Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1.Br[CH2:15][CH2:16][O:17][CH3:18]>CN(C)C=O>[CH3:18][O:17][CH2:16][CH2:15][N:6]1[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]([CH3:3])=[N:5]1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)nn1CCOC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.8 %

Procedure:
To a suspension of sodium hydride (310 mg, 7.8 mmol) in N,N-dimethylformamide (10 mL) was slowly added a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (1000 mg, 6.5 mmol) in N,N-dimethylformamide (5 mL) under ice-cooling, and the mixture was stirred at 0° C. for 10 min, then at room temperature for 20 min. To the reaction mixture was added a solution of 1-bromo-2-methoxyethane (1090 mg, 7.8 mmol) in N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 7 hr. The solvent was evaporated under reduced pressure, and ethyl acetate/tetrahydrofuran and water were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→70/30) to give ethyl 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylate (430 mg, 2.0 mmol) as a colorless liquid. To a solution of the obtained ethyl 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylate (430 mg, 2.0 mmol) in tetrahydrofuran (6 mL) was added 8N aqueous sodium hydroxide solution (1.3 mL), and the mixture was stirred at room temperature for 3 hr. 1N Hydrochloric acid (13 mL) and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (310 mg, 83%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[CH2:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]2)[CH:3]=1.[CH2:27]([NH2:31])[CH2:28][CH2:29][NH2:30]>>[O:25]=[S:17]1(=[O:26])[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[CH2:20][N:14]([C:4]2[CH:3]=[C:2]([NH:30][CH2:29][CH2:28][CH2:27][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[CH2:13])[CH:10]=3)[N:5]=2)[CH2:15][CH2:16]1
Reactant: NCCCN
Reactant: C=Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: C=Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 52 in Scheme 22 by using 4-(4-chloro-6-ethenylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (s, 1 H), 8.05-8.02 (q, J=8 Hz, 1 H), 7.89-7.81 (m, 2 H), 7.77-7.70 (m, 2 H), 7.56-7.54 (t, J=4.4 Hz, 1 H), 6.80-6.74 (m, 1 H), 5.95-5.90 (m, 2 H), 5.36-5.30 (m, 3 H), 4.51 (s, 2 H), 3.71 (s, 2 H), 3.61-3.60 (t, J=3.2 Hz, 2 H), 3.11-3.10 (t, J=5.2 Hz, 2 H), 2.13-2.11 (t, J=5.6 Hz, 2 H).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([OH:11])[N:5]=[C:4](SC)[N:3]=1.[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>>[OH:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([OH:1])[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[N:5]=1
Reactant: C1CSCCN1
Reactant: CSc1nc(O)c([N+](=O)[O-])c(O)n1
Product: O=[N+]([O-])c1c(O)nc(N2CCSCC2)nc1O

Procedure:
4,6-Dihydroxy-5-nitro-2-thiomorpholino-pyrimidine was prepared in analogous manner from 4,6-dihydroxy-2-methylthio-5-nitro-pyrimidine and thiomorpholine. M.p. 220°-223°C.
Reaction SMILES: [CH3:1]N(C)CCNC.[Li]CCCC.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.CI>C1COCC1.Cl>[CH3:1][C:22]1[C:17]2[O:16][CH2:15][CH2:14][O:13][C:18]=2[CH:19]=[CH:20][C:21]=1[CH:23]=[O:24]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CNCCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C=O)ccc2c1OCCO2
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a solution of N,N,N′-trimethylethylenediamine (3.3 g, 32.3 mmol) in THF (100 mL) at −15° C. was dropwise added n-BuLi (19.2 mL, 30.5 mmol, 1.6 M in THF). After stirring at −15° C. for 15 minutes, a solution of solution of 1,4-benzodioxane-6-aldehyde (5.0 g, 30.5 mmol) in THF (10 mL). After 20 minutes, another batch of n-BuLi (5 mL, 3.1 mmol, 1.6 M in THF) was added and stirred for 3 h. The resulting solution was cooled down to −72° C. and the mixture was treated with MeI (25.9 g, 182.5 mmol) slowly. After stirring at −72° C. for 3 h, the mixture was diluted with HCl solution (1M in water). The aqueous layer was extracted several times with diethyl ether. The organic fractions were combined, concentrated and purified with column chromatography (silica, 5-40% ethyl acetate in hexane) to provide the title compound as an off-white compound (1.0 g, 18%): %): MS (ES) m/z 179 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C@H:18]([NH2:20])[CH3:19]>>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C@H:18]([NH:20][C:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)=[O:7])[CH3:19]
Reactant: CC1(C(=O)O)CC1
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Product: C[C@@H](NC(=O)C1(C)CC1)c1ccc2ccccc2c1
Yield: 76 %

Procedure:
Similarly to Example 1d), 1.5 g (15 mmol) of 1-methylcyclopropane-1-carboxylic acid were reacted with 2.6 g (15 mmol) of (1R)-1-naphth-2-ylethylamine to give the title compound. The product was isolated, after purification by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient), as a white solid (2.9 g; 76% yield, melting point 91° C.).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2)nn1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccc2)nn1

Procedure:
Synthesized using compound 65b (982 mg, 5.77 mmol), NBS (1.13 g, 6.35 mmol) and DBPO (70 mg, 0.29 mmol) in carbon tetrachloride according to Method A. Crude product was purified by flash chromatography on silica-gel using hexane/ethyl acetate (4:1) as eluent. Product was used directly in the next step without further characterization. Orange solid. Yield: 53 mg, 4%. (ESI): m/z=250.67 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[CH3:19]I.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:19])[C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cnc2ccccc2c1)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-chloro-pyrimidin-4-yl)-quinolin-3-yl-amine (0.400 g, 1.64 mmol) in DMF (7 mL) at 0° C. was added MeI (0.133 mL, 2.13 mmol) and NaH (60% dispersion in mineral oil, 0.079 g, 1.97 mmol). The reaction mixture was warmed to RT, accompanied by the appearance of a yellow color and solid precipitate. After stirring for 1 h at RT, H2O (25 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. Chromatography on silica gel (1:1 EtOAc:Hexanes) provided the title compound.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]([CH2:29][C@@H:30]1[CH2:32][O:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:1]([N:8]([C@@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[CH2:10][OH:11])[CH2:32][C@H:30]([OH:31])[CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C[C@@H](CO)NCc2ccccc2)cc1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
A mixture of (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (1.15 g) and (2S)-2-(phenoxymethyl)oxirane (661 mg) in ethanol (9.2 ml) was heated to reflux for 3 hours. After allowed to cool to room temperature, the mixture was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give (2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl)amino]-3-(4-nitrophenyl)-1-propanol (1.17 g) as a pale yellow solid.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH2:33][N:34]4C(=O)C5=CC=CC=C5C4=O)[CH:27]=3)[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[C:15]2=[O:25])[CH:31]=[CH:30][CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 28.2 %

Procedure:
A solution of 200 mg (0.31 mmol) of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 20 ml of ethanol was treated with 0.3 ml of hydrazine hydrate. After 20 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 45 mg (28%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2-bromophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 130° C.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([O:6][C@@H:7]([CH2:25][CH3:26])[C@H:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.C([O:37][B:38](OC(C)C)[O:39]C(C)C)(C)C>O1CCCC1>[Si:18]([O:17][C@H:8]([CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C@H:7]([CH2:25][CH3:26])[O:6][C:5]1[CH:27]=[CH:28][C:2]([B:38]([OH:39])[OH:37])=[CH:3][CH:4]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C

Procedure:
Prepared according to the method as described in Example 5b) from (3R,4S)-3-[4-(4-bromophenoxy)-3-(t-butyldimethylsilanyloxy)hexyl]pyridine (0.71 g, Example 88a)), tertbutyl lithium (1.80 ml, 1.7M in hexanes) and tri-isopropylborate (0.74 ml) in dry tetrahydrofuran (25 ml). After work up, the residue was purified by column chromatography eluting with a gradient 0-25% ethanol in ethyl acetate to give the sub-title compound as a foam (0.41 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[CH3:30])=[O:5])[CH3:2].Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[CH3:30])=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1C
Reactant: Clc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ncccn2)C3)cc1C

Procedure:
Step 4—Synthesis of compound vh: (S)-1-ethyl-3-(2-methyl-4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.043 g, 0.10 mmol) and 2-Chloropyrimidine (0.0121 g, 0.106 mmol) were combined, nitrogen purged three times, added N,N-Dimethylformamide (1.50 mL, 19.4 mmol) and N,N-Diisopropylethylamine (0.0730 mL, 0.419 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.43 (d, J=4.7, 2H), 8.12-7.99 (m, 3H), 7.72 (s, 1H), 6.67 (dt, J=10.9, 5.0, 2H), 4.90 (d, J=18.7, 1H), 4.73 (d, J=18.7, 1H), 4.14 (dd, J=17.9, 5.1, 2H), 3.93-3.77 (m, 2H), 3.71 (dd, J=11.2, 2.5, 1H), 3.61 (d, J=12.1, 3H), 3.43 (dd, J=18.5, 7.5, 1H), 3.18-3.06 (m, 2H), 2.74 (s, 2H), 2.26 (s, 3H), 1.25 (d, J=6.6, 3H), 1.08 (t, J=7.2, 3H). LC/MS-m/z+489.3 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:26][C:23]1[CH:22]=[N:21][C:20]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4]2)=[N:25][CH:24]=1
Reactant: Cc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 150 °C

Procedure:
A stirred mixture of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, STEP 1) (20.0 g, 0.081 mol), 2-chloro-5-methylpyrimidine (10.4 g, 0.081 mol) and cesium carbonate (52.5 g, 0.161 mol) in DMF (200 mL) was heated at 150° C. for 6 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (700 mL), washed with aqueous saturated NaHCO3 (200 mL), water (5×200 mL), and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel 60 (1 kg), eluting with 50–100% ethyl acetate in hexane to give the title compound. M.S. (M+1): 341.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH2:15][CH2:14]1)=[O:12].C(N(CC)C(C)C)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:15][CH2:14]1)=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(C(=O)c2cnccc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Yield: 25.9 %

Procedure:
To a solution of 0.10 g (0.25 mmol) [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 3) in 2 mL dichloromethane were added 0.08 mL (0.50 mmol) N,N-diisopropylethylamine followed by dropwise addition of 0.02 mL (0.27 mmol) methanesulfonylchloride. After 16 hours another 0.08 mL (0.50 mmol) N,N-diisopropylethylamine and 0.02 mL (0.27 mmol) methanesulfonylchloride were added. The reaction mixture was poured on water and was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silical gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) followed by a second chromatography on a 10 g silica gel column using a gradient from n-heptane:tert-butyl methyl ether (100:0 to 25:75) to give 31 mg (26%) of the desired compound as a light brown foam. MS (ESI): m/z=478.039 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[C:9](Br)=[CH:8][N:7]=[CH:6][C:5]=1[Br:11])[CH:2]=[CH2:3].[Li]CCCC.[F:17][C:18]1[CH:25]=[C:24]([CH:26]=[O:27])[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>C1COCC1>[CH2:1]([C:4]1[C:5]([Br:11])=[CH:6][N:7]=[CH:8][C:9]=1[CH:26]([OH:27])[C:24]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([F:17])[CH:25]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1c(Br)cncc1Br
Reactant: N#Cc1ccc(C=O)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCc1c(Br)cncc1C(O)c1ccc(C#N)c(F)c1
Reaction time: 0.08 h

Procedure:
To a solution of 4-allyl-3,5-dibromo-pyridine (as described above in Step A) (2.35 g, 8.48 mmol) in THF (100 mL) at −100° C. was added n-BuLi (8.48 mmol), and the mixture was stirred for 5 min. 2-Fluoro-4-formyl-benzonitrile (as described in Example 17, Step A) (1.39 g, 9.33 mmol) in THF (5 mL) was added dropwise via syringe. The reaction mixture was stirred at −78° C. for 1 hr, quenched with saturated NH4Cl (50 mL), and partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified by chromatography on silica gel with hexane: ethyl acetate 7:3-5:5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(F)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.91 min; [M+H]+=252.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][C:7]=1[CH3:16].[OH-].[Na+]>O1CCOCC1>[OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[CH3:16]
Reactant: COC(=O)c1ccc(OCCCO)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1OCCCO
Temperature: 70 °C
Yield: 83 %

Procedure:
To a solution of methyl 4-(3-hydroxypropoxy)-3-methyl-benzoate (0.9 g, 4.01 mmol) in dioxane (8 mL) was added 1N NaOH (5 mL) and the reaction mixture was heated at 70° C. for 22 hours. The solvent was concentrated in vacuo and the crude residue was dissolved in water (20 mL) and extracted with ethyl acetate (1×20 mL). The aqueous layer was acidified with 1 M HCl solution and extracted with ethyl acetate (2×20 mL). The organics were separated, dried with Na2SO4 and concentrated in vacuo to give 4-(3-hydroxypropoxy)-3-methyl-benzoic acid (0.7 g, 87%) as a white solid. ESI-MS m/z calc. 210.0. Found 211.0 (M+1)+; Retention time: 0.95 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 12.5 (bs, 1H), 7.97-7.60 (m, 2H), 7.01 (d, J=8.6 Hz, 1H), 4.57 (s, 1H), 4.11 (t, J=6.2 Hz, 2H), 3.59 (t, J=5.5 Hz, 2H), 2.19 (s, 3H), 1.89 (p, J=6.2 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-:23])=[O:22])=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[F:34].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-:23])=[O:22])=[C:12]2[NH:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[F:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2ncc([N+](=O)[O-])c(Cl)c2cc1OCc1ccccc1
Reactant: N#Cc1ccc(N)c(F)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2ncc([N+](=O)[O-])c(Nc3ccc(C#N)cc3F)c2cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
6-Benzyloxy-4-chloro-7-methoxy-3-nitroquinoline (6.75 g, 19.58 mmol) and 4-amino-3-fluorobenzonitrile (2.46 g, 18.1 mmol) were dissolved in glacial acetic acid (106 ml) and stirred at 50° C. for 18 h overnight. The suspension obtained was subsequently added to water (1 l) and stirred for a further 30 min. The precipitate formed was filtered off with suction, rinsed with water and dried in vacuo, giving 4-(6-benzyloxy-7-methoxy-3-nitro-quinolin-4-ylamino)-3-fluorobenzonitrile (6.69 g, 15.06 mmol) as solid. MS: 445.1 (M+H+), TLC (HPTLC): Rf=0.31 (cyclohexane/ethyl acetate 2:1, parts by volume).
Reaction SMILES: [NH:1]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([NH:33][NH:34]C(OC(C)(C)C)=O)=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])[C@@H:3]([CH3:5])[OH:4].CCOCC>C(O)(C(F)(F)F)=O>[NH:1]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([NH:33][NH2:34])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)NN
Reaction time: 0.25 h

Procedure:
0.91 Gram of Z-Thr-Asn-Leu-Gln-NHNHBoc was dissolved in 8 ml of TFA, and was allowed to stand at a room temperature for 15 minutes. 80 Milliliters of anhydrous ether was added to this solution and the precipitate formed was collected quickly by filtration, washed with anhydrous ether, then was dried under a reduced pressure in a desiccator containing potassium hydroxide-phosphorus pentoxide as the desiccant, to obtain the desired product.
Reaction SMILES: Cl.[CH:2]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.O=[C:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](OCC)=[O:17].C[O-].[Na+]>C(O)C>[CH:2]1([C:7]2[NH:9][C:16](=[O:17])[C:12]3[CH2:13][CH2:14][CH2:15][C:11]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N=C(N)C1CCCC1
Reactant: CCOC(=O)C1CCCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(C2CCCC2)nc2c1CCC2
Temperature: 25 °C

Procedure:
A 250-mL round bottomed flask was charged with cyclopentanecarboximidamide hydrochloride (5.38 g, 36.2 mmol), ethyl 2-oxocyclopentanecarboxylate (5.14 g, 38.7 mmol), and ethanol (100 mL). To the stirred mixture at rt was added sodium methoxide (3.91 g, 72.4 mmol). The resulting mixture was stirred under reflux for 22 h. After cooling to room temperature, the mixture was evaporated under reduced pressure to 25 mL. The residual slurry was cautiously treated with 2N HCl (50 mL). The solution was extracted with ethyl acetate (4×50 mL). The combined extract was washed with saturated sodium chloride (2×25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound which was carried forward into the next step without further purification.