Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:36]=[CH:35][C:19]3[N:20]([CH3:34])[C:21]([C:23]4[N:31]([CH2:32][CH3:33])[C:26]5=[CH:27][N:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:36]=[CH:35][C:19]3[N:20]([CH3:34])[C:21]([C:23]4[N:31]([CH2:32][CH3:33])[C:26]5=[CH:27][N:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2ccncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)ccc3n2C)cc2ccncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of (R)-tert-butyl(1-(2-(1-ethyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (42 mg, 0.084 mmol) in dichloromethane (DCM) (1 mL) was added TFA (0.258 mL, 3.34 mmol) and the reaction stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to afford a yellow oil. This was dissolved in methanol and loaded onto an SCX cartridge (5 g). It was eluted with methanol (3 column volumes) and product eluted as free base with 2M ammonia in methanol. The filtrate from the ammonia fractions was concentrated in vacuo to yield the title compound as a yellow solid (34 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.FC(F)(F)S(O[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[C:28]3=[N:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32][N:27]3[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([C@H:23]2[C:28]3=[N:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32][N:27]3[CH2:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C2=N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(-c4ccccc4Cl)cc3)C2=N1
Temperature: 50 °C
Reaction time: 19 h
Yield: 42.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (16.0 mg) was added to a mixture of (2-chlorophenyl)boronic acid (76.0 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenyl trifluoromethanesulfonate (100 mg) and sodium carbonate (51.4 mg) in EtOH (3 mL), water (1.5 ml) and DMF (dry) (2 mL). The mixture was stirred at 50° C. under nitrogen for 19 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc), dissolved in MeCN/DMSO (4700/300 μM) and purified by preparative HPLC (C18, eluted with water in acetonitrile containing 0.1% TFA). The desired fractions were neutralized with sat. NaHCO3 aq., extracted with EtOAc and washed with brine. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized from MeCN-THF/hexane to give the title compound (38.4 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH:32]3O)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>C(Cl)(Cl)Cl.C(OCC)C>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[CH:32]=[CH:33][O:34][CH2:35][CH2:36]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ccccc1-c1cc(N2C=COCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 65 mg (0.11 mmol) (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide in 2 ml chloroform were added a few drops of a 2.3 N hydrochloric acid solution in diethyl ether. After stirring at room temperature for 2 h, the organic layer was washed with saturated sodium carbonate solution, dried (magnesium sulfate) and evaporated. The residue was purified by flash-chromatography to give 47 mg (75%) of the title compound as white foam. MS m/e (%): 564 (M+H+, 100).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[CH3:22])[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Br:21][C:19]1[CH:18]=[CH:17][C:16]([CH3:22])=[C:15]([CH:10]2[CH2:9][C:8]([CH3:23])([CH3:24])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)[CH:20]=1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Br)ccc1C)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Br)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Temperature: 60 °C
Reaction time: 6 h
Yield: 102.1 %

Procedure:
To a stirred mixture solution of 2-(5-bromo-2-methyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.5 g, 3.56 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(5-bromo-2-methyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.36 g, 97%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=374.0& 376.0.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH2:39])[CH:34]=[CH:35][C:36]=1[F:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH:39][C:24](=[O:26])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Reactant: NCc1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(F)c(Br)c1
Yield: 73.9 %

Procedure:
A solution of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.0 g, 2.478 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (0.648 g, 2.69 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.781 mL, 5.6 mmol) in dichloromethane (45 mL) was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, water and saturated NaCl, and dried over Na2SO4. The organic layer was evaporated to give a pale amber residue. The residue was triturated with a small amount of DCM, then sonicated to give a uniform mixture. A white solid was collected and dried to afford N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1.08 g, 73.9%) as a crystalline solid. LC-MS m/z 589.1 (M+H)+, 0.79 min (ret time).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:15][O:14][C:12]([C:3]1[C:2]([OH:1])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[C:5]([Br:16])[N:4]=1)=[O:13]
Reactant: COC(=O)c1ncc2cccnc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2cccnc2c1O
Reaction time: 1 h

Procedure:
To a solution of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate from Example 1 Step 2 (5.0 g, 24.49 mmol) in CH2Cl2 (100 ml) at room temperature was added N-bromo succinimide (4.36 g, 24.49 mmol). The reaction was stirred for 1 hr. The solids were collected by filtration and dried in vacuo to afford the title compound as an off white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:8][CH:7]=1.O.[NH2:20][NH2:21]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:17])[NH:20][N:21]=2)=[CH:8][CH:7]=1
Reactant: NN
Reactant: COCCOc1ccc(C(=O)CCC(=O)O)cc1
Solvent: CCO
Solvent: O
Product: COCCOc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
6 g (0.024 mole) of 4-(4-(2-methoxy-ethoxy)-phenyl)-4-oxo-butyric acid and 1.2 g (0.024 mole) of hydrazine hydrate are stirred in 90 ml of ethanol at 50° C. for 1 hour. After the mixture has been cooled, the product is filtered off with suction, washed with ethanol and dried.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C[O:25][C:26](=[O:35])[CH:27](Br)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH2:28][CH:27]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH3:16])[CH:6]=[N:5]2)[C:26]([OH:25])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Cc1ccccc1O
Product: Cc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Yield: 71 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-methyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionic acid (12.2 g, 71%) as a white solid; LC-MS [M+H+]=343.2; HPLC (0.17% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), 254 nm, 98.5%, 214 nm, 99.6%. 1H-NMR (300 MHz, CDCl3) δ 1.12-1.22 (m, 2H), 1.50-1.80 (m, 7H), 2.08-2.16 (m, 1H), 2.20 (s, 3H), 2.30-2.38 (m, 1H), 5.49-5.54 (dd, J=10.2, 4.8 Hz, 1H), 5.85-5.86 (d, J=2.7 Hz, 1H), 7.02-7.04 (d, J=7.2 Hz, 1H), 7.20-7.32 (m, 3H), 7.89-7.90 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:18][CH2:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[CH:15][CH2:14]3)[C:9]2=[O:27])=[CH:5][CH:4]=1.CO>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)[C:9]2=[O:27])=[CH:28][CH:29]=1
Reactant: COc1ccc(CN2CCC(N3CC=C(c4ccc(OC)cc4)CC3)C2=O)cc1
Solvent: CCO
Solvent: CO
Product: COc1ccc(CN2CCC(N3CCC(c4ccc(OC)cc4)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-methoxybenzyl)-3-(4-(4-methoxyphenyl)-5,6-dihydropyridin-1(2H)-yl)pyrrolidin-2-one (G) (400 mg, 1.02 mmol), MeOH (4 ml) and ethanol (8 ml) was flushed with nitrogen, followed by the addition of 10% Pd/C (108 mg). Then the mixture was stirred overnight at rt and 25 psi hydrogen pressure. The catalyst was removed by filtration through Celite and the filtrate was concentrated under vacuum. Yield: 400 mg. LCMS (method F) RT 2.36 min, m/z 395.2 (MH+).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].CS[C:9]1[S:13][C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[C:25]([CH3:48])=[N:26][N:27]([C:29]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:28]=4)[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].[C:56](=O)(O)[O-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH3:56][S:3]([C:9]1[S:13][C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[C:25]([CH3:48])=[N:26][N:27]([C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH:28]=4)[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)(=[O:5])=[O:2]
Reactant: CSc1ccc(-c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C)cc23)s1
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(-c3ccc(S(C)(=O)=O)s3)c2c1
Reaction time: 1 h

Procedure:
1 mL aqueous solution of 86 mg oxone was added at room temperature to a solution of 67 mg 4-[5-(methylsulfanyl)-2-thienyl]-6-(3-methyl-1-trityl-1H-4-pyrazolyl)quinoline obtained in Example 155 in tetrahydrofuran, and the mixture was stirred for 1 hour. Further, 60 mg oxone was added thereto and stirred overnight. An aqueous saturated sodium thiosulfate solution was added to the reaction solution, and the mixture was stirred. Then, ethyl acetate, an aqueous saturated sodium bicarbonate solution and water were added thereto, and the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), to give 35 mg of the title compound as a pale yellow amorphous.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[CH2:27][CH2:28][C:29]([OH:31])=O)[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:74]([O:78][C:79](=[O:83])[CH2:80][CH2:81][NH2:82])([CH3:77])([CH3:76])[CH3:75]>CN(C=O)C>[C:74]([O:78][C:79](=[O:83])[CH2:80][CH2:81][NH:82][C:29](=[O:31])[CH2:28][CH2:27][C:4]1[C:5]([CH3:26])=[CH:6][C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:24])[CH3:25])[CH3:22])[CH:15]=3)[O:11][N:10]=2)=[CH:8][C:3]=1[CH2:1][CH3:2])([CH3:77])([CH3:76])[CH3:75]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)NCCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid (43 mg, 0.101 mmol) and DIPEA (40 mg, 0.304 mmol) in DMF (3 mL) is added PyBOP (58 mg, 0.111 mmol) at 0° C. The mixture is stirred for 15 min at 0° C. before β-alanine tert.-butyl ester (20 mg, 0.111 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched with 2 mL water, and the mixture is diluted in sat. aq. NaHCO3-solution, and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and dried to give crude 3-[3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionylamino]-propionic acid tert-butyl ester (46 mg). This material is dissolved in 4 N HCl in dioxane (5 mL) and the mixture is stirred at rt for 18 h. The solvent is evaporated and the crude product is purified on prep. TLC plates with DCM containing 18% of 7 N NH3 in methanol to give 3-[3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionylamino]-propionic acid (37 mg) as a yellow solid; LC-MS: tR=0.86 min; [M+1]+=494.24.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](O)=[O:19])=[CH:15][CH:16]=2)[N:11]([S:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl-].[CH2:41]([O:43][C:44](=[O:52])[C:45]1[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=1)[CH3:42]>CC(C)=O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:19])[NH:51][C:48]3[CH:49]=[CH:50][C:45]([C:44]([O:43][CH2:41][CH3:42])=[O:52])=[CH:46][CH:47]=3)=[CH:15][CH:16]=2)[N:11]([S:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)O)cc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester (100 mg, 0.21 mmol) in acetone (30 mL) and tetrahydrofuran (10 mL) was treated with triethylamine (21 mg, 0.21 mmol) and stirred at room temperature 1 hour. A solution of cianuric chloride (46 mg, 0.25 mmol) in tetrahydrofurane (2 mL) was added dropwise over a period of 1 hour. The reaction mixture was stirred at room temperature for 2 hours, then 4-amino-benzoic acid ethyl ester (51 mg, 0.31 mmol) and a further aliquot of triethylamine (42 mg, 0.42 mmol) were added. The reaction mixture was stirred at room temperature for 48 hours, the solvents were then removed. The residue was purified by flash chromatography, to yield 4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester as a light yellow solid, 100 mg (77%), δH (300 MHz; CDCl3) 8.01-8.08 (4H, m), 7.94 (1H, d), 7.73-7.77 (3H, m), 7.48 (1H, dd), 6.82 (1H, d), 4.38 (2H, q), 3.89 (2H, m), 3.64 (2H, m), 3.47 (3H, s), 1.48 (9H, s), 1.40 (3H, t).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[O:8][C:5]1[N:4]=[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])[C:2]([F:1])=[CH:7][N:6]=1)[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ncc(F)c(N=CN(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (0.10, 0.54 mmol) in CH2Cl2 (2 mL) were added triethylamine (0.20 g, 2.0 mmol) and ethyl chloroformate (0.065 g, 0.60 mmol), and the mixture was agitated on an orbital shaker at room temperature overnight. The reaction was diluted with CH2Cl2 and the solution was washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether gradient) to yield 0.031 g (22%) of the title compound as a white solid: mp 124-126° C.; 1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.19 (d, J=2.2 Hz, 1H), 4.35 (q, J=7.14 Hz, 2H), 3.21 (s, 6H), 1.40 (t, J=7.14 Hz, 3H); HPLC-MS (ESI) m/z 258 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C)C=O.S(Cl)([Cl:31])=O>>[Cl:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1

Procedure:
6-Methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (1.22 g) was stirred in thionyl chloride (10 ml) with dimethylformamide (0.1 ml) at 85° C. for 1 hour. The reaction was evaporated to dryness, and then azeotroped with toluene. The residue was partitioned between methylene chloride and saturated sodium bicarbonate. The organic phase was separated and evaporated to dryness. The saturated sodium bicarbonate phase was basified with 2M sodium hydroxide and was extracted with methylene chloride. The two organic phases were combined and dried over sodium sulphate, filtered and the filtrate evaporated to dryness. This residue was purified by eluting through a silica column with 5% methanol in methylene chloride to yield 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline as a solid, (0.5 g, 39%); NMR: 1.95 (m, 2H), 2.4 (broad m, 6H), 3.55 (m, 4H), 3.98 (s, 3H), 4.26 (t, 2H), 7.36 (s, 1H), 7.41 (s, 1H), 8.83 (s, 1H); m/s: M+H+ 338, 340.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([N:27](CC)CC)C.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>C(Cl)Cl>[CH3:34][CH:33]([CH3:35])[C:32]([NH:27][C:7]1[CH:6]=[CH:5][C:4]([C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1)=[O:36]
Reactant: CC(C)C(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(N)c2)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(NC(=O)C(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 160.8 %

Procedure:
To a solution of {2-[4-(3-aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine (145 mg, 0.416 mmol, prepared in example 3) dissolved in methylene chloride (2.8 mL, anhydrous), was added triethylamine (0.15 mL, 1.04 mmol) under a nitrogen system. The mixture was cooled to 0° C. and isobutyryl chloride (0.13 mL, 1.25 mmol) was added by syringe. The mixture was allowed to warm to room temperature, and stirred overnight, under a nitrogen system. The reaction was quenched with excess water, and the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced vacuum, yielding 280 mg viscous oil. Purification was conducted using a Chromatotron®, on a 4000 μm rotor and eluting with a 1:1 hexane:ethyl acetate solvent system, yielding the title compound (136 mg, 78%) as a slow crystallizing foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][CH2:32][CH2:33]O.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.O>[Cl:31][CH2:32][CH2:33][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: OCCCl
Reactant: Oc1cccc2ncccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: ClCCOc1cccc2ncccc12
Yield: 79.5 %

Procedure:
A 100 ml three-neck oven dry flask was cooled under nitrogen. 5-Hydroxy quinoline (2 g, 14 mmol) was added as well as triphenylphosphine (5.42 g, 21 mmol) suspended in 50 ml anhydrous tetrahydrofuran. 2-Chloroethanol (1.3 ml, 21 mmol) was slowly added to above reaction mixture via syringe, followed by adding DEAD (2.98 ml, 21 mmol) via syringe. A second 1.5 eq of 2-chloroethanol, triphenylphosphine and DEAD was added. The reaction mixture was poured into 100 ml water and extracted by methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatographed (20% ethyl acetate-hexanes) afforded 2.31 g (82%) of product as a solid: mp 75-78° C.