Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH:4]=O)[CH3:3].P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17](C2C=C(C#N)C=CN=2)[CH:16]=1)=[O:14].[C:28](=[O:31])(O)[O-].[Na+]>C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[C:19]([C:3]2[C:15]([C:16]#[N:17])=[CH:19][CH:18]=[CH:4][N:2]=2)=[C:18]([CH:28]=[O:31])[NH:17][CH:16]=1)=[O:14]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccn(-c2cc(C#N)ccn2)c1
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(C=O)c1-c1ncccc1C#N
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A solution of 30 mL (360 mmol) of DMF in 200 mL of methylene chloride is cooled to 5° C. under a nitrogen atmosphere. To this is added 16 mL (180 mmol) of phosphorus oxychloride, maintaining the temperature <10° C. After addition is complete the reaction is stirred for a ½ hour. To this is added dropwise a solution of 4.0 g (18 mmol) of 4-cyano-pyridin-2-yl-1H-pyrrole-3-carboxylic acid methyl ester dissolved in 100 mL of methylene chloride. The reaction mixture is then heated to 40° C. for 48 hours. The reaction mixture is cooled to room temperature and slowly poured in 300 mL of saturated sodium bicarbonate. The organic layer is then extracted from the aqueous layer, dried (Na2SO4) and evaporated. The residue is chromatographed on 150 grams of silica gel using 1/1 ethyl acetate/hexanes as the eluant. Appropriate fractions are combined to yield 0.75 g of 4-(3-cyano-pyridin-2-yl)-5-formyl-1H-pyrrole-3-carboxylic acid methyl ester. 1H NMR (CDCl3) δ 10.1 (s, 1H), 9.4 (s, 1H), 8.8 (m, 1H), 8.1 (m, 1H), 7.75 (m, 1H), 7.5 (m, 1H), 3.75 (s, 3H). Mass spectrum: m/e=256.2 (p+1). TLC (10/1 ethyl acetate/chloroform) Rf=0.7. Continued elution of the column afforded 2.5 grams of the starting pyrrole methyl ester. Step 3:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C@@H:30]([NH2:32])[CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@@H:30]([NH:32][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: C[C@H](N)c1cccc2ccccc12
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc2ccccc12

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with (S)-1-(1-naphthyl)ethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 366.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.40 (d, J=4.6 Hz, 1H); 8.34 (br s, 1H); 8.23 (d, J=8.2 Hz, 1H); 7.97 (d, J=7.6 Hz, 1H); 7.82 (d, J=8.2 Hz, 1H); 7.67 (d, J=6.9 Hz, 1H); 7.47 (t, J=7.7 Hz, 1H); 6.77 (s, 1H); 6.03 (br s, 2H); 1.80 (d, J=6.7 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:27])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:26])[CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:14][C:15]([C:17]1([NH:27][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[I:1])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:26])[CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
Reactant: Cc1cccc(C(=O)O)c1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of 2-iodo-3-methyl-benzoic acid (3.85 g, 14.7 mmol), 2-amino-5-fluoro-indan-2-carboxylic acid ethyl ester (3.00 g, 13.4 mmol), HATU (6.10 g, 16.1 mmol) in anhydrous DMF (6 mL) is added DIPEA (3.30 mL, 20.1 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is recrystallized from EtOAc to give a pure product (147) as white solid (3.90 g, 62%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([F:16])[CH:7]=1.[S:17](=[O:19])=[O:18].O.[ClH:21]>C(O)(=O)C.[Cu](Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[CH:15][C:6]([S:17]([Cl:21])(=[O:19])=[O:18])=[CH:7][C:8]=1[F:16]
Reactant: Cl
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: O=S=O
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Sodium nitrite (0.54 g, 8.0 mmol) was added portion wise to a stirred solution of methyl 4-amino-2-fluorobenzoate (1.0 g, 6.0 mmol) in acetic acid (7 ml) and HCl (concentrated, 2.5 ml) while maintaining the temperature below 15° C. This solution was then added drop wise to a stirred solution of saturated sulfur dioxide, copper (II) chloride (0.25 g, 1.0 mmol) and water (0.5 ml) in acetic acid (5 ml) at 5° C. The reaction mixture was allowed to warm to room temperature and poured over ice water and stirred for a further 15 minutes. The resulting precipitate was collected by filtration, washed with water and dried overnight in a vacuum oven to give the title compound (1.5 g, 55% yield) as a pale brown solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[Na+].CO.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O>[N:29]1([CH2:28][CH2:27][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: ClCCN1CCCCC1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCC(SCCN1CCCCC1)=N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9.6 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 40 ml of a 10% aqueous sodium hydroxide solution and 40 ml of methanol is added dropwise a solution of 5.5 g of 1-chloro-2-piperidinoethane hydrochloride in 20 ml of water over a period of 15 minutes, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-(2-piperidinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from 99% ethanol to obtain 10.5 g of 2-(2-piperidinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 196°-198° C.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([C:28]([C:25]4([C:23]#[N:24])[CH2:27][CH2:26]4)=[O:29])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (260 mg, 0.54 mmol) in DMF (1 mL) at rt, was added 1-cyanocyclopropanecarboxylic acid (66 mg, 0.6 mmol), BOP (287 mg, 0.65 mmol) and DIPEA (0.3 mL, 1.7 mmol). The mixture was stirred for 2 h. The reaction was added water, stirred at rt for 2 h, filtered and rinsed with water to give 6-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (192 mg, 80% yield) as a brown solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.17 (d, J=6.6 Hz, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.11 (d, J=17.8 Hz, 1H), 5.09-4.92 (m, 2H), 4.55 (br. s., 2H), 4.46-3.93 (m, 3H), 3.88-3.59 (m, 2H), 3.50 (d, J=14.1 Hz, 3H), 1.75-1.46 (m, 4H); MS (ES+) m/z: 446.1, 447.2 (M+H); LC retention time: 3.49 min (analytical HPLC Method B).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][CH2:34][C:35](Cl)=[O:36].O>C1COCC1>[CH2:1]([N:8]([CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]1)[C:35](=[O:36])[CH2:34][Cl:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC1(C)OCC(C(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)O1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OCC(C(CN(Cc2ccccc2)C(=O)CCl)c2ccc(Cl)c(Cl)c2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2RS)—N-benzyl-2-(3,4-dichlorophenyl)-2-[(4SR)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamine (3.72 g) and triethylamine (1.63 ml) in THF (30 ml) was added chloroacetyl chloride (0.783 ml) at 0° C., and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.99 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([Cl:17])[CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7]2[N:8]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:9]3[CH:10]=[C:11]([Cl:17])[CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(Cl)ccc12
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)nc2c3ccc(Cl)cc3n(Cc3ccc(OC)cc3)c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NaH (0.62 g, 15 mmol, 60% oil dispersion) was added to a stirred solution of methyl 2-bromo-7-chloro-5H-pyrido[3,2-b]indole-4-carboxylate (3.5 g, 10.3 mmol) in dry DMF (30 mL) under nitrogen in an ice bath. After 5 min, 1-(chloromethyl)-4-methoxybenzene (1.82 mL, 13 4 mmol) was added and the reaction was removed from the bath and left stirring at RT overnight. The reaction was diluted with EtOAc, washed with water (4×) and then brine. Removal of the solvent followed by step gradient silica gel radial chromatography with hexane containing 25 to 50% DCM afforded impure methyl 2-bromo-7-chloro-5-(4-methoxybenzyl)-5H-pyrido[3,2-b]indole-4-carboxylate (4.0 g) as a light yellow fully solid that was used as such. MS (ESI) m/z 460.95 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.31 (1H, d, J=8.24 Hz), 7.69 (1H, s), 7.47 (1H, d, J=1.53 Hz), 7.34 (1H, dd, J=8.39, 1.68 Hz), 6.78-6.82 (2H, m), 6.73-6.76 (2H, m), 5.63 (2H, s), 3.78 (3H, s), 3.73 (3H, s).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:21][CH:20]3[CH:16]([CH2:17][NH:18][CH2:19]3)[CH2:15]2)=[O:13])[NH:4][CH:5]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=1.CCN(C(C)C)C(C)C>C(#N)C>[N:1]1[N:2]=[C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:15][CH:16]3[CH:20]([CH2:19][N:18]([C:23]4[N:28]=[C:27]([CH3:29])[C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=4)[CH2:17]3)[CH2:21]2)=[O:13])[NH:4][CH:5]=1
Reactant: O=C(c1ccccc1-c1nnc[nH]1)N1CC2CNCC2C1
Reactant: Cc1nc(Cl)nc(C)c1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CC3CN(C(=O)c4ccccc4-c4nnc[nH]4)CC3C2)nc(C)c1C
Yield: 28.8 %

Procedure:
The product of Step A (167 mg, 0.421 mmol), Intermediate 56 (66 mg, 0.421 mmol) and DIPEA (0.29 mL, 1.68 mmol) were heated for 2 h at 200° C. in ACN (1.4 mL) in the microwave. The mixture was concentrated in vacuo. The crude product was purified using Agilent HPLC (basic system) to yield impure material. This material was subsequently purified using normal phase chromatography (DCM to 8% 2M NH3 in MeOH/DCM) to afford the title compound (49 mg, 29%). MS (ESI) mass calculated for C22H25N7O, 403.49; m/z found, 404.2. 1H NMR (500 MHz, CDCl3): 8.16 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 7.54-7.49 (m, 1H), 7.48-7.44 (m, 1H), 7.35 (d, J=7.5 Hz, 1H), 3.96-3.89 (m, 1H), 3.85-3.77 (m, 1H), 3.74-3.68 (m, 1H), 3.68-3.55 (m, 2H), 3.42 (br s, 2H), 3.16 (br s, 1H), 3.04-2.96 (m, 1H), 2.89 (br s, 1H), 2.32 (s, 6H), 2.05 (s, 3H).
Reaction SMILES: [CH:1]1([N:7]2[CH:15]([OH:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]1([C:24]([CH:26]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[CH:8]([CH2:26][C:24]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:25])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]2=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCCCC1
Reactant: O=C1c2ccccc2C(O)N1C1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(CC1c2ccccc2C(=O)N1C1CCCCC1)N1CCCCC1
Yield: 73.6 %

Procedure:
A solution of 1.2 g of 2-cyclohexyl-3-hydroxyisoindolin-1-one and 2.2 g of piperidinocarbonylmethylenetriphenylphosphorane in toluene (30 ml) was refluxed for 3 hours. After cooling, the toluene was distilled off and ether was added whereupon triphenylphosphine oxide separated out. After filtration, the filtrate was allowed to stand to giving crude crystals. Recrystallization from ether gave 1.3 g of 2-cyclohexyl-3-piperidinocarbonylmethylisoindolin-1-one.
Reaction SMILES: [CH3:1][CH:2]([S:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:7])=[O:6])[CH2:3][CH3:4].[CH3:13][N+:14]1[CH:18]=[CH:17][NH:16][CH:15]=1>>[CH3:1][CH:2]([S:5]([O-:8])(=[O:7])=[O:6])[CH2:3][CH3:4].[CH2:9]([N+:16]1[CH:17]=[CH:18][N:14]([CH3:13])[CH:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOS(=O)(=O)C(C)CC
Reactant: C[n+]1cc[nH]c1
Product: CCC(C)S(=O)(=O)[O-]
Product: CCCC[n+]1ccn(C)c1
Yield: 79.8 %

Procedure:
Butyl 2-butanesulfonate (24.88 g; 154 mmol) was mixed with 1-methyl imidazolium (12.30 g; 150 mmol) and the reaction mixture was allowed to stand at room temperature (25° C.) for 60 hours. After this period of time, the yellow reaction mixture became solidified. The crystalline mass was crushed, washed two times with ethyl acetate and dried under vacuum, which produced colorless crystals of 1-butyl-3-methyl imidazolium 2-butanesulfonate (33.10 g, 80% yield), melting point 76.1° C. RMN—1H (CDCl3) δ: 9.80 (1H, s, C—H imidazolium); 7.53 (1H, t, J=1.5 Hz, C—H imidazolium); 7.39 (1H, t, J=1.5 Hz, C—H imidazolium); 4.15 (2H, t, J=7.5 Hz, NCH2); 3.92 (3H, s, NCH3); 2.72-2.60 (1H, m, CH3CH2CH(CH3)SO3); 2.20 5-2.05 (1H, m, CH3CH2CH(CH3)SO3); 1.87 (2H, quintet, J=7.5 Hz, CH2); 1.54-1.30 (3H, m, CH3CH2CH(CH3)SO3 and CH2); 1.32 (3H, d, J=6.8 Hz, CH3CH2CH(CH3)SO3); 0.99 (3H, t, J=7.5 Hz, CH3CH2CH(CH3)SO3); 0.94 (3H, t, J−7.5 Hz, CH3). RMN—13C (CDCl3) δ: 137.6; 123.6 and 121.8 (C—H imidazolium); 56.7 (CH3CH2CH(CH3)SO3); 49.2 (NCH2); 36.0 (NCH3); 31.8; 24.6 and 19.0 (CH2); 14.5; 13.1 and 11.5 (CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH:10]=[CH:9]2)([O-:3])=[O:2].[C:15]([O-])([O-])=O.[Cs+].[Cs+].IC.O>CN(C=O)C>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[N:12]=1
Reactant: O=c1ccc2cccc([N+](=O)[O-])c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2cccc([N+](=O)[O-])c2n1
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1,2-dihydro-8-nitroquinolin-2-one, as described above in Step C, (2.55 g, 13.41 mmol) in DMF (80 mL) were added Cs2CO3 (13.11 g, 40.23 mmol) and iodomethane (1.37 mL, 14.75 mmol) and the mixture was stirred vigorously for 2.5 hours. The reaction mixture was poured into water at 0° C. and the solid was isolated by filtration. The resulting solid was dried in vacuo, to yield the above-titled compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=C=O.[NH2:25][CH:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1>>[CH2:16]=[C:14]1[CH2:15][N:8]([C:6]([NH:17][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:7])[CH:9]([C:10]([NH:25][CH:26]2[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29]2)=[O:12])[CH2:13]1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CCCCCN=C=O
Product: C=C1CC(C(=O)NC2CN(C(=O)OC(C)(C)C)C2)N(C(=O)NCCCCC)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, 1-isocyanatopentane, and tert-butyl 3-amino-1-azetidinecarboxylate the title compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=395.2.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[N:5]=1)#[N:2].[C:19]([N:21]=[C:22]([NH2:24])[NH2:23])#[N:20].[OH-].[K+]>COCCO>[NH2:20][C:19]1[N:21]=[C:22]([NH2:24])[N:23]=[C:1]([CH2:3][C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]=2)[N:2]=1
Reactant: N#CCc1nc2ccccc2n1-c1ccccc1
Reactant: N#CN=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Product: Nc1nc(N)nc(Cc2nc3ccccc3n2-c2ccccc2)n1
Yield: 73.5 %

Procedure:
A mixture of 2-cyanomethyl-1-phenyl-1H-benzimidazole (1.8 g), dicyanodiamide (785 mg) and potassium hydroxide (87 mg) in methyl cellosolve was refluxed for 2 hours. After the mixture was cooled, the resultant precipitates were filtered off and washed with water and methanol in turn to give 2,4-diamino-6-(1-phenyl-1H-benzimidazol-2-yl)methyl-1,3,5-triazine (1.8 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Cl.[NH2:22][C:23]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:22][C:23]([CH2:29][CH3:30])([CH2:31][CH3:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(N)(CC)CC
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155 g) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=413.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[C:8]=2[CH:7]=1>C(Cl)Cl.CCCCCC>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[C:8](=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=1
Reactant: COCCOc1ccc2c(c1)C(=O)c1ccccc1C2=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COCCOc1ccc2cc3ccccc3cc2c1
Yield: 50.6 %

Procedure:
Using the procedure outlined in Example 1B, 2-[2-(methoxy)ethoxy]anthraquinone (12A) gave a 50.6% yield of 2-[2-(methoxy)ethoxy]anthracene, mp 131°-134°, (C,H), (CH2Cl2 /hexane).
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]([C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)[N:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)=[CH:60][CH:59]=1>CN(C=O)C.C(OCC)C>[F:77][C:74]1[CH:73]=[CH:72][C:71]([CH:64]([C:61]2[CH:62]=[CH:63][C:58]([F:57])=[CH:59][CH:60]=2)[N:65]2[CH2:66][CH2:67][N:68]([C:5]([C@@H:4]([NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])[CH2:3][CH:2]([CH3:1])[CH3:23])=[O:7])[CH2:69][CH2:70]2)=[CH:76][CH:75]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCN(c2ccccc2)CC1)C(=O)O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)N1CCN(c2ccccc2)CC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 75.8 %

Procedure:
(S)-4-Methyl-2-[(4-phenyl-piperazine-1-carbonyl)-amino]pentanoic acid (0.300 g, 0.939 mmol, Example 17, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.327 mL, 1.88 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.356 g, 0.939 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.271 g, 0.939 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane, then 60% EtOAc in hexane) to provide 0.42 g (76%) of the pure titled compound as a light yellow foam: mp 83-91 ° C. APCI-MS m/z 590.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)=[CH:10][C:11]=1[NH2:12])=[O:5])[CH3:2].[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>O1CCCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:13]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:18][CH:19]=2)=[CH:10][C:11]=1[NH:12][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(N(Cc2ccc(OC)cc2)c2ccc(N3CCOCC3)nc2)cc1N
Reactant: O=Cc1ccccc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N(Cc2ccc(OC)cc2)c2ccc(N3CCOCC3)nc2)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 5.3 %

Procedure:
47 mg of 4-amino-6-[4-methoxybenzyl-(6-morpholinopyridin-3-yl)amino]pyridine-3-carboxylic acid ethyl ester was dissolved in 2 mL of tetrahydrofuran, to which 21.5 mg of benzaldehyde, 3.1 mg of dibutyltin dichloride and 16.4 mg of phenylsilane were added, and stirred at room temperature for 3 days. For every 24 hours in the meantime, 21.5 mg of benzaldehyde, 3.1 mg of dibutyltin dichloride and 16.4 mg of phenylsilane were each added twice. To the reaction mixture water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=1:1) and silica gel thin layer chromatography (chloroform:methanol=20:1) to obtain 3.0 mg of the title compound crude product containing impurities as a light yellow oil. Without further purification, this was used in the next reaction as it was.