Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[O:23]=[C:8]1[C:9]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCCCC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1(Cc2ccncc2)C(=O)N(N2CCCCC2)c2ccccc21

Procedure:
The product obtained from Example 23 could be reacted with sodium hydride and ethyl bromoacetate in a manner similar to Example 8 to render the product as an oil. Mass. Spec. Calcd. for C22H25N3O4 : 394 (M+H). Found: 394.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14](Cl)=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([NH:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: CCn1cc(C(=O)Cl)c(=O)c2ccc(Cl)nc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2ccc(Cl)nc21
Reaction time: 72 h

Procedure:
7-Chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbonyl chloride (22.3 g) in dry dioxan (350 ml) was added slowly to 5-amino-1H-tetrazole (7.9 g) and triethylamine (15.1 ml) in dry dioxan (350 ml) and the mixture kept 3 days at room temperature. The solid was collected and dissolved in aqueous dimethylaminoethanol. The solution was filtered and acetic acid was added to the filtrate. The solid that separated was collected and had m.p. above 400°.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[NH2:22])[CH:10]=1.[C:29]([O:33][C:34](=[O:48])[CH2:35][CH2:36][S:37][CH2:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42](O)=[O:43])([CH3:32])([CH3:31])[CH3:30].CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[NH:22][C:42]([C:41]2[CH:40]=[C:39]([CH:47]=[CH:46][CH:45]=2)[CH2:38][S:37][CH2:36][CH2:35][C:34]([O:33][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:48])=[O:43])[CH:10]=1)=[O:23]
Reactant: Nc1ccc(F)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-fluoro-phenyl)isonicotinamide (200 mg, 0.51 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (200 mg, 0.68 mmol, 1.50 equiv), EDC.HCl (0.18 g, 0.94 mmol, 2.00 equiv), and 4-dimethylaminopyridine (58 mg, 0.48 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5˜ethyl acetate). The product was obtained as 100 mg (29%) of a yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[CH2:15]([N:17]([CH2:32][CH3:33])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23](=[O:24])[C:21]1=[O:22])[CH3:16].[NH4+].[Cl-]>C1COCC1>[CH2:32]([N:17]([CH2:15][CH3:16])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23]([OH:24])([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:21]1=[O:22])[CH3:33]
Reactant: c1ccc2scnc2c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2nc3ccccc3s2)c2c(Br)cccc21
Temperature: -78 °C
Reaction time: 7.5 h
Yield: 14.6 %

Procedure:
To benzothiazole (83.3 mg, 2.0 eq) in anhydrous THF (2 mL) under a nitrogen atmosphere and with stirring was added n-BuLi (0.40 mL, 2.0 eq, 1.53 M in hexanes) at −78° C. (bath temperature). The resulting bright yellow coloured reaction mixture was stirred for 1 hour after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added dropwise. The resulting red coloured solution was stirred at −78° C. for 7.5 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1% to 3% MeOH in CHCl3) to give the title compound as a light yellow solid (20.7 mg, 15%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>ClCCl.CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[O:9]
Reactant: Cc1ccccc1N
Reactant: Cc1cc[nH]c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)c1[nH]ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
2.0 g (15.98 mmol) of 3-methyl-1H-pyrrole-2-carboxylic acid were dissolved in 50 mL of dichloromethane. 5.60 mL (63.9 mmol) of oxalyl chloride were added, followed by 5 drops of DMF. The reaction mixture was stirred at room temperature for 2 hours and then the solvents were evaporated. The black oil residue was dissolved in 50 mL of dichloromethane and 6.85 g (63.9 mmol) of o-toluidine were added dropwise. The reaction was stirred at room temperature for 1 hour and then the solvent was evaporated. The crude product was purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) and then triturated in diisopropylether to give 2.97 g (87% yield) of the title compound as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:34][OH:35].C([O-])(O)=O.[Na+]>>[OH:35]/[N:34]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCC(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCC(=O)O)cc1

Procedure:
In analogy to example 151, step 3, {4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoylamino}-acetic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=446.3 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH:33]=[N:32][C:31]([NH2:34])=[N:30]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:18][C:19]([NH:34][C:31]4[N:32]=[CH:33][N:29]([CH3:28])[N:30]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: Cn1cnc(N)n1
Product: Cn1cnc(NC(=O)CC(c2ccccc2)c2ccc3c(cnn3-c3ccc(F)cc3)c2)n1
Yield: 11 %

Procedure:
Example 137 was prepared from 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoic acid (50 mg, 0.14 mmol) and 1-methyl-1H-1,2,4-triazol-3-amine using General Coupling Method A to give 7 mg (11% yield). MS found: (M+H)+=441.5.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:27]3[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:16]([CH3:26])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH2:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:35]#[CH:36].C(NC(C)C)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:27]3[CH:32]=[CH:31][C:30]([C:36]#[C:35][CH2:34][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:29][CH:28]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:16]([CH3:26])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C3CC3)cc2)cc1C
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C3CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a degassed solution of the above ester (392 mg, 0.707 mmol), N-propargylmorpholine (176 mg, 1.41 mmol) and diisopropyl amine (0.466 mL, 3.3 mmol) in anhydrous tetrahydrofuran (11 mL), bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.053 mmol) and copper(I) iodide (12.0 mg, 0.063 mmol) were added. The reaction mixture was stirred at ambient temperature for 7 h under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5) yielding methyl (Z)-[4-[3-(4-cyclopropylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:18][C:19]1[N:20]=[CH:21][N:22]=[C:23]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[CH:12]=2)[CH:24]=1
Reactant: Nc1cccc(Cn2ccc3ccccc32)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cc(Nc2cccc(Cn3ccc4ccccc43)c2)ncn1

Procedure:
1.077 g 3-Indol-1-ylmethyl-phenylamine (obtained in Step 2, 4.84 mmol) and 0.722 g 4,6-dichloropyrimidine (4.84 mmol) was dissolved in 50 cm3 of isopropyl-alcohol, 1.27 cm3 N,N-diisopropyl-ethylamine (0.939 g, 7.27 mmol) were added and the mixture was refluxed for three days. Then the mixture was evaporated under reduced pressure, 100 cm3 of water was added and it was extracted with 3×70 cm3 ethyl-acetate. Combined organic layer was washed with brine, dried over MgSO4 and evaporated to a yellowish oil. The residue was crystallized from minimal amount of acetonitrile and washed with diethyl-ether to give the desired product as an off-white solid. Overall yield for Step 2 and Step 3: 1.015 g (63%). For analitical results and compound identification see Table 1. The compound was used as a starting material in the preparation of Example 91.
Reaction SMILES: C([N:8]([CH2:16][C:17]1[CH:43]=[CH:42][C:20]([C:21]([NH:23][C@@H:24]([CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[CH:39][CH:38]=[CH:37]3)[C:25]([OH:27])=[O:26])=[O:22])=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(OC(C)(C)C)=O.Cl.O1CCOCC1>CO>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@@H:24]([CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[CH:39][CH:38]=[CH:37]3)[C:25]([OH:27])=[O:26])=[O:22])=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)N[C@@H](CCCNc2cccc3cccnc23)C(=O)O)cc1)Cc1ccccn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N[C@@H](CCCNc1cccc2cccnc12)C(=O)O)c1ccc(CNCc2ccccn2)cc1
Reaction time: 2.5 h

Procedure:
The compound obtained in Example 53-3 (19.0 mg) was dissolved in methanol (0.19 ml) and 4 mol/l hydrochloric acid/dioxane (0.19 ml) was added. After 2.5 hours, the reaction solution was concentrated and azeotropically distilled with methanol. The residue was purified by silica gel column chromatography (1 g, chloroform/methanol/water=7/3/0.5). The obtained title compound was dissolved in methanol. Activated carbon (4 mg) was added to the solution, followed by filtration and concentration. After the addition of 1 mol/l hydrochloric acid and a small amount of methanol, the residue was concentrated and dried under reduced pressure to obtain hydrochloride of the title compound (17.9 mg) as a yellow solid.
Reaction SMILES: CO[C:3]([CH:5](Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH2:13]([NH2:16])[CH2:14][NH2:15].C[O-].[Na+]>CO>[C:6]1([CH:5]2[NH:16][CH2:13][CH2:14][NH:15][C:3]2=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: COC(=O)C(Br)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NCCNC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
Methyl bromophenyl acetate (25 g, 109 mmol) and ethylene diamine (13.1 g, 218 mmol) were mixed in dry MeOH (180 mL) and stirred at room temperature for 15 minutes under nitrogen. Sodium methoxide (6.5 g, 120 mmol) was added in one portion and the mixture heated to reflux for 3.5 hr. The mixture was left stirring overnight at room temperature. The solvent was evaporated in vacuo to give a pale yellow gum, which was partitioned between water (100 mL) and chloroform (100 mL), the pH of the aqueous phase was adjusted with 2M HCl to pH 7.5 and extracted with more chloroform (100 mL). The combined organic phases were dried (MgSO4) and evaporated to give the title compound as a pale yellow solid (17 g, 89%).
Reaction SMILES: C([NH:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][CH:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].O>C(O)(=O)C>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[CH:27][CH:28]=1
Reactant: CC(=O)Nc1ccc(CC2c3ccccc3-c3[nH]c(=O)c4nccn4c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(CC2c3ccccc3-c3[nH]c(=O)c4nccn4c32)cc1
Temperature: 98 °C
Yield: 101.5 %

Procedure:
A mixture of 0.1 g of 10-(4-acetylamino-benzyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 5 ml of 1N sodium hydroxide and 5 ml of water is heated at 98° C. for 16 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is acidified with 1 ml of acetic acid, filtered and the precipitate formed is washed with 1 ml of methanol and air-dried. 90 mg of 10-(4-aminobenzyl)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a yellow solid melting above 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 3.19 and 3.42 (2dd, J=15 and 7 Hz and J=15 and 5 Hz respectively, 1H each: Ar--CH2); 4.41 (dd, J=7 and 5 Hz, 1H: --H10); 4.80 (broad mult., 1H: --NH2); 6.22 and 6.40 (2d, J=7.5 Hz, 2H each: aromatic --H); 7.32 (m, 2H: --H7 and --H8); 7.45 and 7.75 (2 broad d, J=7.5 Hz, 1H each: --H6 and --H9); 7.64 and 8.13 (2 broad s, 1H each: --H of the imidazole); 12.23 (broad s, 1H: --CO--NH--)).
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[Cl:19][CH:3]([C:2](=[O:1])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)Cc1ccccc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Ethyl 3-oxo-4-phenylbutyrate (4.8 g, 23 mmol) and methylene chloride (48 ml) were mixed, and sulfuryl chloride (3.1 g, 1 equivalent) was gradually added thereto dropwise. After the addition, the mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added, and extraction was carried out with ethyl acetate (20 ml). The solvent was evaporated away under reduced pressure and drying was carried out in vacuum to obtain the title compound as a yellow oil (4.8 g, yield: 86%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]1[C:19]2[C@@H:20]3[C@H:25]([CH2:26][CH2:27][C:18]=2[CH:17]=[CH:16][CH:15]=1)[NH:24][CH2:23][CH2:22][CH2:21]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@@H:20]([C:19]5[C:14]([F:13])=[CH:15][CH:16]=[CH:17][C:18]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Fc1cccc2c1[C@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3c(F)cccc3CC[C@@H]21
Yield: 75 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-10-fluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 75% of theory; LC (method 1): tR=2.66 min; Mass spectrum (ESI+): m/z=350 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]1.Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]2)=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCC(c2c[nH]c3ccc(Nc4ccc(C#N)cc4[N+](=O)[O-])cc23)C1
Yield: 16 %

Procedure:
5-Amino-3-(N-methylpyrrolidin-3-yl)-1H-indole and 4-chloro-3-nitrobenzonitrile were used. Sodium acetate was used as base, acetic acid was used as solvent, and the reaction was heated at reflux for 5 hours. Column chromatography afforded the title compound (16%) as a red amorphous solid: Rf =0.35 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 13C NMR (CDCl3) δ 147.4, 137.0, 135.8, 132.1, 131.4, 128.2, 127.8, 122.2, 120.4, 120.3, 118.2, 117.2, 117.1, 112.7, 98.9, 62.7, 56.3, 42.4, 35.0, 32.3; HRMS calculated for C20H19N5O2 361.1541, found 361.1500.
Reaction SMILES: [CH3:1][C:2]1[CH:7](OC(=O)C)[CH2:6][CH2:5][C:4]([CH3:13])([CH3:12])[C:3]=1[C:14]#[C:15][CH:16](OC(=O)C)[CH3:17].C(Cl)Cl.C1(C)C=CC(S(O)(=O)=[O:32])=CC=1>O>[C:14]([C:3]1[C:4]([CH3:13])([CH3:12])[CH2:5][CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:32])/[CH:15]=[CH:16]/[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)OC(C)C#CC1=C(C)C(OC(C)=O)CCC1(C)C
Solvent: O
Solvent: ClCCl
Product: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Yield: 60 %

Procedure:
In a 100 ml. three-necked flask fitted with a mechanical stirrer and a Dean-Stark water separator provided with a reflux condenser, a solution of 7 g. of 2,6,6-trimethyl-3-acetoxy-1-(3-acetoxy-but-1-ynyl)cyclohex-1ene in 70 ml. of methylene chloride is refluxed while stirring. Then 0.7 g. of p-toluenesulfonic acid is added and the reaction mixture is refluxed for an additional 7 hours. The reaction mixture is cooled and then poured into 70 ml. of water. The organic layer is separated, washed with 10% sodium bicarbonate solution and water. Drying over sodium sulfate and subsequent concentration yields 5 g. of a residue which gives, upon distillation using a short Vigreux column, 3 g. or 60% yield of 1-crotonoyl-2,6,6-trimethylcyclohexa-1,3-diene, b.p. 75°-80° C./0.1 mm, nD20 1.5150.
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][C:42]=3[O:44][CH3:45])[CH2:37][CH2:36][CH2:35]2)=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][C:42]=3[O:44][CH3:45])[CH2:37][CH2:36][CH2:35]2)=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCCc3cccc(OC)c32)n1
Product: CCc1nc(NC2CCCc3cccc(OC)c32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.23, 6.78, 5.32, 4.31, 3.71, 2.89–2.77, 2.50–2.35, 1.81–1.65, 1.32, 1.18; HRMS (FAB) calcd for C19H24BrN3O+H 390.1181, found 390.1172.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[N:6]=[C:5]3[C:12]4[CH:13]=[CH:14][N:15]=[CH:16][C:17]=4[C:18](=[O:19])[C:3]=1[C:4]=23.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[N:6]=[C:5]3[C:12]4[CH:13]=[CH:14][N:15]=[CH:16][C:17]=4[C:18](=[O:19])[C:3]=1[C:4]=23
Reactant: Cn1nc2c3c(c(Cl)ccc31)C(=O)c1cnccc1-2
Reactant: CN(C)CCN
Product: CN(C)CCNc1ccc2c3c(nn2C)-c2ccncc2C(=O)c13

Procedure:
5-chloro-2-methylisoquino[5,6,7-cd]indazole-6 (2H)-one of Example 7 (0.013 g) is added to 2-(dimethylamino)ethylamine (0.34 mL). The yellow mixture is heated quickly to reflux for 1 hour. The excess diamine is removed from the orange solution by a gentle stream of nitrogen. The orange mixture obtained is purified by silica gel column chromatography with a gradient elution (1% methanol/chloroform (25 mL), 2% methanol/chloroform (25 mL), 4% methanol/chloroform (25 mL), 8% methanol/chloroform (25 mL), 12% methanol/chloroform (25 mL), 16% methanol/chloroform (25 mL), 24% methanol/chloroform (50 mL)) to yield 5-[[2-(dimethylamino)ethyl]amino]-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one (0.010 g) as a reddish orange solid.
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.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[N:14]=1)(=[O:29])=[O:28]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: Cc1cc(Cl)cc(Cl)c1S(=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 (0.07 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.086 g) as a light yellow solid (0.11 g). MS (ESI−): 453.1 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:3](=[O:4])[CH2:5][CH3:9])[CH:9]=1)=[O:4]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2 h

Procedure:
In a dry flask, 3-proprionyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM). To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided the title compound 2.