Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][CH:23]([C:28](OCC)=[O:29])[CH2:22]4)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl-:33].[Na+].[Li].O>O1CCCC1>[ClH:33].[ClH:33].[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][CH:23]([CH2:28][OH:29])[CH2:22]4)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C1Cc2ccc(-c3cc4ccccc4c(N4CCN(CC)CC4)n3)cc2C1
Reactant: [Cl-]
Agent: [Li]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(-c3ccc4c(c3)CC(CO)C4)cc3ccccc23)CC1
Product: Cl
Reaction time: 0.33 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(2-ethoxycarbonylindan-5-yl)isoquinoline (1.06 g) was dissolved in tetrahydrofuran (6 ml). Under cooling with a cooler of sodium chloride and ice, the solution was added to a suspension of lithium aluminumhydride (0.10 g) in tetrahydrofuran (10 ml), and the mixture was stirred for 20 min. To the resulting solution were sequentially added water (100 ml), a 5N aqueous solution of sodium hydroxide (100 ml) and water (300 ml), and the resulting precipitates were filtered off. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 0.35 g of the free compound of the title compound as a pale yellow amorphous.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN1CCCC1=O.O>[CH2:22]([NH:29][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COCCOc1ccnc(F)c1[N+](=O)[O-]
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCOc1ccnc(NCc2ccccc2)c1[N+](=O)[O-]

Procedure:
2.32 g of 2-fluoro-4-(2-methoxyethoxy)-3-nitropyridine (starting material J3), 4.44 g of potassium carbonate and 1.11 ml of benzylamine in 25 ml of N-methylpyrrolidone are stirred at room temperature for 5 hours. The mixture is diluted with water and then extracted twice with diethylether. The combined ether phases are washed with with water and brine and are then concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate/petroleum ether 1:2). Concentration of the pure fractions and drying in vacuo gives 2.0 g of the title compound as a yellow oil, which crystallizes on standing (m.p. 81–83° C.). The mass spectrum shows the molecular peak MH+ at 304.0 Da.
Reaction SMILES: [S:1](S([O-])=O)([O-:3])=[O:2].[Na+:7].[Na+:8].[C:9]([OH:13])(=[O:12])[CH:10]=[O:11].[OH-].[Na+]>O>[OH:11][CH:10]([S:1]([O-:3])=[O:2])[C:9]([OH:13])=[O:12].[Na:7][Na:8]
Reactant: O=CC(=O)O
Reactant: [Na+]
Reactant: O=S([O-])S(=O)[O-]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(O)S(=O)[O-]
Product: [Na][Na]

Procedure:
The reaction of 358 g of commercially available sodium hydrosulfite in 800 ml of water with 268 g of 50% strength glyoxylic acid and 285 g of 50% sodium hydroxide solution gave the 2-hydroxy-2-sulfinatoacetic acid, disodium salt in a yield of 95%. The solid crude product contained 43% of sulfinic acid (without water of hydration). Crystallization from a methanol/ethanol/water mixture gave the hydrate of the sulfinic acid in nice crystals. The sulfur-containing constituents were determined using iodometry. The sulfinic acid shows a reaction with indanthrene paper at about 75° C.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.O>CO>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([C:11](=[N:4][OH:1])[NH2:12])=[CH:9][CH:8]=1
Reactant: NO
Reactant: N#Cc1ccc(Cl)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=NO)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
A solution of 50% aqueous sodium hydroxide (2.8 g, 36.34 mmol) was mixed in methanol (20.0 mL). Hydroxylamine hydrochloride (2.55 g, 36.34 mmol) was added and the mixture stirred for 5 minutes. 4-Chlorobenzonitrile (4.0 g, 29.08 mmol) was added and the mixture heated to 60° C. The heterogeneous mixture was stirred at 60° C. for 3 hours. The mixture was poured into water (30 mL) and solids dissolved and a precipitate appeared. The methanol was removed at reduced pressure and remaining solids collected by vacuum filtration. The solids were washed with water (2×10 mL). The 4-chlorobenzamidoxime (4.38 g, 25.6 mmol) was obtained as a white solid. (88% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][C:13]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:15][CH2:14]2)=[CH:7][C:6]=1[C:23]1[CH:24]=[CH:25][C:26]2[O:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:28]([C:38]([NH:40][CH3:41])=[O:39])[C:27]=2[CH:42]=1.C(O)(C(F)(F)F)=[O:44]>CO.O.O.CO.C(#N)C.O.C(#N)C>[NH2:1][C:2](=[O:44])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][C:13]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)=[CH:7][C:6]=1[C:23]1[CH:24]=[CH:25][C:26]2[O:30][C:29]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[C:28]([C:38]([NH:40][CH3:41])=[O:39])[C:27]=2[CH:42]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)ccc3OCCN)cc12
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)ccc3OCC(N)=O)cc12

Procedure:
5-(2-(2-Aminoethoxy)-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide, 2 TFA. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Waters XBridge Phenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 1.23-1.33 (m, 2H), 1.60-1.67 (m, 2H), 2.89 (d, J=4.77 Hz, 3H), 3.41 (t, J=5.14 Hz, 2H), 4.40 (t, J=5.14 Hz, 2H), 6.58 (br. s., 2H), 7.01-7.11 (m, 1H), 7.16-7.29 (m, 3H), 7.46 (d, J=8.03 Hz, 1H), 7.52-7.70 (m, 4H), 7.93 (dd, J=8.53, 2.26 Hz, 1H), 7.98-8.05 (m, 3H), 8.07 (s, 1H), 8.41 (d, J=4.77 Hz, 1H), 8.56 (s, 1H). LCMS m/z 565.4 (M+H), Rt=1.628 min. HPLC (Sunfire C18) Rt=5.048 min., 99.9% purity and (XBridge Phenyl C18) Rt=10.531 min., 100% purity.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:43]=[C:44]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:45][NH:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1)=[O:48]>CN(C=O)C.O>[Br:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([N:64]1[CH2:63][CH2:62][N:61]([C:44](=[O:43])[CH2:45][NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:51][CH:50]=2)=[O:48])[CH2:66][CH2:65]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(F)ccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2Br)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-bromo-5-fluoro-benzoic acid (56.4 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 60 mg (44.6% yield) of biphenyl-4-carboxylicacid {2-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.34%, 1H NMR: (CDCl3) δ 7.96-7.88 (d, 2H), 7.72-7.64 (d, 2H), 7.64-7.54 (m, 3H), 7.52-7.43 (t, 2H), 7.43-7.35 (m, 1H), 7.35-7.28 (m, 1H), 7.08-6.98 (m, 2H), 4.4-4.24 (d, 2H), 4.07-3.85 (m, 2H), 3.8-3.7 (m, 2H), 3.66-3.58 (m, 1H), 3.52-3.42 (m, 1H), 3.42-3.33 (m, 1H), 3.33-3.2 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:6]=1)=[O:4].[F:19][B-](F)(F)F.F[B-](F)(F)F.Cl[N+]12CC[N+](F)(CC1)CC2C.C(OCC)C.Cl>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([F:19])=[C:8]([O:10][CH3:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:6]=1)=[O:4]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(OC)n(-c2ccccc2F)n1
Agent: CC1C[N+]2(F)CC[N+]1(Cl)CC2
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nn(-c2ccccc2F)c(OC)c1F
Reaction time: 8 h
Yield: 32.6 %

Procedure:
200 mg (0.8 mmol) of 1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid methyl ester were dissolved in 2 ml of acetonitrile and 745 mg (1.99 mmol) of 1-chloro-methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) were added. The mixture was stirred overnight. Then, irrespective of the incomplete reaction, diethyl ether, water and 2 N hydrochloric acid were added, the organic phase was separated, the solvent evaporated and the residue subjected to preparative HPLC. 70 mg (33%) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.O.O.[C:12](O)(=[O:16])[C:13](O)=[O:14]>>[CH3:9][N:8]1[C:13](=[O:14])[C:12](=[O:16])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]1=2
Reactant: CNc1ncccc1N
Reactant: O=C(O)C(=O)O
Solvent: O
Product: Cn1c(=O)c(=O)[nH]c2cccnc21

Procedure:
3-amino-2-(N-methylamino)-pyridine (0.1 mol)and oxalic acid dihydrate (0,12mol) was dissloved in 4N HCI (400 ml). The solution was refluxed for 8 hours and then cooled to room temperature whereby the title compound precipitated as crystals. The crystals were separated by filtration and then washed with water. m.p. 271°-272° C.
Reaction SMILES: [C:1]([O:5][C:6](N([C:13]1[C:22]2C(=CC=C[CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C@H](CO)C)=[O:7])(C)(C)[CH3:2].S(Cl)([C:26]1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[CH3:2][CH2:1][O:5][C:6]([CH3:26])=[O:7].[CH3:21][CH2:22][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C[C@@H](CO)N(C(=O)OC(C)(C)C)c1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCC
Product: CCOC(C)=O
Temperature: -30 °C
Yield: 214.6 %

Procedure:
N-t-butyloxycarbonylnaphthylalaninol (3.71 g; 12.3 mmol) was dissolved in pyridine (15 ml) and the solution was cooled to -30° C. Tosyl chloride (2.36 g; 12.4 mmol) was added and the mixture was stirred to clearness at -30° C. and then put into the refrigerator overnight. Pyridine was removed in vacuo and the product was extracted with ether (4×30 ml). The organic layer was washed with 1N HCl (2×30 ml), H2O (1×30 ml), NaHCO3 5% (2×30 ml) and saturated NaCl (1×30 ml), then dried over Na2SO4, filtered and stripped to leave an oily residue which was crystallized from AcOEt/hexane (4.6 g; 82% yield).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: N#Cc1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncccc1Oc1ccc(Br)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A RBF was charged with 3-chloro-2-cyanopyridine (40 g, 289 mmol), 4-bromophenol (49.9 g, 289 mmol) and cesium carbonate (113 g, 346 mmol). The reactants were suspended in 50 mL of DMSO and allowed to stir at 85° C. overnight. The reaction was cooled to RT and 600 mL of water was added to it. The reaction was filtered and the solid washed with water, then air dried to provide 3-(4-bromophenoxy)-picolinonitrile as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][C:53]=1[S:59][CH2:60]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:60][S:59][C:53]2[CH:54]=[C:55]([CH3:58])[CH:56]=[CH:57][C:52]=2[CH3:51])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: Cc1ccc(C)c(SCCO)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCSc4cc(C)ccc4C)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 70.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (68 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (97 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-[(2,5-dimethylphenyl)sulfanyl]-1-ethanol (60 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (79 mg, yield 66%).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH:12]=[N:13][CH:14]=[CH:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CC(C)=O.O1CCOCC1.[Pd]>[CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH2:12][N:13]([C:31](=[O:33])[CH3:32])[CH2:14][CH2:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3NC3CCC3)CC2)c(F)c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(=O)N1CCc2nc(N3CCN(Cc4ccc(F)cc4F)CC3)c(NC3CCC3)nc2C1
Temperature: 45 °C
Reaction time: 50 h
Yield: 51.1 %

Procedure:
To N-cyclobutyl-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine (0.500 g, 1.218 mmol) in acetone (25 mL) and dioxane (25 mL) was added palladium, 10 wt % on activated carbon (0.052 g, 0.487 mmol) as a slurry in dioxane (3 mL) under nitrogen. Next, acetic anhydride (1.144 mL, 12.18 mmol) was added at 23° C. The mixture was stirred under hydrogen at 310 kPa for 50 hr at 45° C. The crude mixture was filtered through Celite™, rinsed with dioxane, and concentrated via rotary evaporation. The crude material was purified via medium pressure chromatography using a 10% to 100% gradient eluant of EtOAc in heptanes on an NH 60 μM size 60 column (Shoko Scientific Purif-Pack™) to give the title compound 1-(3-(cyclobutylamino)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone (284 mg, 51.1%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.56-1.72 (m, 2H), 1.97-2.06 (m, 2H), 2.07 (s, 1.3H), 2.08 (s, 1.7H), 2.18-2.27 (m, 2H), 2.52-2.66 (m, 4.9H), 2.69 (t, J=5.9 Hz, 1.1H), 2.99 (br s, 4H), 3.59 (s, 2H), 3.69 (dt, J=11.5, 6.0 Hz, 2H), 4.27-4.46 (m, 3H), 5.89 (d, J=7.3 Hz, 0.4H), 5.93 (d, J=7.8 Hz, 0.6H), 7.02-7.13 (m, 1H), 7.17-7.27 (m, 1H), 7.41-7.55 (m, 1H); ESI-MS m/z [M+H]+ 457.0.
Reaction SMILES: [CH2:1]([C:7]1[CH:21]=[C:20]([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])[CH:19]=[CH:18][C:8]=1[O:9][CH2:10][CH:11]1[CH2:15][O:14]C(C)(C)[O:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl>O1CCCC1>[CH2:1]([C:7]1[CH:21]=[C:20]([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])[CH:19]=[CH:18][C:8]=1[O:9][CH2:10][CH:11]([OH:12])[CH2:15][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC2COC(C)(C)O2)c(CCCCCC)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CCCCCC)c1
Yield: 98.5 %

Procedure:
A mixture of 13.6 g of 4-((2-hexyl-4-tetradecylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane, 10 ml of 5% hydrochloric acid and 250 ml of tetrahydrofuran was heated at reflux for 4 hours, then allowed to cool and the tetrahydrofuran removed under reduced pressure. The mixture was then extracted several times with ethyl acetate. The organic extracts were combined, washed with aqueous sodium bicarbonate, dried and the solvent evaporated, giving 12.3 g of the desired compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3](=[O:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6]
Reactant: COc1cc(F)ccc1C(C)(C)CC(O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(F)ccc1C(C)(C)CC(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 2.3 g (8.42 mmol) of 1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol in 40 mL of dichloromethane was added the 4.96 (11.70 mmol) of Dess-Martin periodinane. After 1 hour, the mixture was concentrated and diluted with ether-hexanes (1:9) and filtered through a pad of silica gel, washing with 1:1 ether-hexanes. Use of a second pad of silica gel washing with EtOAc-hexanes (1:9) afforded the title compound as an oil. The product was dried under vacuum to a constant weight of 2 g (85%).
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[N+](=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C(Cl)Cl>[C@H:1]12[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@H:8]1[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]2
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)OCC
Reactant: C1=CCCC=CCC1
Agent: CCOC(=O)C1(C(=O)OCC)[C@@H]2CC/C=C\CC[C@@H]21
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)[C@@H]2CCC=CCC[C@@H]21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1,5-cyclooctadiene (5.27 mL, 43.0 mmol) and Rh2(OAc)4 (100 mg, 0.23 mmol) in CH2Cl2 (5 mL) was added dropwise in 3 h a solution of diethyl diazomalonate (1.0 g, 5.37 mmol) in CH2Cl2 (5 mL). This solution was stirred for 24 h at rt. The CH2Cl2 was evaporated and the excess of cyclooctadiene was removed by filtration over a glass filter filled with silica (eluens: heptane). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EtOAc:heptane, 1:10) to afford IIa.8 (1.03 g, 72%).
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:20]N1C(=O)CCC1=O>O1CCCC1.C(Cl)(Cl)Cl>[Br:20][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Br)(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 2-phenylmalonate (15 ml) in 200 ml of tetrahydrofuran, kept at 0° C. and under nitrogen atmosphere, 3.475 g of sodium hydride are added and the mixture is kept 30 minutes under stirring at 0° C., then it is brought to room temperature. After cooling again to 0° C., the reaction mixture is added with 14.3 g of N-bromosuccinimide. After about 15 minutes, the white solid which separated is filtered off and the filtrate is concentrated to dryness to give a residue which is redissolved in chloroform and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give 15.66 g of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:5]([CH3:18])[C:4]=1[CH3:19].C([O-])(=O)C.[Na+].[Br:25]Br.O>C(O)(=O)C>[Br:25][C:8]1[C:7]([CH3:9])=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:5]([CH3:18])=[C:4]([CH3:19])[C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)c(NC(=O)OC(C)(C)C)c(C)c1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(C)c(C)c(NC(=O)OC(C)(C)C)c(C)c1Br
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-methoxy-2,3,6-trimethylphenylcarbamate (12.7 g, 47.9 mmol) and sodium acetate (4.72 g, 57.5 mg) in acetic acid (50 ml) was added at room temperature bromine (8.42 g, 52.7 mmol) and the resulting mixture was stirred at the same temperature for 1 hour. Water (80 ml) was added into the reaction mixture. The crystals precipitated were collected by filtration and dissolved into ethyl acetate. The solution was washed with an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from methanol to obtain 15.0 g (91% yield) of the title compound. Melting point: 159-161° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8]1.[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.C(Cl)Cl>[C:35]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)=[O:33])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3)) and Scheme AT using N-{3-[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 526.0 (M+H)+.