Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:35]=[CH:34][N:14]3[C:15](=[O:33])[C:16](/[CH:25]=[C:26](\[CH3:32])/[C:27]([O:29]CC)=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO.O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:35]=[CH:34][N:14]3[C:15](=[O:33])[C:16](/[CH:25]=[C:26](\[CH3:32])/[C:27]([OH:29])=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C(C)=C/c1c(N2CCOCC2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C/C(=C\c1c(N2CCOCC2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.3 %

Procedure:
The ethyl (E)-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-methyl-2-propenoate (14 mg) obtained in (A) was dissolved in tetrahydrofuran (4 ml) and methanol (1 ml), added with a solution of lithium hydroxide (1.4 mg) in water (1 ml) and stirred at room temperature for 1.5 hours. The reaction mixture was added with water and washed with ether, and then the aqueous layer was made acidic with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (4.4 mg) as yellow powder.
Reaction SMILES: [N:1]#[N:2].C(OC([NH:13][C@@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:15]([OH:31])[CH2:16][C@@:17]1([C:28]([NH2:30])=[O:29])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:1]#[N:2].[NH2:13][C@@H:14]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@H:15]([OH:31])[CH2:16][C@@:17]1([C:28]([NH2:30])=[O:29])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)[C@]1(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)CCCN1c1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: NC(=O)[C@]1(C[C@@H](O)[C@@H](N)Cc2ccccc2)CCCN1c1ccccc1
Yield: 94.6 %

Procedure:
A solution of 0.45 g of N2 -[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N1 -phenyl-L-prolinamide in 20 ml of ethanol was hydrogenated over 10% palladium-on-carbon for 4 hours to give 0.315 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -phenyl-L-prolinamide in the form of a white solid; MS: m/e 354 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH3:22])[C:9]1[N:10]=[C:11](O)[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([N:8]([CH3:22])[C:9]1[N:10]=[C:11]([Cl:25])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(N(C)Cc3ccccc3)cc2c1
Product: COc1ccc2c(Cl)nc(N(C)Cc3ccccc3)cc2c1
Temperature: 0 °C
Yield: 75 %

Procedure:
A solution of 3-(benzyl(methyl)amino)-6-methoxyisoquinolin-1-ol (1.8 g, 6.12 mmol) in POCl3 (10 mL) was refluxed for 4 h. After concentration, the residue was taken into a mixture of 100 mL of DCM and 50 mL of water, cooled to 0° C., neutralized with 3 N NaOH, dried over MgSO4, and concentrated to give N-benzyl-1-chloro-6-methoxy-N-methylisoquinolin-3-amine (1.44 g, 4.60 mmol, 75% yield) as a yellow solid. MS: MS m/z 313.15(M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:4][CH:3]=1.[N+:37]([C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[O:48])=[CH:42][CH:41]=1)([O-:39])=[O:38]>CN(C)C=O>[O:31]=[C:29]1[NH:28][C:27](=[O:32])[CH:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([O:20][CH2:19][C:17]3[N:16]([CH3:35])[C:15]4[CH:36]=[C:11]([O:10][CH2:9][CH2:8][C:5]5[CH:6]=[CH:7][C:2]([NH:1][C:47]([NH:46][C:43]6[CH:42]=[CH:41][C:40]([N+:37]([O-:39])=[O:38])=[CH:45][CH:44]=6)=[O:48])=[CH:3][CH:4]=5)[CH:12]=[CH:13][C:14]=4[N:18]=3)=[CH:22][CH:23]=2)[S:30]1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(N)cc3)cc21
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(NC(=O)Nc4ccc([N+](=O)[O-])cc4)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-[4-[6-[2-(4-aminophenyl)ethoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (4 g) and N,N-dimethylformamide (10 ml) was added 4-nitrophenyl isocyanate (0.16 g) and the mixture was stirred at room temperature for 1 hour and allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To the residue was added ethyl acetate. The precipitate was isolated by filtration and purified by preparative normal phase medium pressure liquid chromatography using ethyl acetate:tetrahydrofuran=4:1 as the eluant to give 1-[4-(2-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]ethyl)phenyl]-3-(4-nitrophenyl)urea. To a solution of the product in a mixture of tetrahydrofuran and methanol (1:1, 10 ml) was added 4N hydrogen chloride in 1,4-dioxane (2 ml) and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated and the residue was recrystallized from a mixture of methanol and tetrahydrofuran to afford the title compound (0.16 g, mp 170° C.(dec)).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.CC(C)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=3)[CH:8]=2)[N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Solvent: CC(C)=O
Solvent: O
Product: Fc1ccc(COc2ccc3nc(Cl)ccc3c2)cc1
Yield: 22 %

Procedure:
To a stirred solution of 2-chloro-6-hydroxy-quinoline (0.6 g, 3.0 mmol) in acetone (15 ml) potassium carbonate (0.55 g, 4.0 mmol) and 4-fluorobenzylbromide (0.76 g, 4.0 mmol) were added at ambient temperature. Then the reaction mixture was heated to reflux for 3 h. Upon cooling to ambient temperature water was added and the whole mixture extracted twice with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane, ethyl acetate 1:0=>1:4) yielded 2-chloro-6-(4-fluoro-benzyloxy)-quinoline as a white solid (0.19 g, 20%), MS 288.8 [(M+H)+].
Reaction SMILES: [C:1]([C:3]1[CH:44]=[CH:43][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:14]3[C:22]([O:23][CH:24]([F:26])[F:25])=[CH:21][C:20]([CH3:27])=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4C(OC(C)(C)C)=O)([O:12][CH3:13])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC(F)F)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(OC)C)N(COCC[Si](C)(C)C)C=2C=1)#N.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:26][CH:24]([F:25])[O:23][C:22]1[C:14]([C:10]([C:8]2[NH:7][C:6]3[CH:43]=[CH:44][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)([O:12][CH3:13])[CH3:11])=[C:15]2[C:19](=[C:20]([CH3:27])[CH:21]=1)[NH:18][CH:17]=[CH:16]2
Reactant: COC(C)(c1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COC(C)(c1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: COC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC(F)F)cc(C)c2[nH]ccc12
Temperature: 60 °C

Procedure:
To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (475 mg, 0.758 mmol) in THF (7.6 mL) at room temperature, ethylenediamine (0.51 mL, 7.58 mmol) was added followed by TBAF (1M in THF, 7.6 mL, 7.6 mmol) and the reaction was stirred at 60° C. After 6 hours the reaction was cooled to room temperature, additional ethylenediamine (0.51 mL, 7.58 mmol) and TBAF (1M in THF, 7.6 mL, 7.6 mmol) were added and the reaction was stirred at 60° C. overnight. The reaction was cooled to room temperature, quenched with NH4Cl and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.68-12.85 (m, 1H) 11.19 (br. s., 1H) 8.09 (m) 7.83 (m) 7.69-7.74 (m) 7.47-7.58 (m) 7.31 (t, J=2.78 Hz, 1H) 6.89-6.96 (m) 6.70-6.77 (m) 6.46-6.58 (m) 3.01-3.17 (m, 3H) 2.46 (s, 3H) 2.07 (s, 3H). HRMS calcd. for C21H18F2N4O2 (M+H)+ 397.1471. found 397.1482.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1>>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])=[CH:18][CH:19]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: Cc1ccc(C)cc1
Product: Cc1ccc(CON2C(C)(C)CC(O)CC2(C)C)cc1
Yield: 28.8 %

Procedure:
A mixture of 8.60 g (0.05 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 106.17 g (1.0 mol) of p-xylene under a nitrogen atmosphere is heated at reflux for 48 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is washed with 10 w/v % ascorbic acid (1×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from heptane to give 4.00 g (59% yield) of a white solid melting at 92.5-93° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([C:38]1[CH:49]=[CH:48][C:41]([C:42](N(OC)C)=[O:43])=[CH:40][N:39]=1)#[N:37]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:42]([C:41]2[CH:48]=[CH:49][C:38]([C:36]#[N:37])=[N:39][CH:40]=2)=[O:43])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccc(C#N)nc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3ccc(C#N)nc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 6-cyano-N-methoxy-N-methylnicotinamide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([C:14]1[CH:15]=[C:16]([CH:20]([C:23]2[NH:24][CH:25]=[CH:26][CH:27]=2)CC)[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+].[CH3:31][CH2:32]OCC>>[O:7]([C:14]1[CH:19]=[C:18]([CH2:17][CH2:16][CH2:20][C:23]2[NH:24][CH:25]=[CH:26][CH:27]=2)[CH:31]=[CH:32][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOCC
Reactant: CCC(c1cccc(Oc2ccccc2)c1)c1ccc[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: c1ccc(Oc2cccc(CCCc3ccc[nH]3)c2)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a slurry of lithium aluminum hydride 1.0892 g (27.3 mmol) in 200 ml of ether under a nitrogen atmosphere, a solution of 2 g (6.82 mmol) of 1-hydroxy-3-(3-phenoxyphenyl-1-(2-pyrrolyl)propane, dissolved in ether was added over a period of 5 min. The mixture was stirred at room temperature for 19 hours and then refluxed for an additional 75 min. The mixture was cooled in an ice bath and 1 ml of water was added followed by 1 ml of 15% w/w NaOH solution followed by 3 ml of water. The mixture was stirred for 30 min. The solids were filtered off and the filtrate was evaporated to dryness yielding 2 g of amber oil. After three chromatographic runs (on silica gel for dry column chromatography), in which the eluants were mixtures of ethyl acetate and hexane, 1.26 g of pure product 10 was obtained as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[N:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Reactant: Clc1ncccn1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(c4ncccn4)CC3)cc2)C(=O)O1

Procedure:
Using an analogous procedure to that described in Example 25, the TFA salt of Example 2 was reacted on a 1.5 mM scale with 2-chloropyrimidine, to give the title compound. Yield=220 mg, 36%.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].COC(OC)(N(C)C)C.C(OCC)(=O)C.[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][C:32]2=[O:40])[CH:28]=[CH:29][CH:30]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[CH:3][N:4]([CH3:6])[CH3:5])[C:32]2=[O:40])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C1Cc2ccccc2N1c1cccc(Cl)c1
Reactant: COC(OC)N(C)C
Agent: COC(C)(OC)N(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21

Procedure:
By the procedure of Example A1, but substituting an equivalent of dimethylformamide dimethylacetal for the dimethylacetamide dimethylacetal, using first methylene chloride and then 7.5% ethyl acetate in methylene chloride in chromatography and recrystallization from ether-pentane, 1-(3-chlorophenyl)-2(1H,3H)-indolone (10 g, 0.041 mole) was converted to title product, 3.73 g, m.p. 116°-118°.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].Cl.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]1[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=1)[CH:15]=[C:14]2[C:30](Cl)=[O:31].[K+].[Br-]>CO>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]1[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=1)[CH:15]=[C:14]2[C:30]([NH:4][C:3]([NH2:5])=[NH:2])=[O:31]
Reactant: O=C(Cl)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Br-]
Solvent: CO
Product: N=C(N)NC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12
Reaction time: 2 h

Procedure:
3.11 g (32.55 mmol) of guanidine hydrochloride are added to a solution of 1.76 g (32.55 mmol) of sodium methoxide in 60 cm3 of methanol at a temperature in the region of 20° C. under an argon atmosphere. After stirring at this temperature for 2 hours, the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 60 cm3 of 1,2-dimethoxyethane, and 2.46 g (6.51 mmol) of 5-chloro-3-chlorocarbonyl-1-(quinolin-4-yl)-1H-indole hydrochloride are added. After stirring at the reflux temperature of the solvent for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in 250 cm3 of water and the suspension is filtered and then dried. The residue is purified by chromatography on silica gel [eluent: dichloromethane/methanol (85/15 by volume)]. After the fractions containing the expected product have been concentrated to dryness under reduced pressure (2.7 kPa), 1.2 g of 5-chloro-3-guanidinocarbonyl-1-(quinolin-4-yl)-1H-indole are obtained in the form of a beige-colored powder melting at a temperature above 260° C. Mass spectrum (CI): m/e 363 (M+H)+)+ (base peak). IR spectrum (KBr): 3466; 3398; 3322; 1636; 1593; 1571; 1510; 1451; 1383; 1356; 1265; 1219; 881; 810; 792; 775 and 649 cm−1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][O:11][CH3:12])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:26][C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@H:21]1[CH:22]=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:26][C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@H:21]1[CH:22]([OH:23])[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][O:11][CH3:12])=[CH:4][CH:3]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COCOCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCOCc1ccc(C(O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
1.6M n-Butyl lithium-hexane solution (104 ml, 167 mmol) was added dropwise to a solution of 1-bromo-4-(methoxymethoxymethyl)benzene (38.6 g, 167 mmol) in tetrahydrofuran (350 ml) at -78° C. in a nitrogen stream over 30 minutes. This reaction solution was stirred at -78° C. for 30 minutes and then a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (27.5 g, 83.5 mmol) in tetrahydrofuran (300 ml) was added dropwise thereto over 1 hour. This reaction solution was stirred at -70° C. for 2 hours and then warmed and saturated aqueous ammonium chloride was added thereto at -20° C. To the reaction mixture, a liquid mixture of ethyl acetate with water was added. The organic layer was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting oily residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=4:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[α-hydroxy-4-(methoxymethoxymethyl)benzyl]pyrrolidine (24.1 g, yield: 59.8%) as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17](Br)=[C:16]([CH3:19])[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:36]=[O:37]>CCCCCC.O1CCCC1>[CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH:36]=[O:37])=[C:16]([CH3:19])[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(C)c(Br)c3cnnc(OCc4ccccc4)c32)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(Cn2c(C)c(C=O)c3cnnc(OCc4ccccc4)c32)cc1
Yield: 36 %

Procedure:
440 mg (1.0 mmol) of 7-benzyloxy-3-bromo-1-(4-methoxybenzyl)-2-methylpyrrolo[2,3-d]pyridazine, 735 μl (1.2 mmol) of a 15% strength solution of n-butyllithium in hexane and 160 μl (1.2 mmol) of dimethylformamide are reacted in 25 ml of tetrahydrofuran as described for Example 2a. Yield: 36%, m.p.: 139°-145° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[N:7]([CH2:15][C:16]#[N:17])[CH:6]=1)(=[O:4])=[O:3].CC1C=C2C([CH:23]=[CH:24][NH:25]2)=CC=1.C(N)CN.Cl>CO.C(O)C.O.C(=S)=S>[NH:17]1[CH2:23][CH2:24][N:25]=[C:16]1[CH2:15][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6]1
Reactant: Cc1ccc2c(S(C)(=O)=O)cn(CC#N)c2c1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: O
Solvent: NCCN
Solvent: CO
Product: Cc1ccc2c(S(C)(=O)=O)cn(CC3=NCCN3)c2c1
Temperature: 142 °C
Reaction time: 0.33 h

Procedure:
(3-Methanesulfonyl-6-methyl-indol-1-yl)-acetonitrile (0.4 g, 1.611 mmole) prepared from 6-methylindole as described in Steps 1-4 above, was added to ethylene diamine (4.3 ml, 438 mmole) in a reaction tube. A single drop of carbon disulfide was carefully added. The mixture was heated in a microwave reactor at 142° C. for 30 minutes. Upon cooling, the reaction mixture was poured into a mixture of ice and water, stirred 20 minutes and filtered. The colorless precipitate collected was washed with water (20 ml) and dried under vacuum at room temperature. The free base thus obtained (420 mg, 90% yield) was converted into the hydrochloride salt by first dissolving in methanol and then adding an excess of HCl in ethanol. The mixture was stripped to dryness and recrystallized from a mixture of ethyl acetate-methanol to afford 344 mg of 1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-6-methyl-1H-indole, mp >300° C. as the hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[C:35]([CH3:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:29]=[C:30]4[C:35]([CH3:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Cc1cc(Br)cnc1N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 130 °C
Yield: 17.2 %

Procedure:
1.25 g (2.81 mmol) {1-[4-(2-Bromo-2-phenyl-acetyl)phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 631.4 mg (3.38 mmol) 2-amino-5-bromo-3-methyl-pyridine, 2.15 g molecular sieves (4 Å, dried over night at 120° C. in a drying oven), 363.5 mg (2.81 mmol) N,N-diisopropylethylamine in 12 mL 2-propanol (degassed for 15′) in a microwave vial, sealed with a microwave cap, were heated at 130° C. for 17 hours in a heating block. The reaction mixture was sucked off via a glass fibre filter and the filter was washed with dichloromethane. After evaporation to dryness, the residue was redissolved in dichloromethane (200 mL), washed with an 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate (50 mL) and brine (100 mL) and dried (sodium sulfate). After filtration and removal of the solvent the residue was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 256.7 mg (17.1%) of the title compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][N:14]=[CH:13]1.FC1C=CC=C2C(OC(=O)C=12)=O.ClC1C=C2C(=O)OC(=O)C2=CC=1Cl.CC1C=C2C(=O)OC(=O)C2=CC=1>C(Cl)Cl>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:4](=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]([OH:6])=[O:11])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: NCCCn1ccnc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cc1ccc2c(c1)C(=O)OC2=O
Agent: O=C1OC(=O)c2c(F)cccc21
Agent: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)NCCCn1ccnc1

Procedure:
A mixture of 0.01 mole of phthalic anhydride, 0.01 mole of 3-(1H-imidazol-1-yl)propanamine and 30 ml. of methylene chloride was stirred at room temperature for 3 hours and concentrated. The residue was recrystallized from ethanol whereby the desired product, m.p. 160°-162° C., was obtained. By substituting 3-fluorophthalic anhydride, 4,5-dichlorophthalic anhydride, and 4-methylphthalic anhydride for the phthalic anhydride of this example, the compounds set forth in Table XX below were obtained.