Nc1cccc(C2CC2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: Nc1ccc(Br)c(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of 6-cyclopropylpyridin-2-amine (2 g, 14.93 mmol), methanol (25 mL) was added N-bromosuccinimide (2.64 g, 14.93 mmol) portionwise. After stirring at room temperature for 30 minutes, mixture was evaporated and the residue obtained was purified on column (SiO2) using 10% ethyl acetate in hexanes as eluent. This afforded 2.1 gm (68.5% yield) of title compound. 1H NMR (CDCl3, 300 MHz): δ 7.45-7.43 (d, 1H), 6.16-6.13 (d, 1H), 4.30-4.20 (bs, 2H), 2.40-2.30 (m, 1H), 1.00-0.90 (m, 2H), 0.85-0.80 (m, 2H). MS: m/z=215.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH:23]=[O:24])([CH3:4])([CH3:3])[CH3:2].CC(=CC)C.[O-:31]Cl=O.[Na+]>C(O)(C)(C)C.O>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:25])=[C:10]([CH:11]=1)[C:23]([OH:31])=[O:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
A solution of 3-(4-benzyloxy-2-formyl-phenyl)-acrylic acid tert-butyl ester (6.70 g, 19.8 mmol) in tert-butanol (150 mL) was treated with 2-methyl-2-butene (50 mL) and cooled to 0° C. A solution of NaClO2 (17.0 g, 188 mmol) and NaH2PO4 (17.0 g, 142 mmol) in H2O (200 mL) was added, and the mixture was stirred at 0° C. for 15 min. The ice bath was removed, and the mixture was stirred at room temperature for 2 h. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified using silica gel chromatography (hexanes/EtOAc 9/1 to 0/10) to afford the title compound as white solid (6.78 g, 96%). 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 5.12 (s, 2H), 6.20 (d, 1H, J=16.2 Hz), 7.13 (dd, 1H, J=3.6, 9.0 Hz), 7.34-7.45 (m, 5H), 7.58 (d, 1H, J=8.8 Hz), 7.64 (d, 1H, J=2.4 Hz), 8.41 (d, 1H, J=16.2 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Oc1ccc2ncccc2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc4ncccc4c3)c2cc1OC
Yield: 46.4 %

Procedure:
Using 4-chloro-6,7-dimethoxyquinoline (90 mg) and commercially available 6-hydroxyquinoline (176 mg), reaction and purification were carried out in the same manner as described in Example 8 to obtain 62 mg of the title compound (yield: 46%).