Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:13]([Cl:23])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:25][N:26]1[C:30]([C:31]([C:33]2[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=2)=[O:32])=[CH:29][N:28]=[CH:27]1>>[N:1]1([C:5]2[C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:13]([Cl:23])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:31]([C:30]4[N:26]([CH3:25])[CH:27]=[N:28][CH:29]=4)([C:33]4[CH:34]=[N:35][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:37][CH:38]=4)[OH:32])[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccc(Oc2c(N3CCC3)nc3ccc(Br)cc3c2Cl)cc1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CCC3)c(Oc3ccc(Cl)cc3)c(Cl)c2c1

Procedure:
The title compound was prepared using 2-(azetidin-1-yl)-6-bromo-4-chloro-3-(4-chlorophenoxy)quinoline (Intermediate 9, step d) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) according to the procedure of
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][C:11]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(O)ccc1C(=O)c1ccc(Br)cc1
Temperature: 90 °C
Yield: 123.5 %

Procedure:
To a solution of (4-bromophenyl)[2-methyl-4-(methyloxy)phenyl]methanone (27) (1.12 g, 3.67 mmoL) in benzene (25 mL) was added AlCl3 (1.98 g, 14.85 mmol). The mixture was heated at 90° C. for 3 h. Upon cooling, water (25 mL) was added, and the mixture was extracted with Et2O. The organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography on silica gel (EtOAc:hexanes) to yield 1.32 g (86%) of compound 28. 1H NMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H), 6.63 (dd, J=2.4 Hz, 8.4 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 10.10 (s, 1H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[CH:15]([C:21]([O:23][CH3:24])=[O:22])[C:16]([CH3:20])(Br)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+]>C(#N)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[C:15]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([CH3:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C1=C(C)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Yield: 23.3 %

Procedure:
A mixture of methyl 7-(2-phenoxyacetamido)-3-methyl-3-bromocepham-4-carboxylate (210 mg.) in acetonitrile (5 cc) and anhydrous sodium acetate (100 mg.) was heated under reflux for 6.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution washed with water, dried and then concentrated. The residue was crystallized from a mixture of ether and methanol to yield crystals (40 mg.) of methyl 7-(2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 124°-125° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=O)[CH:2]=[CH2:3].C(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.CO[CH:32](OC)[CH2:33][NH2:34].O1CCOCC1>O1CCOCC1>[CH2:1]([N:4]1[CH:32]=[CH:33][N:34]=[C:5]1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH:2]=[CH2:3]
Reactant: COC(CN)OC
Reactant: C=CCNC(=O)c1sccc1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CCn1ccnc1-c1sccc1-c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of N-allyl-3-(2,4-dichlorophenyl)thiophene-2-carboxamide (8.60 g, 27.5 mmol) in DCM (309 mL, 4820 mmol) was added phosphorus pentachloride (6.54 g, 31.4 mmol) and 4 M hydrochloric acid in 1,4-dioxane (0.51 mL, 2.00 mmol) and the mixture was heated to 60° C. for 2 hrs. The reaction was cooled to room temperature and aminoacetaldehyde dimethyl acetal (33.9 mL, 311 mmol) was slowly added. The resulting mixture was heated at 60° C. for 2.5 hrs. To the reaction mixture was added 4 M hydrochloric acid in 1,4-dioxane (200 mL, 783 mmol) and the mixture was stirred at 60° C. overnight. After cooling to room temperature, the suspension was filtered through a Celite pad and the solid residue was washed with 1,4-dioxane. The filtrate was evaporated down and the resulting residue was dissolved in water (300 mL) and extracted with EtOAc (2×150 mL). The water layer was basified by addition of solid NaHCO3 until pH 9, and the aqueous was extracted with EtOAc (3×300 mL). All organics were combined and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 8-25% EtOAc in DCM) to give crude product which was further purified by column chromatography (SiO2, elution with 45% MeCN: 50% DCM: 5% EtOAc) to provide 7.12 g of product (76%). LC/MS (FA), ES+ 337. NMR (400 MHz, d6 DMSO) δ: 7.80 (d, J=5.3 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.35 (dd, J=2.0, 8.3 Hz, 1H), 7.26 (d, J=5.3 Hz, 1H), 7.13 (d, J=1.3 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.98 (d, J=1.3 Hz, 1H), 5.47-5.58 (m, 1H), 4.98-5.02 (m, 1H), 4.75-4.82 (m, 1H), 4.19-4.23 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][S:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:8][C:7]=1[NH2:18])#[N:2].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].O>CN1C(=O)CCC1>[C:1]([CH2:3][CH2:4][S:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:8][C:7]=1[NH:18][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1)#[N:2]
Reactant: N#CCCSc1cc(N)c(SCCC#N)cc1N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#CCCSc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(SCCC#N)cc1N
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
2,5-Bis[(cyanoethyl)thio]-1,4-phenylenediamine (13.9 g, 50 mmol) was dissolved in 90 mL of NMP in a 250 mL 3-necked round-bottom flask under nitrogen purge. The resultant clear red solution was cooled to 0˜5° C. in an ice bath, followed by addition of freshly distilled triethylamine (TEA) by syringe. After stirring for 10 minutes, a mixture of 4-nitrobenzoyl chloride (10.2 g, 55 mmol) and 90 mL of NMP was added into the stirred red solution drop by drop over a period of 0.5 h. The resultant solution was stirred at 0˜5° C. for 2 h and at room temperature for 1 h, followed by addition of 800 mL of water with stirring. The resultant yellow precipitate was collected by filtration, followed by washing with 800 mL of deionized water twice and 300 mL of methanol once. The obtained product was extracted with methanol using a Soxhlet extractor for 24 h. A yellow solution was collected and evaporated, followed by drying at 60° C. under vacuum overnight, giving the title compound as a red powder (13.1 g, yield 61%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[C:16]1([CH:22]=[CH:23][CH2:24]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:24][CH:23]=[CH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(Cl)cnn1CC=Cc1ccccc1
Yield: 88.6 %

Procedure:
To a suspension of 16.5 g (100 mmoles) of 4,5-dichloro-3(2H)-pyridazinone and 150 g (163 mmoles) of anhydrous potassium carbonate in 100 ml of anhydrous dimethylformamide a solution of 16.8 g (110 mmoles) of 3-phenyl-2-propenyl chloride in 5 ml of anhydrous dimethylformamide is dropped under stirring and cooling at a temperature below 15° C. The reaction mixture is stirred at room temperature for a day and poured onto 600 ml of water under stirring. The separated crystals are filtered, washed with water, dried and optionally purified by treating with aluminium oxide in a benzene solution. Thus 24.9 g (89%) of the desired compound are obtained. M.p.: 98°-99° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([Mg]Br)[CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:31])[CH2:35][CH3:36])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Reactant: CC[Mg]Br
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C(=O)CC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 64A(i), but using N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-formyl-2-methoxyphenyl)-octanamide (prepared as described in Preparation 63A) and ethylmagnesium bromide, the title compound was obtained as a foam-like substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[OH:28])[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[OH:28])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:18]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1O
Yield: 100 %

Procedure:
The title compound (37 mg, 100%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3-ethoxy-4-hydroxy-benzaldehyde. MS: 370.5 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.O.C(=O)(O)[O-].[Na+].[IH:16]>>[I:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: CSc1nccc(Cl)n1
Reactant: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CSc1nccc(I)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 g (0.31 mole) of 4-chloro-2-methylthiopyrimidine is solubilised in 300 mL of hydriodic acid at room temperature. The reaction mixture is stirred at room temperature for 8 hours. The reaction mixture is poured into 1.2 L of water and the pH adjusted to 8 with solid sodium bicarbonate. The mixture is extracted with dichloromethane and washed with sodium thiosulfate. After concentration the oily residue gives 74 g of 4-iodo-2-methylthiopyrimidine.
Reaction SMILES: [Br:1]B1C2CCCC1CCC2.C(Cl)Cl.[C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)#[CH:15].C(O)(=O)C.[OH-].[Na+].OO>>[Br:1][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH2:15]
Reactant: BrB1C2CCCC1CCC2
Reactant: C#CC1CCCCC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C=C(Br)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9-bromo-9-bora-bicyclo[3.3.1]nonane 1 M in DCM (33 mL, 33 mmol) at 0° C. was added ethynylcyclohexane (3.6 mL, 28 mmol) under argon via syringe slowly dropwise in portions over 10 min. The reaction mixture was allowed to stir 3 h, at which point acetic acid (4.8 mL, 83 mmol) was added dropwise in portions over 20 min. After 1 h additional, sodium hydroxide (17 mL, 166 mmol) was added slowly, followed by cautious addition of hydrogen peroxide (8.5 mL, 83 mmol). The reaction mixture was allowed to stir rapidly 1 h, then was warmed to ambient temperature. The reaction mixture was partitioned between hexanes and water, and the organic layer was washed with saturated aq. Sodium bicarbonate, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting liquid was filtered through a 3 cm pad of silica gel, rinsing with 200 mL hexanes, and the filtrate was concentrated in vacuo to give crude (1-bromovinyl)-cyclohexane as a clear/colorless oil which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[C:4]2[CH:15]=[C:14]([S:16][CH3:17])[CH:13]=[CH:12][C:5]=2[S:6][C:7]=1[C:8](OC)=[O:9].[NH2-:19].[Li+]>>[CH3:1][N:2]([CH3:18])[C:3]1[C:4]2[CH:15]=[C:14]([S:16][CH3:17])[CH:13]=[CH:12][C:5]=2[S:6][C:7]=1[C:8]([NH2:19])=[O:9]
Reactant: [NH2-]
Reactant: COC(=O)c1sc2ccc(SC)cc2c1N(C)C
Agent: [Li+]
Product: CSc1ccc2sc(C(N)=O)c(N(C)C)c2c1
Yield: 64 %

Procedure:
Prepared from methyl 3-dimethylamino-5-(methylthio)benzo[b]thiophene-2-carboxylate by reaction with lithium amide as described in Example 19. Purification of the crude product by flash chromatography (silica gel, elution with 30% ethyl acetate in hexane) gives 64% of product; mp=140°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25](Cl)(=[O:27])=[O:26])[CH:24]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:27])=[O:26])[CH:24]=1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1cccc(COCc2ccc(F)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 5-fluoro-2-methyl-benzenesulfonyl chloride (0.057 g) as a light yellow gum (0.0476 g). MS (ESI−): 403.2 ([M−H]−)
Reaction SMILES: C([O:8][C:9]([CH:11]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH:45]([CH3:47])[CH3:46])=[CH:40][CH:39]=1)[O:12][C:13]1[CH:37]=[CH:36][C:16]([C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:20]=2)=[O:18])=[CH:15][CH:14]=1)=[O:10])C1C=CC=CC=1>O1CCOCC1.C(O)C.[Pd]>[C:9]([CH:11]([C:38]1[CH:39]=[CH:40][C:41]([CH2:44][CH:45]([CH3:46])[CH3:47])=[CH:42][CH:43]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:20]=2)=[O:18])=[CH:36][CH:37]=1)([OH:10])=[O:8]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(C(=O)OCc3ccccc3)c3ccc(CC(C)C)cc3)cc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(C(=O)O)c3ccc(CC(C)C)cc3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-[3-[4-[(benzyloxycarbonyl)(4-isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyrate (0.36 g) was dissolved in a mixture of 1,4-dioxane (10 ml) and ethanol (10 ml), and 10% palladium on carbon (0.2 g) was added. The mixture was stirred under hydrogen atmosphere at 25° C. for 2 hours. Removal of the catalyst and evaporation of the solvent gave ethyl 4-[3-[4-[(carboxy)(4-isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyrate (0.23. g) as powder.
Reaction SMILES: [Cl-:1].[CH3:2][NH+:3]([CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C.[O:28]1[CH2:47][CH:29]1[CH2:30][O:31][CH2:32][CH2:33][CH2:34][Si:35]([CH3:46])([O:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[O:36][Si:37]([CH3:40])([CH3:39])[CH3:38]>C(O)(C)C>[Cl-:1].[CH3:2][N+:3]([CH3:20])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:47][CH:29]([OH:28])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][Si:35]([CH3:46])([O:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[O:36][Si:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: CCCCCCCCCCCCCCCC[NH+](C)C
Reactant: C[Si](C)(C)O[Si](C)(CCCOCC1CO1)O[Si](C)(C)C
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCC[N+](C)(C)CC(O)COCCC[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 80 °C

Procedure:
A 500-ml, three-necked, round-bottomed flask was equipped with a stirrer, addition funnel, dry ice/acetone condenser, thermometer and electric heating mantle. The flask was flushed continuously with argon. The flask was charged with 167.2 g (0.55 equivalent) of dimethyl hexadecyl ammonium chloride (Sartomer Chemical Company, West Chester, Pa.), 0.028 g (0.27 milliequivalent) of triethylamine (Aldrich), and 250 g of isopropanol. To the stirred flask contents 65.2 g of the epoxy trisiloxane of Example 1 was added over a ten-minute period. The reaction mixture was stirred and heated at 80° C. for five hours to form a clear solution. The reaction mixture was cooled to ambient temperature and flushed overnight with dry argon. The solvent and other low-boiling materials were removed by rotary evaporation at 45° C. The yield of the quaternary ammonium salt (Compound II), a light yellow oil, was 118 g (87%). The elemental analysis was as follows:
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[C:17]([C:13]1[CH:12]=[C:11]([C:10]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:46]=[C:44]([NH:43][C:33]3[CH:34]=[CH:35][C:36]([N:37]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]4)=[C:31]([O:30][CH3:29])[CH:32]=3)[N:45]=2)[CH:16]=[CH:15][CH:14]=1)#[N:18]
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cccc(C#N)c1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1-c1cccc(C#N)c1

Procedure:
The title compound was prepared from ethyl 3-dimethylamino-2-(3-cyano-benzoyl)-acrylate (85 mg, 0.31 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (116 mg, 0.31 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (41 mg, 29%). Mp 195-197° C.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:26])[CH2:6][N:7]([C:12](=[O:25])[C@H:13]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])[NH:14][N+]([O-])=O)[CH2:8][CH2:9][O:10][CH3:11])[CH3:3].[H][H]>C(O)C.[Pd]>[ClH:1].[CH2:2]([O:4][C:5](=[O:26])[CH2:6][N:7]([C:12](=[O:25])[C@H:13]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])[NH2:14])[CH2:8][CH2:9][O:10][CH3:11])[CH3:3]
Reactant: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)N[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CN(CCOC)C(=O)[C@@H](N)CCCNC(=N)N
Yield: 81 %

Procedure:
To a solution of 4.0 g of NG -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in 50 ml of ethanol was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 150 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitation with ethanol-ethyl ether gave 3.0 g (81%) of L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in the form of a powder.
Reaction SMILES: O1CCCC1.C([O:8][C:9](=[O:40])[CH:10]([NH:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH2:11][C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[S:22]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)(=[O:24])=[O:23])[CH:13]=1)C.[OH-].[Li+].Cl>CO>[CH2:37]([O:36][C:34]([NH:33][CH:10]([CH2:11][C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[S:22]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)(=[O:23])=[O:24])[CH:13]=1)[C:9]([OH:40])=[O:8])=[O:35])[CH:38]=[CH2:39]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)O
Yield: 91.1 %

Procedure:
A tetrahydrofuran (1.0 mL) and methanol (0.5 mL) solution of 2-allyloxycarbonylamino-3-{3-[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionic acid ethyl ester (59 mg, 0.108 mmol) was stirred with 2M aqueous lithium hydroxide (0.5 mL) at room temperature for 40 minutes. The reaction was acidified to pH 1 with 1M hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (51 mg, 91%). MS (Cl) m/z 518 (M+1). B. 2-Allyloxycarbonylamino-3-{3-[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionic acid ethyl ester
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1>CS(C)=O>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: C=Cc1ccc(C)nc1
Solvent: CS(C)=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CCc2ccc(C)nc2)C1
Yield: 3 %

Procedure:
Preparation of the title compound was carried out according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, 1 mmol), 2-methyl-5-vinylpyridine (1 mL, 2.3 mmol) and Nan (120 mg, 3 mmol) in DMSO (4 ml) at 120° C. for 48 h to obtain 10 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH2:36][C@@H:37]([NH2:39])[CH3:38])[CH:35]=1.CCN(C(C)C)C(C)C>CCO>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH2:36][C@@H:37]([NH:39][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:10][C:11]3[C:12]([N:28]=2)=[CH:13][C:14]2[CH2:15][N:16]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[C:17](=[O:20])[C:18]=2[CH:19]=3)[CH3:38])[CH:35]=1
Reactant: O=C1c2cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc3cc2CN1CCN1CCCC1
Reactant: Cc1ccc(Cl)cc1C[C@H](C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(Cl)cc1C[C@H](C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN1CCCC1)C3
Yield: 59.7 %

Procedure:
A solution of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (50 mg, 0.126 mmol), (1S)-2-(5-chloro-2-methylphenyl)-1-methylethylamine (30 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH was heated at 80° C. for 24 h. Then the solvent was evaporated and the residue was purified by column (silicagel, DCM:MeOH 95:5) to give 2-(4-((1S)-2-(5-cloro-2-methylphenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (41 mg, 59%) as yellow solid. ESI-MS: m/z (MH+) 545.5. 1H NMR (300 MHz, CDCl3): δ 7.96 (d, J=44.8 Hz, 1H), 7.51 (d, J=66.3 Hz, 1H), 7.20 (m, 2H), 7.03 (m, 2H), 5.86 (m, 1H), 4.59 (m, 2H), 3.93 (m, 3H), 2.96-3.13 (m, 8H), 2.32 (s, 3H), 1.91 (m, 4H), 1.38 (d, J=7.35 Hz, 3H).