Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[N:24]1([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:18]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C1(NC(=O)c2ccncc2N2CCCCC2)Cc2ccccc2C1
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccncc1N1CCCCC1
Reaction time: 68 h
Yield: 101.9 %

Procedure:
A 100 mL round bottom flask which contains 2-[(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4′-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (355, 370 mg, 0.94 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2 mL) is added followed by the LiOH monohydrate (100 mg, 2.38 mmol). After 68 h, tlc analysis (silica, 50% EtOAc/Heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 20 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.35 g, 96%).
Reaction SMILES: C([O:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=O)C.[C:14](Cl)(=O)C.C(=O)(O)[O-].[Na+]>CO>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]#[C:6][CH2:5][OH:4]
Reactant: CC(=O)Cl
Reactant: CC(=O)OCC#CCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCC#CCO
Reaction time: 16 h
Yield: 92 %

Procedure:
The crude acid 29 (6.333 g) was treated with a 1% solution of acetyl chloride in methanol (60 mL). After 16 h, sodium bicarbonate (1.966 g, 23.4 mmol) was added. The mixture was dried (MgSO4), filtered through celite and evaporated in vacuo. Purification by flash chromatography on silica gel (30-40% ethyl acetate/hexanes) gave 7-Hydroxy-hept-5-ynoic acid methyl ester 30 (3.022 g, 19.3 mmol, 92% from 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol 27).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].F[C:11](F)(F)[S:12](O)(=[O:14])=[O:13]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([Cl:8])[C:3]=1[Cl:9]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Clc1cccc(Cl)c1Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Cl)c(Cl)c1Cl

Procedure:
A mixture of 133 g (1.38 mol) of methanesulfonic acid and 67 g (0.56 mol) of thionyl chloride was heated to reflux with stirring for one hour. The temperature increased from 50° C. to 160° C. as the reaction to form methanesulfonic acid anhydride progressed. The resulting mixture was cooled to below 50° C. and then 50.0 g (0.28 mol) of 1,2,3-trichlorobenzene and 4.2 g (0.028 mol) of trifluoromethanesulfonic acid were added. This mixture was heated with stirring and allowed to react at 140° C. for 18 hours and at 160° C. for 2 hours. The resulting mixture solidified on cooling. It was taken up in 600 mL of dichloromethane and the resulting solution was washed with 2×100 mL of water, 100 mL of 1 M aqueous sodium bicarbonate solution, and 100 mL of water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain 58.5 g of a 9:1 mixture of the title compound and its isomer. This was recrystallized from ethanol to obtain 46 g (63 percent of theory) of the title compound as a white solid melting at 159-160° C. The structure was confirmed by its 1H NMR spectrum (CDCl3): 8.02(d, 1H, J=8.6 Hz), 7.60(d, 1H, 8.7 Hz), 3.28(s, 3H) and its 13C NMR spectrum (CDCl3): 140.1, 138.5, 134.6, 132.8, 126.7, 42.6.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>C1COCC1>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12]=1[C:13]#[N:14]
Reactant: OC1CCCCC1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N)cccc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a solution of cyclohexanol (19.1 g, 0.191 mol) in anhydrous THF (500 mL) was added NaH (7.6 g, 40% in mineral oil, 0.191 mol) in small portions at 0° C. under nitrogen. The mixture was stirred at room temperature for 1 h and a solution of 2-amino-6-fluorobenzonitrile (20.0 g, 0.15 mol) in anhydrous THF (150 mL) was added drop-wise at room temperature. The reaction mixture was heated to reflux overnight then cooled to room temperature and most of the THF removed under reduced pressure. Ice water (100 mL) was added to the concentrated reaction mixture followed by EtOAc (500 mL). The organic layer was separated and successively washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 25-30% EtOAc in hexanes to give 2-amino-6-(cyclohexyloxy)benzonitrile as a light yellow oil (17.9 g, 56%). 1H NMR (400 MHz, CDCl3) δ 1.32-1.43 (m, 3H), 1.51-1.55 (m, 1H), 1.62-1.69 (m, 2H), 1.79-1.95 (m, 4H), 4.31-4.36 (m, 3H), 6.23-6.27 (m, 2H), 7.18 (d, J=8.0 Hz, 1H). MS 329 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27](OCC)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27]([NH:33][CH2:34][CH:35]([OH:37])[CH3:36])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfonyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-amino-2-propanol employing methods similar to those described in Example 202 and was obtained as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.33 (t, J=5.1 Hz, 1 H), 8.56 (s, 1 H), 7.67 (s, 1 H), 7.21 (dd, J=8.2, 5.4 Hz, 2 H), 7.01 (t, J=8.5 Hz, 2 H), 4.37 (t, J=7.7 Hz, 2 H), 4.12 (s, 2 H), 4.08 (m, 2 H), 3.62 (m, 1 H), 3.35 (m, 1 H), 3.14 (t, J=6.7 Hz, 2 H), 2.95 (s, 3 H), 2.19 (m, 2 H), 1.27 (d, J=6.4 Hz, 3 H); HRMS C23H26FN3O6S (M+H)+ calcd 492.1526, found 492.1623.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.N12CCN(CC1)CC2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C(OCC)(=O)C.CCCCCCC>[CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][O:8][S:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](COS(=O)(=O)c2ccc(Cl)cc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a solution of ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (60.00 g, 454.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (63.67 g, 567.6 mmol) in ethyl acetate 600 mL) at 15° C. was added 4-chlorobenzenesulfonyl chloride (100.6 g, 476.7 mmol) and the resulting cloudy solution stirred for 2 h before being warmed to room temperature. The resulting solution was stirred at room temperature for 4 h before cold water (300 mL) was added and the resulting mixture stirred at room temperature overnight. The mixture was diluted with heptane (600 mL) and the organic layer was separated and washed with water (3×600 mL). The mixture was concentrated under vacuum to provide a yellow oil which was treated with heptane (200 mL). The mixture was concentrated to remove any remaining ethyl acetate and heptane (500 mL) was added once more to induce crystallization. The thick white suspension was filtered, washed with heptane, and suction dried to provide 4-chloro-benzenesulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (129.93 g, 93.3%, 98.9% pure HPLC, 99.89% e.e) as a white solid.
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].Cl[CH2:18]/[CH:19]=[CH:20]/[C:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[O:22]>CN(C=O)C>[CH2:27]([N:23]([CH2:24][CH2:25][CH3:26])[C:21](=[O:22])/[CH:20]=[CH:19]/[CH2:18][S:14][C:9]1[N:8]=[C:7]([NH2:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH2:28][CH3:29]
Reactant: CCCN(CCC)C(=O)/C=C/CCl
Reactant: Nc1cc(Cl)nc(S)n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)/C=C/CSc1nc(N)cc(Cl)n1
Reaction time: 8.5 h

Procedure:
4-Chlorocrotonyl chloride (1.02 g, 7.35 mmol) in ether (10 ml) is combined with dipropylamine (1.64 g, 16.17 mmol) in ether (5 ml) at -15° C. in a flame dried flask. The reaction is warmed to ambient temperature, stirred for 1 to 2 hours, quenched with water (30 ml), extracted with ethyl acetate (2×30 ml), washed with saline (30 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (60/40). The appropriate fractions are combined (Rf =0.53, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give 4-chloro-N,N-dipropylcrotonamide. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in DMF (5 ml) and sodium hydride (0.06 g, 2.55 mmol) at ambient temperature followed by the addition of 4-chloro-N,N-dipropylcrotonamide (0.23 g, 1.13 mmol). The reaction is stirred for 2 to 15 hours, quenched with excess water, extracted with ethyl acetate (3×20 ml). The extracts are combined, washed with saline (20 ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (60/40). The appropriate fractions are combined (Rf =0.40, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give the title compound, mp 139-142° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22].C(N(CC)CC)C.C>CN(C)C=O.CO>[C:20]([NH:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)(=[O:24])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C(=O)Cl
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)C(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: -10 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a suspension of 1 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 50 ml of anhydrous dimethylformamide, maintained under an argon atmosphere at a temperature in the region of -10° C., are successively added 0.9 g of isobutyryl chloride and a solution of 0.4 g of triethylamine in 5 ml of anhydrous dimethylformamide. The mixture is stirred for 1 hour at the same temperature and 0.4 g of isobutyryl chloride is added. The mixture is stirred for 30 minutes at the same temperature and for 1 hour while allowing the temperature to return gradually to 20° C. The insoluble material formed is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 70° C. The product obtained (1.63 g) is dissolved in 30 ml of methanol and, after addition of decolorizing charcoal, the solution is filtered, diluted with 40 ml of distilled water and stored for 45 minutes at a temperature in the region of 20° C. The insoluble material formed is separated out by filtration, washed with 5 ml of distilled water and with 5 ml of acetone and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.38 g of 10-isobutyramido-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one is thus obtained, decomposing without melting above 260° C. [N.M.R. spectrum: [300 MHz; (CD3)2SO d6 ; δ in ppm]: 1.09 and 1.12 [2d, J=7.5 Hz, 6H: --CH(CH3)2 ]; 2.48 [mt, 1H: --CH(CH3)2 ]; 6.15 (d, J=8.5 Hz, 1H: --CH-- 10); 7.35 and 7.45 (2t broad, J=8.5 Hz, 1H each: --H7 and --H8); 7.47 and 7.85 (2d broad, J=8 Hz, 1H each: --H6 and --H9); 7.52 and 7.58 (2s, 1H each: --H of the imidazole); 8.46 (d, J=8.5 Hz, 1H: --NHCO-- at 10); 12.48 (broad s, 1H: --CONH-- of the ring)].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[CH2:22][C:23]([NH2:25])=[O:24])[N:9]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].[CH3:30][CH:31]([OH:33])[CH3:32].[H-].[Na+].O>CN(C=O)C>[CH:31]([O:33][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[CH2:22][C:23]([NH2:25])=[O:24])[N:9]=2)=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28])([CH3:32])[CH3:30]
Reactant: CC(C)O
Reactant: NC(=O)Cn1ccc2c(-c3noc(-c4ccc(F)c(C(F)(F)F)c4)n3)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of 2-(4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (100 mg) and 2-propanol (35 μl) in DMF (3 ml) was added 60% NaH (12 mg) at 0° C., followed by stirring at room temperature for 9 hours. The reaction solution was added with water (5 ml) to complete the reaction, and extracted with as a mixed solvent of chloroform:CH3OH (8:2). The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=98:2 to 93:7), and crystallized with diethyl ether to obtain 2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (25 mg) as a pale yellow solid.
Reaction SMILES: C1(C(=[N:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:19][C:18]([C:28]([C:33]3[N:34]=[CH:35][N:36]([C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:37]=3)([OH:32])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]([O-:60])(=O)[CH3:58].[Na+].[Cl-].O[NH3+].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C1COCC1.CO.C1COCC1.N1C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[CH:19]=[C:18]([C:28]([OH:32])([C:33]3[N:34]=[CH:35][N:36]([C:38]([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:37]=3)[CH:29]([CH3:31])[CH3:30])[CH:17]=[CH:16][C:15]=2[NH:14][C:57](=[O:60])[CH3:58])=[CH:22][CH:23]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)C(O)(c1ccc(N=C(c2ccccc2)c2ccccc2)c(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Nc1ccc(C(O)(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(C)C)cc1-c1ccc(F)cc1
Reaction time: 22 h
Yield: 86.9 %

Procedure:
To a solution of 1-[6-[(diphenylmethylene)amino]-4′-fluoro[1,1′-biphenyl]-3-yl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (110 mg) in THF-methanol (1:1) (6 ml) were added anhydrous sodium acetate (29.6 mg) and hydroxyammonium chloride (18.7 mg) at room temperature, and the mixture was stirred for 22 h. The reaction mixture was concentrated, diluted with ethyl acetate, washed with 0.5N aqueous sodium hydroxide solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product (118 mg) of 1-[6-amino-4′-fluoro[1,1′-biphenyl]-3-yl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol as a yellow oil. To a solution of this product (116 mg) and pyridine (29.6 μl) in THF (2 ml) was added dropwise acetic anhydride (28.3 μl) at 0° C., and the mixture was stirred at room temperature for 16 h. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chomatography (eluent; hexane:ethyl acetate=3:1→3:2) to give the colorless amorphous title compound (79.6 mg).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:5][C:4]=1[F:20].[CH3:23][C:24]([O:27][C:28]([N:30]1[CH2:35][CH:34]=[C:33](OS(C(F)(F)F)(=O)=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])[CH3:25].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1CCCC1=O>[CH3:26][C:24]([O:27][C:28]([N:30]1[CH2:31][CH:32]=[C:33]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]3=[O:19])=[CH:5][C:4]=2[F:20])[CH2:34][CH2:35]1)=[O:29])([CH3:23])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 108 h

Procedure:
A mixture of (S)-(-)-N-[[3-[4-trimethylstannyl-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (690 mg), 3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (step 2 of EXAMPLE 20, 500 mg), tris(dibenzylidenacetone)dipalladium(0) (14 mg) and triphenylarsine (37 mg) in N-methyl-2-pyrrolidinone (7.5 mL) is degassed, stirred under N2 at ambient temperature for 4.5 days, diluted with ethyl acetate, washed with water (3×40 mL) and saline (20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 120 g), eluting with a gradient of methanol/methylene chloride (1/99-2/98), and those fraction having an Rf =0.27 by TLC (methanol/chloroform, 2×5/95) are pooled and concentrated to give the title compound, 1H NMR (CDCl3, 400 MHz) 7.39, 7.22, 7.13, 7.01, 5.92, 4.82, 4.06, 3.80, 3.67, 3.61, 2.47, 2.03, 1.49 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[Br:11]N1C(=O)CCC1=O>C(O)(=O)C>[Br:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:8][N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccnc2[nH]ncc12
Solvent: CC(=O)O
Product: Clc1ccnc2[nH]nc(Br)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
4-chloro-1H-pyrazolo[3,4-b]pyridine (6) 1 g (6.53 mmoles) in acetic acid (100 mL) cooled to 0° C. was added N-bromosuccinimide 2.31 g (13.06 mmol and the resulting RM was stirred for 4 hr at rt. After completion of the SM, the RM was quenched with ice water and extracted with dichlromethane (2×10 mL). The combined organic layer was dried over sodium sulphate, and the solvent evaporated to yield compound 7 (Yield: 0.9 g, 60%). 1H NMR (400 MHz, CDCl3): δ 13.19 (br s, 1H), 8.21 (s, 1H), 7.39 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[CH:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[CH2:7].O>C(OCC)(=O)C>[O:13]=[C:9]1[CH2:10][CH2:11][CH2:12][N:8]1[CH:6]([C:5]1[N:4]=[CH:3][NH:2][N:1]=1)[CH3:7]
Reactant: c1nc[nH]n1
Reactant: C=CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(c1nc[nH]n1)N1CCCC1=O
Yield: 63 %

Procedure:
This product is synthesised, in 63% yield, from 1,2,4-triazole and 1-vinyl-2-pyrrolidinone by a similar method described in Example 1. On account of the higher water solubility of this product, ethyl acetate (3×50 ml) is used to extract it from the aqueous phase during washing. The product distils as a pale yellow oil, 150°/0.05 mbar.
Reaction SMILES: ClCCl.Cl.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[NH:19])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>O>[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[N:19][C:27](=[O:29])[CH3:28])=[CH:8][CH:7]=1
Reactant: N=c1ccccn1Cc1ccc(Cl)nc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)N=c1ccccn1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
Anhydrous dichloromethane (20 mL) was added to 118 mg (0.46 mmol) of 1-[(6-chloropyridin-3-yl)methyl]pyridine-2(1H)-imine hydrochloride obtained by the alternative method described in Synthesis Example 14, following which 159 μL (1.16 mmol, 116 mg) of triethylamine and 33 μL of acetyl chloride were added and the mixture was stirred at room temperature for 15 minutes. The reaction was stopped by adding water to the reaction mixture, and liquid-liquid extraction was carried out with chloroform and water. The organic phase was washed with a saturated aqueous solution of ammonium chloride, then concentrated. With the addition of hexane thereto, a solid settled out. The solid was collected by filtration and washed, then thoroughly dried, giving 21 mg of the target compound (yield, 17%).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:15]=[N:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][N:14]=[CH:15][C:7]=1[Br:6]
Reactant: O=C(O)c1ccncc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccncc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
H2SO4 (2.5 mL, 48.3 mmol, 1.0 eq.) was added to a solution of 3-bromoisonicotinic acid (9.7 g, 48.3 mmol, 1.0 eq.) in MeOH (150 mL). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The mixture was then cooled to room temperature and concentrated under vacuum. The residue was dissolved in EtOAc (200 mL). The pH of the solution was adjusted to 10 with Na2CO3. The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with water (1×200 mL) and saturated aqueous NaCl (2×100 mL). The mixture was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:20) to yield 3-bromoisonicotinic acid methyl ester (4.4 g) as a colorless liquid.