Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:6][C:3]=1[CH:4]=O.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].C(OC)(OC)OC.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:6][C:3]=1[CH2:4][NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26]
Reactant: CN(C)CCN
Reactant: Cc1cccc(-c2nn3ccccc3c2-c2ccc(F)c(C=O)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccc(F)c(CNCCN(C)C)c2)n1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A solution of 2-fluoro-5-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-benzaldehyde (0.05 g, 0.15 mmol), N,N-dimethyl-ethylenediamine (0.013 g, 0.15 mmol), trimethyl orthoformate (2 mL) in MeOH (5 mL) is stirred for 2 hours at room temperature. The reaction is then treated with sodium borohydride (6.8 mg, 0.18 mmol) and stirred overnight. The reaction is then quenched with 2N NaOH and stirred for 30 minutes. The solution is diluted in CH2Cl2 and washed with saturated aqueous NaHCO3, brine, and dried over sodium sulfate. The solvent is removed in vacuo to afford 0.06 g (100%) of desired product. MS ES+ m/e 404.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@@H:5]([C@H:7]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[C:4](=[O:26])[O:3]1.ONC(=O)[C@@H](O)[C@@H](C(N1CCN(C2C=CC=CN=2)CC1)=O)CC(C)C.C(N(CC)CC)C.[CH3:60][C@H:61]1[NH:66][CH2:65][CH2:64][N:63]([C:67]2[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[CH:69][N:68]=2)[CH2:62]1>CN(C=O)C>[CH3:27][C:2]1([CH3:1])[O:3][C:4](=[O:26])[C@H:5]([C@@H:7]([C:8]([N:66]2[CH2:65][CH2:64][N:63]([C:67]3[CH:72]=[C:71]([C:73]([F:76])([F:74])[F:75])[CH:70]=[CH:69][N:68]=3)[CH2:62][C@H:61]2[CH3:60])=[O:10])[CH2:22][CH:23]([CH3:24])[CH3:25])[O:6]1
Reactant: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1OC(C)(C)OC1=O
Reactant: C[C@@H]1CN(c2cc(C(F)(F)F)ccn2)CCN1
Agent: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O

Procedure:
To a 55/45 diastereoisomeric mixture of pentafluorophenyl (2S)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate and pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate (Intermediate 1, 484.8 mg; 1.22 mmol; 1.0 eq.) and triethylamine (339.13 μl; 2.45 mmol; 2.0 eq.) in DMF (10.0 mL) was added (3R)-3-methyl-1-[4-(trifluoromethyl)pyridin-2-yl]piperazine (Intermediate 9, 300 mg; 1.22 mmol; 1.0 eq.). After 14 h of reaction at RT, the solvent was evaporated and the residue dissolved in ether and extracted with water (3×). The combined organic layers were dried and evaporated to give an oil. This residue was purified by chromatography to give the title product (170 mg; 30.4% as a mixture of 2 diastereoisomers). M+(ESI): 458.4. HPLC (Condition A): Rt: 4.1 min (HPLC purity: 91.8%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])=[O:5].[Br:14][CH2:15][CH2:16]Br>CN(C=O)C>[Br:14][CH2:15][CH2:16][C:7]([CH3:13])([S:4]([CH3:3])(=[O:5])=[O:6])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.33 g, 58.3 mmol) was washed with hexanes (2×10 mL) in a 100 mL two neck round bottom flask under nitrogen then suspended in DMF (30 mL). The suspension was treated dropwise with ethyl 2-(methylsulfonyl)propanoate (10.0 g, 55.49 mmol) in DMF (10 mL). The mixture was stirred 30 min at RT, cooled to 0° C., and treated drop-wise with 1,2-dibromoethane (5.17 mL, 58.8). The mixture was allowed to warm to room temperature while stirring overnight. The mixture was quenched with saturated aq ammonium chloride (100 mL) and extracted with diethyl ether (4×50 mL). Combined organics were washed with 50% saturated sodium chloride (4×50 mL), dried (MgSO4), and concentrated in vacuo. Crude material was purified via silica chromatography (350 g, 230-400 mesh) and an eluent of EtOAc in hexanes (10-20%) to afford the title compound as a pale yellow oil (7.9 g, 50%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.05 Hz, 3H) 1.64 (s, 3H) 2.49-2.59 (m, 1H) 2.78 (ddd, J=13.89, 10.16, 6.64 Hz, 1H) 3.05 (s, 3H) 3.33-3.41 (m, 1H) 3.46-3.54 (m, 1H) 4.22-4.37 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 5-chloro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=363.1 [M+H]+.
Reaction SMILES: [CH2:1]([C@@:8]1([OH:32])[C@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([CH2:21][OH:22])[O:10][C@H:9]1[N:23]1[CH:30]=[C:29]([Br:31])[C:27](=[O:28])[NH:26][C:24]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:33][CH:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:35](O)=[O:36].CN(C)C=O.C1(N=C=NC2CCCCC2)CCCCC1>C1CCCCC1>[SH:33][CH:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:35]([O:22][CH2:21][C@H:11]1[O:10][C@@H:9]([N:23]2[CH:30]=[C:29]([Br:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([OH:32])[C@@H:12]1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:36]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@]2(O)Cc2ccccc2)cc1Br
Reactant: CCCCCCCCCCCCCCCCC(S)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCC(S)C(=O)OC[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)[C@@](O)(Cc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
10 mmol of 2',3'-O-dibenzyl-5-bromouridine and 20 mmol of 2-mercaptostearic acid were added to 400 ml of dimethylformamide containing 40 ml of N,N'-dicyclohexylcarbodiimide, and the mixture was stirred for 3 hours. The resulting reaction mixture was then concentrted at 0.2 atm. at a temperature of 60° C. 200 ml of cyclohexane was added to the residue, and the mixture was heated at a temperature of 80° C for 2 hours while refluxing. The reaction mixture was filtered to recover the residue, and the residue was washed three times with cyclohexane. The resulting residue was then added to 100 ml of dimethylformamide followed by heating at a temperature of 80° C to dissolve the residue. The solution was allowed to cool to room temperature and 100 ml of water was added to the solution. The white precipitate formed was collected by filtration and air-dried to obtain 5.6 mmol (56% yield) of 5'-O-(2-mercaptostearoyl)-2',3' -O-dibenzyl-5-bromouridine as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1.[CH2:17]([NH2:19])[CH3:18].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C1COCC1>[CH2:17]([NH:19][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1)[CH3:18]
Reactant: O=Cc1cc2cc3c(cc2nc1Cl)OCO3
Reactant: CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCNc1nc2cc3c(cc2cc1C=O)OCO3
Temperature: 160 °C
Yield: 91 %

Procedure:
To a solution of 6-chloro-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (1.0 g, 4.24 mmol) in dioxane (10 mL) was added ethylamine (3.58 mL, 70% in water) and the mixture was heated at 160° C. under microwave irradiation for 45 min. After cooling to RT, the mixture was poured into a mixture of THF:1 N HCl aq. solution=1:1 (25 mL) and stirred for 25 min at RT. The mixture was brought to pH=7 with a saturated aq. solution of NaHCO3 and extracted with CH2Cl2 (50 mL). The organic layer was washed with H2O (3×30 mL), brine (30 mL), dried over Na2SO4, filtered and evaporated to give 6-(ethylamino)-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde RBO 35180 as a yellow solid (941 mg, 91% yield).
Reaction SMILES: [N+:1]([C:4]1[O:19][C:7]([CH:8]=[C:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]3=[N:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]=3[NH:10][C:9]2=[CH:8][C:7]2[O:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc2c1=NC(=Cc1ccc([N+](=O)[O-])o1)N=2
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Nc1cccc2c1NC(=Cc1ccc([N+](=O)[O-])o1)N2C(=O)Nc1cccc(Cl)c1
Yield: 65.6 %

Procedure:
51.2 g of 2-(5-nitro-furfurylidene)-amino-benzimidazole are dissolved in a mixture of 120 ml of chloroform and 80 ml of dimethylformamide, whereupon 30.6 g (0.2 moles) of 3-chlorophenyl-isocyanate are slowly added. The crystalline reaction mixture is stirred at room temperature for 7 hours while a mixture of 40 ml of dimethylformamide and 60 ml of chloroform are added. The precipitated crystals are filtered off, washed with 100 ml of chloroform and dried in vacuo at 40° C. to 60° C. Thus 54 g of 1-(3'-chlorophenyl-carbamoyl)-2-(5-nitro-furfurylidene)-amino-benzimidazole are obtained. Mp.: 210°-212° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][OH:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C[C@H](C[C@@H](C)CCCCC)C(O)=O)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][OH:18])[CH2:9][C@@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Agent: CCCCC[C@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Product: CCCCC[C@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Yield: 76 %

Procedure:
A procedure similar to that used to prepare compound 158 was used except that (S)-2-((S)-2-methyl-heptyl)-succinic acid 4-tert-butyl ester 166 (5.78 g, 20.18 mmol) was used as a reactant to give 167 as an oil (4.18 g, 76%). 1H NMR (400 MHz, CDCl3) δ 3.64–3.58 (m, 1H), 3.84–3.42 (m, 1H), 2.28–2.20 (m, 1H), 2.09–2.02 (m, 1H), 1.43 (s, 9H), 1.26–1.18 (m, 8H), 1.11–1.04 (m, 2H), 0.87–0.83 (m, 6H); MS (APCI) m/z 217 (M+−55, 50%, −tBu).
Reaction SMILES: [C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([N+:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH3:33][C:34]([O:39][C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1)([C:36]([OH:38])=[O:37])[CH3:35]>>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([N+:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH3:1][CH2:2][O:37][C:36]([C:34]([O:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)([CH3:33])[CH3:35])=[O:38]
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Agent: CCCCCCCCCCCCCCCC[n+]1ccccc1
Agent: O=C([O-])c1ccccc1O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1

Procedure:
Cetylpyridinium salicylate (2 mmol) and clofibric acid (2 mmol) were grinded for 15 minutes in a mortar until a colourless cream was obtained. Identity and purity of the obtained product was confirmed via 1H NMR. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=9.13 (d, J=6.3 Hz, 2H), 8.60 (t, J=7.7 Hz, 1H), 8.16 (t, J=7.0 Hz, 2H), 7.67 (d, 8.0 Hz, 1H), 7.28 (d, J=9.1 Hz, 2H), 7.14 (t, J=6.7, 1H), 6.84 ((d, J=9.1 Hz, 2H), 6.61 (m, 2H), 4.59 (t, J=7.5 Hz, 2H), 1.89 (m, 2H), 1.47 (s, 6H), 1.22 (s, 27H), 0.84 (t, J=7.0 Hz, 3H). mp 8° C., T5%onset 197° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>O1CCOCC1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[CH2:9][CH2:8]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: OCCOCCN1CCNCC1
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1N1CCN(CCOCCO)CC1
Reaction time: 48 h

Procedure:
Grams 5.9 of 1-(2-hydroxyethoxyethyl)piperazine and 2.7 g of 2-chloronicotinic acid in 50 ml dioxane were refluxed for 3 days. The reaction mixture was then cooled and allowed to rest for 2 days, afterwards the solvent was removed and the residue crystallized from absolute ethanol, gave 1.1 g of 2-{4-[2-(2-hydroxy ethoxy)ethyl]piperazin-1-yl}nicotinic acid melting at 172°-174° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[Cl:14].[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1.CCCCCC>[Cl:14][C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][C:2]=1[CH:23]=[O:24]
Reactant: Clc1cc(CN2CCCC2)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(CN2CCCC2)cc1Cl
Reaction time: 0.5 h

Procedure:
Reaction under N2 atmosphere. A solution of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (25.8 g, 93.96 mmol) in THF (200 ml) was stirred at −78° C. for 15 min A 2.5 M n-BuLi solution in hexane was added to the mixture over a period of 15 min. After 30 min, a solution of DMF (7.3 ml, 93.96 mmol) in THF (50 ml) was added dropwise to the mixture. The reaction temperature was allowed to rise to r.t. slowly, and the mixture was stirred overnight. The reaction was quenched by the addition of water at 0° C. The mixture was extracted with EtOAc (3×150 ml). The combined organic layer was washed with brine, dried (MgSO4), filtered and the solvent was evaporated in vacuo.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:30])[C:20]=2[N:19]=[C:18]1[CH2:31][O:32][N:33]=[C:34]([CH3:36])[CH3:35])(C)(C)C>ClCCl>[NH2:30][C:21]1[C:20]2[N:19]=[C:18]([CH2:31][O:32][N:33]=[C:34]([CH3:36])[CH3:35])[N:17]([CH2:16][CH2:15][NH2:14])[C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CCN
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 274.3 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a suspension of tert-butyl[2-(4-amino-2-isopropylideneaminooxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (4.8 g) in dichloromethane (100 mL). The reaction became homogeneous and was stirred at ambient temperature. At 2.5 hours and 3.5 hours more trifluoroacetic acid (10 mL and 5 mL respectively) was added. After a total reaction time of 4 hours the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (×3) and then placed under high vacuum overnight to provide 9.97 g of propan-2-one O-{[4-amino-1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}oxime as a yellow solid. Based on the weight this material was assumed to contain 5 equivalents of trifluoroacetic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+]([O-])=O)=[C:6]([CH:11](C2C=CC=CC=2)[OH:12])[C:7]=1[N+:8]([O-:10])=[O:9].ClC1C([N+]([O-])=O)=CC([N+]([O-])=O)=C(C(C2C=CC=CC=2)O)C=1.[CH3:43][NH:44][CH3:45]>CO>[CH3:43][N:44]([CH3:45])[C:4]1[CH:3]=[CH:2][C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH2:11][OH:12])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1C(O)c1ccccc1
Reactant: CNC
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(C(O)c2ccccc2)cc1Cl
Solvent: CO
Product: CN(C)c1ccc([N+](=O)[O-])c(CO)c1

Procedure:
(5-Chloro-2,6-dinitro-phenyl)-phenyl-methanol (13) (0.5 g, 1.90 mmol) or (5-chloro-2,4-dinitro-phenyl)-phenyl-methanol (14) (0.5 g, 2.67 mmol) were treated with 2M solution of dimethylamine in methanol (6 mL) and the solution was heated in a microwave reactor (CEM Focused Microwave™ Synthesis System Model Discover) at 50-55° C. for 15 minutes. The solvent was removed in vacuo and each residue was coevaporated with dichloromethane (2×10 mL) and applied onto a column of silicagel. The column was eluted with dichloromethane/ethanol (49:1) to give compounds 17 and 18.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(C(NCCc2c[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.5 %

Procedure:
2.0 g of tryptamine (12.5 mmol) were dissolved in DCM (50 mL) and treated in one portion with triethylamine (1.74 mL. 12.5 mmol, 1 eq) and trityl chloride (3.44 g, 12.3 mmol). The resulting solution was stirred for 24 h at room temperature while protected from light. Volatiles were evaporated and the residue treated with aqueous HCl (1 N). The solid formed was filtered and washed with small portions of ether then dissolved in aqueous sodium hydrogen-carbonate and extracted into DCM. The organic layer was dried and evaporated to give 4.48 g (89% ) of 3-(N-trityl-(2-aminoethyl))-indole, which was used without further purification.
Reaction SMILES: COC1C=CC2C=C(C3C=CC=CC=3N)CCCC=2C=1.Cl.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1(CCOC2C=C[C:54]([CH2:55][NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[C:63]3[CH2:69][CH2:68][CH2:67][C:66]4[CH:70]=[C:71]([O:74][CH3:75])[CH:72]=[CH:73][C:65]=4[CH:64]=3)=CC=2)CCCCCC1>>[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][N:56]([CH2:55][CH3:54])[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[C:63]3[CH2:69][CH2:68][CH2:67][C:66]4[CH:70]=[C:71]([O:74][CH3:75])[CH:72]=[CH:73][C:65]=4[CH:64]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc2c(c1)CCCC(c1ccccc1NCc1ccc(OCCN3CCCCCC3)cc1)=C2
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc2c(c1)CCCC(c1ccccc1N)=C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1=Cc2ccc(OC)cc2CCC1

Procedure:
Synthesized from 2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenyl]amine (454 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenyl]amine (345 mg). This compound (343 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (309 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[Si]([N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CN1CCN([Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Yield: 312 %

Procedure:
0.5 g (1.85 mmol) of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (II, R1 : ethyl; X: chloro) and 1.07 g (0.50 mmol) of 4-(t-butyldimethylsilyl)-1-methyl piperazine (III, R2, R3 and R4 : methyl; R5 : t-butyl) are added to 100 ml of acetonitrile and then heated with stirring. A solution of 1.60 g (0.50 mmol) of tetrabutyl ammonium fluoride trihydrate in 5 ml of acetonitrile is added dropwise to the reaction mixture. After heating with stirring for 3 hours,the solvent is stripped off and water is added thereto to give a solid. After filtering and drying, 0.52 g (85% yield) of a solid compound is afforded.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH:15]=[CH2:16]>O1CCOCC1.C1(C=CC(O)=CC=1)O>[CH3:12][O:13][C:14](=[O:17])[CH2:15][CH2:16][C:7]1([CH2:16][CH2:15][C:14]([O:13][CH3:12])=[O:17])[CH2:6][C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8]1=[O:11]
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: C=CC(=O)OC
Agent: Oc1ccc(O)cc1
Solvent: C1COCCO1
Product: COC(=O)CCC1(CCC(=O)OC)Cc2ccc(Br)cc2C1=O
Temperature: 50 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
To 6-bromo-1-indanone (25 g, 0.12 mol) in dioxane (150 mL) was added Triton B (2.48 mL, 6.3 mmol) and hydroquinone (5 mg, 0.05 mmol). After stirring the mixture for 10 min at 50° C. methylacrylate (21.5 mL, 0.24 mol) in 50 mL dioxane was added. The mixture was stirred for 4 h at 50° C. and 14 h at RT. Then 2 mL methylacrylate was added and the reaction was stirred for 1 h at 50° C. The reaction mixture was poured onto water, extracted with EA and the solvents were evaporated. The residue was purified by MPLC (340 g silicagel, gradient:CH/EA 100:0 to 50:50) to give 3-[6-Bromo-2-(2-methoxycarbonyl-ethyl)-1-oxo-indan-2-yl]-propionic acid methyl ester (38 g, 84%).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[N:9][N+:10]([O-:12])=[O:11])=[CH:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][N:25]=1>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:6]2[CH2:7][CH2:8][N:4]([CH:1]=[CH:2][CH3:3])[C:5]2=[N:9][N+:10]([O-:12])=[O:11])=[CH:26][N:25]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CC=CN1CCNC1=N[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC=CN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture comprising 6.0 g of 1-(1-propenyl)-2nitroiminoimidazolidine, 7.0 g of potassium carbonate, 70 ml of DMSO and 7.4 g of 2-chloro-5-chloromethylpyridine was stirred at 60° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=2/1) to give 8.6 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino -3- (1propenyl)imidazolidine.