Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1B(O)O.O>COCCOC>[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1[C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1cnc(I)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Yield: 55.5 %

Procedure:
--To a degassed mixture of 5-bromo-2-iodopyrimidine 2 (4.0 g, 14.0 mmol) tetrakis(triphenylphosphine)palladium (323 mg, 0.28 mmol), DME (30 ml), and aqueous 2M sodium carbonate (50 ml) was added 2,3-difluoro-4-octyloxyphenylboronic acid 3 (4.42 g, 15.4 mmol) dropwise in DME (10 ml) under an atmosphere of nitrogen. The mixture was heated under reflux overnight; water was added to the mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (twice) and the combined organic solutions were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (5% to 10% ethyl acetate-light petroleum; the crude material was preloaded onto silica in dichloromethane) to give the phenylpyrimidine 4 (3.1 g, 55%) (from methanol), m.p. 74.6° C.; νmax /cm-1 (KBr) 2920, 2850, 1625, 1475, 1420, 1310 and 1090; δ0.91(1H, t, Me), 1.2-1.55(10H, m), 1.85 (2H, quint, OCH2CH2), 4.11 (2H, t, OCH2), 6.82 (1H, ddd, 5'-H), 7.83 (1H, ddd, 6'-H) and 8.86 (2H, s, 4- and 6-H); m/z 288 (M+ -C8H16), 286 (M+ -C8H16), 178 and 155.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.C[O-].[Na+].[CH:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=O>CO>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23](/[CH:21]=[CH:9]/[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:24][CH:25]=1
Reactant: CC(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A 2 L 3-necked round-bottomed flask equipped with a stirrer, a nitrogen bubbler, an addition funnel and a thermometer was charged with 1-(4-chloro-2-(phenylamino)phenyl)ethanone (79.3 g, 323 mmol) and methanol (628 g, 793 mL). The reaction was treated while stirring with a solution of sodium methoxide (25 wt % in methanol, 119 mL, 520 mmol) followed by addition of methyl 4-formylbenzoate (53.0 g, 323 mmol). The reaction mixture was allowed to stir overnight. At this time, the reaction was cooled in an ice bath. The resulting solids were collected by filtration, washed with cold methanol and dried to afford 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-benzoic acid methyl ester (115 g, 90.9%) as a red solid. This material was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:21]([CH2:20][Cl:19])=[O:22])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)CCl)CC1
Reaction time: 2 h
Yield: 383.5 %

Procedure:
To a solution of 1-ethoxycarbonylpiperazine (1.5 mL, 10 mmol) in 40 mL CH2Cl2, was added triethylamine (2 mL, 14 mmol) and chloroacetyl chloride (0.8 mL, 5.0 mmol) at 0° C. The resulting reaction mixture was stirred at amibent temperature for 2 hours. The reaction mixture was washed with water, 2N NaHSO4 and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo to afford 1-ethoxycarbonyl-4-chloromethylcarbonylpiperazine (4.5 g) as an yellow oil, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C(OCC)(=O)C>[N+:1]([C:4]1[C:5](=[O:10])[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1cccnc1O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Sodium hydride (1.57 g of a 60% dispersion in mineral oil, 0.039 mole) was washed with hexanes three times (10 mL each) and suspended in dimethylformamide (25 mL). The stirred suspension was cooled in an ice bath, then 3-nitro-2-hydroxypyridine (5.00 g, 0.036 mole) was added in small portions over a 25-minute period. After the addition was complete, the reaction was stirred at 0° C. for 10 minutes, then room temperature for 30 minutes. The reaction mixture was recooled in an ice bath. t-Butyl bromoacetate (5.25 mL, 0.036 mole) was added. The reaction was stirred at 0° C. for 1 hour, then 1.5 hours at room temperature. The reaction mixture was diluted with ethyl acetate (80 mL), and ice (80 g) was added. The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (4×100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was removed, and the resulting residue was chromatographed through silica gel using 10% ethyl acetate/dichloromethane as eluent. The pure fractions were combined, and the solvent was removed under vacuum to afford 6.77 g (75% yield) of the title compound as yellow solid. Rf =0.30 (silica gel, 20% ethyl acetate in dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:12])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)nc1
Solvent: ClCCCl
Product: ClCc1ccc(Cl)nc1
Reaction time: 4 h
Yield: 95.7 %

Procedure:
A mixture of 70.3 g of 2-chloro-5-(hydroxymethyl) pyridine and 50 ml of 1,2-dichloroethane was dropwise added to a mixture of 87.4 g of thionyl chloride and 100 ml of 1,2-dichloroethane during 30 minutes in a water bath of 5°-20° C. The mixture was stirred for an hour and a half at room temperature and for 4 hours and a half under refluxing. After concentrating, to the residue were added 200 ml of chloroform and 60 ml of water and then added portionwise 20 g of sodium hydrogen carbonate under stirring. The organic phase was separated, treated with active carbon and concentrated to obtain 75.9 g of 2-chloro-5-(chloromethyl)pyridine as a yellowish brown solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:41]I>C1C=CC=CC=1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][I:41])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCI)CC1

Procedure:
2-11 (10.42 g, 0.048 mol) was dissolved in 400 ml benzene, imidazole (4.66 g, 0.068 mol), triphenylphosphine (15.24 g, 0.05 mol) and iodine (0.048 mol) were added at room temperature. After 6 hours the reaction mixture was filtered and the filtrate was evaporated to give a dark residue. This was purified by flash chromatography on silica gel eluting with 10% EtOAc-hexanes to give 2-12 as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([N:19]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[N:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:27]2[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][OH:35])[C@@H:29]([OH:37])[C@H:28]2[OH:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:24][C:22]1[CH:21]=[N:20][N:19]([C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@@H:27]3[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][OH:35])[C@@H:29]([OH:37])[C@H:28]3[OH:38])=[C:10]([NH:9][CH2:8][CH:7]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:18]=2)[CH:23]=1
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc([N+](=O)[O-])cn4)nc32)[C@H](O)[C@@H]1O
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
The title compound can be prepared by dissolving N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenylethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate QD) in methanol and adding a 2:1 by mass mixture of activated carbon and iron (III) chloride (40 mol % with respect to the substrate), followed by a large excess (100-fold with respect to the substrate) of hydrazine monohydrate. The resulting mixture is stirred at 65° C. for 3 hours, then filtered, before being concentrated under reduced pressure. Trituration of the residue with petroleum ether and subsequent filtration would give the desired product as a colourless solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:32])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16](/[C:24](/[CH3:31])=[CH:25]/[C:26](OCC)=[O:27])[CH:15]=[CH:14][C:13]1=2>C1(C)C=CC=CC=1.C1COCC1>[CH3:11][C:12]1([CH3:32])[CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[C:18]2[CH:17]=[C:16](/[C:24](/[CH3:31])=[CH:25]/[CH2:26][OH:27])[CH:15]=[CH:14][C:13]1=2
Reactant: CCOC(=O)/C=C(\C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C/C(=C\CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.5M, 50 ml) was added dropwise to a solution of ethyl (E)-3-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)crotonate (6.30 g) in THF (100 ml) at −78° C. and the mixture was stirred at −78 0° C. for 15 minutes. The mixture was washed with 1N HCl and brine, dried and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate=10:1) to give the titled compound (4.33 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C.[F-].[K+]>[NH2:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=1[OH:10]
Reactant: COc1cc(O)c([N+](=O)[O-])c(Cl)c1
Agent: Cl[Sn]Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(O)c(N)c(Cl)c1
Yield: 73 %

Procedure:
A solution of 3-chloro-5-methoxy-2-nitrophenol [1] (450 mg) and tin(II) chloride dihydrate (2 g, 4 eq.) in ethyl acetate (30 mL) was heated under reflux for 4 h. The mixture was cooled, diluted with ethyl acetate and aqueous potassium fluoride. The mixture was filtered through celite. The organic layer was washed with brine and dried over MgSO4. Evaporation of the solvent afforded the title compound (280 mg) as a pale solid. NMR (DMSO-d6): 9.74 (m, 1H), 6.33 (d, 1H, J=2.4 Hz), 6.30 (d, 1H, J=2.4 Hz), 4.19 (m, 2H), 3.60 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(I)cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To the solution of 1-(4-Iodo-phenyl)-ethanone (Aldrich, 125 g, 508 mmol) in glacial acetic acid (600 mL) was added the bromine (Aldrich, 79.3 g, 508 mmol, in 50 mL of acetic acid) and stirred at room temperature for 10 hours. It was concentrated under reduced pressure. The residue was then diluted with ethyl acetate (100 mL) and washed with brine (3×50 mL). The organic solution was concentrated. The title compound was obtained as yellow solid by recrystallization from diethyl ether (150 g, 91%). 1H NMR (300 MHz, CDCl3) δ 4.39 (s, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.87 (d, J=8.5 Hz, 2 H) ppm; MS (DCl/NH3) m/z 246 (M−Br)+, 264 (M−Br+NH4)+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:5][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:2][CH:3]=[CH2:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCCO
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of but-3-en-1-ol (2.39 mL, 27.73 mmol) in DMF was added imidazole (3.78 g, 55.46 mmol), and tert-butyldimethylsilyl chloride (6.3 g, 41.59 mmol). The mixture was stirred at room temperature overnight. Saturated NH4Cl was added and the mixture was extracted with ethyl acetate three times. Combined organic extracts were washed twice with water and brine then dried over Na2SO4. The solvent was evaporated in vacuo to give title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:10][C:11]([F:23])([F:22])[C:12]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][N:13]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:14]1[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([C:11]([F:10])([F:22])[F:23])=[N:13]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(CC(=O)OC(C)(C)C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
404 mg of Hünig-base and 469 mg of tert-butyl bromoacetate, dissolved in 2 ml of dichloromethane, are added to a solution of 50 mg of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate in 10 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours. After addition of saturated sodium bicarbonate solution, the mixture is extracted with ethyl acetate, the organic phase is separated off and dried over sodium sulphate and the solvent is removed under reduced pressure. This gives 742 mg of ethyl 1-(2-tert-butoxy-2-oxoethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Va-10) in a purity of about 78% (LCMS).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[CH2:16]([O:15][C:13](=[O:14])[C:12](=[CH:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)OCC
Temperature: 145 °C

Procedure:
A mixture of aniline (25.6 g, 0.28 mol) and diethyl 2-(ethoxymethylene)malonate (62.4 g, 0.29 mol) was heated at 140-150° C. for 2 h. The mixture was cooled to room temperature and dried under reduced pressure to afford 2-phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next step without further purification. 1H NMR (d-DMSO) δ 11.00 (d, 1H), 8.54 (d, J=13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13-7.17 (m, 3H), 4.17-4.33 (m, 4H), 1.18-1.40 (m, 6H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Cl[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)#[N:2]
Reactant: ClCCOCCCl
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C#N)CCOCC1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
Ethyl cyanoacetate (22.6 g, 0.2 mol) and bis(2-chloroethyl)ether (14 g, 0.1 mol) were added to a suspension of potassium carbonate (70 g, 0.5 mol) in N,N-dimethylformamide (150 ml), and the mixture stirred at 100° C. for 72 hours. The cooled mixture was partitioned between water and diethyl ether (500 ml), the layers separated and the aqueous solution extracted with diethyl ether (3×200 ml). The combined organic solutions were washed with 2N hydrochloric acid (3×100 ml), brine (2×100 ml), dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. This crude product was purified by column chromatography on silica gel using ethyl acetate:cyclohexane (50:50) as eluant, to afford the title compound, 9.3 g.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12]([N:19]1[C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=O)[O:21]C1=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:24]2[C:23]([C:22]=1[OH:21])=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ncccc12
Product: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O

Procedure:
Diethyl malonate can then be reacted with the 1-benzyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (2) to yield the intermediate 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (3) as shown in Scheme 3:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>C(Cl)Cl>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC[C@@H]1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: ClCCl
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) was added to 100 mL of methylene dichloride and stirred for 30 minutes. (S)-epichlorohydrin (21 g, 0.23 mol) was then added. The mixture was stirred at room temperature (25° C.) for 20 hours. Filtered, and the solvent was evaporated to provide 55 g of colorless oil in 93% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][C:60]1[CH:61]=[CH:62][C:63]([F:74])=[C:64]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][OH:73])[CH:67]=2)[CH:65]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH:58][CH2:59][C:60]4[CH:65]=[C:64]([C:66]5[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][OH:73])[CH:67]=5)[C:63]([F:74])=[CH:62][CH:61]=4)=[O:27])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Reaction time: 72 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-amino)carbonyl]benzoic acid (0.045 g, 0.1 mmol) in CH2Cl2 (2 mL) was stirred under argon at room temperature. HBTU (0.038 g, 0.1 mmol) was added followed by [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (0.0231 g, 0.1 mmol) and triethylamine (28 μL, 0.2 mmol). The resulting mixture was stirred for three days. The solvents were pumped off and the residue was purified on the CombiFlash (12 g silica gel column) eluted with 70-100% EtOAc/hexane) to afford the title compound. LC-MS m/z 664.8 (M+H)+, 1.75 min (ret time).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].[CH3:13][NH2:14]>>[CH3:13][N:14]1[C:2](=[O:3])[C:1]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN
Product: Cn1c(=O)[nH]c2ccccc2c1=O

Procedure:
6 g isatoic anhydride was stirred in 100 ml dry tetrahydrofurane(THF) and methylamine was passed through the mixture for 5 min. The resulting solution was evaporated and the residue was again dissolved in THF (100 ml) and charged with 15 ml 30% phosgene solution in toluene. The mixture was heated to reflux and additional 15 ml phosgene solution was added. After 4 hours reflux the mixture was cooled and evaporated to dryness. The residue was treated with water and the crystals were collected by filtration. The yield was 3.5 g. M.p. 240.4°-240.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](O)[N:3]=1.O=P(Cl)(Cl)[Cl:12]>>[Cl:12][C:4]1[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)nc(Cl)n1

Procedure:
To a 50 ml single neck round-bottomed flask was added 4,6-dimethylpyrimidin-2-ol (5.0 g, 0.04 mol) followed by POCl3 (15.0 ml, 0.097 mol). The resulting suspension was heated to reflux overnight. Heating was stopped. After cooling, the mixture was concentrated, poured into crushed ice and extracted with diethyl ether (100 ml×2). The organic layer was washed with 10% NaHCO3 solution, dried over Na2SO4 and evaporated to get a pale yellow solid. Yield: 3.3 g (58%) 1H NMR (400 MHz, CDCl3): δ 2.48 (s, 6H), 6.97 (s, 1H). LCMS: (ES+) m/z=143.6 (M+H)+
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][O:9][C:4]2=[CH:3][CH:2]=1.CN(C)[CH:12]=[O:13].P(Cl)(Cl)(Cl)=O>>[O:9]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH:7]=[C:8]1[CH:12]=[O:13]
Reactant: CN(C)C=O
Reactant: c1ccc2occc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2ccccc2o1
Temperature: 50 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a mixture of 2,3-benzofuran (23.63 g, 0.2 mol) and N,N-dimethylformamide (22 g, 0.3 mol) was added phosphorous oxychloride (46 g, 0.3 mol) dropwise. Upon completion of addition, the mixture was stirred for 1 hr, then warmed to 50° C. and kept at that temperature for 60 hrs. It was then poured into ice (250 mL). The resulting aqueous mixture was neutralized to pH6 by the addition of aqu. 2N NaOH and extracted with ether (3×300 mL). The organics were combined, dried with MgSO4 and concentrated. The residue was distilled to afford 9.21 g of 2-benzofurancarboxaldehyde as a pale yellow oil (b.p.=98°-100° C. at 0.6 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Br:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>C(OCC)C>[Br:12][C:13]1[CH:14]=[C:15]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8](=[O:9])(=[O:10])[NH2:11])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: CCOCC
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Br)c1
Yield: 48 %

Procedure:
The title compound was synthesized as described for Example 178 in 48% yield, starting from 2-aminobenzenesulfonamide and 3-bromobenzenesulfonyl chloride. The product solidified after the extractive work up. Diethyl ether (25 mL) was added and the crystals were crushed with a glass stick. The mixture was filtered and the solid was rinsed with diethyl ether and dried in vacuo at ambient temperature.