Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.CN(CCN(C)C)C.C([Li])CCC.[F:28][C:29]([F:36])([F:35])[C:30](OCC)=[O:31].Cl>COC(C)(C)C.C(OCC)(=O)C.O>[NH2:8][C:5]1[C:4]([C:30](=[O:31])[C:29]([F:36])([F:35])[F:28])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cn1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: Nc1ncc(Cl)cc1C(=O)C(F)(F)F
Temperature: -20 °C

Procedure:
N-(5-chloro-2-pyridinyl)-2,2-dimethylpropanamide (20.0 g, 94.0 mmol) and TMEDA (12.0 g, 103 mmol) were dissolved in t-butyl methyl ether (150 mL), and while stirring the reaction solution at −20° C., n-butyl lithium (2.66 M hexane solution, 88.3 mL) was added dropwise thereto. After stirring the reaction solution at 0° C. for 2 hours, the solution was cooled to −78° C. and ethyl trifluoroacetate (16.8 mL, 140 mmol) was added thereto. The temperature of the reaction solution was raised to 0° C. and the solution was stirred for 3 hours. Then, water and 2 N hydrochloric acid were sequentially added, and the pH of the reaction solution was adjusted to about 9. After the solution was diluted with ethyl acetate, the organic layer was separated and the solvent was evaporated under reduced pressure. To the residue, acetic acid (60 mL), concentrated hydrochloric acid (20 mL) and water (40 mL) were added, and the solution was stirred for 10 hours under heating at 100° C. After the solution was cooled to room temperature, the resulting solid was collected by filtration and washed with ethyl acetate. The obtained solid and sodium acetate (7.64 g) were mixed in water (15 mL) and t-butyl methyl ether (70 mL), and the solution was stirred at room temperature for 30 minutes. The solution was diluted with ethyl acetate, which was then washed with water and saturated brine, and dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure, whereby the objective compound (10.1 g, 47.8%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=O)[CH:12]=[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:27].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH2:12][C:13]([C:18]4[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=4)([C:14]([F:17])([F:16])[F:15])[O:27][N:29]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1cc2c(Cl)cccc2s1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2cc3c(Cl)cccc3s2)=NO1
Yield: 27.8 %

Procedure:
Stir a mixture of 1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-one (1.05 g, crude, 2.43 mmol), NaOH (389 mg, 9.72 mmol) and NH2OH—HCl (335 mg, 4.8 mmol) in MeOH (8 mL) and water (8 mL) at ambient temperature for 4 hours. After removal of solvent under vacuum, dilute the residue with ice water (20 mL). Extract the aqueous mixture with EtOAc (15 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole as white solid (305 mg, 28.1%). MS (m/z): 450 (M+1). 1H NMR (400 MHz, CDCl3) δδ 7.74 (d, J=8.0, 1H), 7.64-7.60 (s, 1H), 7.57-7.53 (m, 2H), 7.47-7.43 (m, 1H), 7.40-7.32.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][C:11]([O:19][CH2:20][C:21]#[CH:22])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CO.O.[OH-].[Na+]>CCOCC>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([O:19][CH2:20][C:21]#[CH:22])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C#CCOc1cc(C(=O)OCC)n(-c2ncc(Cl)cc2Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: C#CCOc1cc(C(=O)O)n(-c2ncc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a 100 mL flask, ethyl 1-(3,5-dichloropyridin-2-yl)-3-(prop-2-ynyloxy)-1H-pyrazole-5-carboxylate (0.3 g, 0.88 mmol), methanol (10 mL), water (10 mL) and sodium hydroxide (0.04 g, 0.88 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. When reacted completely, water (40 mL) was added. The water (40 mL), ether (50 mL) were added and partitioned, acidified with concentrated hydrochloric acid to pH of 4, extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and concentrated at reduced pressure to give the product (0.27 g) as slight yellow solid in 73% yield. Melting point: 151-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28].C(N(CC)CC)C.C1COCC1.C([O:50][CH2:51][C:52](Cl)=[O:53])(=O)C>C(OCC)(=O)C>[OH:53][CH2:52][C:51]([N:32]1[CH2:33][CH2:34][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:31]1)=[O:50]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1c(C(=O)NC2CCNC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(C(=O)NC2CCN(C(=O)CO)C2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.6 %

Procedure:
To a mixture of the thus-obtained 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-pyrrolidin-3-yl-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carboxamide (153 mg, 0.327 mmol), triethylamine (99.7 μL, 0.720 mmol) and THF (3 mL) was added acetoxyacetyl chloride (38.7 μL, 0.360 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate). The obtained oil was dissolved in THF (4 mL) and ethanol (12 mL), 8N aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with water, acidified with 1N hydrochloric acid (8.5 mL), and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/methanol=10/0-9/1). Recrystallization of the obtained solid from ethyl acetate-THF gave the title compound (121 mg, 72%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14](Br)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1c(Br)sc(Br)c1NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)sc(Br)c1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Palladium tetrakis-triphenylphosphine (19.3 mg, 17 μmol) was added to a degassed solution of dibromide 4 (150 mg, 334 μmol) and 4-chlorophenylboronic acid 5 (54.8 mg, 350 μmol) in ethanol: water:toluene (2:1:1, 1.67 mL) and sodium carbonate (177 mg, 1.6 mmol). The resulting mixture was heated under N2 and stirred for 1 h at 80° C. The mixture was then cooled filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 6 (76.8 mg, 48%) as a solid: LRESIMS m/z 479.8 [M+H]+, calcd. for C20H16Br1Cl1N1O4S1 480.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:15])[CH2:10][CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(C)(C)C.[C:23]1([C@@H:29]2[CH2:33][O:32][C:31](=[O:34])[NH:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.S(=O)(=O)(O)O>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:15])[CH2:10][CH2:11][C:12]([N:30]1[C@H:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:33][O:32][C:31]1=[O:34])=[O:14]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: C=C(CCC(=O)O)c1ccc(F)cc1F
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=C(CCC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(F)cc1F
Temperature: 12.5 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 (100 g) in dichloromethane (800 ml), added triethylamine (97.4 g) at 25-30° C. and the reaction mixture was stirred for 15 minutes at the same temperature. The reaction mixture was cooled to 10-15° C. and added pivaloyl chloride (63 g) to the reaction mixture over a period of 45 minutes. Temperature of the reaction mixture was raised to 25-30° C. and the reaction mixture was stirred for 2 hours at 25-30° C. After completion of the reaction, added (R)-4-phenyloxazolidin-2-one compound of formula-3 (69 g), 4-dimethylamino pyridine (21 g), dimethyl formamide (37 ml) and followed by dichloromethane (200 ml) to the above reaction mixture. Heated the reaction mixture to 45° C. and stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30° C. Sulfuric acid was added to the reaction mixture and stirred for 15 minutes. Both organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure and isopropyl alcohol was added to the obtained residue at 25-30° C. and stirred for 15 minutes at the same temperature. The reaction mixture was cooled to 0-10° C. and then stirred for 1½ hour at the same temperature. Filtered the obtained solid, washed with chilled isopropyl alcohol and then dried to get title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:18](=O)[C@H:17]2[NH:20][C:21](=O)[C@@H:12]1[CH2:13][CH:14]=[CH:15][CH2:16]2.C1COCC1.C(OCC)C>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:18][C@H:17]2[NH:20][CH2:21][C@@H:12]1[CH2:13][CH:14]=[CH:15][CH2:16]2
Reactant: O=C1N[C@H]2CC=CC[C@@H]1N(c1ccc3ccccc3c1)C2=O
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: O=C1N[C@H]2C/C=C\C[C@@H]1N(c1ccc3ccccc3c1)C2=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Temperature: 120 °C

Procedure:
Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene-8,10-dione (0.8 g, 2.74 mmol) was dissolved in a solution of Dibal (THF, 1 M, 28 mL). The reaction was carried out in a large scale CEM microwave reaction vessel. The reaction mixture was heated to 120° C. for 0.5 h and then allowed to cool to room temperature. A one-liter Erlenmeyer flask was charged with diethyl ether (400 mL) and the reaction mixture was poured into the diethyl ether. A water solution of saturated Rochelle salts was added dropwise until gas stopped evolving and then water saturated with Rochelle salts (approximately 200 mL) was poured into the reaction mixture. The resulting mixture was stirred at room temperature until both phases were clear. The reaction mixture then was poured into a separatory funnel and the aqueous layer was discarded. The diethyl ether was dried with anhydrous magnesium sulfate and the solvent was removed using reduced pressure to yield a clear colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13]C(C)([O-])C.[K+].CI.Cl>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[N:9]2[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2ccc(F)cc2N1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CCc2ccc(F)cc21
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To an ice cold solution of 7-fluoro-3,4-dihydro-1H-quinolin-2-one (16.5 g, 0.1 mol) in DMF (200 mL) was added potassium tert-butoxide (22.4 g, 0.2 mol) in 2 portions. The reaction mixture was stirred at 0° C. for 30 min before MeI (25.4 g, 0.18 mol) was added. After the addition, the reaction mixture was allowed to warm up to room temperature slowly and stirred at room temperature over night. The reaction mixture was diluted with EtOAc (500 mL), then poured into 200 mL of 1 N aq. HCl. After extraction with EtOAc (200 mL, 3×), the combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give crude title compounds as oil (16.0 g, 89% yield). It was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][C:64]([F:67])([F:66])[F:65])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][C:64]([F:67])([F:66])[F:65])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.1 %

Procedure:
To a solution of 50 mg (0.26 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 82 mg of TBTU (0.26 mmol) in 4 ml DMF, were added 0.22 ml (1.28 mmol) of N,N-diisopropyl-ethyl amine. After stirring for 5 min at rt, 101 mg (0.33 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-amine were added. After stirring for 4 h at rt, the reaction mixture was diluted with 40 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:4) to give 106 mg light brown foam (43%). MS (ISP) 529.4 (M+H)+.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH2:31]>>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1cccc(C)c1Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2,6-dimethylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.14 (s, 6H), 2.31 (s, 3H), 4.40 (d, J=3.2 Hz, 2H), 5.52 (bs, 1H), 5.71 (s, 1H), 6.90 (bs, 1H), 7.04-7.14 (m, 4H), 7.46 (t, J=9.4 Hz, 1H), 8.45 (d, J=4.8 Hz, 1H); MS (ESI) m/z 335.0 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH:20]([NH2:24])[CH2:19][CH2:18]2>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:24][CH:20]2[C:21]3[C:17](=[CH:16][C:15]([O:14][CH3:13])=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: COc1ccc2c(c1)CCC2N
Product: COc1ccc2c(c1)CCC2NC(=O)c1ccc(OC)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and 5-methoxy-2,3-dihydro-1H-inden-1-amine (Example 121-2a)(47%). MS (M+H, 312).
Reaction SMILES: [Br:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.Cl.[NH2:9][CH2:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1([C:5]([NH:9][CH2:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])=[O:7])[CH2:4][CH2:3]1
Reactant: O=C(O)C1(Br)CC1
Reactant: CCCC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)CNC(=O)C1(Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A mixture of 2.57 g of 1-bromocyclopropanecarboxylic acid 4 [H. M. R. Hoffmann et al. J. Org. Chem. 54, 6096 (1989)], 2.22 g of 1-amino-2-pentanone hydrochloride 5 [M. Jackman et al. J. Am. Chem. Soc. 70, 2884 (1948)] and 3.36 g of N,N′-dicyclohexylcarbodiimide in 234 ml of methylene chloride in the presence of 2.46 ml of triethylamine is stirred overnight at room temperature. Then, it is filtered, the filtrate is concentrated by evaporation, and the residue is chromatographed on silica gel with ethyl acetate/hexane. 2.74 g of 1-bromo-N-(2-oxopentyl)-cyclopropane-1-carbamide 6 is obtained as a crystallizing oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH:24]=[CH:23][N:22]=[CH:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.[CH2:30]([Br:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C>[Br-:37].[CH2:30]([N+:22]1[CH:23]=[CH:24][C:13]2[C:14](=[N:15][C:16]([NH:17][CH:18]([CH3:20])[CH3:19])=[C:11]([N:8]3[CH2:7][CH2:6][CH:5]([O:4][C:3]4[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=4[F:1])[CH2:10][CH2:9]3)[N:12]=2)[CH:21]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)Nc1nc2cnccc2nc1N1CCC(Oc2ccc(F)cc2F)CC1
Solvent: CC#N
Product: CC(C)Nc1nc2c[n+](Cc3ccccc3)ccc2nc1N1CCC(Oc2ccc(F)cc2F)CC1
Product: [Br-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a yellow-orange suspension of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine (5.1 g, 12.77 mmol) in ACN (63.8 mL) was added benzyl bromide (2.184 g, 12.77 mmol) over 1 minute at 23° C. The mixture was stirred at 80° C. for 4 h to furnish a red-brown solution, cooled to 23° C., and then concentrated via rotary evaporation to give 6-benzyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-3-(isopropylamino)pyrido[3,4-b]pyrazin-6-ium bromide (7.30 g) as a red-brown solid, which was used directly in the next step without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]1[CH:20](Br)Br)([CH3:3])[CH3:2].C(=O)([O-])[O-:24].[Ca+2].O>C(O)C>[CH:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]1[CH:20]=[O:24])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(C(Br)Br)c(-c2ccc(F)cc2)c2cccnc21
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2cccnc21

Procedure:
1 g of the product of step 1, above, in 35 ml of 100% ethanol is mixed with 0.4g of calcium carbonate (powdered) and 15 ml of water. The mixture is refluxed for about 4 hours, then cooled, quenched with water and extracted with ethyl acetate. The extracts are dried and then evaporated to dryness to yield a dark amber gum, which is chromatographed on prep. plates, using petroleum ether/ether (85/15) and the largest (second of three) major band eluted with ethyl acetate to obtain the title product of this example as yellow solids, mp 95°-101°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12]Br.O>ClCCl.[Fe]>[Br:12][C:7]1[C:2]([OH:1])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=[C:5]([CH3:8])[CH:6]=1
Reactant: CC(=O)c1cc(C)ccc1O
Reactant: BrBr
Agent: [Fe]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(C)cc(Br)c1O
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
To a solution of 21.5 g (0.143 mol) of 20 in 40 mL of dry dichloromethane, 0.3 g of iron turnings was added, and then a solution of 10.7 mL (34.2 g, 0.215 mol) of bromine in 100 mL of dichloromethane was added dropwise by vigorous stirring for 20 min. This mixture was refluxed for 30 min, and then 300 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with 2×100 mL of dichloromethane. The combined organic extract was washed by saturated aqueous Na2SO3, dried over K2CO3, and then evaporated to dryness. Rectification of the residue in vacuum gave 15.7 g (48%) of the title product (bp 105-115° C./1 mm).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:34][C@@H:35]([CH2:54][CH3:55])[C@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[C:41]1=[O:53])[C:37](O)=[O:38].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@@H:4]([OH:26])[CH2:3][C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[C:41]1=[O:53])[CH:35]([CH3:34])[CH2:54][CH3:55])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
A solution containing the product from Example 8B (5.67 g, 12.5 mmol) in THF (124 mL) was treated with the product from Example 7B (3.8 g, 12.5 mmol), DEPBT (5.59 g, 18.7 mmol), and N,N-diisopropylethylamine (10.8 mL, 62.0 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with acetone to give the title compound (4.42 g, 48% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.68 (d, J=6.25 Hz, 3 H), 0.82 (m, 14 H), 0.92 (m, 1 H), 1.30 (m, 1 H), 1.50 (m, 2 H), 1.79 (m, 1 H), 2.43 (m, 3 H), 2.68 (m, 3 H), 2.89 (m, 1 H), 3.10 (m, 3 H), 3.57 (m, 3 H), 3.89 (m, 2 H), 4.13 (m, 2 H), 4.34 (s, 2 H), 4.79 (d, J=5.52 Hz, 1 H), 6.80 (d, J=9.56 Hz, 1 H), 7.11 (m, 12 H), 7.50 (d, J=8.82 Hz, 1 H), 7.66 (t, J=7.54 Hz, 1 H), 7.83 (d, J=9.19 Hz, 1 H).