Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][C:3]=1[CH:11]=[O:12].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]1([C:2]2[N:7]=[C:6]3[CH:8]=[CH:9][S:10][C:5]3=[CH:4][C:3]=2[CH:11]=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cc2sccc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cc2sccc2nc1-c1ccccc1
Temperature: 100 °C
Yield: 86.5 %

Procedure:
To a solution of 5-chlorothieno[3,2-b]pyridine-6-carbaldehyde (396 mg, 2.01 mmol) in DME/water (10 mL/2 mL) was added phenylboronic acid (306 mg, 2.51 mmol), K2CO3 (833 mg, 6.03 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol). The mixture was degassed before being heated in a sealed tube at 100° C. for 5 h. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (25 mL), washed with water (2×10 mL) and washed with brine (10 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 0-40% EtOAc in heptane) to give the title compound (416 mg, 86%) as a white solid. δH (CDCl3) 10.15 (s, 1H), 8.88 (s, 1H), 8.97 (d, J 6 Hz, 1H), 7.69 (d, J 6 Hz, 1H), 7.50-7.65 (m, 5H). LCMS (ES+) 240.2 (M+H)+, RT 3.46 minutes (Method 2).
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=O)[C:6]=2[CH:5]=[CH:4]1.[CH3:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[O:31])[CH3:30])([CH3:17])[CH3:16]>C(O)C.O>[CH3:17][C:15]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[O:31])[CH:30]=[CH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][NH:3]2)([CH3:14])[CH3:16]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(=O)c1ccccc1OCCCNC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NCCCOc1ccccc1C(=O)C=Cc1cccc2[nH]ccc12
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
3 ml of 50% sodium hydroxide solution and then 1.484 g of indole-4-carboxaldehyde were added to a solution of 2.55 g of 1-[2-{3-(1,1-dimethylethylamino)-propoxy}-phenyl]-ethanone in 35 ml of ethanol and the mixture was stirred under an inert atmosphere for 20 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 2.804 g of 1-[2-{3-(1,1-dimethylethylamino)-propoxy}-phenyl]-3-[1H-indol-4-yl]-2-propen-1-one.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=C[C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]([O:24][CH3:25])=O)[N:13]=1>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]2[O:24][C:25]3[C:3]([C:8](=[O:11])[C:9]=2[CH3:10])=[CH:2][CH:7]=[CH:6][CH:5]=3)[N:13]=1
Reactant: CCC(=O)c1ccccc1O
Reactant: COC(=O)c1cc2ccccc2cn1
Product: Cc1c(-c2cc3ccccc3cn2)oc2ccccc2c1=O
Yield: 76 %

Procedure:
2-Isoquinolin-3-yl-3-methyl-chromen-4-one was prepared in 76% yield using method A, starting from 2′-hydroxy-propiophenone and methyl isoquinoline-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10]([O:12][CH3:22])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCSc1ccccn1)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](CCSc1ccccn1)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyric acid (0.75 g, 2.40 mmol) in methanol (16 mL) and toluene (50 mL) was added a 2.0M solution of (trimethylsilyl)diazomethane (3.12 mmol) dropwise. After 3 h, the reaction mixture was concentrated to give methyl 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyrate as an oily residue which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.[OH:20][CH2:21][C:22]1[C:23](=[O:29])[N:24]=[C:25]([SH:28])[NH:26][N:27]=1>C(O)C>[C:11]([C:9]1[CH:10]=[C:5]([C:3]2[N:26]3[N:27]=[C:22]([CH2:21][OH:20])[C:23](=[O:29])[N:24]=[C:25]3[S:28][CH:2]=2)[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=c1nc(S)[nH]nc1CO
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Solvent: CCO
Product: CC(C)(C)c1cc(-c2csc3nc(=O)c(CO)nn23)cc(C(C)(C)C)c1O

Procedure:
14.4 g (0.044 mol) of 2-bromo-1-(3,5-di-tert.butyl-4-hydroxyphenyl)-ethanone (Example 1a1) and 7.0 g (0.044 mol) of 6-hydroxymethyl-3-mercapto-2H-1,2,4-triazin-5-one from step (a1) were heated to boiling for 4 hours in 300 ml of ethanol. The reaction mixture, evaporated under reduced pressure, was dissolved in 300 ml of chloroform and treated with 100 ml of saturated sodium hydrogen carbonate solution. The chloroform phase was finally separated off, dried and evaporated. Chromatography of the crude product over silica gel using ethyl acetate/methanol (99:1) as eluent gave colorless needles.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.C([O:23][C:24](=[O:31])[N:25]([CH2:27][CH2:28][CH2:29][NH2:30])C)(C)(C)C.Cl>CO>[C:16]([OH:18])(=[O:23])[CH3:17].[C:24]([OH:23])(=[O:31])[CH3:2].[CH3:24][NH:25][CH2:27][CH2:28][CH2:29][NH:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(-c2cnc3ccc(F)nn23)s1
Agent: Cl
Solvent: CO
Product: CC(=O)O
Product: CNCCCNc1ccc2ncc(-c3ccc(C(C)=O)s3)n2n1

Procedure:
Prepared as in example 5.6.3 from 1-[5-(6-fluoro-imidazo[1,2-b]pyridazine-3-yl)-thiophen-2-yl]-ethanone (50 mg, 0.2 mmol) and N-(3-aminopropyl)-N-methylcarbamic acid tert-butyl ester [150349-36-3] (72 mg, 0.4 mmol) and deprotected with anhydrous HCl in methanol. Purification by preparative RP-HPLC provided 1-{5-[6-(3-methylamino-propylamino)-imidazo[1,2-b]pyridazin-3-yl]-thiophen-2-yl}-ethanone diacetate as a yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.92-1.96 (m, 5H) 2.24 (t, J=7.45 Hz, 1H) 2.62 (s, 2H) 2.80 (s, 2H) 3.23-3.31 (m, 2H) 3.61 (t, J=7.33 Hz, 1H) 6.79 (d, J=9.60 Hz, 1H) 7.70-7.74 (m, 1H) 7.92 (d, J=4.04 Hz, 1H) 8.06 (br. s., 1H). LRMS (ESI) m/z 330.1 [(M+H)]+, calc'd for C16H19N5OS: 329.43.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Cl.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CN(C)C=O>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][N:10]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:9]1[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=2[S:7][CH:8]=1
Reactant: CN(C)CCCCl
Reactant: Fc1ccc2c(Nc3ccncc3)csc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN(c1ccncc1)c1csc2cc(F)ccc12
Temperature: 0 °C
Yield: 74.2 %

Procedure:
6-Fluoro-3-(4-pyridinylamino)benzo[b]thiophene (3.30 g, 13.5 mmol) was added portionwise as a powder to a suspension of sodium hydride (60% oil dispersion, 1.35 g, 33.8 mmol, washed with hexanes) in 50 mL dimethylformamide. After the anion formation was completed, 3-dimethylaminopropyl chloride hydrochloride (2.56 g, 16.2 mmol) was added as a powder and the resultant mixture was stirred at 70-75° C. for two hours. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and dried (anhydrous magnesium sulfate), filtered and concentrated to 4.6 g of a brown oil. Elution through silica with 10% methanol in dichloromethane via flash column chromatography yielded 3.3 g of a yellow oil. Kugelrohr distillation (210-220°/0.1 mm Hg) yielded 2.8 g of a clear colorless oil which eventually solidified to a white solid, mp 82-84°.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:26]=[CH:25][C:18]4[N:19]([CH3:24])[C:20]([CH2:22][OH:23])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CC1C=CC=CC=1>[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:26]=[CH:25][C:18]4[N:19]([CH3:24])[C:20]([CH2:22][O:23][C:33](=[O:35])[CH3:34])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cn1c(CO)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OCc1nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1C
Yield: 74.4 %

Procedure:
A mixture of 1.9 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazole-2-methanol, 1.55 parts of acetic acid anhydride and 45 parts of methylbenzene is stirred and refluxed for 2 hours. The reaction mixture is cooled, washed with a diluted ammonium hydroxide solution and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane (20:20 by volume). The product is filtered off and dried, yielding 1.5 parts (74.4%) of {5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-ylmethyl}acetate; mp. 201.1° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.CN1C(=O)CCC1.[CH2:34]([CH2:36][NH2:37])[OH:35].Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:37][CH2:36][CH2:34][OH:35])=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 110 °C

Procedure:
To a solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (143.3 g, 0.402 mol) in EtOH (1.3 L) was added NMP (0.5 L) and ethanolamine (27.75 g, 0.454 mol). Distilled EtOH over a period of 2 h and the resulting reaction mixture was heated at 110° C. for 45 min. Cooled to 60° C. and added water dropwise (0.47 L), followed by addition of 1N HCl (0.2 L) to pH 2-3. Cooled to room temperature and diluted by dropwise addition of water (1.2 L). The solids which precipitated were collected by filtration, washed with water and dried under vacuum at 70° C. to afford a tan solid. 1H NMR (d6-DMSO) δ 10.41 (1H, t, J=5.5 Hz), 8.53 (1H, s), 8.00 (1H, s), 7.39-7.35 (2H, m), 7.15-7.10 (2H, m), 4.92 (1H, t, J=5 Hz), 4.15 (2H, s), 3.58 (3H, s), 3.55-3.53 (2H, m), 3.44-3.40 (2H, m); ES+ MS: 372 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:17]([O:20][C:21]1[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27](O)=O)=[CH:23][CH:22]=1)[CH2:18][CH3:19]>>[CH2:17]([O:20][C:21]1[CH:22]=[CH:23][C:24](/[CH:25]=[CH:26]/[C:27]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[CH:30][CH:31]=1)[CH2:18][CH3:19]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CCCOc1ccc(C=CC(=O)O)cc1
Product: CCCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CCC)c(=O)n3CCC)cc1
Yield: 32.4 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.01 g (14.6 mmol) of 4-propoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.71 g (yield 33%) of Compound 49 as pale brown needles.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[CH:5]1([NH:11][C:12]2[CH:13]=[C:14]([C@@H:18]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:19]3[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH:5]1([NH:11][C:12]2[CH:13]=[C:14]([C@@H:18]([N:32]3[CH2:37][CH2:36][N:35]([CH2:1][CH2:2][CH3:3])[CH2:34][CH2:33]3)[C:19]3[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CCC=O
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCN1CCN([C@@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NC3CCCCC3)c2)CC1
Reaction time: 8 h
Yield: 61498.2 %

Procedure:
To a room temperature solution of propionaldehyde (40.6 μL 0.56 mmol) and COMPOUND 27 (250 mg; 0.56 mmol) in 1,2-dichloroethane was added sodium triacetoxy borohydride (380 mg; 1.79 mmol) and acetic acid (31.9 μL; 0.56 mmol). The reaction mixture was stirred overnight then was washed with saturated sodium bicarbonate, followed by water. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 5% methanol in dichloromethane gave COMPOUND 73 (169 g; 62% yield). Purity (HPLC-215 nm): >99%; Optical purity (Chiral HPLC-215 nm): >99%. 1H NMR (400 MHz, CD3OD) δ 0.99 (t, J=7.91 Hz, 2H), 1.10-1.16 (m, 3H), 1.28-1.33 (m, 4H), 1.61-1.65 (m, 4H), 1.75-1.79 (m, 4H), 1.83-1.90 (m, 4H), 2.97-3.01 (m, 2H), 3.13-3.15 (m, 2H), 3.17-3.28 (m, 8H), 3.42-3.46 (m, 2H), 3.52-3.54 (m, 1H), 5.08 (s, 1H) 7.24-7.29 (m, 3H), 7.48-7.51 (m, 3H), 7.55-7.57 (m, 1H), 7.62 (d, J=7.42 Hz, 1H). Found: C, 56.59; H, 7.89; N, 8.25. C31H46N4O×4.3HCl×0.6H2O has C, 56.56; H, 7.89; N, 8.51%. [α]D16=+14.5 deg [c 0.50, MeOH].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][CH:7]=[C:6]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1.C1OCCOCCOCCOCCOC1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:35]=1>O1CCCC1.O>[C:13]([O:12][C:11](=[O:17])[N:10]([CH2:9][C:6]1[CH:5]=[C:4]([Br:3])[N:8]([S:40]([C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)(=[O:42])=[O:41])[CH:7]=1)[CH3:18])([CH3:14])([CH3:15])[CH3:16]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CN(Cc1c[nH]c(Br)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 7.4 g) in tetrahydrofuran (300 mL) was added a solution of tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (44.5 g) in tetrahydrofuran (60 mL) at 0° C., and 15-crown-5 (40.7 g) and pyridine-3-sulfonyl chloride (30.1 g) were added at the same temperature. The mixture was stirred at room temperature for 30 min, water was added and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a mixed solvent of diisopropyl ether-hexane=1:1 to give the title compound as colorless crystals (yield 45.2 g, 68%).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[N:15][C:14]=3[C:24]([OH:26])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC(C=O)=CC=1.[CH2:35]([O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH2:50])[CH:45]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:24]([C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:26])[CH:45]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)c1nc(-c2ccncc2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: O=Cc1ccncc1
Product: O=C(OCc1ccccc1)c1cccc(NC(=O)c2nc(-c3ccncc3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-pyridine-4-yl-1H-imidazole-4-carboxylic acid (prepared according to the procedure of Example 70, steps a and b, with the modification that pyridine-4-carboxaldehyde was used instead of 2-dimethylamino-benzaldehyde in step a) was reacted with 3-amino-benzoic acid benzyl ester according to the procedure of Example 177, step a to afford 3-{[5-(2-adamantan-1-yl-ethyl)-2-pyridine-4-yl-1H-imidazole-4-carbonyl]-amino}-benzoic acid benzyl ester. The benzyl group was removed following the procedure of Example 1, step e, to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 13.20 (1H, br s), 9.88 (1H, s), 8.67 (2H, dd), 8.47 (1H, s), 8.00 (3H, m), 7.64 (1H, d), 7.41 (1H, t), 3.01 (2H, m), 1.95 (3H, br s), 1.65 (6H, m), 1.55 (6H, s), 1.44 (2H, m). The product was converted to the maleic acid salt and lyophilised from water/dioxan. Found: C, 60.81; H, 6.48; N, 8.95%. C32H34N4O7.2.5 mols H2O requires: C, 60.85; H, 6.22; N, 8.87%.
Reaction SMILES: [BrH:1].[Br:2][CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=O.[CH:15]([NH2:17])=[S:16]>CN(C)C=O>[BrH:2].[BrH:1].[NH:11]([C:8]1[S:9][CH:10]=[C:6]([C:4]2[N:17]=[CH:15][S:16][CH:3]=2)[N:7]=1)[C:12]([NH2:14])=[NH:13]
Reactant: NC=S
Reactant: N=C(N)Nc1nc(C(=O)CBr)cs1
Agent: Br
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc(-c2cscn2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
A mixture of 1.8 g (5.2 mmol) of 2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide, 0.34 g (5.5 mmol) of thioformamide, and 10 ml of dimethylformamide was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was triturated with acetonitrile. The resulting precipitate was collected by filtration, washed with acetonitrile, and dried to afford 1.74 g (85%) of 2-guanidino-4-(4-thiazolyl)thiazole dihydrobromide. This was dissolved in 10 ml of water, and 1 ml of saturated sodium bicarbonate solution was added. The resulting precipitate was collected by filtration, washed well with water, then acetonitrile, then dried in vacuo to afford 1.17 g of 2-guanidino-4-(4-thiazoyl)thiazole as a white solid, mp 220°-222°; nmr (DMSO-d6) (δ): 8.96 (s, 1H); 7.96 (s, 1H); 7.18 (s, 1H); 7.0 (b, 4H); calcd. for C7H7N5S2 : C, 37.32; H, 3.13; N, 31.09; found: 36.94; H, 3.52; N, 29.74.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[N:20]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[CH:3]1.[CH3:31][C:32](C)([O-])[CH3:33].[K+].C(Br)C=C.O>CN(C)C=O>[CH2:33]([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[C:4]2[C:12]1[N:20]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH:13]=1)[CH:32]=[CH2:31]
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(O)cc34)cc3cccnc32)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C=CCBr
Product: C=CCOc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
A solution of 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-ol [2.1 g, Reference Example 14(a)] in dry dimethylformamide (50 mL) was treated with potassium tert-butoxide (620 mg) at 0° C. under nitrogen. After stirring for 10 minutes the mixture was treated with allyl bromide (480 μl) and then allowed to warm slowly to ambient temperature. Stirring was continued for a further 6 hours after which time the mixture was poured carefully into water and the aqueous phase extracted exhaustively with ethyl acetate. The combined organic extracts were washed twice with brine (100 mL), then dried over sodium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound (1.2 g) as a yellow foam, m.p. 257-259° C. MS: 458(MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(O[CH2:24][CH3:25])(=O)C.CO>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([N:7]1[CH2:8][CH2:4][CH:24]([CH2:25][N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH2:5][CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:13]([N:7]1[CH2:8][CH2:4][CH:5]([CH2:24][CH2:25][N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CCOC(C)=O
Reactant: CCCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Fc1ccc2c(ccn2CC2CCN(Cc3ccccc3)CC2)c1
Product: Fc1ccc2c(ccn2CCC2CCN(Cc3ccccc3)C2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 36 %
Yield: 15 %

Procedure:
5-Fluoro-indole (391 mg, 2.89 mmol) in DMF (2 mL) was added drop-wise to a stirred suspension of sodium hydride (60%, 116 mg, 3.04 mmole) in DMF (2 mL) at 0° C. After 30 minutes compound a) (987 mg, 3.47 mmol), dissolved in DMF (6 mL), was added and the reaction mixture was stirred at 50° C. over night. The mixture was diluted with ethyl acetate, washed three times with water and dried over sodium sulfate. Evaporation of the solvent gave the crude product as a mixture of two constitution isomers. Silica gel chromatography (heptane-ethyl acetate-methanol, 20:80:5) gave the sub-title compound (138 mg, 15%) and 1-[2-(1-benzyl-pyrrolidin-3-yl)-ethyl]-5-fluoro-1H-indole (338 mg 36%).