Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2](=[CH2:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:13](O)[CH3:14].N1C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C=O.C(Cl)Cl>[CH2:13]([O:6][C:5](=[O:7])[CH2:4][CH2:3][C:2]([Br:1])=[CH2:8])[CH3:14]
Reactant: C=C(Br)CCC(=O)O
Reactant: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=C(Br)CCC(=O)OCC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a solution of 3.73 g (0.0208 mol) of unpurified 4-bromo-pent-4-enoic acid in 3 ml chloroform with 1 drop of N,N-dimethylformamide was added 1.18 ml (0.0162 mol) of thionyl chloride. After this mixture had been heated to 60° C. for 30 minutes, it was added to a solution of 2.46 ml (0.0436 mol) ethanol and 1.97 ml (0.024 mol) pyridine and 13 ml methylene chloride. After stirring for 30 minutes, the reaction mixture was concentrated in vacuo. To the residue was added diethyl ether and water. The resulting mixture was transferred to a separatory funnel where the phases were separated. The isolated organic layer was dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to yield 3.5 g of 4-bromo-pent-4-enoic acid ethyl ester as an oil which was purified via vacuum distillation.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][CH2:28][CH2:29][C:30](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:30]([CH2:29][CH2:28][OH:27])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)CCO
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(CCO)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 3-hydroxypropanoic acid, the title compound was obtained in 61% purity by HPLC. MS(ESI+): m/z=407.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH2:25][CH3:26])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CCC1NCCc2ccc(F)cc21
Product: CCC1c2cc(F)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][CH:4]=1.[C:9]([N:12]1[CH2:16][C:15](=O)[N:14]=[CH:13]1)(=[O:11])[CH3:10]>>[C:9]([N:12]1[CH2:16][CH2:15][N:14]=[C:13]1[NH:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][CH:4]=1)(=[O:11])[CH3:10]
Reactant: Cn1nccc1N
Reactant: CC(=O)N1C=NC(=O)C1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1ccnn1C

Procedure:
5-Amino-1-methyl pyrazole hydrochloride (mp 143-145, from base described in Ber. 98, 3374, 1965) (40.0 g.) and 1-acetyl-2-imidazolinone (43.0 g.) were reacted as described in Example I to give 42.4 g. product mp 158°-166° (crystallized from CH3CN)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:24][CH2:23][C:22]5[C:18](=[CH:19][N:20]([CH2:25][CH2:26]O)[N:21]=5)[C:17]=4[S:28][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:49]>C(Cl)Cl>[Br:49][CH2:26][CH2:25][N:20]1[CH:19]=[C:18]2[C:22]([CH2:23][CH2:24][C:16]3[C:15]4=[C:10]([NH:9][C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=5)[N:11]=[CH:12][N:13]=[C:14]4[S:28][C:17]=32)=[N:21]1
Reactant: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCc2nn(CCBr)cc2-4)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.5 %

Procedure:
To a stirring solution of 2-{6-[(3-chloro-4-fluorophenyl)amino]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl}ethanol (11.4 g, 27.4 mmol) in CH2Cl2 (240 mL) were added triphenylphosphine (13.5 g, 48.0 mmol) and carbon tetrabromide (17.0 g, 48 mmol). The mixture was stirred at room temperature for 1.5 h, and the solvent was then removed under reduced pressure. The crude residue was purified via flash chromatography (1:1 hexanes/EtOAc) to afford the desired product (4.0 g, 30%) as an off-white solid. 1H-NMR (CDCl3) δ 3.05 (t, 2H), 3.27 (t, 2H), 3.66 (s, 2H), 4.40 (t, 2H), 6.93 (s, 1H), 7.05 (t, 1H), 7.34-7.40 (m, 1H), 7.44 (s, 1H), 7.78 (dd, 1H), 8.40 (s, 1H); LCMS RT=3.81 min; [M+H]+=478.2, 480.2.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[C:15](OC([O-])=O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(O)C.[OH-].[Na+]>[NH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: C1CC(C2CCNCC2)CCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Temperature: 10 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution is prepared of 41 g (0.17 M) of 4,4′-bipiperidine dihydrochloride in 250 ml of ethanol and 250 ml of 2N sodium hydroxide. A solution of 18.5 g (0.085 M) of t-butyl dicarbonate in 100 ml of ethanol are added slowly, at 0° C. The reaction mixture is agitated for 1 hour at 10° C. and the ethanol is then removed by an evaporator, under reduced pressure. The residual aqueous phase is saturated with sodium chloride and extracted with ethyl acetate. The organic phase obtained is dried over magnesium sulphate and concentrated under reduced pressure. The crude product is purified by silica gel chromatography in eluting with the aid of a dichloromehane/methanol/aqueous ammonia mixture (8/2/0.4; v/v/v). 16.5 g of the compound sought after are thus obtained as a white solid (yield=72%).
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43]>>[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:4][CH:3]=2)=[CH:47][CH:46]=1)(=[O:44])=[O:43]
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc(Cn3c(CC4(C(=O)O)CCCC4)nc4cc(OCc5ccc6ccccc6n5)ccc43)cc2)cc1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate and 4-(methylsulfonyl)phenyl boronic acid in Step A. MS (ESI): mass calcd. for C38H35N3O5S, 645.23; m/z found, 646.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.22-8.18 (m, 1H), 8.10-8.06 (m, 1H), 8.00-7.96 (m, 2H), 7.85-7.80 (m, 1H), 7.76-7.72 (m, 1H), 7.72-7.67 (m, 3H), 7.57-7.52 (m, 3H), 7.46-7.41 (m, 1H), 7.18-7.14 (m, 1H), 7.14-7.10 (m, 2H), 7.08-7.03 (m, 1H), 5.42 (s, 2H), 5.39 (s, 2H), 4.15-4.04 (m, 1H), 3.09 (s, 3H), 2.27-2.19 (m, 3H), 2.05 (s, 2H), 1.77-1.68 (m, 2H), 1.28-1.24 (m, 1H), 1.00-0.91 (m, 1H).
Reaction SMILES: [Cl-].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5].[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].O1CCOCC1>O.O1CCOCC1>[F:12][C:13]([F:18])([F:17])[C:14]([O-:16])=[O:15].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)C(F)(F)F
Agent: CCCC[n+]1ccn(C)c1
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])C(F)(F)F

Procedure:
Analogously to Example 1, 23.0 g (0.132 mol) of 1-butyl-3-methylimidazolium chloride are reacted with 28.0 g of approx. 80% aqueous trifluoroacetic acid, CF3C(O)OH (50% excess). 100 ml of 1,4-dioxane are subsequently added, and 112 ml of HCl- and CF3C(O)OH-containing water/dioxane azeotrope are distilled off at atmospheric pressure (85-101° C.). After four further azeotropic distillations with 100 ml of 1,4-dioxane each time, a further 19 g of approx. 80% aqueous trifluoroacetic acid are added to the residue. 100 ml of 1,4-dioxane are subsequently added, and 105 ml of HCl- and CF3C(O)OH-containing water/dioxane azeotrope are distilled off at atmospheric pressure. After three further azeotropic distillations with 100 ml of 1,4-dioxane each time and drying of the distillation residue under reduced pressure at 1.3 Pa and 70° C., 1-butyl-3-methylimidazolium trifluoroacetate is obtained. The yield is approximately quantitative.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH:42]([N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH3:47])[C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C.C1COCC1>[C:51]([O:50][C:48]([N:46]([CH:42]([C:38]1[CH:37]=[CH:36][CH:41]=[C:40]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:12]3=[N:13][CH:14]=2)[CH:39]=1)[C:43]([OH:45])=[O:44])[CH3:47])=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CN(C(=O)OC(C)(C)C)C(C(=O)O)c1cccc(Br)c1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)O)N(C)C(=O)OC(C)(C)C)c3)cc12

Procedure:
To a mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (0.545 g, 1.1 mmol) and (3-Bromo-phenyl)-(tert-butoxycarbonyl-methyl-amino)-acetic acid (0.39 g, 1.1 mmol) in a 20 mL microwave reaction flask was added THF (3 mL), acetonitrile (3 mL), and sodium carbonate (1 N in water, 3 mL, 6 mmol). The resulting suspension was purged with nitrogen for 1 minute. Dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (39 mg, 48 μmol) was added and the purging was continued for another minute. The flask was sealed and was irradiated in a microwave reactor to 90° C. for 10 minutes. The reaction mixture was adjusted to pH 4 by addition of 1 N hydrochloric acid, extracted with ethyl acetate (10 mL×3). The combine organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford (tert-butoxycarbonyl-methyl-amino)-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid as a off white solid (490 mg, 72%). MS: m/z 619 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[N:34]=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[N:34]=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)n1

Procedure:
Example 29 was prepared from bis(4-fluorophenyl)acetic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.4 Hz), 7.99 (m, 1H), 7.84 (s, 1H), 7.63 (t, 1H, J=8.0 Hz), 7.39–7.32 (m, 4H), 7.03–6.97 (m, 4H), 6.87 (d, 1H, J=7.6 Hz), 4.91 (s, 1H), 3.39 (dd, 2H, J=5.2, 11.2 Hz), 3.07 (d, 2H, J=11.6 Hz), 2.62 (m, 1H), 2.55 (t, 2H, J=6.4 Hz), 2.34 (m, 1H), 2.16 (t, 2H, J=11.2 Hz), 1.93–1.73 (m, 6H), 1.16 (d, 6H, J=6.8 Hz); ESMS m/e: 535.4 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12]CC)=[O:11])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]1[C:21]([O:23]CC)=[O:22]>O.C(O)C>[CH3:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=[O:11])[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:5]1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1c(-c2ccccc2)c(C(=O)OCC)n(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)c(-c2ccccc2)c(C(=O)O)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A solution of sodium hydroxide (101 g, 2.53 mol) in water (340 mL) was added to a solution of diethyl 1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylate (80 g, 0.25 mol) in ethanol (340 mL) and heated at reflux for 15 h. Ethanol was removed under reduced pressure and the residue diluted with water (200 mL) and chilled to 0° C. Concentrated hydrochloric acid (˜150 mL) was slowly added to adjust pH to ˜2, while maintaining temperature below 10° C. and the mixture was stirred for 30 min. The precipitated solid was filtered, washed with water (100 mL) and petroleum ether (200 mL) and dried under vacuum at 60° C. to afford 1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylic acid (60 g, 91%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:14]2([CH3:19])OCC[O:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12].Cl>CC(C)=O>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:14](=[O:15])[CH3:19])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC1(c2ccc([N+](=O)[O-])c(Oc3c(Cl)cccc3Cl)c2)OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1ccc([N+](=O)[O-])c(Oc2c(Cl)cccc2Cl)c1
Yield: 99 %

Procedure:
A mixture of 2-[3-(2,6-dichlorophenoxy)-4-nitrophenyl]-2-methyl-1,3-dioxolane (3.9 g) and 3N hydrochloric acid (15 ml) in acetone (30 ml) was refluxed for 2.5 hours. The mixture was concentrated under reduced pressure. To the residue were added water (50 ml) and ethyl acetate (60 ml). The organic layer was dried and concentrated to give an amorphous powder of 3'-(2,6-dichlorophenoxy)-4'-nitroacetophenone (3.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[N:58]([NH2:62])[CH:57]=[C:56]2[CH3:63]>CN(C=O)C.O.CCOC(C)=O>[F:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[N:58]([NH:62][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:57]=[C:56]2[CH3:63]
Reactant: Cc1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (645 mg, 2.78 mmol), HCTU (1.25 g, 3.02 mmol), and DIPEA (1.35 mL, 7.73 mmol) in DMF (15 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-3-methyl-indol-1-ylamine (380 mg, 2.31 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated in ether to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (533 mg, 61%) as a solid. MS: 379 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 11.84 (s, 1H), 9.21 (s, 1H), 8.32 (d, 1H), 8.17-8.15 (m, 1H), 7.66-7.61 (m, 1H), 7.47-41 (m, 2H), 7.36-7.34 (m, 2H), 7.05 (dt, 1H), 2.76 (s, 3H), 2.26 (s, 3H). IC50=6 nM.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.C1C(=O)N([Br:28])C(=O)C1.O>CN(C=O)C>[Br:28][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[CH:1]=[CH:2][CH:3]=[C:4]4[C:19]=3[C:8]([C:9]3[C:20]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3)=[CH:7][CH:6]=[CH:5]4
Reactant: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c3cccc4cccc(c5cccc1c52)c43
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.5 %

Procedure:
Following the scheme shown in FIG. 18, perylene (252 mg, 1 mmol) was dissolved in DMF (45 ml), and a solution of NBS (178 mg) dissolved in DMF (10 ml) was added gradually. This was agitated at room temperature for 24 hours. H2O (200 ml) was added, and the product was precipitated and suction filtered. The product was recrystallized with hexane to obtain yellow-brown compound (1) (187 mg, mixture).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH3:20][O:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[CH3:20][O:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:28])[N:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: COc1nc(C(=O)O)c(-c2cccc(C)c2)s1
Product: COc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(C)c2)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Methoxy-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=508.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([O:10][C:11]3[C:16]([Cl:17])=[CH:15][C:14]([NH:18][S:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=4[Cl:32])(=[O:21])=[O:20])=[CH:13][C:12]=3[Cl:33])=[N:7][C:6]=2[CH:34]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[Cl:32][C:23]1[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=1[S:19]([NH:18][C:14]1[CH:15]=[C:16]([Cl:17])[C:11]([O:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:34][C:6]=3[N:7]=2)=[C:12]([Cl:33])[CH:13]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2sc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)nc2c1
Product: CS(=O)(=O)Nc1ccc2sc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)nc2c1

Procedure:
2-Chloro-N-[3,5-dichloro-4-(5-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide was synthesized from N-[4-(5-Amino-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide (456) and methanesulfonyl chloride (Aldrich) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.87 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.20 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.44 (d, J=1.7 Hz, 1H), 7.32 (s, 2H), 7.21 (dd, J=8.7, 1.6 Hz, 1H). MS (EI): m/z 644 (M−H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[O:14][C:13]([C:15]2[O:19][C:18]([SH:20])=[N:17][N:16]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[CH2:1]([S:20][C:18]1[O:19][C:15]([C:13]2[O:14][C:10]([Br:9])=[CH:11][CH:12]=2)=[N:16][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Sc1nnc(-c2ccc(Br)o2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Brc1ccc(-c2nnc(SCc3ccccc3)o2)o1
Reaction time: 2 h

Procedure:
Benzylbromide (6.18 g, 36.1 mmol) was added over 5 minutes time-period to a mixture of 5-(5-bromo-furan-2-yl)-[1,3,4]oxadiazole-2-thiol (8.5 g, 36.1 mmol), trietylamine (6.96 g, 68.8 mmol) and ethanol (100 ml, 99%). The reaction mixture was stirred at room-temperature for 2 hours. Aqueous sodium hydroxide (50 ml, 1 M) and water (100 ml) was added followed by extraction with diethylether (3×50 ml). The organic phase was washed with water (3×50 ml), dried and evaporated. The product was isolated as a red solid. Yield 10.7 g (92%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[NH2:13][CH2:14][CH2:15]O>C(OCC)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[NH:13][CH2:14][CH2:15][S:12]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: NCCO
Solvent: CCOCC
Product: CC(C)c1ccccc1N=C1NCCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of (2-isopropylphenyl)isothiocyanate (2.00 g) in diethylether (20 ml) was added 2-aminoethanol (0.69 g). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. To the obtained oil was added concentrated hydrochloric acid (5 ml). The mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured into an aqueous solution of 20% sodium hydroxide (25 ml). The mixture was extracted with dichloromethane (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-1,3-thiazolidine (1.80 g, yield: 73%) as a white crystal. M.p. 76–77° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C@@H:24]([OH:25])[CH2:23][CH2:22][C@@:21]2([CH3:26])[C@H:3]1[CH2:4][CH2:5][C:6]1[C:7]3[C@:17]([CH3:27])([CH2:18][CH2:19][C:20]=12)[C@@H:10]([C@H:11]([CH3:16])[CH2:12][CH2:13][CH2:14][OH:15])[CH2:9][CH:8]=3>C1C=CC=CC=1.[Ru](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:25][C@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:26])[C@@H:3]([CH2:4][CH2:5][C:6]3[C:7]4[C@:17]([CH3:27])([CH2:18][CH2:19][C:20]=32)[C@@H:10]([C@H:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[O:15])[CH2:9][CH:8]=4)[C:2]1([CH3:1])[CH3:28]
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C[C@H](CCC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.8 %

Procedure:
4,4-Dimethyl-5α-chola-8,14-dien-3β,24-diol (0.21 g) is dissolved in benzene (21 ml). Tris(triphenylphosphine) ruthenium(II)chloride (1.04 g) is added and the mixture is stirred at room temperature for 20 hours. Purification by column chromatography gives the title compound (129 mg). 1H-NMR (CDCl3, 300 MHz): δ=9.79 (1H, s); 5.36 (1H, s); 1.05 (3H, s); 1.01 (3H, s); 0.95 (3H, d); 0.82 (3H, s); 0.80 (3H, s).