Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].C([CH:16]([C:20](Cl)=[O:21])[C:17](Cl)=[O:18])C.[CH2:23]([O:25]CC)[CH3:24]>>[CH2:23]([O:25][C:20]([C:16]1[C:17](=[O:18])[N:2]([CH3:1])[C:3]2[C:4]([C:5]=1[OH:6])=[CH:9][CH:10]=[C:11]([CH3:13])[N:12]=2)=[O:21])[CH3:24]
Reactant: CNc1nc(C)ccc1C(=O)OC
Reactant: CCOCC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Product: CCOC(=O)c1c(O)c2ccc(C)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9.0 g. (0.05 mole) of methyl 2-methylamino-6-methylnicotinate in 150 ml. of anhydrous diethyl ether was added 3.75 g. (0.025 mole) of ethyl malonyl chloride. The mixture was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was dissolved in 10 ml. of ethanol. This solution was added to a solution of 1.15 g. (0.05 g. atoms) of sodium in 75 ml. of ethanol. The mixture was stirred at room temperature for 5 minutes and was filtered. The filter cake was triturated with 100 ml. of water and this mixture was acidified with glacial acetic acid. The insoluble material was collected, air dried and was recrystallized from ethyl acetate to give 1.5 g. of the title compound, m.p. 143°-5° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@:10]([CH2:29][O:30][S:31]([CH3:34])(=[O:33])=[O:32])([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][CH:6]1OC)(=[O:3])[CH3:2].[C:35]1([S:41][Si](C)(C)C)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>ClCCl>[C:1]([O:4][C@@H:5]1[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@:10]([CH2:29][O:30][S:31]([CH3:34])(=[O:33])=[O:32])([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:9][C@H:6]1[S:41][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:3])[CH3:2]
Reactant: COC1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Reactant: C[Si](C)(C)Sc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](Sc2ccccc2)O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
Method a. A stirred solution of 209 (738 mg, 1.49 mmol) in anhydrous dichloromethane (6.4 mL) was added phenylthiotrimethylsilane (2.42 mL, 12.8 mmol) and cooled to 0° C. Trimethylsilyl triflate (0.67 mL, 3.67 mmol) was added dropwise and the solution was stirred at room temperature for 4 h. The reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate (100 mL) and extracted with dichloromethane (2×200 mL). The combined extract was dried (MgSO4) and the solvent removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel with dichloromethane as eluent to give the product 210 as a clear oil (564 mg, 66%) and unreacted starting material (191 mg, 26%); Method b. A stirred solution of 211 (86 mg, 0.165 mmol) in anhydrous dichloromethane (0.49 mL) was added phenylthiotrimethylsilane (0.16 mL, 0.825 mmol) and cooled to 0° C. Trimethylsilyl triflate (0.037 mL, 0.206 mmol) was added and the solution was stirred at room temperature for 2 h. The reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate (15 mL) and the resulting mixture was extracted with dichloromethane (2×25 mL). The combined extract was dried (MgSO4) and the solvent removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel with dichloromethane as eluent to give the product 210 as a clear oil (75 mg, 79%); 1H NMR (CDCl3): δ 7.47-7.19 (15H, m, Bn, SPh), 5.48 (1H, d, J 3.6 Hz, H-2), 5.34 (1H, dd, J 3.7, 5.2 Hz, H-1), 4.54-4.36 (7H, m, H-3, H-5□, Bn), 3.66 (1H, d, J 9.7 Hz, H-5), 3.48 (1H, d, J 9.5 Hz, H-5), 2.89 (3H, s, SO2CH3), 2.09 (3H, s, OCCH3); 13C NMR (CDCl3): δ 169.93 (C═O), 137.69, 137.08, 132.65, 132.45, 129.15, 128.53, 128.52, 128.18, 128.14, 128.08, 127.91, 127.85 (Bn, SPh), 87.99, 84.35, 80.34, 75.33, 74.20, 73.67, 70.83, 69.34 (C-1, C-2, C-3, C-4, C-5, C-5′, Bn), 37.27 (SO2CH3), 20.68 (OCCH3); MS FAB: 463 (M−SPh, 100%), 595 (M+Na, 24%). Found. C, 61.17; H, 5.55; C29H32O8S2 requires C, 60.82; H, 5.63%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH3:18])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10].[CH3:19][O:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>C(O)C>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH:8]([CH3:18])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[O:10])[CH2:30][CH2:31]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(CC2CCNCC2)cc1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(CC2CCN(C(C)C(=O)c3ccc(Cl)cc3)CC2)cc1
Reaction time: 48 h
Yield: 100.2 %

Procedure:
2.80 g (0.02 mol) of potassium carbonate are added to a solution of 5 g (0.02 mol) of 2-bromo-4'-chloropropiophenone and 4.15 g (0.02 mol) of 4-(4-methoxybenzyl)-piperidine in 60 ml of dry ethanol and the mixture is heated under reflux for 5 hours, with stirring, and then left to stand for 48 hours. It is left to cool and filtered, the filter cake being washed with alcohol, and the filtrate is evaporated. An orange oily residue remains, which is taken up in a mixture of water and diethyl ether. The organic phase is separated off and the aqueous phase is extracted a second time with diethyl ether. The organic phases are combined, dried and evaporated to give 7.45 g of an orange-yellow oily residue, which crystallises partially at ambient temperature and which is used as such in the subsequent reduction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[CH:4][C:3]=1[F:11].P([O-])([O-])([O-])=[O:13].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[F:11][C:3]1[CH:4]=[C:5]([C:8]2([CH3:10])[CH2:9][O:13]2)[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=P([O-])([O-])[O-]
Reactant: C=C(C)c1ccc(F)c(F)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(c2ccc(F)c(F)c2)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a biphasic solution of 1,2-difluoro-4-isopropenyl-benzene (0.81 g, 5.1 mmol) in CH2Cl2 (50 mL) and 50 mL of phosphate buffer (made by dissolving 0.3 g of NaHPO4 and 0.35 g of NaH2PO4 in 50 mL water, pH=8) at 0° C., was added a solution of 3-chloroperoxybenzoic acid (approx. 75% solid, 3.32 g, 10.2 mmol) via a dropping funnel fitted with a cotton plug dropwise in two batches. The solution was stirred at room temperature overnight. It was extracted with CH2Cl2, washed with sat. Na2S2O4 solution followed by water. The organic layer was finally washed with sat. NaHCO3, separated, dried over Na2SO4, filtered and solvent was removed in vacuo. 2-(3,4-Difluorophenyl)-2-methyl-oxirane was obtained as a pale yellow oil (0.65 g, 74% yield). It was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2C(=CC=C[CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1[C:30]2N=C[CH:33]=[CH:34][C:29]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[CH3:56][N:57]([CH2:70][CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][N:73]=1)[C:58](=[O:69])[C@H:59]([NH:67][CH3:68])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:12])[N:67]([CH3:68])[C@@H:59]([C:58](=[O:69])[N:57]([CH3:56])[CH2:70][CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][N:73]=1)[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:14][C:15]1[CH:16]=[CH:33][C:34]2[C:23](=[CH:22][CH:21]=[CH:30][CH:29]=2)[CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N(C)CCc1ccccn1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl) propionic acid (11.2 g, 34 mmol), 1-hydroxy-7-azabenzotriazole (5.2 g, 38 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.9 g, 36 mmol) were dissolved in dichloromethane (100 mL). The reaction mixture was stirred for 15 min. Ethyldiisopropylamine (7.0 mL, 41 mmol) was added. (2R)-N-Methyl-2-(methylamino)-3-phenyl-N-(2-(2-pyridyl)ethyl)propionamide (7.9 g, 27 mmol) dissolved in dichloromethane (20 mL) was added. The reaction mixture was stirred for 16 h. The reaction mixture was added to aminomethylresin (17.3 g, 13.5 mmol). The reaction mixture was stirred for 6 h. The reaction mixture was filtrated. The organic layer was washed with sat. aqueous sodium hydrogen carbonate solution (2×150 mL). The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate as eluent, to give 14.9 g N-Methyl-N-[(1R)1-(N-methyl-N-{(1R)-1-[N-methyl-N-(2-(pyridinyl)ethyl)carbamoyl]-2-phenylethyl}carbamoyl)-2-(2-naphthyl)ethyl]carbamic acid tertbutyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:12]([F:22])[CH:11]=1)=[O:8]>[Pt](=O)=O.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)=[C:12]([F:22])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(-c2ccncc2)c(F)c1)c1cc(Cl)ccc1O
Agent: O=[Pt]=O
Solvent: CO
Product: Cl
Product: O=C(Nc1ccc(C2CCNCC2)c(F)c1)c1cc(Cl)ccc1O
Reaction time: 5 h
Yield: 36 %

Procedure:
A mixture of 5-chloro-N-[3-fluoro-4-(pyridin-4-yl)phenyl]-2-hydroxybenzamide (compound of Reference Example 186; 0.104 g, 0.303 mmol), platinum(IV) oxide (0.100 g, 0.440 mmol) and methanol (10 ml) was stirred under ice cooling for 5 hours under hydrogen atmosphere. The reaction mixture was filtered, and the residue obtained by evaporation of the solvent of the filtrate under reduced pressure was purified by column chromatography on silica gel. 2N Hydrochloric acid was added to the obtained purified substance, and the mixture was refluxed for 1 hour. The solvent was evaporated under reduced pressure to give the title compound (0.021 g, 18%) as a colorless solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][NH2:10])[CH2:2]2.C([O-])([O-])=O.[K+].[K+].Cl[C:18](=[CH2:21])[C:19]#[N:20]>O.CO>[NH2:20][C:19]1[N:9]([CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)[N:10]=[CH:21][CH:18]=1
Reactant: NNC1CN2CCC1CC2
Reactant: C=C(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1ccnn1C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Quinuclidinyl-hydrazine (D2) (5.0 g, 35.5 mmol) was added to a solution of K2CO3 (4.90 g, 35.5 mmol) in water (13 ml) and the ice-cooled solution was stirred vigorously while 2-chloroacrylonitrile (3.10 g, 2.83 ml, 35.5 mmol) was added dropwise over 1 minute. The solution was then stirred at room temperature overnight. The mixture was diluted with MeOH, evaporated to a slurry under reduced pressure, suspended in saturated aqueous potassium carbonate and extracted with EtOAc (3×100 ml), followed by CHCl3 (4×250 ml). The organic extracts were dried (Na2SO4), filtered and evaporated to dryness under reduced pressure to yield a brown oil, which was purified by column chromatography (neutral alumina eluting with chloroform), to yield a faster running fraction (E3) (44 mg) and a slower running fraction (E4) (32 mg). Both were crystallised separately by trituration with diethyl ether, to yield white crystalline solids.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C@@H:8]([NH2:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1)[CH3:2].[C:20]1([CH2:26][C:27](O)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C.O>[CH2:1]([C:3]1[N:4]=[C:5]([CH:8]([NH:19][C:27](=[O:28])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1)[CH3:2]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCc1coc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1coc(C(Cc2ccc([N+](=O)[O-])cc2)NC(=O)Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine, 50, (2.9 g, 11 mmol), phenylacetic acid (1.90 g, 14 mmol) and 1-hydroxybenzotriazole (HOBt) (0.94 g, 7.0 mmol) in DMF (100 mL) at 0° C., is added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDCI) (2.68 g, 14 mmol) followed by triethylamine (6.0 mL, 42 mmol). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:16]1([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH:27]=4)[CH2:24][C:23](=[O:39])[NH:22][C:9]=3[CH:10]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert-butyl ester (Example M146) (276 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (200 mg, 93%).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([Cl:23])=[O:22]>>[ClH:23].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Product: Cl
Product: O=C(Nc1ccc(N2CCN3CCC2CC3)cc1)c1cccc(F)c1

Procedure:
Was prepared by Method G from 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine and 3-fluorobenzoyl chloride. Mp. >270° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH2:12]O)[N:8]=[C:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.C(N(S(F)(F)[F:29])CC)C>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH2:12][F:29])[N:8]=[C:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1cc2cc(F)c(CO)nc2nc1C(F)(F)F
Product: CCOC(=O)c1cc2cc(F)c(CF)nc2nc1C(F)(F)F

Procedure:
In a similar procedure to Example 12, Stage 3, ethyl 6-fluoro-7-hydroxymethyl-2-trifluoromethyl-[1,8]-naphthyridine-3-carboxylate was reacted with N,N-diethylaminosulfur trifluoride to give the required product. as a pale brown solid, 1H NMR (CDCl3) δ: 8.74 (1H, s), 8.03 (1H, d), 5.83 (2H, double doublet), 4.51 (1H, q), 1.45 (3H, t).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[N:18]1([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCNC1
Reactant: Clc1nccnc1OCCOc1ccccc1
Product: c1ccc(OCCOc2nccnc2N2CCCNCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) and homopiperazine (250 mg, 2.5 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 141 mg (75%) of the title product. Anal. (C17H22N4O2.0.35EtOAc) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]Br.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][S:11]([O-:14])(=[O:13])=[O:12].[Na+:15]
Reactant: BrCCc1ccccc1Br
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCc1ccccc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A solution of 1-bromo-2-(2-bromoethyl)benzene (6.23 g, 23.6 mmol) in ethanol (20.5 mL) was added to a solution of sodium sulfite (3.12 g, 24.7 mmol) in water (25.0 mL). The mixture was heated at 100° C. for 24 hours. The reaction mixture was filtered, and the filtrate was then left to stand at 3° C. overnight. The resulting white crystals were collected by filtration and dried to give sodium 2-(2-bromo-phenyl)ethanesulfonate (4.00 g, 59%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1)[C:2]#[CH:3].I[C:22]1[CH:23]=[C:24]([CH3:29])[C:25]([CH3:28])=[CH:26][CH:27]=1.N1CCCC1.CO>C(Cl)(Cl)Cl.[Cu]I.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>[CH3:29][C:24]1[CH:23]=[C:22]([C:3]#[C:2][CH2:1][O:4][CH2:5][CH2:6][N:7]2[C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=[C:11]([NH2:20])[C:10]=3[N:9]=[CH:8]2)[CH:27]=[CH:26][C:25]=1[CH3:28]
Reactant: Cc1ccc(I)cc1C
Reactant: C#CCOCCn1cnc2c(N)nc3ccccc3c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCNC1
Product: Cc1ccc(C#CCOCCn2cnc3c(N)nc4ccccc4c32)cc1C
Temperature: 25 °C
Yield: 14.2 %

Procedure:
Under a nitrogen atmosphere, 1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.9 mmol), copper (I) iodide (0.036 g, 0.2 mmol), 4-iodo-ortho-xylene (0.5 g, 2.1 mmol) and pyrrolidine (10 mL) were combined and stirred at ambient temperature. Dichlorobis(triphenylphosphine)palladium(II) (0.066 g, 0.1 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. Analysis by TLC (30% methanol in chloroform) indicated that starting material was still present. The reaction mixture was heated at 65° C. overnight. The pyrrolidine was removed under reduced pressure. The resulting residue was triturated with dichloromethane containing methanol. The insoluble material was isolated by filtration and then recrystallized from toluene (40 mL) to provide 0.1 g of 1-(2-{[3-(3,4-dimethylphenyl)-2-propynyl]oxy}ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 214-216° C. Analysis: Calculated for C23H22N4O: % C, 74.57; % H, 5.99; % N, 15.12. Found: % C, 74.24; % H, 5.98; % N, 15.08.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][NH2:10])([CH3:3])[CH3:2].[CH:15]1([O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH:24]=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.[BH4-].[K+]>C1(C)C=CC=CC=1>[CH:15]1([O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH2:24][NH:10][CH2:9][CH2:8][O:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)Oc1ccccc1OCCN
Reactant: O=Cc1cccc(OC2CCCC2)c1
Agent: [BH4-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccccc1OCCNCc1cccc(OC2CCCC2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.5 g of 2-(2-isopropoxyphenoxy)ethylamine (2.56 mmol) and 0.49 [lacuna] of 3-cyclopentyloxybenzaldehyde (2.56 mmol) are mixed together in 20 ml of toluene. The solution is refluxed for 12 hours, while continuously removing the water formed. The toluene is then evaporated off, the residue is taken up in 20 ml of methanol and the solution is cooled to 0° C. 0.28 g of potassium borohydride (5.12 mmol) is added portionwise and the mixture is stirred for 3 hours at room temperature. The methanol is evaporated off, the residue is taken up in dichloromethane and the organic phase is washed with water and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under vacuum. The title product is isolated by chromatography on a column of silica (eluent: 98/1.5/0.5 dichloromethane/methanol/aqueous ammonia). 0.77 g of the title product is obtained in the form of a pale yellow oil:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[NH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:31]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: Nc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c1F)C2
Yield: 31.9 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 4-aminoisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 75 mg of the target compound.
Reaction SMILES: [NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:23]([OH:25])=[O:24])[CH2:3][CH2:4][NH:5]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>CN(C=O)C>[NH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-L-Dab(Fmoc)-OH (132 mg, 0.3 mmol, PepTech) and piperidine (0.2 mL, 2.02 mmol) were dissolved in DMF (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and the residue was used directly in the subsequent step without further purification.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:31]=[C:30]([C:38](O)=O)[N:29]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[N:31]=[C:30]([C:38]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=4)[N:14]=3)[N:29]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27])[CH3:16]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4ccc(S(N)(=O)=O)cc4)no3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.75 mmol) and 4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.4) (0.19 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.114 g, 41%). MS (ISP) 560.2 [(M+H)+]; mp 250.5° C.