Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:8]=1[CH2:9][NH:10][C:11](=[O:17])[CH:12](OC)OC.C([O-])([O-])=O.[Na+].[Na+]>>[Cl:6][C:7]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]2[C:8]=1[CH:9]=[N:10][C:11]([OH:17])=[CH:12]2
Reactant: COC(OC)C(=O)NCc1cccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1cc2ccc(F)c(Cl)c2cn1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Sulfuric acid (18M; 0.19 mL, 3.4 mmol) was added to N-(2-chloro-3-fluorobenzyl)-2,2-dimethoxyacetamide (72.6 mg, 0.250 mmol) at ambient temperature. The mixture was stirred at 50° C. for 16 h. After cooling to rt, the mixture was poured into ice, basified with saturated Na2CO3 until pH=8, and extracted with EtOAc (3×30 ml). The extracts were washed with water (3×20 ml), brine (20 ml), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ=7.05 (s, 1H), 7.41 (dd, J=8.4 & 9.2 Hz, 1H), 7.56-7.60 (m, 1H), 9.11 (s, 1H). MS(ES+): m/z=198.14/200.02 (100/88) [MH+]. HPLC: tR=2.48 min (polar—5 min, ZQ3).
Reaction SMILES: [O:1]=[S:2]1(=[O:10])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8]O.O=S(Cl)[Cl:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:13][CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][S:2]1(=[O:10])=[O:1]
Reactant: O=S1(=O)CCCN1CCO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S1(=O)CCCN1CCCl
Temperature: 40 °C
Yield: 29.6 %

Procedure:
To a solution of 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-ethanol (0.14 g, 0.847 mmol) in DCM (4 mL) was added SOCl2 (0.151 g, 1.27 mmol) and the reaction mixture was heated to 40° C. for 2 h. The mixture was cooled to room temperature, diluted with DCM, poured into a sat. NaHCO3 solution (10 mL) and the aqueous layer was extracted with DCM (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.046 g, 30%) as an orange oil which was used with no further purification. MS: 184.1 (M+H+).
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24]>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cccc(Br)c1Cl
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1c1cccc(Cl)c1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 1-bromo-2,3-dichlorobenzene were used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:21]3[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=3[CH:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)[CH:5]=[N:6][C:7]=1[C:8]([N:10]1[CH2:13][CH:12]([F:14])[CH2:11]1)=[O:9].[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:21]3[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=3[CH:19]=[C:18]([C:27]([NH:30][C:31]3[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=3)=[O:29])[CH:17]=2)[CH:5]=[N:6][C:7]=1[C:8]([N:10]1[CH2:11][CH:12]([F:14])[CH2:13]1)=[O:9]
Reactant: Cn1ccc(N)n1
Reactant: CC1(C)Cc2c(Oc3cnc(C(=O)N4CC(F)C4)c(F)c3)cc(C(=O)O)cc2O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CC(F)C4)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid (1.360 g, 3.363 mmol), 3-amino-1-methyl-pyrazole (653 mg, 6.730 mmol), and triethylamine (0.94 ml, 6.730 mmol) in 20 mL of DCE was added HATU (2.56 g, 6.730 mmol). The mixture was stirred at 60° C. for 2 hr, quenched with water, and extracted with 3×CHCl3. The combined organic layer was washed with 2×H2O, dried with Na2SO4, and concentrated to provide an oil that was purified by SFC to give a white solid (874 mg, 54% yield). 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1 H) 8.20 (d, J=2.02 Hz, 1 H) 7.24-7.33 (m, 2 H) 7.15-7.22 (m, 1 H) 7.09 (dd, J=10.86, 2.27 Hz, 1 H) 6.82 (d, J=2.27 Hz, 1 H) 5.37 (d, J=56.84 Hz, 1 H) 4.62-4.79 (m, 1 H) 4.53 (dd, J=12.13, 1.77 Hz, 2 H) 4.27-4.42 (m, 1 H) 3.80 (s, 3 H) 2.92 (s, 2 H) 1.50 (s, 6 H); LCMS for C24H23F2N5O4 m/z 484.20 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:27]3[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.Cl.CN.C[CH2:40][N:41](C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:40][NH:41][C:33]([C@H:30]1[CH2:31][CH2:32][C@H:27]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[N:18]4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:28][CH2:29]1)=[O:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A DMF solution (3 mL) of trans-4-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid (260 mg, 0.56 mmol) and methylamine hydrochloride (379 mg, 5.6 mmol) in a sealed tube was charged with DIEA (0.98 mL, 5.6 mmol), 0.6M HOAt in DMF (0.93 mL, 0.56 mmol), and then EDC (161 mg, 0.84 mmol). The reaction mixture stirred at rt for 16 h. The reaction mixture was concentrated to solids, taken up in CH2Cl2, charged with silica, and concentrated to brown solids. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 5 g/25 mL cartridge, eluting with 2%˜7N NH3 in MeOH/CH2Cl2]. The purified material was recrystallized from MeOH/CH2Cl2/diethyl ether to the desired product as a light yellow solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.56-1.73 (m, 4H), 1.85-1.91 (m, 2H), 2.01-2.06 (m, 2H), 2.17-2.25 (m, 1H), 2.52 (d, 3H, J=4.4 Hz), 3.12-3.20 (m, 1H), 6.17 (s, 2H), 7.09 (d, 1H, J=4.8 Hz), 7.51-7.59 (m, 4H), 7.73 (d, 1H, J=4.8 Hz), 7.90 (dd, 1H, J=2.0 Hz, 8.4 Hz), 8.09 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=8.8 Hz), 8.23 (s, 1H), 8.30 (d, 2H, J=7.6 Hz), 8.51 (d, 1H, J=8.4 Hz); MS (ES+): m/z 477.0 [MH+]; HPLC: tR=2.1 min (Micromass Platform II, polar—5 min).
Reaction SMILES: [C:1]1([C:7](=[N:15][OH:16])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:25](OCC)(=[O:27])[CH3:26].Cl>C1COCC1.O>[OH:27][C:25]1([CH3:26])[O:16][N:15]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ON=C(Cc1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(O)ON=C(c2ccccc2)C1c1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
The deoxybenzoin oxime (Step 1) was dissolved in anhydrous THF (565 mL) under a nitrogen atmosphere. The solution was cooled to −20° C. The solution was treated with lithium diisopropylamide (2 M, 800 mL, 1.60 mol) while allowing the reaction temperature to warm to 10-15° C. The reaction mixture to was cooled to −10° C. to −20° C. and anhydrous ethyl acetate (218 mL) was added to the solution while allowing the reaction temperature to rise to a maximum of 25° C. and held for 30 minutes at 25° C. The reaction mixture was cooled to about 0° C. Water was added to a quench flask and cooled to 0-5° C. The pre-cooled reaction mixture was transferred from the reaction flask to the quench flask while maintaining the temperature of the quench mixture below 25° C. The quenched mixture was cooled to 0-5° C. Hydrochloric acid (12 M) was added to the mixture, keeping the temperature below 25° C. during the addition by controlling the addition rate and stirred until all the solids dissolve (˜5 minutes). The pH of the stirred mixture was measured to be pH 3-4. The layers were separated and the organic layer was removed. Heptane was added to the organic layer with stirring. The organic layer was distilled until the pot temperature reached 90-91° C. The solution was cooled to 5° C. and filtered. The solid was washed with two 300 mL portions of ethyl acetate-heptane (20/80), cooled to 5° C. The solid product was dried on the funnel for several hours then dried at ambient under vacuum with a nitrogen sweep over the weekend to yield the isoxazoline (108.75 g, 57.7%).
Reaction SMILES: [OH:1][CH:2]([C:6]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[H-].[Na+].Cl[C:24]1[N:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1>CN(C=O)C>[CH3:30][C:27]1[N:26]=[N:25][C:24]([O:1][CH:2]([C:6]([O:19][CH3:20])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([OH:5])=[O:4])=[CH:29][CH:28]=1
Reactant: COC(c1ccccc1)(c1ccccc1)C(O)C(=O)O
Reactant: Cc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccccc1)(c1ccccc1)C(Oc1ccc(C)nn1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
1.3 g (4.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid dissolved in DMF were added dropwise to a suspension of 0.43 g of NaH (14.3 mmol, 80% in white oil) in 10 ml of DMF. After stirring to room temperature for 30 minutes, the mixture was treated with 0.6 g (4.8 mmol) of 3-chloro-6-methylpyridazine in 10 ml of DMF and stirred overnight at room temperature. To complete the reaction, 0.6 g (4.8 mmol) of 3-chloro-6-methylpyridazine were then added again and the mixture was kept at 60° C. for 5 hours. It was poured onto ice water, extracted three times with ethyl acetate, the aqueous phase was brought to pH 2 with half-concentrated hydrochloric acid and the precipitate which was deposited was extracted with ethyl acetate. These ethyl acetate phases were dried with magnesium sulfate and then filtered and the solvent was stripped off under reduced pressure. 800 mg of the brown residue (1.19 g) were purified by means of MPLC, it being possible to isolate 199 mg of the desired product as a white solid.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[CH:9]=[CH:10][C:11]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)=[O:17])=[C:14]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][CH2:44][CH3:45])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[S:13][C:12]=2[CH:46]=1)(=O)=O)[CH2:2][CH2:3][CH3:4].CCOCC.[ClH:52]>C(OCC)(=O)C>[ClH:52].[CH2:1]([S:5][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:20][CH:19]=3)=[O:17])=[C:14]([C:33]3[CH:34]=[CH:35][C:36]([S:39]([CH2:42][CH2:43][CH2:44][CH3:45])(=[O:41])=[O:40])=[CH:37][CH:38]=3)[S:13][C:12]=2[CH:46]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)c1ccc(-c2sc3cc(S(=O)(=O)CCCC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCSc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)CCCC)cc3)sc2c1

Procedure:
5.4g of [6-(n-Butylsulfonoyl)-2-[4-(n-butylsulfonoyl)phenyl]benzo[b]thien-3-yl][4-[2-(1piperidinyl)ethoxy]-phenyl]methanone was dissolved in ethyl acetate (EtOAc) and a solution of ether, saturated with HCl, was added until no more precipitate was formed. The liquid was decanted off and the solid was triturated with ether. The title compound was crystallized from hot EtOAc to afford 3.74 g, as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:46])=[C:4]([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[CH:32]=2)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3C2CCCCO2)[CH3:9])[CH:7]=1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[Cl:1][C:2]1[C:3]([CH3:46])=[C:4]([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[CH:32]=2)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1cnn(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-{4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (0.040 g) was dissolved in CH2Cl2 (0.4 mL) and then TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour. After evaporated to dryness, the residue was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C23H28ClN8O (M+H)+: m/z=467.2. found: 467.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[C:10](F)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1>>[Cl:8][C:9]1[C:10]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:20])([F:19])[F:21])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1
Reactant: Oc1ccccn1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccccn3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2-hydroxypyridine and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 234.2–235.4° C. 1H NMR (acetone-d6/300 MHz) 8.14 (dd, 1H, J=4.8 Hz, 1.4 Hz), 7.92 (m, 2H), 7.70 (s, 1H), 7.14 (m, 2H), 6.99 (s, 1H), 5.88 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=7.2 Hz). ESLRMS m/z 372 (M+H). ESHRMS m/z 372.0252 (M+H, Calc'd 372.0250). Anal. Calc'd for C16H9ClF3NO4: C, 51.70; H, 2.44; N, 3.77; Cl, 9.54. Found: C, 51.70; H, 2.44; N, 3.71; Cl, 9.65.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]3[O:17][C:16]([CH3:19])(O)[CH2:15][CH2:14][C:13]=3[C:20]=2[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:24]>CCOCC>[Cl:24][C:16]1([CH3:19])[CH2:15][CH2:14][C:13]2[C:20]([CH3:21])=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]=2[O:17]1
Reactant: Cl
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(O)O2
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(Cl)O2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a solution of 5 g (16 mmol) of rac-3,4-dihydro-6-(phenylmethoxy)-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ol in 50 mL of anhydrous ether was added 5 g of 4 A molecular sieves. The mixture was stirred mechanically with ice-bath cooling while HCl gas was bubbled in for 30 min. Stirring was continued at 0° C. for 30 min and then the solvent was removed in vacuo. The residue was treated with 500 mL of hexane and the solution was decanted. The hexane solution was then treated with 10 g of anhydrous CaCl2 and the mixture stirred for 2 hr. The solids were filtered and the filtrate was concentrated in vacuo to a volume of ca. 20 mL. Crystallization was induced by cooling to -10° C. and stirring, then the remaining solvent was removed in vacuo giving 4.9 g (92.8% yield) of rac-2-chloro-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran as a colorless solid. The chlorochroman decomposed upon attempted column or thin layer chromatography. It was stored at 0° C.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[NH3:16]>>[CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]([C:11]([OH:13])=[O:12])[CH:5]2[C:14](=[NH:16])[OH:15])[CH:2]=[CH2:3]
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: N
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(=N)O
Yield: 60 %

Procedure:
A mixture of 102 g of allyl-bicyclo[2.2.1]-hept-5-ene-2,3-dicarboxylic acid anhydride, prepared according to Example 1 in U.S. Pat. No. 3,105,839, and 68.1 g of 25% aqueous ammonia solution is refluxed with cooling at 95°-102° C. for 70 minutes, while stirring. The water and excess ammonia are then distilled off under reduced pressure (6,133 Pa). When the internal temperature reaches 120° C., 54 ml of aqueous ammonia have been distilled off. An orange-coloured, viscous residue remains, and is distilled under a pressure of 13.3 Pa. 62.07 g of allyl-bicyclo[2.2.1]-hept-5-ene-2,3-dicarboxylic acid imide pass over between 132° and 135° C., corresponding to a yield of 60% of theory. The imide is a yellow oil of refractive index nD20 1.5421 and viscosity η25 345 Pa.s at 25° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:15]([C:16]([NH:18][CH3:19])=[O:17])=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[O:13][C:5]2=[N:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39]>CC(N(C)C)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:15]([C:16](=[O:17])[NH:18][CH3:19])=[C:14]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[O:13][C:5]2=[N:6][C:7]=1[N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: COC(=O)CCCCBr
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCC(=O)OC)S(C)(=O)=O)c(I)cc12
Temperature: 150 °C
Yield: 46.1 %

Procedure:
5-iodo-N-methyl-6-(methylsulfonamido)-2-p-tolylfuro[2,3-b]pyridine-3-carboxamide (100 mg, 0.206 mmol) was dissolved in dimethylacetamide (10 mL) and K2CO3 (39.9 mg, 0.288 mmol) was added then followed by methyl 5-bromopentanoate (0.059 mL, 0.412 mmol). The mixture was heated at 150° C. in the microwave for 20 min. Conversion approx 75% by LCMS, after which addition of additional methyl 5-bromopentanoate (3 eqs) and K2CO3 (2 eqs) did not result in additional conversion. Filtration and purification by HPLC (TFA/CH3CN/H2O) afforded 57 mg (0.095 mmol, 46%) methyl 5-(N-(5-iodo-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)pentanoate MS-ES [M+H]+=599.8, LC RT=1.61 min, Method A.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:17]2[C:16](=[O:22])[CH2:21][CH2:20][CH2:19][CH:18]=2)=[CH:6][C:7]([CH3:10])=[CH:8][N:9]=1
Reactant: O=C1C=CCCC1
Reactant: Cc1cnc(Cl)c(C=O)c1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: Cc1cnc(Cl)c(C(O)C2=CCCCC2=O)c1
Yield: 92 %

Procedure:
The clear solution of 2-Chloro-5-methylnicotinaldehyde (10 mmol, 1.55 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 92% yield (2.22 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][OH:26].CCOC(/N=N/C(OCC)=O)=O.O[C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[C:42](=[O:58])[N:43]([CH:50]1[CH2:55][CH2:54][C:53](=[O:56])[NH:52][C:51]1=[O:57])[C:44]2=[O:49]>C1COCC1.CO>[O:57]=[C:51]1[CH:50]([N:43]2[C:44](=[O:49])[C:45]3[C:41](=[CH:40][CH:48]=[CH:47][C:46]=3[O:26][CH2:25][C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)[C:42]2=[O:58])[CH2:55][CH2:54][C:53](=[O:56])[NH:52]1
Reactant: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Reactant: OCc1ccco1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccco4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.7 %

Procedure:
To a solution of triphenylphosphine (630 mg, 2.4 mmol) and furan-2-yl-methanol (0.17 mL, 2.0 mmol) in THF (10 mL) was added a solution of DEAD (0.38 mL, 2.4 mmol) in THF (0.6 mL) at 0° C. After 5 min, 4-hydroxy-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (550 mg, 2.0 mmol) was added to the mixture. The mixture was allowed to warm to room temperature and kept for 4 h. The solvent was removed in vacuo, and the residue was purified by column chromatography (Silca Gel) to give an oil. The oil was slurried in methanol (10 mL) for 3 h to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(furan-2-ylmethoxy)-isoindole-1,3-dione as a yellow solid (310 mg, 44% yield): mp, 184-186° C.; 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H, CHH), 2.42-2.61 (m, 2H, CH2), 2.80-2.95 (m, 1H, CHH), 5.07 (dd, J=5, 13 Hz, 1H, NCH), 5.35 (s, 2H, CH2), 6.49 (dd. J=2, 3 Hz, 1H, Ar), 6.68 (d. J=8 Hz, 1H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.68-7.71 (m, 2H, Ar), 7.83 (t J=8 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.93, 48.77, 62.55, 110.72, 111.38, 115.72, 116.64, 120.35, 133.35, 136.89, 143.99, 149.15, 155.12, 165.21, 166.73, 169.88, 172.76; Anal Calcd for C18H14N2O6+0.1H2O: C, 60.71; H, 4.02; N, 7.87; H2O, 0.51. Found: C, 60.47; H, 3.97; N, 7.73; H2O, 0.38.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([F:20])[C:14]([O:18][CH3:19])=[C:15]([F:17])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:15]1[CH:16]=[C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:12]=[C:13]([F:20])[C:14]=1[O:18][CH3:19]
Reactant: OB(O)c1ccncc1
Reactant: COc1c(F)cc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)cc(-c2ccncc2)cc1F

Procedure:
In a microwave vial, a mixture of pyridin-4-ylboronic acid (160 mg, 1.3 mmol), 5-bromo-1,3-difluoro-2-methoxybenzene A5a (223 mg, 1 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) is dissolved/suspended in dimethylformamide (3 mL). To the mixture are added cesium carbonate (978 mg, 3 mmol) and water (3 mL). The vial is sealed and subjected to microwave irradiation (150° C., 15 min). The mixture is filtered through a syringe filter and washed with ethyl acetate. Water is added and the mixture extracted with ethyl acetate (4×). The organic phase is dried over sodium sulfate and concentrated. The crude material is purified by flash chromatography (ethyl acetate/hexanes gradient) to afford 4-(3,5-difluoro-4-methoxyphenyl)pyridine A5b as a white solid: 1H-NMR (400 MHz, CDCl3) δ 8.69 (d, J=6 Hz, 2H), 7.44 (d, J=6 Hz, 2H), 7.22 (d, J=9.6 Hz, 2H), 4.09 (s, 3H); MS calcd. for C12H10F2NO ([M+H]+): 222.1, found: 222.1.