Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:7](C(OC(C)(C)C)=O)[C:6]=2[CH:32]=1.[Cl:33]CCl.[C:36]1(=[O:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38](=[O:45])[O:37]1>CCOCC>[ClH:33].[NH2:10][C:8]1[NH:7][C:6]2[CH:32]=[C:2]([NH:1][C:38]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=3[C:36]([OH:46])=[O:37])=[O:45])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCOCC
Product: Cl
Product: Nc1nc2ccc(NC(=O)c3ccccc3C(=O)O)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To a 100 mL round-bottomed flask equipped with a magnetic stir bar was added tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.142 g, 0.317 mmol), dichoromethane (10 mL) and isobenzofuran-1,3-dione (0.047 g, 0.317 mmol). The stirring solution was allowed stir for 24 hours at room temperature. Volatiles were evaporated under reduced pressure. The resulting residue was dissolved up in a 1:1:2 mixture of concentrated HCl, H2O and THF (10 mL) and allowed to stir for seven hours with ventilation. Volatiles were then evaporated under reduced pressure. The resulting solid was rinsed thoroughly with ether providing the title compound (0.083 g, 81% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.95 (d, 1H), δ 7.71 (m, 2H), δ 7.59 (m, 2H), δ 7.47 (m, 1H), δ 7.30 (t, 1H) ppm; 13C NMR (75 MHz, CD3OD) δ 170.1, 132.9, 130.9, 130.2, 128.6, 126.5, 123.4, 118.2, 117.8, 112.1 ppm; HRMS (ESI) Calcd for C15H12N4O2 (M+) 296.0909. Found 296.0915.
Reaction SMILES: [CH3:1][S:2][CH:3]([S:6][CH3:7])[S:4][CH3:5].[Li]CCCC.Br[CH:14]1[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]2)[CH:19]=[CH:18][CH:17]=[C:16]3[CH2:15]1>C1COCC1.CCCCCC>[CH3:1][S:2][C:3]([S:6][CH3:7])([S:4][CH3:5])[CH:15]1[C:16]2=[C:25]3[C:20](=[CH:19][CH:18]=[CH:17]2)[CH:21]=[CH:22][CH:23]=[C:24]3[CH2:14]1
Reactant: CSC(SC)SC
Reactant: BrC1Cc2cccc3cccc1c23
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSC(SC)(SC)C1Cc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tris(methylthio)methane (22 g) was dissolved in THF (100 ml) under N2 at -78° C. 1.6 M BuLi in hexane solution (95 ml) was added slowly to yield a dense white precipitate. 1-Bromoacenaphthene (31.4 g) was dissolved in 20 ml of dry THF and added slowly to the above suspension to yield, after 10 minutes, a colorless solution. This was allowed to warm to room temperature, with the development of a brown color, and stirred overnight.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[N:17]=1>ClCCl.CN(C)C=O>[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[O:9])[N:17]=1
Reactant: Nc1ccc(SCc2csc(N)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)Cc2csc(N)n2)cc1
Yield: 86.3 %

Procedure:
A solution of 3-chloroperbenzoic acid (4.9 g) in dichloromethane (100 ml) was dropwise added to a solution of 2-amino-4-(4-aminophenylthiomethyl)thiazole (5.1 g) in a mixture of dichloromethane (200 ml) and N,N-dimethylformamide (10 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 1.5 hours with stirring. The precipitates were collected by filtration, washed with ethyl acetate and dried in vacuo to give solid. The solid was recrystallized from ethanol to give 2-amino-4-(4-aminophenylsulfinylmethyl)thiazole (4.70 g, yield: 86.3%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@H:13]([NH:26][C:27]([C@H:29]1C[C@@H:30]1C1SC=CC=1)=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1.O.NN>C(O)C>[NH2:3][CH2:12][C@H:13]([NH:26][C:27](=[O:28])[C@H:29]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:30])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1
Reactant: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC[C@H](C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 60 °C
Yield: 102.6 %

Procedure:
A mixture of (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic acid {(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide (330 mg, 0.66 mmol) and ethanol (20 mL) was treated dropwise with hydrazine monohydrate (0.32 mL, 6.6 mmol), and the resulting reaction was maintained at 60° C. overnight. The mixture was allowed to cool to room temperature and the solids were removed by filtration. The filtrate was concentrated to dryness, and triturated with ethyl acetate (15 mL), and the mixture was filtered. The collected solids were air dried, then dissolved in diethyl ether (5 mL). The resulting solution was treated with concentrated HCl (0.1 mL), and the precipitate was collected by filtration to afford (2S)-N-((1R)-2-amino-1-[4-((S)-2-methylbutoxy)phenyl]-ethyl)-2-phenylpropionamide (120 mg, 52% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 7.33 (d, J=8.6 Hz, 2H), 7.16 (dd, J=5.1, 1.3 Hz, 1H), 6.98 (d, J=8.6 Hz, 2 H), 6.89 (dd, J=5.1, 3.5 Hz, 1H), 6.85 (d, J=3.3 Hz, 1H), 5.17 (dd, J=8.7, 5.9 Hz, 1H), 3.86 (dd, J=9.1, 5.8 Hz, 1H), 3.79 (dd, J=9.1, 6.3 Hz, 1H), 3.27-3.31 (m, 2H), 2.57 (ddd, J=9.3, 5.7, 4.2 Hz, 1H), 2.00 (ddd, J=8.3, 5.2, 4.2 Hz, 1H), 1.85 (dq, J=13.1, 6.6 Hz, 1H), 1.55-1.64 (m, 2H), 1.25-1.34 (m, 2H), 1.03 (d, J=6.8 Hz, 3 H), 0.97 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 373.1 [(M+H)+, calcd for C21H29N2O2S 373.2].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][O:12][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(CCO)cc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution 45.0 g of the compound obtained in Step 216-2 in DMF (50 ml) was added 29.0 g of imidazole and 32.0 g of TBSCl, and stirred at room temperature for 16 hours. Water was added to the solution, and the resulting mixture was extracted with Et2O. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: n-hexane/EtOAc=10/1; v/v) to obtain 62.0 g of the title compound (colorless oil).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:70]1[CH:74]=[C:73]([CH2:75][CH2:76][NH2:77])[N:72]=[CH:71]1>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:77][CH2:76][CH2:75][C:73]2[N:72]=[CH:71][NH:70][CH:74]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: NCCc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCCc3c[nH]cn3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [2-(1H-imidazol-4-yl)ethyl]amine (22.2 mg, 0.2 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (26 mg, 85%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: [C:1](#N)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]([Mg]Cl)[CH2:11][CH3:12].C([O:17]CC)C>>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1](=[O:17])[CH2:10][CH2:11][CH3:12]
Reactant: CCOCC
Reactant: N#Cc1ccccc1N
Reactant: CCC[Mg]Cl
Product: CCCC(=O)c1ccccc1N
Reaction time: 5 h

Procedure:
A solution of anthranilonitrile (1 equiv., Aldrich) in diethyl ether (2.4 M) was cooled to 0° C. and treated with propylmagnesium chloride (2.5 equiv., Aldrich; 2.0 M in Et2O) in a dropwise manner over the course of an hour. After addition of 25% of the Grignard reagent, an additional {fraction (1/10)} volume of Et2O was added. The cooling bath was removed and stirring of the suspension continued for 5 hours. The reaction was returned to 0° C. and cautiously quenched with 3 N HCl. The cooling bath was removed and stirring continued for 30 minutes. The mixture was made basic by the addition of solid NaOH. The contents were extracted thrice with ethyl acetate; brine was added to help break up the suspension. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was chromatographed eluting with 95:5 hexanes/ethyl acetate.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH3:14])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[C:1]([O:9][CH2:10][CH:11]([CH3:14])[CH2:12][O:13][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(CO)COC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(COC(=O)c1ccccc1)COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 3-benzoyloxy-2-methylpropanol (369 mg; 1.9 mmol), dihydropyran (273 mg; 3.25 mmol) and pyridinium p-toluenesulfonate (50 mg; 0.2 mmol) in anhydrous dichloromethane (10 ml) was stirred at room temperature for 2 hours. Dihydropyran (200 mg; 2.38 mmol) and pyridinium p-toluenesulfonate (50 mg; 0.2 mmol) were further added thereto, and the resultant mixture was stirred for 3 hours. Ether (50 ml) was added to the reaction mixture, which was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was purified by TLC using a mixture of ethyl acetate and benzene (1:4) to give 1-benzoyloxy-2-methyl-3-tetrahydropyranyloxypropane (466.3 mg; yield, 88%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15].C(=O)(O)[O-].[Na+]>O>[F:10][C:11]([F:21])([F:20])[C:12]1[C:5]2[C:3](=[C:2]([CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)[O:4][C:14](=[O:15])[CH:13]=1
Reactant: Cc1c(O)cccc1O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
A slurry of 2-methylresorcinol (12.4 g, 0.100 mole) and ethyl 4,4,4-trifluoroacetoacetate (18.4 g, 0.100 mole) was added slowly to 100 ml of ice cold sulfuric acid with vigorous stirring. After completion of addition, the solution was allowed to warm to room temperature and was subsequently stirred for 24 hours. The reaction mixture was then slowly added to 500 ml of ice water (300 g ice and 200 ml water) with vigorous stirring. The desired product precipitated from the solution as a light pink solid. The solid was then isolated by vacuum filtration, transferred to a 500 ml beaker, 200 ml of water was added to achieve a slurry and the pH was adjusted to 6 with sodium bicarbonate. The solid was then filtered and recrystallized from ethanol-water to yield 19.5 g (80%) of the desired product. The melting point of the product was 197°-198 ° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:19]1([C:25]2[CH:29]=[C:28]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([CH2:37][OH:38])[CH2:33][CH2:32]3)[O:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:38][CH2:37][CH:34]2[CH2:33][CH2:32][N:31]([CH2:30][C:28]3[O:27][N:26]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:29]=3)[CH2:36][CH2:35]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
Triethylamine (12.1 mL) and p-toluene sulfonylchloride (6.61 g) were added sequentially to a room temperature mixture of the compound prepared in Example 64 (7.86 g) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed sequentially with a saturated aqueous sodium bicarbonate solution and brine. The combined organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to obtain the title compound (1.52 g) having the following physical data.
Reaction SMILES: [I-].[CH2:2]([N+:4]1([CH2:15][CH3:16])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH:5]1[CH3:14])[CH3:3].[OH2:17]>>[OH-:17].[CH2:15]([N+:4]1([CH2:2][CH3:3])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH:5]1[CH3:14])[CH3:16].[CH2:15]([N+:4]1([CH2:2][CH3:3])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH:5]1[CH3:14])[CH3:16]
Reactant: O
Agent: CC[N+]1(CC)C(C)CCC2CCCCC21
Agent: [I-]
Product: [OH-]
Temperature: 25 °C

Procedure:
The hydroxide version of N,N-diethyl-2-methyldecahydro-quinolinium cation was prepared by ion exchange as described in the procedure below. To a solution of 20 gm (0.06 mol) of N,N-diethyl-2-methyldecahydro-quinolinium iodide in 80 ml water, 80 gm of OH-ion exchange resin (BIO RAD® AGI-X8) was added, and the resulting mixture was allowed to gently stir at room temperature for few hours. The mixture was filtered and the ion exchange resin was rinsed with additional 30 ml water (to ensure removing all the cations from the resin). The rinse and the original filtrate were combined and titration analysis on a small sample of the filtrate with 0.1 N HCl indicated a 0.5M OH ions concentration (0.055 mol cations). Scheme 1 below depicts the synthesis of the templating agent.
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:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][C:8]2([CH3:22])[CH3:21])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:21][C:8]1([CH3:22])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccnc1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(c2cccnc2)Nc2ccc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (296.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° 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 4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (266.4 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=283.1.
Reaction SMILES: [C:1]([O-])(C)(C)[CH3:2].[K+].[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=O)[C:17]([O:19][CH3:20])=[O:18].O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH:1][CH3:2])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COCc1ccccc1C(=O)C(=O)OC
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC=C(C(=O)OC)c1ccccc1COC
Temperature: 5 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
At 5° C. 11.2 g (0.1 mol) of potassium tert-butanolate was added to a A mixture of 37.1 g (100 mmol) of ethyltriphenylphosphonium bromide was added under a nitrogen blanket to 300 ml of absolute tetrahydrofuran. At 5° C., 11.2 g (0.1 mol) of potassium tert-butanolate was added. After the mixture had been stirred for 1 hour at 5° C., 20.8 g (100 mmol) of methyl 2-methoxymethylphenylglyoxylate in 100 ml of tetrahydrofuran was dripped in. The mixture wa stirred for 1 hour at 5° C. and for 1 hour at 25° C., 200 ml of water was added and extraction carried out with methylene chloride. After the combined organic phases had been washed with water and dried, the solvent was removed under reduced pressure. The residue was purified chromatographically in a silica gel column (methyl tert-butyl ether/n-hexane=1/2). There was obtained 17.2 g (78%) of the above-mentioned ester as an oil (Z/E isomer=1/9) (compound no. 25).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCBr
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 71.6 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.13 g of sodium ethoxide was added thereto. A solution of 5.5 g of hexadecyl bromide in 20 ml of ethanol was added thereto at room temperature with stirring. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 4.37 g of diethyl 2-acetamido-2-hexadecylmalonate.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[Li+].[OH-]>C1COCC1.CO>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([CH:15]([NH:28][C:29]([NH:31][C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)=[O:30])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])=[O:40])=[CH:10][CH:11]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The propionic acid ethyl ester prepared in step D was dissolved in THF (6 mL) and MeOH (3 mL). A solution of 2 M LiOH (3 mL) was then added and the reaction was stirred at room temperature for 30 minutes. The solvents were evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed with 1N HCl (2×), brine (2×), dried over MgSO4, filtered, and concentrated to a syrup. Addition of hexane followed by trituration precipitated the title compound (270 mg, 0.48 mmol) as a cream colored solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CN1C(=O)CCC1.CO>[NH2:18][CH:15]1[CH2:16][CH2:17][N:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]3[NH:2][C:28](=[O:29])[NH:26][N:27]=3)[N:4]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(C#N)cc3ccccc23)C1
Reactant: CCOC(=O)NN
Solvent: CN1CCCC1=O
Solvent: CO
Product: NC1CCN(c2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 175 °C
Yield: 17 %

Procedure:
To a crude reaction mixture containing tert-butyl (1-(3-cyanoisoquinolin-1-yl)pyrrolidin-3-yl)carbamate (786 mg) was added ethyl hydrazinecarboxylate (242 mg, 2.323 mmol) in NMP (5 mL). The resulting suspension was heated at 175° C. overnight and was subsequently cooled, diluted with MeOH, and filtered. The crude product was purified using mass-triggered HPLC eluting with a gradient of 20-45% ACN in water (acid mode). The product-containing fractions were concentrated to give the title compound (117 mg, 17.0% over 2 steps). ESI-MS m/z [M+H]+ 297.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:12]([C:25]#[N:26])=[CH:11][C:10]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1.ClC1C=C(Cl)C=CC=1C1N=C(NCC(C)C)C(C#N)=CC=1C1C=CC(Cl)=CC=1.CO[CH2:64][C:65](Cl)=[O:66].[H-].[Na+].NC1C2C(=NC(C3C=CC(Cl)=CC=3Cl)=C(C3C=CC(Cl)=CC=3)C=2)N(CC(C)C)[C:73](=[O:100])[C:72]=1OC>>[C:73]([N:26]([C:25]1[C:12]2[C:13](=[N:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH:11]=2)[N:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16](=[O:20])[C:17]=1[O:18][CH3:19])[C:65](=[O:66])[CH3:64])(=[O:100])[CH3:72]
Reactant: COCC(=O)N(CC(C)C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reactant: COc1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(CC(C)C)c1=O
Reactant: COCC(=O)Cl
Agent: CC(C)CNc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: [H-]
Agent: [Na+]
Product: COc1c(N(C(C)=O)C(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(CC(C)C)c1=O

Procedure:
N-(6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-3-cyanopyridin-2-yl)-N-isobutyl-2-methoxyacetamide (prepared by the reaction of 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-(isobutylamino)pyridine-3-carbonitrile with 2-methoxyacetyl chloride using the conditions of EXAMPLE 62 Step A) was reacted with NaH using the conditions of EXAMPLE 80 affording 4-amino-7-(2,4-dichlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-3-methoxy-1,8-naphthyridin-2(1H)-one which was acylated according to the procedure of EXAMPLE 64 affording the title compound. HPLC/MS: 586.0 (M+1), 5587.8 (M+3); Rt =4.64 min.