Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH2:5][CH2:4][C@@:3]1([CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)CO.C1C[O:21][CH2:20]C1>>[OH:21][CH2:20][C@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: C1CCOC1
Reactant: CN1C(=O)CC[C@]1(CO)COc1cccnc1
Product: CN1C[C@H](CO)C[C@H]1COc1cccnc1

Procedure:
A 1.0 g (4.2 mmol) sample of 3-((-1-methylhydroxymethyl-5-oxo-2-(S)-pyrrolidinyl)methoxy)pyridine, from step 48a above, was dissolved in 15 mL of anhydrous THF, 12.7 mL of BH3 was added, and the mixture was heated at reflux for 2.5 hours. The reaction was quenched with methanol, the solvent was evaporated, and the residue was dissolved in anhydrous ethanol. Cesium fluoride was added, and the resultant solution was stirred under reflux for 16 hr. Evaporation of the solvent and purification of the residue on a silica gel column, eluting with 100:8 to 10.1 chloroform:methanol gave 600 mg of the title compound as a mixture of cis and trans product.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:8]([S:14](Cl)(=[O:16])=[O:15])([S:10](Cl)(=[O:12])=[O:11])[CH3:9].C(S(Cl)(=O)=O)S(Cl)(=O)=O.C(N(CC)CC)C.C(O)(O)CCCC.C(S(Cl)(=O)=O)CS(Cl)(=O)=O>C(COC)OC>[CH:8]1([S:14](=[O:16])(=[O:15])[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][S:10]1(=[O:12])=[O:11])[CH3:9]
Reactant: OCCCCCO
Reactant: CC(S(=O)(=O)Cl)S(=O)(=O)Cl
Agent: CCCCC(O)O
Agent: O=S(=O)(Cl)CCS(=O)(=O)Cl
Agent: O=S(=O)(Cl)CS(=O)(=O)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC1S(=O)(=O)OCCCCCOS1(=O)=O
Reaction time: 0.75 h

Procedure:
1,5-Pentanediol (4.17 g, 0.04 mole) was dissolved in 350 ml of glyme in a 1 liter round bottom flask and the solution brought to -20° C. 1,1-ethanedisulfonyl chloride, synthesized in the same manner as the methanedisulfonyl chloride, (Example I) was dissolved in 25 ml of glyme and this solution added dropwise to the solution in the flask. Triethylamine (8.08 g, 0.08 mole) was dissolved in 125 ml of glyme and this solution was added to the pentanediol/ ethanedisulfonyl chloride solution over a 1 hour period. After the additions were completed, the mixture was brought to 25° C. over a 45 minute period in a water bath. The mixture was roto-evaporated under reduced pressure, at a temperature below 35° C. The residue was washed three times with 20 ml of 5% sodium bicarbonate the resulting emulsion being separated by centrifugation. Water was decanted from the final oil wash, and methylene chloride was added. This solvent apparently dissolved all or most of the impurities, leaving the product suspended in the solution. The product was obtained by vacuum filtering the solution through Whatman #5 qualitative filter papers.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[NH:4][C:5]([CH3:13])=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[C:3](=[O:14])[NH:4][C:5]([CH3:13])=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(C)[nH]c(=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)[nH]c(=O)c1OCc1ccccc1
Temperature: 4 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 3-hydroxy-4-ethoxycarbonyl-6-methyl-2-pyridinone (prepared by the method of Feist et al., Chem. Ber., 1902, vol. 35, p. 1545; 23.9 g, 121 mmol) and benzyl bromide (14.4 mL, 121 mmol) in DMF (400 mL) at 0° C. was added cesium carbonate (39.7, 121 mmol). The resulting mixture was stirred at 4° C. for 48 h. More benzyl bromide was added (2.8 mL, 24 mmol) and the mixture was stirred at 4° C. for another 72 h. The solvent was removed in vacuo and the residue was suspended in CH2Cl2. The solids were removed by filtration and the filtrate solvent was removed in vacuo. The residue was purified by flash column chromatography using 1:3 EtOAc:hexanes as eluant to give the title compound (18 g; HPLC RT=15.04 min, method B).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.[F:33][C:34]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]2)=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[N:39]2.[OH-].[K+]>C1(C)C=CC=CC=1>[F:33][C:34]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][CH:47]([N:30]3[CH2:29][CH2:28][N:27]([C:25]4[CH:26]=[C:17]([O:16][CH3:15])[CH:18]=[C:19]5[C:24]=4[N:23]=[CH:22][CH:21]=[CH:20]5)[CH2:32][CH2:31]3)[CH2:46][CH2:45]2)=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[N:39]2
Reactant: O=C1CCN(c2ccc(F)c3cccnc23)CC1
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN(C3CCN(c4ccc(F)c5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 30 °C
Reaction time: 2.5 h

Procedure:
Toluene (118 g), sodium triacetoxyborohydride (44.5 g) were mixed at 0° C. to room temperature. To this mixture was charged a premixed toluene solution of 6-methoxy-8-(1-piperazinyl)quinoline (Step 1, 160 g, 27.4 wt % in toluene) and 1-(5-fluoroquinolin-8-yl)piperidin-4-one (Step 3, 41 g). The resulting mixture was stirred for 2 to 3 hours at about 30° C. KOH solution (443 g 9% in water) was charged to quench the residual sodium triacetoxyborohydride. Heptane (118 g) was added to further precipitate the product. The product was then filtered and washed with ethanol (2×100 ml). Yield 68 g, 86%. This crude product (67 g) was dissolved in 586 g dichloromethane and passed through a charcoal/celite pad to remove palladium. The dichloromethane was distilled off while 400 g of ethanol was slowly added at the same time. The resulting slurry was filtered and washed with ethanol twice (65 g+100 g). The product was dried in oven at 55° C. overnight. Purification recovery yield 59.9 g, 89.4%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:23]([O:38][C@H:39]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:40][C:41]([OH:43])=O)(=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(Cl)CCl.CI.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:23]([O:38][C@H:39]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:40][C:41]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:43])(=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC(C)(C)[Si](OCCCN)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CI
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)NCCCO
Yield: 90.9 %

Procedure:
In the same manner as described in Example 20-(1), 3-amino-1-(t-butyldiphenylsilyloxy)propane (470 mg, 1.5 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (680 mg, 1.5 mmol) in the presence of EDC MeI (595 mg, 2.0 mmol) and then deprotected with TBAF (1.0 M in THF, 2.0 mL, 2.0 mmol) in THF (10 mL) to afford 698 mg (91%) of 3-[(R)-3-tetradecanoyloxytetradecanoylamino]-1-propanol as an off-white solid.
Reaction SMILES: B.[Na].FC(F)(F)C(O)=O.CO[N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH:15]=1.O>O1CCCC1.Cl>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[CH2:13][NH2:12])=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: CON=Cc1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCc1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Suspended in 160 ml of anhydrous tetrahydrofuran were 3.783 g (0.100 mol) of sodium boron hydride, and a solution of 11.402 g (0.100 mol) of trifluoroacetic acid in 20 ml of anhydrous tetrahydrofuran was added dropwise to the suspension at room temperature. The resultant mixture was stirred for 10 minutes. A solution of 5.726 g (0.02 mol) of O-methyl-3-(4-nitrobenzyloxy)benzaldoxime in 20 ml of anhydrous tetrahydrofuran was added dropwise to this mixture. The mixture was stirred at room temperature for 3 hours and heated under reflux further for 2 hours. After cooling the mixture, 20 ml of water were added under chilling with ice water, and the solvent was then distilled off under reduced pressure. The residue was extracted with chloroform, and the solvent was distilled out of the resultant extract under reduced pressure, thereby obtaining a crude product. The crude product was dissolved in 800 ml of 2 N hydrochloric acid, and the solution was washed with chloroform and then neutralized with 50% sodium hydroxide, followed by extraction with chloroform. The solvent was distilled out of the resultant extract under reduced pressure, thereby obtaining 4.234 g (yield: 82%) of the title compound.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[C:40]([C:44]#[CH:45])([CH3:43])([CH3:42])[CH3:41]>[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[CH3:41][C:40]([CH3:43])([CH3:42])[C:44]#[C:45]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[CH2:6][CH3:7]
Reactant: C#CC(C)(C)C
Reactant: CCN(C/C=C/Cl)Cc1cccc(Br)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
To 10 ml tetrahydrofuran were added 1.44 g (5 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-bromobenzylamine, 47.6 mg (0.25 mmol) of copper (I) iodide and 22.4 mg (0.1 mmol) of palladium acetate and 52.5 mg (0.2 mmol) of triphenylphosphine, and further, 1.0 ml (10 mmol) of n-butylamine and 0.74 ml (6 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 20-hours at room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=20/1). The desired fractions were put together and concentrated under reduced pressure to obtain 1.37 g (yield: 82%) of the above identified compound as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1OCCN1CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCN2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.8 %

Procedure:
To an ice cold stirring solution of crude 3-(2-hydroxyethyl)oxazolidin-2-one (15.1 g, 115 mmol) in dichloromethane (40 mL) was added triethylamine (18 mL, 129 mmol), and 4-(N,N-dimethylamino)pyridine (0.143 g, 1.2 mmol). A slurry of 4-toluenesulfonyl chloride (25.0 g, 131 mmol) in dichloromethane (50 mL) was then added dropwise. The reaction mixture was stirred for 3 d at room temperature, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was slurried in isopropanol and filtered to give 23.88 g (73%) of a white solid.
Reaction SMILES: C1(C[O:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[C:27](O)([CH3:29])[CH3:28])=[O:10])C=CC=CC=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:21]1([CH2:20][O:19][C:17]([N:14]2[CH2:15][CH2:16][N:11]3[C:9](=[O:8])[O:10][C:27]([CH3:29])([CH3:28])[CH:12]3[CH2:13]2)=[O:18])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)N2CCN(C(=O)OCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Bis(phenylmethyl)2-(1-hydroxy-1-methylethyl)-1,4-piperazinedicarboxylate (1.7 g, 4.2 mmol) was dissolved in N,N-dimethylformamide (20 mL). 60% Sodium hydride (0.25 g, 6.3 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (200 ml), and then washed with an aqueous sodium hydrogen carbonate solution. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) and recrystallized from ethyl acetate-hexane to obtain the title compound (0.97 g, yield 76%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:21][C:22]1[C:27]([F:28])=[C:26]([O:29][CH2:30][CH3:31])[CH:25]=[CH:24][C:23]=1O.C1(N=C=NC2CCCCC2)CCCCC1.O>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]([O:20][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH3:31])=[C:27]([F:28])[C:22]=3[F:21])=[O:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC(=O)O)CC2)CC1
Reactant: CCOc1ccc(O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC(=O)Oc3ccc(OCC)c(F)c3F)CC2)CC1
Reaction time: 0.5 h

Procedure:
In a 3-L three-neck flask equipped with a stirrer, a thermometer and a dropping funnel, 32.0 g (114.9 mmol) of 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propionic acid and 20.0 g (114.9 mmol) of 2,3-difluoro-4-ethoxyphenol were dissolved in 1000 ml of dichloromethane at room temperature under nitrogen atmosphere, and 15.4 g (126.4 mmol) of 4-dimethylaminopyridine was added thereto. The solution was stirred for 30 minutes thereafter, and then 26.1 g (126.4 mmol) of dicyclohexylcarbodiimide was dissolved in 400 ml of dichloromethane to prepare a solution, which was added dropwise to the reaction mixture at room temperature. After dropwise adding, the solution was stirred at room temperature for 14 hours. 500 ml of water was added to the reaction solution, insoluble materials were filtered, and then the filtrate was washed with 300 ml of 3M hydrochloric acid, 300 ml of water, 300 ml of a saturated aqueous sodium hydrogencarbonate solution and 600 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off from the reaction solution under reduce pressure to obtain 56.4 g of a concentrated substance, which was then purified by means of a silica gel column chromatography with a mixed solvent of heptane/ethyl acetate (7/3) used as a developing solvent to obtain 51.4 g of 2,3-difluoro-4-ethoxyphenyl 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propionate as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=[O:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[CH3:22][S-:23].[Na+]>O1CCOCC1.O>[CH3:19][C@H:14]1[O:15][C@@H:16]([CH3:18])[CH2:17][N:12]([C:9]2[C:8]([CH:20]=[O:21])=[CH:7][C:6]3[C:2]([S:23][CH3:22])=[N:3][O:4][C:5]=3[C:10]=2[F:11])[CH2:13]1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice cold solution of 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde (Intermediate 534, 0.3 g, 0.916 mmol) in dioxane was added sodium thiomethoxide (21% aq solution, 0.134 mL, 1.923 mmol) and stirred at room temperature for 12 hours. Reaction mixture was diluted with water and extracted with EtOAc (50 mL). Organic phase washed with brine (2×10 mL), dried over anhydrous sodium sulfate and, filtered, concentrated to give tilt product as white solid. Yield: 280 mg (90%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[O:12][CH3:13])=[C:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:6]2=[O:21].[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[NH2:22][C:23]1[N:24]=[CH:25][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[O:12][CH3:13])=[C:9]([CH:14]2[CH2:16][CH2:15]2)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:6]3=[O:21])=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(OC)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(OC)c(-c3ccc(N)nc3)ccn2c1=O
Yield: 59.9 %

Procedure:
Methyl 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (50 mg, 0.16 mmol), and 2-aminopyridine-5-boronic acid pinacol ester (42.9 mg, 0.20 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as an orange solid (35 mg, 57%).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)[C:5](=[O:15])[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:36][C:37]1[CH:38]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:41][CH:42]=1>ClCCl.CN(C)C=O>[F:44][C:43]([F:45])([F:46])[C:39]1[CH:38]=[C:37]([NH:36][C:10](=[O:12])[C:9]([N:6]2[C:5](=[O:15])[C:4]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:3]([CH:2]([F:1])[F:22])[O:8][CH2:7]2)([CH3:13])[CH3:14])[CH:42]=[CH:41][CH:40]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C(=O)O)N1COC(C(F)F)=C(c2ccccc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)Nc1cccc(C(F)(F)F)c1)N1COC(C(F)F)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
To a stirred suspension of 2-(6-difluoromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoic acid (0.70g) in dichloromethane was added oxalylchloride (0.22 ml) followed by 1 drop of dimethylformamide. The reaction mixture was stirred at ambient temperature for 30 minutes and then cooled to 0° C. To the solution was added in turn triethylamine (0.36 ml), 3-aminobenzotrifluoride (0.34 g) and then triethylamine (0.36 ml). The reaction mixture was stirred at 0° C. for 30 minutes and at ambient temperature for 2 hours then washed in turn with water, 2M hydrochloric acid, water, 1M sodium carbonate and water. The organic solution was dried (magnesium sulphate) and evaporated under reduced pressure to give N-(3-trifluoromethylphenyl)-2-(6-difluoromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 2, 0.25 g) as a beige solid, m.p. 58-60° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[S:21]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)([C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.2 %

Procedure:
To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.9 g, 5.02 mmol) in anhydrous pyridine (10 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (1.0 g, 5.27 mmol). The suspension was allowed to warm to room temperature and stirred for 24 h. After this time, the suspension was poured onto crushed ice and extracted with EtOAc. The organic layer was separated, washed with water, brine, dried (MgSO4) and concentrated under reduced pressure to give the title compound (15) (1.1 g, 69%) as a light yellow colored solid. 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.94-5.17 (m, 1H), 3.33-3.56 (m, 4H), 2.46 (s, 3H), 1.79-2.28 (m, 2H), 1.43 (s, 9H); MS (APCI, M+H+) C16H24NO5S, calcd. 342.1. found 286.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[N:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[N:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1cnc2c(n1)CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCCOc1cnc2c(n1)CCCC2
Yield: 99.9 %

Procedure:
291 mg (1.5 mmol) of 2-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoxaline was dissolved in 15 ml of methylene chloride. To the resultant solution was added 0.25 ml (1.8 mmol) of triethylamine and then, 0.13 ml (1.65 mmol) of methanesulfonyl chloride was added dropwise thereto. The resultant mixture was stirred at room temperature for 2.5 hours to effect a reaction. To the resultant reaction mixture was added chloroform to obtain a mixture. The mixture was extracted with an aqueous potassium carbonate solution to thereby obtain an organic layer and an aqueous layer. The aqueous layer was subjected to extraction with chloroform to obtain an additional organic layer. The two organic layers were combined, dried over sodium sulfate, and subjected to filtration, followed by concentration, to thereby obtain 408 mg of 2-(2-methanesulfonyloxyethoxy) -5,6,7,8-tetrahydroquinoxaline. The thus obtained 2-(2-methanesulfonyloxyethoxy)-5,6,7,8-tetrahydroquinoxaline was dissolved in 10 ml of acetonitrile. To the resultant solution were added 0.31 g (2.25 mmol) of potassium carbonate and 294 mg (1.8 mmol) of 1-(2-pyridyl)piperazine, and the resultant mixture was heated under reflux for 24 hours. Then, the mixture was subjected to filtration to filter off insoluble substances, which were then washed with acetonitrile, to thereby obtain a filtrate. The solvent of the filtrate was distilled off in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was charged in a column of 20 g of silica gel (Art7734, manufactured and sold by E. Merck, Darmstadt) and eluted with chloroform-methanol (100:1), to thereby obtain 522 mg of 2-[2-{4-(2-pyridyl)-1-piperazinyl}ethoxy]-5,6,7,8-tetrahydroquinoxaline (compound 517) (yield: 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([C:15]#[C:16][CH2:17][O:18][CH3:19])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].C(N(CC)CC)C>C1(C)C=CC=CC=1.[Pt]=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6]
Reactant: COCC#Cc1cc(C(=O)NC2CC2)cc(Br)c1C
Agent: O=[Pt]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCCCc1cc(C(=O)NC2CC2)cc(Br)c1C

Procedure:
To a stirred solution of 3-bromo-N-cyclopropyl-5-(3-methoxy-prop-1-ynyl)-4-methyl-benzamide and platinum oxide (0.04 equiv.) in toluene (˜0.12 M) was added triethylamine (0.2 equiv.). The resultant solution was hydrogenated at 1.8 Barg for 3 h and then filtered to remove the catalyst. The solution was concentrated to ˜4 volumes and then heptane added (8 volumes). The resultant slurry was filtered to afford the product as an off-white solid. 1H NMR (500 MHz, Acetone-d6): δ 7.87 (m, 2 H), 7.65 (s, 1 H), 3.35 (t, J=6.12 Hz, 2 H), 3.27 (s, 3 H), 2.93-2.86 (m, 1 H), 2.75 (t, J=7.91 Hz, 2 H); 2.39 (s, 3 H), 1.80-1.72 (m, 2 H), 0.75-0.67 (m, 2 H), 0.61-0.56 (m, 2 H). HRMS (ES, M+H) Calcd 326.0767. Found 326.0756.