Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:17]([C:33]3[CH:41]=[C:40]([O:42][CH3:43])[C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[O:31][CH3:32])(=[O:23])=[O:22])=[O:19])=[CH:12][N:13]2[CH3:16])=[CH:9][CH:8]=1.CN(C)[CH:46]=[O:47]>O1CCCC1>[CH:46]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:17]([C:33]3[CH:41]=[C:40]([O:42][CH3:43])[C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[O:31][CH3:32])(=[O:23])=[O:22])=[O:19])=[CH:12][N:13]2[CH3:16])=[CH:9][CH:8]=1)=[O:47]
Reactant: CN(C)C=O
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(C=O)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.8 ml of 2.5 M solution in hexane) was added to a stirred solution of 6-bromo-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)-sulfonamido]-2-oxoethyl}-1-methyl-1H-indole (from Example 92, 400 mg, 0.67 mmol) in anhydrous tetrahydrofuran at −75° C. under a nitrogen atmosphere. After 30 minutes dimethylformamide (0.15 ml) was added to the orange solution, and after a further 30 minutes the mixture was allowed to warm to 0° C. before quenching with excess 1 N hydrochloric acid. Ethyl acetate was added and the organic layer was separated and washed with water. The organic layer was dried (magnesium sulphate), and the solvents removed in vacuo. The residue was flash chromatographed using 1% methanol in dichloromethane as eluant, and the product was crystallised from dichloromethane and diethyl ether mixture to give the title compound (187 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])=[CH:5][CH:4]=1.[O:16]=[C:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)CC)(C)C.[Li+].[Br-]>C1COCC1>[C:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH:18]([C:17](=[O:16])[CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:5]=1)#[N:15]
Reactant: N#Cc1ccsc1-c1ccc(CBr)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)C(Cc1ccc(-c2sccc2C#N)cc1)C(=O)OCC
Yield: 97.7 %

Procedure:
A mixture of 50 g of 2-(4-bromomethylphenyl)-3-cyanothiophene, prepared above, 40 g of ethyl 3-oxohexanoate, prepared in Example 1, 300 ml of THF, 62 ml of diisopropylethylamine and 15.6 g of LiBr is refluxed for 15 h. It is concentrated under vacuum, a dilute solution of hydrochloric acid is added and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with water, dried and evaporated to give 62.4 g of ethyl 2-[4-(3-cyano-2-thienyl)benzyl]-3-oxohexanoate in the form of an oil, which is used without further purification.
Reaction SMILES: C(O[C:4]([O:10][CH2:11][CH3:12])(OCC)[CH2:5][CH3:6])C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[CH2:23][S:22][C:21]2=[S:26])=[CH:16][CH:15]=1>C(OC(=O)C)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:24](=[O:25])[C:23](=[C:4]([O:10][CH2:11][CH3:12])[CH2:5][CH3:6])[S:22][C:21]2=[S:26])=[CH:18][CH:19]=1
Reactant: CCOC(CC)(OCC)OCC
Reactant: O=C1CSC(=S)N1c1ccc(Cl)cc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(CC)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O

Procedure:
Following the procedures of Example 1, triethylorthopropionate is reacted with 3-(4'-chlorophenyl)-rhodanine in acetic anhydride for 51/2 hours to give 3-(4'-chlorophenyl)-5-(1'-ethoxypropylidene)-rhodanine. To a suspension of the latter (25 g., 0.0765 m.) in 200 ml. of dioxane and 200 ml. of water is added 50 ml. of 10% sodium hydroxide solution. The mixture is stirred at room temperature for 4 hours and then concentrated in vacuo at 40°-45°C. The residual solution is washed with ether, decolorized and acidified with dilute hydrochloric acid to yield 3-(4'-chlorophenyl)-5-(1'-hydroxypropylidene)-rhodanine, m.p. 145°-149°C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:28])[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:28][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCC2)cn1
Yield: 56 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using cyclobutylamine (1 M in DMF) instead of methylamine, to the title compound (66 mg, 56%) which was obtained as a white solid. MS: m/e=364.4 [M+H]+.
Reaction SMILES: CS([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1)(=O)=O.[CH3:30][OH:31]>>[CH3:30][O:31][C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Reactant: CO
Product: COc1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Yield: 4 %

Procedure:
In the same manner as in Example 110 and using 2-(methylsulfonyl)-5-[3-[4-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using methanol instead of 3-fluorobenzyl alcohol, the title compound (yield 4%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:19][C:20]1[CH:56]=[CH:55][CH:54]=[CH:53][C:21]=1[CH2:22][NH:23][C:24]([C@@H:26]1[C:30]([CH3:32])([CH3:31])[S:29][CH2:28][N:27]1[C:33](=[O:52])[C@@H:34]([OH:51])[C@@H:35]([NH:43][C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:56]=[CH:55][CH:54]=[CH:53][C:21]=1[CH2:22][NH:23][C:24]([C@@H:26]1[C:30]([CH3:32])([CH3:31])[S:29][CH2:28][N:27]1[C:33](=[O:52])[C@@H:34]([OH:51])[C@@H:35]([NH:43][C:44](=[O:50])[C@@H:45]([NH:46][C:5](=[O:7])[CH2:4][O:3][CH2:1][CH3:2])[CH:47]([CH3:49])[CH3:48])[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:25]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: CCOCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Ethoxyacetic acid (28 μl), HOBt (41 mg), and HDC.HCl (63 mg) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 of Example 8 in DMF (5 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was recrystallized from ethyl acetate/n-hexane to obtain the title compound (153 mg).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH:15]1([N:20]2[C:24]([NH2:25])=[C:23]([C:26]#[N:27])[C:22]([CH2:28][CH3:29])=[N:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:20]2[C:24]([NH:25][C:12]([C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]=[CH:3][CH:4]=3)=[O:13])=[C:23]([C:26]#[N:27])[C:22]([CH2:28][CH3:29])=[N:21]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C(Cl)c1ccnc2ccccc12
Reactant: CCc1nn(C2CCCC2)c(N)c1C#N
Agent: Cl
Product: CCc1nn(C2CCCC2)c(NC(=O)c2ccnc3ccccc23)c1C#N
Temperature: 250 °C
Yield: 214 %

Procedure:
4-Quinolinecarboxylic acid chloride hydrochloride (3.8 g, 6.5 mmol) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carbonitrile (2.8 g, 13.7 mmol) were combined and heated in an oil bath at 250° C. for 7 minutes. The reaction mixture was cooled to room temperature and the obtained solid was collected by filtration on a glass frit and was washed with chloroform. The residue was recrystallized from ethyl acetate to afford 5.0 g (100%) of 1-cyclopentyl-3-ethyl-4-cyano-5-(4-quinolinecarboxamido)-1H-pyrazole as a white solid, m.p. 156°-161° C., after drying at 110° C. for 7 hours in high vacuum.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[Cl:18].Cl>C1(C)C=CC=CC=1.O>[C:20]([CH:19]([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)[C:1]([O:5][CH2:6][CH3:7])=[O:8])#[N:21]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of diethyl carbonate (4.1 mL, 33.88 mmol) in toluene (150 mL) at r.t, sodium hydride (1.43 g, 60% in mineral oil, 35.75 mmol) and 3,4-dichlorophenyl acetonitrile (6.34 g, 34.09 mmol) were added. The content was stirred at 80° C. overnight. After cooling to r.t, HCl was added (1 N in H2O, 100 mL). The content was extracted with ethyl acetate (3×). The combined organic layer was washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography with hexane/ethyl acetate (6/1) to give 7.42 g product (85% yield) as brown oil. 1H NMR (400 MHz, CDCl3) δ[ppm]: 7.60 (1H, broad s), 7.54 (1H, d, J=8.3 Hz), 7.35 (1H, broad d, J=8.3 Hz), 4.72 (1H, s), 4.29 (2H, q, J=14.2 Hz, 7.0 Hz), 1.28 (3H, t, J=6.7 Hz). LRMS calculated for C11H9Cl2NO2 M+ 257. found 257.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:17]=[C:16]2[CH3:32])=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>CCO.O>[CH3:32][C:16]1[N:15]([CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:33])=[O:3])=[CH:10][CH:9]=2)[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:17]=1
Reactant: CCOC(=O)c1ccc(OCCCn2c(C)nc(-c3ccccc3)c2-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
(Scheme 2 (I)) To a solution of 4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-benzoic acid ethyl ester (0.80 g, 1.8 mmol) in EtOH (20 mL) was added NaOH (10 N, 4.0 mL, 40.0 mmol). The resulting mixture was stirred at rt for 3 hours, diluted with water, acidified to pH˜1 using 1N HCl, extracted by CH2Cl2, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: MeOH/CH2Cl2). This compound was obtained as a white dry foam in HCl salt form (0.80 g, 1.8 mmol, 99% yield): 1H NMR (DMSO): δ1.93 (m, 2H), 2.67 (s, 3H), 3.97 (t, 2H), 4.13 (t, 2H), 6.85 (d, J=8.82 mHz, 2H), 7.33 (s, 5H), 7.43 (m, 2H), 7.55 (m, 3H), 7.86 (d, J=8.82 mHz, 2H), 12.64 (b, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C:10](=[N:13]O)[CH2:9]2)=[CH:4][CH:3]=1.N.CO>[Ni].O>[C:5]1([C@H:8]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: ON=C1CC[C@H](c2ccc(Br)cc2)C1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: NC1CC[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 32 h
Yield: 92.1 %

Procedure:
A solution of Example 1C (10 g, 39.4 mmol) and 7M NH3/MeOH (100 mL) was added to Ra—Ni 2800, water slurry (40.0 g, 682 mmol) in a 50 mL pressure bottle. The mixture was stirred at room temperature for 32 hours at 30 psi. HPLC indicated complete reaction. The mixture was filtered through a nylon membrane, concentrated, and diluted with MTBE (300 mL) and 2N NaOH (150 mL). The layers were separated and the organic layer was washed with water (100 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated to afford the title compound (5.86 g, 36.3 mmol, 92%). MS (LCMS) m/z 162 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27]>O>[Cl:1][C:2]1[C:3]([O:12][CH2:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: CCCCCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOC(=O)COc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrophenol (100 g), anhydrous potassium carbonate (86.6 g) and dimethylformamide (500 g) was heated at 50° C., and amyl 2-chloroacetate (90.2 g) was dropwise added thereto in 30 minutes, followed by allowing to stand at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, and water (1500 g) was added thereto, followed by extraction with ethyl acetate (1500 g). The organic layer was separated, washed with water and concentrated under reduced pressure. The residue was distilled under reduced pressure to give 4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)nitrobenzene (Compound (III)) (129 g) as a pale yellow oil. Yield, 77%. b.p., 160 °-165° C./0.7 mmHg.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[N:16][C:17]([O:20][C@@H:21]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22]3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[N+:29]([O-:31])=[O:30])(C)(C)C.Cl>CCO>[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([O:20][C:17]1[N:16]=[N:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N+:29]([O-:31])=[O:30])[CH:10]=3)=[CH:19][CH:18]=1)[CH2:22]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1[N+](=O)[O-]

Procedure:
The product of Example 34C (350 mg, 0.79 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 2 mL, 8 mmol) in EtOH (5 mL) at ambient temperature for 1 h. The mixture was concentrated and the title compound was purified by chromatography (SiO2, EtOAc: MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.1) as white solid (250 mg, 93%). 1H NMR (300 MHz, MeOH-D4) δ 1.54-1.66 (m, 1 H), 1.72-2.02 (m, 2 H), 2.07-2.24 (m, 1 H), 2.35-2.57 (m, 1 H), 2.79-3.18 (m, 5 H), 3.48-3.69 (m, 1 H), 5.27-5.47 (m, 1 H), 7.10 (d, J=8.8 Hz, 1 H), 7.22 (d, J=9.5 Hz, 1 H), 7.66 (s, 1 H), 7.98 (d, J=9.2 Hz, 1 H), 8.08 (dd, J=9.0, 2.2 Hz, 1 H), 8.68 (d, J=2.4 Hz, 1 H) ppm. MS (DCl/NH3): 342 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:25][CH2:24][CH2:23]1>>[N:22]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: C1CNC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCC3)cc2c1=O
Yield: 45 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with azetidine according to the GPA affording 15 mg (45%) of a red powder. Rt=3.92 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[N:4][N:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:25][CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])=[N:4][N:3]=[C:2]2[NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[CH2:27][CH2:28]2)=[CH:7][CH:8]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1ccc2c(-c3ccccc3OC)nnc(Cl)c2c1
Product: COc1ccc2c(-c3ccccc3OC)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(2-methoxyphenyl)phthalazine described with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[Na].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>C1(C)C=CC=CC=1>[CH3:1][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Into a flask containing diethyl malonate (20 g, 0.125 mol) was added sodium (2.0 g, 0.087 mol). The reaction mixture was stirred for 1 h at room temperature and then allowed to warm to 120° C. (oil bath temperature) for 50 min. To this yellow suspension of the solid mass was added toluene (120 mL) followed by addition of a solution of 2-chloro-3-nitropyridine 1 (12.8 g, 0.08 mol) in 40 mL of toluene. The reaction mixture was refluxed for 8 h, and then stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in 30% H2SO4 (60 mL). This reaction mixture was heated to 125° C. (oil bath) for 7 h, cooled and poured into ice (200 g). The reaction mixture was neutralized with saturated NaHCO3 solution, filtered through Celite, extracted several times with ether. The combined extracts were dried over anhydrous Na2SO4. The solvent was evaporated and the residue was distilled under reduced pressure to provide 6.65 g (60%) of the desired product 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1>[Pd].CO>[F:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1N
Reaction time: 5 h
Yield: 92.8 %

Procedure:
1-(1-(2-Fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (1.65 g, 4.68 mmol) was added in a 200-mL round-bottomed flask. Methanol (30 mL) was added as the solvent. Pd/C (10% wet) (0.2 g, 4.68 mmol) was added. The reaction was stirred under a hydrogen balloon for 5 h. The filtrate was collected after filtration and it was concentrated in vacuo to give the title product (1.4 g, 93% yield).
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:33])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:34][CH2:35][C@H:36]([OH:51])[CH2:37][O:38][C:39]1[CH:48]=[CH:47][C:46]([OH:49])=[C:45]2[C:40]=1[CH2:41][CH2:42][C:43](=[O:50])[NH:44]2>>[CH2:1]([NH:7][C:8]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][CH:29]([NH:34][CH2:35][C@H:36]([OH:51])[CH2:37][O:38][C:39]4[CH:48]=[CH:47][C:46]([OH:49])=[C:45]5[C:40]=4[CH2:41][CH2:42][C:43](=[O:50])[NH:44]5)[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzensulfonamide (which was obtained in Example 225) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=5.1 Hz, 3H), 1.20-1.35 (m, 8H), 1.35-1.50 (m, 2H), 1.75-1.90 (m, 2H), 2.39 (t, J=5.1 Hz, 2H), 2.50-2.75 (m, 5H), 2.82 (t, J=5.1 Hz, 2H), 3.05 (q, J=5.1 Hz, 2H), 3.40-3.55 (m, 2H), 3.75-3.85 (m, 3H), 4.90 (brs, 1H), 6.30 (t, J=5.1 Hz, 1H), 6.44 (d, J=6.6 Hz, 1H), 6.59 (d, J=6.6 Hz, 1H), 6.76 (d, J=6.9 Hz, 1H), 6.85 (d, J=6.9 Hz, 1H), 7.46 (d, J=6.9 Hz, 2H), 7.50 (d, J=6.9 Hz, 2H), 8.67 (s, 1H), 8.84 (s, 1H), 9.10 (brs, 1H), 9.50 (brs, 1H); MS (ES) m/z: 709.2 (MH+); HRMS Calcd. for C36H49N6O7S(MH+): 709.3383. Found: 709.3391.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[F:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=2)=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Reactant: O=C=Nc1ccc(F)c(F)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 3,4-difluoro-phenyl isocyanate (0.075 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 55 as a colorless solid (0.062 g, 35%). LCMS m/z (%)=423 M+H+ (37Cl, 23), 421 M+H+ (35Cl, 67), 1H NMR (400 MHz, acetone-d6) δ: 8.199 (d, J=2.44 Hz, 1H), 8.181 (d, J=2.42 Hz, 1H), 8.166 (d, J=2.37 Hz, 1H), 8.147 (d, J=2.08 Hz, 1H), 8.106 (d, J=2.65 Hz, 1H), 8.085 (d, J=2.68 Hz, 1H), 7.967 (s, 1H), 7.880 (d, J=2.61 Hz, 1H), 7.627 (t, 1H), 7.594 (d, J=3.86 Hz, 1H) 7.563 (d, J=8.96 Hz, 1H), 4.669 (m, 1H), 4.242 (s, 3H), 1.874 (d, J=6.61 Hz, 3H), 1.713 (d, J=6.61 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:10]2[CH2:11][CH:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([CH2:13]3)[CH2:9]2)=[O:26])=[CH:23][CH:22]=1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
A 19.35 g sample of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g of sodium carbonate and 17.5 g of p-chlorobenzoyl chloride are reacted in benzene. The benzene is evaporated and the dark purple residue is dissolved in 200 ml of chloroform and washed successively with 5% sodium carbonate, 0.5N hydrochloric acid and then with water and dried over sodium sulfate giving a dark purple oil. Addition of ether gives the product 3-p-chlorobenzoyl-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as grey crystals, mp 98°-100° C.
Reaction SMILES: [Br:1]Br.[C:3]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=[O:5])[CH3:4].O>CO>[Br:1][CH2:4][C:3]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5]
Reactant: CC(=O)C1Cc2ccccc2C1
Reactant: BrBr
Solvent: CO
Solvent: O
Product: O=C(CBr)C1Cc2ccccc2C1
Reaction time: 1 h

Procedure:
10 g of pure bromine are rapidly added at 0° C. to a solution of 10 g of 2-acetylindane in 150 ml of anhydrous methanol. After one hour at ambient temperature, 100 ml of water are added and the whole is stirred for 12 hours. After extracting twice with 200 ml of diethyl ether each time, and washing the organic phase with a sodium hydrogen carbonate solution and then with water, the expected product is dried over magnesium sulphate and concentrated.