Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:29]([F:32])([F:31])[F:30])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(OC(C)(C)C)=O)[CH:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:9][C:6]1[CH:5]=[C:4]([CH:10]([C:29]([F:30])([F:32])[F:31])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1c(Cl)cc(C(/C=C/c2ccc3[nH]ccc3c2)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.8 %

Procedure:
To a stirred solution of (E)-tert-butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole-1-carboxylate (0.2 g, 0.40 mmol) in CH2Cl2 (10.0 mL) was added TFA (70 mg, 0.61 mmol) and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown solid (0.2 g, 97%): mp 132.9-138.8° C.; 1H NMR (400 MHz, CDCl3) δ 11.19 (br, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (m, 1H); ESIMS m/z 387.98 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH:11]([CH3:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CN(P(N(C)C)N(C)C)C.[H-].[Na+].[CH3:27][CH2:28][CH2:29]I>C1(C)C=CC=CC=1.CN(P(N(C)C)N(C)C)C.C1(C)C=CC=CC=1>[CH:11]([C:5]([CH2:27][CH2:28][CH3:29])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Reactant: CCCI
Agent: CN(C)P(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCC(C(=O)OCC)(C(=O)OCC)C(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of diethylisopropylmalonate (10.1g) in 15 ml of a 25% solution of HMPT (hexamethylphosphorus triamide) in toluene was added dropwise over 15 minutes to a suspension of sodium hydride (70 mM) in 25% HMPT/toluene (15 ml) at 50°-70° C. N-propyl iodide (17.0g) was then added over 30 minutes at 70°-100° C. and the mixture stirred at 120°-130° C. for 11/2 hours. After cooling, methylated spirits (10 ml) was added and the mixture poured onto a mixture of ice/hydrochloric acid. The product was extracted with ether, the ethereal extracts washed with sodium bicarbonate (X2), then water and dried over anhydrous magnesium sulphate. Removal of the solvent gave diethyl 2-isopropyl-2-propylmalonate as a yellow liquid b.p. 92°-94°/1 mm Hg. 87% yield.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([C:11](=[O:22])[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3][CH2:2]1.C(O[Al](OC(C)C)OC(C)C)(C)C.CC(O)C.Cl>C1(C)C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[C:8]([C@@H:11]([OH:22])[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3][CH2:2]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2c(c1)OCOC2
Agent: CC(C)O[Al](OC(C)C)OC(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccc2c(c1)OCOC2

Procedure:
A mixture (S)-tert-butyl 1-(4H-benzo[d][1,3]dioxin-7-yl)-1-oxopropan-2-ylcarbamate (I3c) (680 mg, 2.21 mmol), triisopropoxyaluminum (140 mg, 0.69 mmol) and propan-2-ol (3 mL, 38.9 mmol) in toluene (3 mL) was stirred at +65° C. for 15 hours. The reaction mixture was allowed to cool down and poured into 1M HCl (50 mL) and extracted with EtOAc (2×50 mL). The organic phase was washed with water, brine, dried over MgSO4, filtered and solvents removed by evaporation to afford a crude product as a colourless solid. The crude product was first purified by Flash chromatography, (solvent A=Heptane, solvent B=EtOAc+10% MeOH). An gradient of 10% B to 50% B in A was used. The obtained product was crystallised from DCM/Heptane to afford the subtitle compound colourless needles. Yield 414 mg (60%)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([N:19]=O)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.CCOCC.O>C1COCC1>[NH2:19][N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:22][CH:21]=2)[CH2:14][CH2:15]1
Reactant: O=NN1CCC(Cc2ccc(Cl)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NN1CCC(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A suspension of LiAlH4 (535 mg, 14.1 mmol) in dry THF (10 mL) was heated to refux with stirring. The mixture was removed from the heat source and a solution of 4-(4-chlorobenzyl)-1-nitrosopiperidine (1.68 g, 7.04 mmol) in dry THF (10 mL) was added with stirring so as to maintain a gentle reflux. After addition, the reaction was allowed to stir at reflux for 10 min. The reaction was allowed to cool to 25° C. and ether (60 mL) was added. Water (10 mL) was slowly added with stirring so as to destroy the excess hydride. The ether layer was separated and the aqueous portion was washed with ether. The combined ether portion was dried over Na2SO4 and the solvent was removed to give a near colorless liquid. This was filtered through a column of silica gel (2.5×10 cm) with 2% EtOH/98% CHCl3 elution to remove a low TLC Rf impurity. Solvent removal and drying in vacuo (0.005 Torr, 25° C.) gave a colorless liquid that solidified with scratching (1.20 g, 76%): mp 49-51° C.; 1H NMR (CDCl3) 1.24-1.52 (m, 3H), 1.56-1.68 (m, 2H), 2.00 (t, J=10, 2H), 2.48 (d, J=6.6, 2H), 2.86 (bs, 2H), 3.08 (d, J=11, 2H), 7.05 (d, J=8.4, 2H), 7.23 (d, J=8.4, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([NH:17]C(=O)OC(C)(C)C)=[N:12][CH:13]=[C:14](Br)[N:15]=1.[CH2:25]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH3:26].Cl.O1CCOCC1>COCCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14]([N:33]2[CH2:32][CH2:31][N:30]([S:27]([CH2:25][CH3:26])(=[O:28])=[O:29])[CH2:35][CH2:34]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1-c1cc2ccccc2o1
Reactant: CCS(=O)(=O)N1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cc4ccccc4o3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
A solution of tert-butyl N-[3-(benzofuran-2-yl)-5-bromo-pyrazin-2-yl]carbamate, 1-ethylsulfonylpiperazine (164.5 mg, 0.9228 mmol) and 2-methoxyethanol (3 mL) were heated at 100° C. for 3 hours. The reaction mixture was allowed to cool to RT, treated with HCl in dioxane (384.5 μL of 4 M, 1.538 mmol) and allowed to stir at RT for 3 hours. The mixture was concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an orange solid (15.5 mg, 12% Yield). 1H NMR (DMSO) d 1.24 (3H, t), 3.11 (2H, q), 3.45 masked signal, 3.51 (4H, m), 6.12 (2H, br s), 7.30 (1H, m), 7.34 (1H, m), 7.47 (1H, s), 7.71 (2H, m), 7.98 (1H, s) ppm; MS (ES+) 388.01
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[CH3:13].[I-:14].[Na+].CN(C)CCN(C)C>[Cu](I)I>[I:14][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[CH3:13]
Reactant: Cc1cc(O)cc2cc(Br)cnc12
Reactant: [I-]
Agent: I[Cu]I
Agent: CN(C)CCN(C)C
Agent: [Na+]
Product: Cc1cc(O)cc2cc(I)cnc12

Procedure:
In a similar procedure to Step 1 of Example 13A, 3-bromo-8-methyl-quinolin-6-ol (preparation described in Example 13 Stage 1) was reacted sodium iodide, copper iodide and N,N,N′,N′-tetramethyl-ethane-1,2-diamine to give the required product, 3-iodo-8-methyl-quinolin-6-ol, as a brown coloured solid (MH+ 286).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.P(Br)(Br)[Br:11]>C(Cl)(Cl)Cl>[Br:11][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: OCc1ccncc1Cl
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: Clc1cnccc1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-chloropyridin-4-yl)methanol (700 mg, 4.9 mmol) in anhydrous chloroform (15 mL) was added dropwise a solution of phosphorus tribromide (460 μL, 4.9 mmol) in anhydrous chloroform (5 mL) at 0° C. The mixture was stirred for 8 hours at room temperature. The solid was filtered and washed with dichloromethane to afford crude 4-(bromomethyl)-3-chloropyridine, which was used for the next step without further purification; 1H NMR (400 MHz, MeOd4): δ 4.95 (s, 2H), 8.21 (d, J=6.0 Hz, 1H), 8.30 (d, J=6.0 Hz, 1H), 9.09 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[CH2:8][C:7](=[O:9])[O:6][C:4]1=[O:5])[CH3:2].[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH2:23][O:24][C:25]3[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=3)[NH2:28])=[N:20]2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH2:23][O:24][C:25]3[CH:26]=[C:27]([NH:28][C:7](=[O:9])[CH2:8][C:3]([CH2:10][CH3:11])([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])[CH:29]=[CH:30][CH:31]=3)=[N:20]2)=[CH:15][CH:14]=1
Reactant: CCC1(CC)CC(=O)OC1=O
Reactant: Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2,2-diethylsuccinic acid anhydride and 3-(7-fluoro-2-quinolinylmethoxy)aniline; colourless crystals of m.p. 166°-167°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][CH:18]([F:21])[CH2:19][NH2:20].Cl.C(N(CC)CC)C>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:20]([CH2:19][CH:18]([F:21])[F:17])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCC(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CC(F)F
Temperature: 110 °C
Yield: 60.3 %

Procedure:
3-(Benzyloxy)-2-methyl-4H-pyran-4-one (432 mg, 2.0 mmol) was mixed with 2,2-difluoroethylamine (655 mg, 8.0 mmol) and triethylamine hydrochloride (1.10 g, 8.0 mmol) in pyridine (6 mL) in a sealed vial. The reaction mixture was heated at 110° C. for overnight. The solid was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was mixed with water, and then extracted with ethyl acetate. The organic layer was washed with water and brine. The product was purified by column chromatography on silica gel with 5% methanol in ethyl acetate as eluant to give 3-(benzyloxy)-1-(2,2-difluoroethyl)-2-methylpyridin-4(1H)-one (337 mg) as pale-yellow solid. Yield=60%; 1H NMR (MeOD-D4, 90 MHz) δ (ppm): 7.66 (d, J=7.1 Hz, 1H), 7.16-7.55 (m, 5H), 6.46 (d, J=7.1 Hz, 1H), 5.55 (t, J=55.0 Hz, 1H), 4.45 (t, J=14.8 Hz, 1H) and 2.20 (s, 3H); MS m/z 280 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][C@@H:8]([C:17](N1[C@H](C)[C@H](C2C=CC=CC=2)OC1=O)=[O:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-:34].OO.CCCCCCC>C1COCC1.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:17]([OH:18])=[O:34])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Compound 156 (5.608 b, 12.59 mmol) was dissolved in THF/H2O (60 mL/14 mL) and cooled to 0° C. LiOH (1N, 18.89 mL) and H2O2 (35%, 4.45 mL, 50.4 mmol) were combined, and then added to the reaction dropwise keeping T<5° C. the reaction was stirred at 0° C. for 4 hours, and quenched with Na2SO3 (6.3 g) and NaHSO3 (3.4 g) in 50 mL H2O added dropwise. The reaction was stirred for 15 minutes, and the layers separated. The aqueous layer was extracted with EtOAc (3×100 mL), and the combined extracts dried over MgSO4, filtered, and rotovapped to give an oil. The crude material was dissolved in EtOAc (10 mL) and added dropwise to heptane (250 mL). The suspension was stirred for 20 minutes, and the solids filtered and washed with heptane. The filtrate was washed with 60° C. H2O (100 mL), dried over MgSO4, filtered, and rotovapped to give 157 as an oil (3.52 g). the material was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25]([O:28][CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])[CH:26]=[CH2:27]>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:45]1[CH2:46][CH2:47][CH:42]([C:40]([C:32]2[N:31]([CH2:30][CH2:29][O:28][CH2:25][CH:26]=[CH2:27])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=2)=[O:41])[CH2:43][CH2:44]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: CN(CC(CCS(C)(=O)=O)c1ccccc1)C(=O)c1ccccc1
Product: C=CCOCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3ccccc3)c3ccccc3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(1-(2-allyloxyethyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: C([N:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=1)[C:5](=[O:7])[CH3:6])(=O)C.[CH3:16][C:17]1[N:22]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:21](=[O:28])[C:20]([N+:29]([O-:31])=[O:30])=[C:19](OS(C(F)(F)F)(=O)=O)[CH:18]=1.N>>[C:5]([NH:4][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:19]2[CH:18]=[C:17]([CH3:16])[N:22]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:21](=[O:28])[C:20]=2[N+:29]([O-:31])=[O:30])=[CH:12][CH:13]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)N(C(C)=O)c1ccc(CBr)cc1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Agent: N
Product: COC(=O)Cn1c(C)cc(Cc2ccc(NC(C)=O)cc2)c([N+](=O)[O-])c1=O

Procedure:
It is prepared from 7.3 g (27 mmol) of N-acetyl-N-[4-(bromomethyl)phenyl]acetamide and 4 g (13.4 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate. The crude product is treated with ammonia.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[N:14][C:13]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[N:21][C:12]2=3)[CH2:5][CH2:4]1.[CH3:24][C:25]1[C:26]2[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:27]=2[N:28]=[C:29]([CH:31]=O)[N:30]=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[ClH:1].[CH3:24][C:25]1[N:30]=[C:29]([CH2:31][NH:2][CH:3]2[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][N:11]3[C:16](=[O:17])[CH:15]=[N:14][C:13]4[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[N:21][C:12]3=4)[CH2:7][CH2:8]2)[NH:28][C:27]2=[N:33][C:34](=[O:37])[CH2:35][CH2:36][C:26]=12
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Reactant: Cc1nc(C=O)nc2c1CCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCC4=NC(C)=C5CCC(=O)N=C5N4)CC3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[2-(4-amino-1-piperidinyl)ethyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one hydrochloride (0.097 g, 0.287 mmol) in 1:1 MeOH/DCM (16 mL) was added 4-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2-carbaldehyde (0.064 g, 0.287 mmol), NaHCO3 (0.12 g, 1.44 mmol) and excess Na2SO4. The solution was stirred at ambient temperature for 16 h followed by the addition of NaBH(OAc)3 (0.182 g, 0.861 mmol). The resulting solution was stirred for an additional 2 h, then concentrated onto silica gel and the crude residue was purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the free base of the desired product as a yellowish oily film (0.072 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])[CH:7]=1.C([C@H]1NC2C(=CC(F)=CC=2)NC1=O)C>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][C:11](=[O:12])[C@H:9]([CH3:10])[NH:8]2
Reactant: C[C@H](Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O
Agent: CC[C@H]1Nc2ccc(F)cc2NC1=O
Product: C[C@@H]1Nc2cc(F)ccc2NC1=O

Procedure:
N-(5-Fluoro-2-nitrophenyl)-L-alanine was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-6-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 181 ([M+H]+); Anal. Calcd for C9H9FN2O: C, 59.99; H, 5.03; N, 15.55. Found: C, 59.89; H, 4.88; N, 15.46.
Reaction SMILES: C1(C(=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].[Br:23][C:24]1[CH:25]=[C:26]([Cl:31])[C:27](Cl)=[N:28][CH:29]=1>CN(C=O)C>[NH2:14][CH:15]([C:27]1[C:26]([Cl:31])=[CH:25][C:24]([Br:23])=[CH:29][N:28]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Clc1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(N)c1ncc(Br)cc1Cl
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
Ethyl 2-(diphenylmethyleneamino)acetate (10.2 g, 38.2 mmol) was added to sodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0° C., and the mixture was stirred for 30 min. To this was added 5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was quenched with 2 N HCl solution and then stirred for 4 h at ambient temperature. The mixture was extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as a liquid (1.3 g, 20%): 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.89 (s, 1H), 5.09 (s 1H), 4.23 (m, 2H), 2.27 (br s, 2H), 1.26 (m, 3H); ESIMS m/z 293.05 ([M+H]+); IR (thin film) 3381, 3306, 1742, 759, 523 cm−1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)C)[CH2:21]4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1.Cl.O1CCNC1=O.Cl[C:38]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[O:39]>>[CH3:44][O:43][CH2:42][CH2:41][O:40][C:38]([NH:25][C@H:22]1[CH2:23][CH2:24][N:20]([C:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:9][C@H:8]([CH2:7][NH:6][C:3]4[CH:4]=[CH:5][O:1][N:2]=4)[O:12][C:11]3=[O:13])=[CH:15][C:16]=2[F:29])[CH2:21]1)=[O:39]
Reactant: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Reactant: COCCOC(=O)Cl
Agent: Cl
Agent: O=C1NCCO1
Product: COCCOC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4(3(S)-aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (419 mg, 0.73 mM) and 2-methoxyethyl chloroformate (450 mg, 3.27 mM) gave the title compound (442 mg).
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH:19]3[CH2:21][CH2:20]3)O)[CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22][C:23]1[C:24]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:25]=2[O:26][C:27](=[O:29])[CH:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH:19]3[CH2:21][CH2:20]3)[C:28]3[C:27](=[O:29])[O:26][C:25]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:24]=4[C:23]=3[OH:22])[CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1cc(O)c2c(o1)CCCCCC2
Reactant: O=S(=O)(Nc1ccccc1)c1cccc(C(O)C2CC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=c1oc2c(c(O)c1C(c1cccc(S(=O)(=O)Nc3ccccc3)c1)C1CC1)CCCCCC2
Yield: 10.7 %

Procedure:
To a solution of 437 mg of N-phenyl-3-(cyclopropylhydroxymethyl)-benzenesulfonamide of Preparation 88 in 100 mL of dichloromethane in the presence of molecular sieves 3A is added 282.5 mg of 4-hydroxy-5,6,7,8,9,10-hexahydro-cycloocta[b]pyran-2-one of formula BBB-followed by 52.0 mg of p-toluenesulfonic acid monohydrate. The reaction is heated at reflux for 1 h and 30 min and then concentrated in vacuo. The resulting oil is dissolved in ethyl acetate and treated with water and 1N aqueous sodium hydroxide. The layers are separated and the organic layer is washed with a second portion of 1N aqueous sodium hydroxide. The combined aqueous layers are treated with 5% aqueous hydrochloric acid and extracted with three portions of ethyl acetate. The combined organics are dried (sodium sulfate) (Na2SO4) and concentrated to afford a yellow oil which is chromatographed over 80 g of silica (eluted with 15% hexane/ethyl acetate) to afford 74 mg of material. This material is rechromatographed as above (elution with 50% hexane/ethyl acetate) to afford 67.3 mg of the title product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][OH:16])[CH2:9]2)[CH:5]=[C:4]([Cl:17])[N:3]=1.CCN(C(C)C)C(C)C.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[C:27]1([NH:33][C:34](=[O:35])[O:16][CH2:15][C@H:10]2[O:11][CH2:12][C@@H:13]([CH3:14])[N:8]([C:6]3[CH:5]=[C:4]([Cl:17])[N:3]=[C:2]([NH2:1])[N:7]=3)[CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: C[C@@H]1CO[C@H](CO)CN1c1cc(Cl)nc(N)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CO[C@H](COC(=O)Nc2ccccc2)CN1c1cc(Cl)nc(N)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a 20-mL screw-cap vial was added [(2S,5R)-4-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-2-morpholinyl]methanol (100 mg, 0.387 mmol), Hunig's base (0.135 mL, 0.773 mmol) and CHCl3 (10 mL). The reaction was cooled to 0° C., then phenyl isocyanate (0.046 mL, 0.425 mmol) in CHCl3 (2 mL) was added dropwise via syringe. The solution was allowed to warm to room temperature and then stirred overnight. An additional portion of Hunig's base (0.135 mL, 0.773 mmol) and phenyl isocyanate (0.046 mL, 0.425 mmol) was added, and the reaction stirred at 60° C. overnight. The solvents were removed in vacuo, and the residue was purified by flash chromatography to afford the title compound (123 mg). LC-MS (ES) m/z=378 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].II.O=[C:19]([CH:21]=[C:22]([CH3:24])[CH3:23])[CH3:20]>>[C:4]([O:3][C:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][C:22]([CH3:24])([CH3:23])[CH:21]=[C:19]2[CH3:20])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(=O)C=C(C)C
Agent: II
Product: CC1=CC(C)(C)Nc2ccc(NC(=O)OC(C)(C)C)cc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of N-Boc-1,4-phenylenediamine (5.0 g) and iodine (1.3 g) in mesityl oxide (25 ml) was stirred at 100° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue was chromatographed on Al2O3 (Alumina B, act. III) in heptane/dichloromethane=8/2 as eluent.