Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.[C:29](OC(=O)CC)(=O)[CH2:30]C>>[O:14]=[C:12]1[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH:9]([CH2:8][NH:7][C:6](=[O:5])[CH2:29][CH3:30])[O:13]1
Reactant: CCC(=O)OC(=O)CC
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Product: CCC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1

Procedure:
The compound is prepared from {3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (232 mg, 0.60 mmol) and propionic anhydride (120 mg, 0.96 mmol) following the method described for Example 5. The crude product is purified by silica gel column chromatography (2% to 5% MeOH in EtOAc) to give the title compound as solid. MS (m/z): 344 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ8.16 (br. t, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.52 (d, J=7.1 Hz, 2H), 7.27 (d, J=7.4 Hz, 2H), 4.97 (d, J=7.4 Hz, 1H), 4.80–4.65 (m, 1H), 4.10 (t, J=7.7 Hz, 2H), 3.94 (t, J=6.9 Hz, 2H), 3.41–3.99 (m, 2H), 2.49–2.47 (m, 2H), 2.09 (q, J=5.8 Hz, 2H), 0.93 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[CH3:24]I>C1COCC1.C(OCC)(=O)C>[Cl:16][C:11]1[CH:10]=[C:9]([C@@H:8]2[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C@H:2]2[NH:1][CH3:24])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (4 mL) was added methyl iodide (0.026 ml) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (30 mg).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 66.9 %

Procedure:
A mixture of 5-fluoro-2-nitroanisole (3.00 g, 17.5 mmol), tert-butyl piperazine-1-carboxylate (4.57 g, 24.5 mmol) and potassium carbonate (3.63 g, 26.3 mmol), in dimethyl sulfoxide (20 mL) was heated at 90° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled and diluted with water (100 mL). The resulting precipitate was filtered and dried to give a bright yellow solid. The solid was suspended in a 5:1 solution of petroleum ether/diethyl ether (50 mL), sonicated for 2 minutes, filtered and dried to give the title compound (I1) (3.95 g, 66%) as a bright yellow solid; 1H NMR (300 MHz, d6-DMSO) δ 1.42 (s, 9H), 3.46 (brs, 8H), 3.90 (s, 3H), 6.52 (s, 1H), 6.57 (d, 1H, J=9.5 Hz) and 7.89 (d, 1H, J=9.3 Hz). LCMS Method B: rt 7.45 min; m/z 338.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH:8]1([CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.I[CH2:28][CH2:29][CH3:30]>CC(C)=O>[CH:8]1([CH2:14][CH2:15][N:16]([CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCCI
Reactant: COc1cccc(CCNCCC2CCCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(CCc1cccc(OC)c1)CCC1CCCCC1

Procedure:
48 g of potassium carbonate were added to a solution of 17.8 g of the product of Step B in 180 ml of acetone and after the addition of 17.5 ml of 1-iodopropane, the mixture was refluxed under an inert atmosphere for 41/2 hours and was filtered. The filtrate was evaporated to dryness and the residue was taken up in ether. 100 ml of 2 N sodium hydroxide solution was added to the mixture and the decanted organic phase was washed with water, dried and evaporated to dryness to obtain 19.25 g of N-(2-cyclohexylethyl)-3-methoxy-N-propyl-benzeneethanamine in the form of a yellow oil which was used as is for the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH3:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([Si](C)(C)C)([F:19])([F:18])[F:17].Cl>O1CCCC1.O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:14])[C:16]([F:19])([F:18])[F:17])[C:10]([CH3:15])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1nn(Cc2ccccc2)cc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(Cc2ccccc2)cc1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of 1-benzyl-3-methyl-1H-pyrazole-4-carbaldehyde (compound 314.2, 1.20 g, 5.99 mmol) in tetrahydrofuran (15 mL) was added CF3SiMe3 (1.33 mL, 9.01 mmol) and TBAF (0.11 mL, 0.11 mmol, 1M solution in THF). The mixture was stirred for 10 min at room temperature under nitrogen. This was followed by the addition of aqueous HCl (6 M) (1 mL). The reaction mixture was stirred for another 10 min at room temperature, then diluted with 50 mL of H2O. The aqueous phase was extracted with 3×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/5-1/2) as the eluent to furnish 1.15 g (71%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[CH:15]=[CH:16][N:17]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CO[C@@H]2CCC[C@H]2c2ccn[nH]2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: c1ccc(CO[C@@H]2CCC[C@H]2c2ccn(C3CCCCO3)n2)cc1
Yield: 97.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 148d by using the 5-[(1S,2R)-2-(benzyloxy)cyclopentyl]-1H-pyrazole (320 mg, 1.32 mmol) prepared in Example 149a, 3,4-dihydro-2H-pyran (0.723 mL, 7.92 mmol), p-toluenesulfonic acid hydrate (50 mg, 0.266 mmol) and dichloromethane (5.0 mL), to yield the title compound (421 mg, 98%) in the form of a diastereomeric mixture as a colorless oil.
Reaction SMILES: B.C1COCC1.[CH:7]1([S:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.CO>C1COCC1>[CH:7]1([S:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][NH2:19])=[CH:20][CH:21]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: N#Cc1ccc(CSC2CCCC2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(CSC2CCCC2)cc1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Add borane-THF complex (13.6 mL, 13.6 mmol, 1M solution in THF) dropwise to a solution of 4-(cyclopentylthiomethyl)-benzonitrile (1.5 g, 6.8 mmol) in anhydrous THF (8 mL) at room temperature and heat the mixture at reflux overnight. Cool to room temperature, add methanol cautiously and stir vigorously until gas evolution stops. Concentrate in vacuo and purify the crude mixture by SCX chromatography to obtain the title compound (0.86 g, 59%). MS (ES+) m/z: 205 (M-NH3+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: FC(F)(F)Oc1ccccc1CBr
Product: Nc1nc(N)c2c(N3CCN(Cc4ccccc4OC(F)(F)F)CC3)cccc2n1
Yield: 54 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-(trifluoromethoxy)benzyl bromide (94.4 mg; 0.37 mmol) to obtain 45.5 mg. (54% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (br s, 1H), 10.0 (br s, 1H), 8.94 (br s, 1H), 7.69 (m, 3H), 7.42 (m, 3H), 7.27 (d, J=7.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.65 (s, 2H), 3.04 (d, J=10.4 Hz, 2H), 2.89 (m, 4H), 2.36 (t, J=11.2 Hz, 2H). ESIMS+419.5 m/z
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.Cl.[N:47]1([CH2:53][C:54]([NH2:56])=[O:55])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:50]3[CH2:51][CH2:52][N:47]([CH2:53][C:54]([NH2:56])=[O:55])[CH2:48][CH2:49]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1
Yield: 78.8 %

Procedure:
rac-(4S*,5R*)-2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (110 mg, 0.2 mmol) was added to the mixture of triethylamine (140 uL, 1.0 mmol) and 2-piperazin-1-yl-acetamide dihydrochloride (52 mg, 0.24 mmol, Matrix Scientific) in 3 mL of dichloromethane at 0° C. The mixture was allowed to react for 16 h then concentrated to dryness under reduced pressure. Purification of the crude residue by flash column chromatography (40 g of silica gel, eluting with a gradient of 5 to 100% of 9:1 ethyl acetate-methanol and ethyl acetate) provided 105 mg of rac-2-{4-[(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide as white solids.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:46].O1CCOCC1>C(Cl)Cl>[ClH:46].[ClH:46].[ClH:46].[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:29]=[CH:30][C:31]([C:34]3([NH2:38])[CH2:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc([N+](=O)[O-])cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccc([N+](=O)[O-])cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl (1-{4-[2-(4-nitrophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (7.70 mg, 0.0128 mmol) was dissolved in DCM (0.5 mL). 4M HCl/dioxane (0.5 mL) was added to the mixture and stirred at room temperature for 4 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (8.04 mg, quant.) as an orange solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.72 (br s, 2H), 8.65 (s, 1H), 8.19-8.14 (m, 2H), 8.13-8.10 (m, 1H), 8.00-7.96 (m, 1H), 7.73-7.68 (m, 2H), 7.62-7.56 (m, 2H), 7.42-7.36 (m, 3H), 7.33-7.29 (m, 1H), 7.18-7.12 (m, 1H), 6.96-6.92 (m, 1H), 6.75 (dd, J=8.0, 4.8 Hz, 1H), 2.69-2.44 (m, 4H), 2.28-2.15 (m, 1H), 1.93-1.78 (m, 1H); LCMS: 501 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH:22]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccc(Cl)c(Cl)c1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccc(Cl)c(Cl)c1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(3,4-dichlorobenzyl)-4-phenyl-5-oxohexanoic acid (5.48 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. Then the reaction solution is cooled to room temperature, diluted with water (250 ml.), and extracted with ether to remove the excess p-chlorobenzaldehyde. The aqueous phase is then acidified with dilute hydrochloric acid (15 ml.). The organic material which separates is extracted into ether, washed with saturated brine, and dried over Na2SO4. The ether is removed in vacuo, and trituration of the residue with ethanol (25 ml.) produces 1.6 g. of solid. Recrystallization from butyl chloride gives material with m.p. 155°-156.5°C.
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: CN1CCN([Si](C)(C)C(C)(C)C)CC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
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: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1>>[Br:10][C:11]1[CH:12]=[C:13]([O:19][CH3:20])[C:14]([O:17][CH3:18])=[CH:15][C:16]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: O=C(O)c1ccccc1
Reactant: COc1ccc(Br)cc1OC
Product: COc1cc(Br)c(C(=O)c2ccccc2)cc1OC

Procedure:
By reaction of benzoic acid with 1-bromo-3,4-dimethoxybenzene, in a manner analogous to that of Example 3(a), there is obtained (2-bromo-4,5-dimethoxyphenyl)-phenylmethanone, m.p. 71°-72° C.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1>C(OCC)C.[Ag]=O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([O:18][CH2:1][CH2:2][CH3:3])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1
Reactant: CCCI
Reactant: COC(=O)[C@@H](O)Cc1ccc(Br)cc1
Agent: O=[Ag]
Solvent: CCOCC
Product: CCCO[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Temperature: 50 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
0.22 ml (2.31 mmol) of propyl iodide is added to a mixture of 793 mg (3.48 mmol) of silver oxide and 300 mg (1.16 mmol) of methyl (S)-3-(4-bromophenyl)-2-hydroxypropionate in 3 ml of diethyl ether. The reaction mixture is stirred at 50° C. for 12 hours. The mixture is filtered and then the solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 291 mg of methyl (S)-3-(4-bromophenyl)-2-(propyloxy)propanoate are obtained in the form of an oil. Yield=83%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:4]([C:5]([O-:7])=O)[C:3]=1[C:12]([O-:14])=[O:13].[Na+].[Na+].[CH3:17][C:18]1=[C:19]([CH3:25])[C:20]([O:22][C:23]1=[O:24])=O>O.C1(C)C=CC=CC=1>[CH3:25][C:19]1[C:20](=[O:22])[N:1]([C:2]2[CH:10]=[C:9]([N:11]3[C:5](=[O:7])[C:4]([CH3:8])=[C:3]([CH3:2])[C:12]3=[O:13])[CH:8]=[C:4]3[C:5]([O:14][C:12](=[O:13])[C:3]=23)=[O:7])[C:23](=[O:24])[C:18]=1[CH3:17]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: Nc1cc(N)c(C(=O)[O-])c(C(=O)[O-])c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C)C(=O)N(c2cc3c(c(N4C(=O)C(C)=C(C)C4=O)c2)C(=O)OC3=O)C1=O
Temperature: 100 °C
Yield: 115.7 %

Procedure:
7.20 g (0.039 mol) of disodium 3,5-diaminophthalate, dissolved in 200 ml of water, are added to a solution of 8.82 g (0.078 mol) of dimethylmaleic anhydride in 80 ml of toluene. This mixture is boiled under reflux for 1 hour. It is then evaporated to dryness in a rotary evaporator, the residue is dissolved, at 90° C., in 100 ml of N,N-dimethylacetamide and 50 ml of water and the solution is rendered acid to Congo Blue with 10% strength hydrochloric acid. After cooling, the slurry-like mixture is filtered and the residue is rinsed with acetone and then dried in vacuo at 80° C. The dry residue is then suspended in 100 ml of acetic anhydride and this mixture is warmed to about 100° C. for 1 hour. It is then evaporated to dryness and the residue is recrystallised from 1,2-dichlorobenzene. 8.9 g (69% of theory) of 3,5-bis-(dimethylmaleimidyl)-phthalic anhydride are obtained; colour: light brownish; melting point 298° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>C1COCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]([C:14]#[N:15])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(C#N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 44.94 %

Procedure:
3,5-Bis(trifluoromethyl)-phenylacetonitrile (1.4 mL, 1.0 eq.) was dissolved in THF (20 mL). The reaction mixture was cooled to −78° C. where a solution of NaHMDS (35% in THF) (4.34 mL, 1.05 eq.) was added dropwise. The reaction mixture was allowed to warm to 10° C. and stirred for 15 min. Then it was cooled to −78° C. where ethyl bromoacetate (0.87 mL, 1.0 eq.) was added. The reaction mixture was then allowed to warm to room temperature where it was stirred for 16 h. Reaction mixture was poured into water (50 mL) and was extracted with EtOAc (3×20 mL) The combined organic layers were washed with brine solution (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 3.5 g of crude product, which was purified by chromatography (4% ethyl acetate in hexane) to give 1.2 g of ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-3-cyanopropanoate (Yield 44.94%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:6]2[C:2]([CH3:1])=[CH:3][C:4]([NH2:7])=[N:5]2)=[CH:11][CH:10]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1cc(N)nn1Cc1ccc(F)cc1

Procedure:
Prepared in analogy to example 10a) starting with 5-methyl-1H-pyrazol-3-ylamine and 4-fluorobenzyl bromide. The title compound was obtained as a white solid (Yield=14%). MS ISP (m/e): 206.1 (100) [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][C:5]1([C:18]([O:20]CC)=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.O.[OH-].[Li+].CCO.Cl>O>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH2:4][CH2:3][N:2]([CH3:23])[CH3:1])([C:18]([OH:20])=[O:19])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C1(CCN(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
1-tert-Butyl 4-ethyl 4-(2-(dimethylamino)ethyl)piperidine-1,4-dicarboxylate from step A (328 mg, 1.0 mmol) was treated overnight with lithium hydroxide monohydrate (210 mg, 5 mmol) in 1:1 EtOH:H2O (5 mL) at 60° C. The reaction was cooled to room temperature, neutralized to pH 6 with 1 N aq. HCl, and concentrated under vacuum. The residue was purified by prep HPLC and lyophilized twice to give the title compound (191 mg, 64%) as a white solid. MS (ES+) [M+H]+=301.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]2[N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].O>CN1C(=O)CCC1>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:5]3=[CH:12][CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]3[N:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)c1cccc2c1nc(Cl)c1ccncc12
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Yield: 45.3 %

Procedure:
Methyl 5-chlorobenzo[c][2,6]naphthyridine-7-carboxylate (1.0 eq, 48 mg, 0.176 mmol) and 3-chloroaniline (3.0 eq, 60 ul, 0.56 mmol) were stirred under microwave heating at 120° C. in NMP (0.3 ml) for 10 minutes. Water was added and the solid isolated by filtration. Trituration in methanol and filtration afforded methyl 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxylate as a solid (29 mg, 45% yield). LCMS (ES): >85% pure, m/z 364 [M+1]+.