Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#N)=[CH:16][CH:15]=1.Cl.[O:23]1CCCC1.C(OCC)C>C(OCC)C>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][C:18]([C:17]1[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:23]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C1CCOC1
Reactant: ClCc1ccccc1Cl
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: O=C(Cc1ccccc1Cl)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 74 %

Procedure:
To diethylether (250 mL) was added magnesium (6.04 g) and a catalytic amount of iodine, and the mixture was stirred. Thereto was gradually added dropwise 2-chlorobenzyl chloride (20.0 g), and the mixture was stirred for 1 hour from the time when the temperature of such mixture began to rise. Thereto was added a solution of 4-chlorobenzonitrile (18.8 g) in tetrahydrofuran/diethylether (20 mL/50 mL), and the mixture was stirred for 3 hours. To the reaction mixture was added an aqueous 2N hydrochloric acid solution (150 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=40/1 to 20/1) to obtain (2-chlorobenzyl)(4-chlorophenyl)methanone (24.40 g; yield: 74%) as a powder.
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH:9][C:10]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([F:36])[CH:27]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[N:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO>C(Cl)(Cl)Cl>[CH:1]1([NH:6][C:7]([NH:9][C:10]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[C:28]([F:36])[CH:27]=2)([C:18]2[NH:19][C:20](=[O:24])[CH:21]=[CH:22][CH:23]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(C(Cc2ccccc2)(NC(=O)NC2CCCC2)c2cc(F)cc(C(F)(F)F)c2)n1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1cccc(=O)[nH]1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
1-Cyclopentyl-3-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(6-methoxypyridin-2-yl)-2-phenylethyl)urea (25 mg, 0.049 mmol) was stirred in CHCl3 (1 mL) in a pyrex tube at room temperature. TMSI (0.04 mL) was added and the reaction mixture was refluxed for 3 h. Additional TMSI (0.04 mL) was added. The mixture was refluxed for an additional two hours. The mixture was cooled to room temperature and MeOH (1 mL) was added. The reaction mixture was concentrated. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, came out 100% EtOAc) to give 1-cyclopentyl-3-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(6-oxo-1,6-dihydropyridin-2-yl)-2-phenylethyl)urea (13 mg, yield: 54%) as a white solid. LC-MS ESI (10-90% MeOH in H2O with 0.1% TFA in a 4-min run), retention time=3.75 min, 488.12 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 12.06 (s, br, 1H), 7.52 (dd, J=8.8, 7.3 Hz, 1 H), 7.19 (t, J=7.0 Hz, 2 H), 7.12 (t, J=7.3 Hz, 2 H), 6.94 (s, br, 1 H), 6.83 (d, J=10 Hz, 1 H), 6.68 (d, J=7.3 Hz, 2 H), 6.61 (d, J=7.1 Hz, 1 H), 6.30 (d, J=8.8 Hz, 1 H), 6.15 (s, br, 1 H), 5.22 (s, br, 1 H), 4.32 (d, J=12.2 Hz, 1 H), 3.88-3.98 (m, 1 H), 3.19 (d, J=12.7 Hz, 1 H), 1.92-1.86 (m, 1 H), 1.83-1.74 (m, 1 H) 1.65-1.48 (m, 4 H), 1.43-1.35 (m, 1 H) 1.25-1.18 (m, 1 H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([C:15]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[O:16])[CH:3]=1.[CH2:28](B(O)O)[CH2:29][CH2:30][CH3:31]>C1COCC1.O>[CH2:28]([C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:15]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[O:16])[CH:3]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCB(O)O
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1ccc(OCC(=O)O)c(C(=O)c2cnn(-c3ccccc3)c2)c1

Procedure:
A solution of ethyl [4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate (472 mg, 1.1 mmol), 1-butylboronic acid (102 mg, 1.0 mmol) and Pd (dppf)Cl2 (72 mg, 0.05 mmol) in THF (10 mL) and water (1 mL) under argon was refluxed for 24 h. The reaction mixture was extracted with CH2Cl2, the organic phase was filtered through celite and concentrated, and the residue was purified by flash chromatography (SiO2, EtOAc:heptane, 1:10 to 1:1). The purest fraction was concentrated (˜10 mg), and the residue was hydrolysed according to GP3: LC/MS (an 10p8): Rt 2.59 min, m/z 379.1 [M+H]+; 1H NMR (CDCl3): δ 0.88 (t, J=7.5 Hz, 3H), 1.29 (m, 2H), 1.49 (m, 2H), 2.48 (m, 2H), 4.51 (s, 2H), 6.84 (m, 1H), 7.14 (m, 1H), 7.30 (m, 2H), 7.42 (m, 2H), 7.65 (m, 2H), 7.97 (s, 1H), 8.46 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(CN2CCc3c(ncnc3-c3ccccn3)C2)cc1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
Part C: To a solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (4.75 g, 18.3 mmol) in 1,4-dioxane (80 mL) at 25° C. was added sequentially 2-(tributylstannyl)pyridine (98%, 5.95 mL, 18.3 mmol), tri-2-furylphosphine (0.85 g, 3.66 mmol), and palladium (II) acetate (0.205 g, 0.914 mmol). The resulting mixture was heated slowly to reflux over ˜0.25 h and then was stirred at reflux for 5.0 h. After cooling to room temperature the mixture was diluted with water and ethyl acetate, and the mixture filtered. The phases were separated, and the organic phase washed with water and brine, dried over anhyd. sodium sulfate, filtered, and concentrated. Column chromatography (elution: 0-5% 2M ammonia in methanol/chloroform) afforded 7-benzyl-4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (2.15 g, 39%) as a red oil; Mass Spec.: m/c: 303.15 (M+H)+ [calc'd: 303.15]; 1H NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 8.68 (m, 1H), 8.01 (m, 1H), 7.83 (m, 1H), 7.42-7.27 (m, 6H), 3.80 (m, 4H), 3.31 (m, 2H), 2.80 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:29][C:12]2=[CH:13][C:14]3[C:15](=[O:28])[N:16]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH:39]([NH2:41])[CH3:40].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH:39]([NH:41][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:29][C:12]2=[CH:13][C:14]3[C:15](=[O:28])[N:16]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:40]
Reactant: CC(N)Cc1cc(F)ccc1F
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Yield: 83.8 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.59 g, 1.43 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.29 g, 1.72 mmol), n-butanol (50 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight undr argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a bown solid product, 0.65 g, 83.8% yield. MS: 540.8 [M−H]−. 1H-NMR (DMSO-d6, 300 MHz): δ 13.42 (s, 1H), 11.26 (s, 1 Hz), 10.86 (d, 1H, J=8.0 Hz), 8.12 (s, 1H), 8.01 (s, 1H), 7.32-7.31 (m, 1H), 7.24-7.21 (m, 1H), 7.13-7.11 (m, 1H), 6.88-6.84 (m, 1H), 6.14 (d, 1H, J=7.5 Hz), 4.19-4.14 (m, 2H), 3.37-3.33 (m, 3H), 3.15 (m, 2H), 3.01-2.99 (m, 2H), 2.49 (s, 3H), 2.34 (s, 3H), 1.78-1.77 (m, 2H), 1.33 (d, 3H, J=6.5 Hz).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]3[C:16](=O)O[C:13](=[O:14])[C:12]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[NH2:46])[C:40]([OH:42])=[O:41]>C(O)(=O)C>[C:1]1([C:7]2[C:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:9]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:11]3[C:12]=2[C:13](=[O:14])[N:46]2[C:45]4[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][C:37]=4[N:36]=[C:16]23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)c2c1c(-c1ccccc1)c(-c1ccccc1)c(-c1ccccc1)c2-c1ccccc1
Reactant: Nc1ccc(C(=O)O)cc1N
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)nc1n2C(=O)c2c(-c3ccccc3)c(-c3ccccc3)c(-c3ccccc3)c(-c3ccccc3)c2-1
Temperature: 105 °C
Reaction time: 72 h

Procedure:
Into a reaction vessel equipped with a condenser, light nitrogen purge and magnetic stirrer, 10 g (0.022 mol) of tetraphenylphthalic anhydride and 3.35 g (0.022 mol) of 3,4 diaminobenzoic acid are added, along with 100 ml of acetic acid. The gray colored reaction mixture is heated to reflux temperature. After several hours the reaction begins to take-on a dark yellow color. The reaction mixture is then left for a further 72 hours at slightly below reflux temperature (105° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:27](OC)([O:30]C)[O:28]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:27]([OH:30])[OH:28])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=2[O:9][CH2:8]1
Reactant: COB(OC)OC
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3-dimethyl-7-t-butyl-2,3-dihydro-benzofuran (1.42 g, 7 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (8.25 mL, 14 mmol) and trimethyl borate (1.5 mL, 14 mmol), the title compound was obtained as a foam that was used as such for the next step without purification and characterization. 5-Bromo-3,3-dimethyl-7-t-butyl-2,3-dihydro-benzofuran can be prepared as described by Janusz et al. in J. Med. Chem. 1998, 41, 1124-1137.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[FH:25].[F-].[K+].C(Cl)Cl.CCOCC>C(#N)C>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[F:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](F)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
8.7 g (21.2 mmol) of 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl bromide were dissolved in 30 ml of anhydrous acetonitrile and the solution was heated under reflux with 5.0 g (64 mmol) of potassium hydrogen difluoride. After 3 hours, the starting material was no longer detectable (TLC: methylene chloride/ether, 9:1). The solution was filtered and concentrated and the crude product was recrystallized from ether. Yield 5.74 g (77%), melting point 65°-67° C., [α]D20 =+21.2 (c=1.07 in chloroform) [A. Bertho, loc. cit.: melting point 68°-69° C., [α]DS20 =+21.5 (chloroform)]. 1H NMR (CDCl3): δ=5.58 (dd, 1-H), J1,2 =1.9, J1,F =48.4 Hz; [L. D. Hall et al., Can. J. Chem. 47, 1 (1969): δ=5.57 (dd, 1-H), J1.2 =1.7, J1,F =48.6 Hz].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH:17]=1)[OH:16].[C:19](=[O:22])([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:16][C:15]2[CH:17]=[C:11]([Cl:10])[CH:12]=[C:13]([O:18][C:2]3[CH:9]=[CH:8][C:5]([CH:19]=[O:22])=[CH:4][CH:3]=3)[CH:14]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Oc1cc(O)cc(Cl)c1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(F)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2cc(Cl)cc(Oc3ccc(C=O)cc3)c2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 32 %

Procedure:
p-Fluorobenzaldehyde (7.7 g), 5.9 g of 5-chlororesorcinol and 12.3 g of anhydrous potassium carbonate were added to 50 ml of dimethyl sulfoxide and stirred for 12 hours at 100° C. After completion of the reaction, 100 ml of water and 200 ml of ethyl acetate were added to carry out phase separation. After three times of washing with 50 ml of 10% sodium chloride aqueous solution and subsequent drying over anhydrous magnesium sulfate, the solvent was evaporated. The resulting oily material was subjected to silica gel column chromatography (hexane:ethyl acetate (7:1)) to obtain 3.5 g of 1,3-bis(4-formylphenoxy)-5-chlorobenzene.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([I:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]([O:20]CC)=O)[N:8]=2)=[N:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1>C1COCC1>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([I:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[O:20])[N:8]=2)=[N:2]1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccc(I)cc2n1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1nc(Nc2cc[nH]n2)c2ccc(I)cc2n1
Temperature: -40 °C
Reaction time: 5 h
Yield: 35.1 %

Procedure:
To a suspension of ethyl 4-(1H-pyrazol-3-ylamino)-7-iodoquinazoline-2-carboxylate (0.130 g, 0.31 mmol) in THF (5 mL) at −40° C. was added (4-fluorophenyl)magnesium bromide (1.0 M solution in THF, 0.797 mL, 0.79 mmol). The mixture was stirred at −40° C. for 5 h, quenched with 1.0 N HCl (2.0 mL), and concentrated under reduced pressure. The residue wad purified on preparative HPLC (Phenomenex phenylhexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O) to afford (4-(1H-pyrazol-3-ylamino)-7-iodoquinazolin-2-yl)(4-fluorophenyl)methanone as a yellow solid (0.050 g, 34%). 1H NMR (300 MHz, DMSO-d6) δ 6.72 (s, 1H), 7.35 (t, 2H), 7.64 (s, 1H), 8.00 (d, 1H), 8.08 (dd, 2H), 8.28 (s, 1H), 8.55 (d, 1H), 10.88 (s, 1H), 12.55 (s, 1H); LC-MS (ESI) m/z 460 (M+H)+.
Reaction SMILES: [CH2:1]([PH:8](=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:23]=[C:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:1]([P:8]([CH2:23][CH:24]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38])(=[O:9])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[PH](O)Cc1ccccc1
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
Benzylphosphinic acid (2.3 g, 15 mmol) in 150 mL of dry dichloromethane was cooled to 0° C. under a nitrogen atmosphere. Triethylamine (6.5 g, 65 mmol) was added followed by trimethylsilyl chloride (5.8 g, 54 mmol) while the reaction temperature was maintained at 0° C. After 30 minutes dibenzyl 2-methylenepentanediote (2) in 20 mL of dichloromethane was added over 5 minutes. The reaction mixture was left to warm to room temperature and stirred overnight. The clear solution was cooled to 0° C. and quenched with 5% hydrochloric acid and with brine, dried (MgSO4) and evaporated to give a clear yellow liquid. Purification by flash chromatography and elution with 1:1 hexane/ethyl acetate containing 10% acetic acid yielded 2.0 g (28%) of benzyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3, R=CH2Ph, R1+H) as a clear light yellow oil. Rf 0.37 (1:1 Hex./EtOAc, 10%AcOH).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:18][CH2:19][CH3:20])([CH2:15][CH2:16][CH3:17])[C:11]2[C:6](=[CH:7][C:8]([F:21])=[CH:9][CH:10]=2)[C:5]1=[O:22].CSC(SC)=C1C(=O)C(CCCC)(CCCC)C2C(=CC=CC=2)C1=O.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[S:57]([NH2:60])(=[O:59])=[O:58].NC1C=CC(OCC2C=CC=CC=2)=CC=1S(N)(=O)=O>>[O:58]=[S:57]1(=[O:59])[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[NH:50][C:3]([C:4]2[C:13](=[O:14])[C:12]([CH2:18][CH2:19][CH3:20])([CH2:15][CH2:16][CH3:17])[C:11]3[C:6]([C:5]=2[OH:22])=[CH:7][C:8]([F:21])=[CH:9][CH:10]=3)=[N:60]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCCC1(CCC)C(=O)C(=C(SC)SC)C(=O)c2cc(F)ccc21
Agent: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Agent: Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 5D, substituting the compound of Example 14H for the compound of Example 5C, and also substituting 2-aminobenzenesulfonamide for the compound of Example 2D. 1H NMR (300 MHz, DMSO-d6): δ 0.58 (m, 2 H) 0.67 (m, 6 H) 0.93 (m, 2 H) 2.01 (m, 2 H) 2.17 (m, 2 H) 7.72 (m, 7 H) 13.48 (s, 1 H).
Reaction SMILES: [O:1]1[C:5]2[C:6](=O)[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.[OH-].[Na+].P(Cl)(Cl)([Cl:36])=O>>[Cl:36][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2][O:1][C:5]=12
Reactant: O=c1[nH]ccc2ccoc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Clc1nccc2ccoc12

Procedure:
A solution of 6-H-furo[2,3-c]pyridin-7-one (1.0 g) in phosphorous oxychloride (10 ml) was stirred at 110° C. for 30 minutes under dry nitrogen. The mixture was cooled, poured onto ice/water (50 ml) and basified to pH10 with 2N sodium hydroxide solution. The mixture was extracted with ether (3×50 ml), the combined extracts dried over sodium sulfate and filtered. Removal of the solvent in vacuo gave the title compound (1.0 g) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1>C(=S)=S>[Br:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][C:15]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(C)=O)c(Br)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
A round-bottomed flask was charged acetyl chloride (4.20 g, 53.56 mmol, 1 eq), AlCl3 (7.13 g, 53.56 mmol, 1 eq), and carbon disulfide (80 mL). To the mixture was added dropwise a solution of 3-bromoanisole (9.75 g, 52.13 mmol) in carbon disulfide (20 mL) and stirred for 16 h. The resulting solution was diluted with ice water (100 mL) and extracted with CH2Cl2 (50 mL×3). The extracts were washed with H2O, brine, and 1N NaOH (30 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:10) to afford the title compound (6.2 g, 51%).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][NH:12][NH2:13].CO>C(Cl)(Cl)Cl.Cl>[CH2:1]([NH:8][C:9](=[O:10])[N:12]([CH3:11])[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: CNN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(N)C(=O)NCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of Benzyl isocyanate (1.85 mL, 15.0 mmol) in 7.5 mL of CHCl3 was treated with methyl hydrazine (795 μL, 15.0 mmol) at 0° C. and stirred at the same temperature for 2 h. The resulting mixture was dissolved in 1N HCl (200 mL) and the solution was washed with CHCl3 (50 mL×3). The aqueous phase was adjusted to pH 12 with 2 M NaOHaq and then extracted with CHCl3 (100 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from hexane-CHCl3 to afford (1.7 g, 9.5 mmol, 63%) as a colorless crystal. Rf=0.44 (CHCl3:MeOH=9:1); 1H NMR (400 MHz, DMSO-d6) δ 7.28-7.19 (5H, m), 4.47 (2H, s), 4.20 (2H, d, J=6.3 Hz), 2.96 (3H, s); 13C NMR (99.5 MHz, DMSO-d6) δ 159.3, 141.1, 128.1, 127.1, 126.5, 43.1, 37.8; LC/MS [ESI+] (m/z) 180.3 (M+1)+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:8]([O:15][CH2:16][CH:17]1[O:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.O>[CH2:1]([O:5][CH2:18][CH:17]([OH:19])[CH2:16][O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: c1ccc(COCC2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOCC(O)COCc1ccccc1
Temperature: 80 °C
Yield: 48.2 %

Procedure:
n-Butanol (2.5 ml, 27 mmol) is added to a suspension of sodium hydride (50% in mineral oil; 1.3 g, 27 mmol) in DMF (5 ml) and the mixture is then heated to 80° C. for 1.0 hours when all the sodium hydride is consumed. A solution of 2,3-epoxypropyl benzyl ether (benzyl glycidylether*) (4.52 g, 27 mmol) in DMF (5 ml) is added slowly to the n-butoxide solution. The mixture is then heated to 80° C. for 16 hours, diluted with water and extracted with ether. The ether layer is dried and concentrated to give an oil which is distilled to provide the desired product (3.1 g), bp 125°-130°/0.8-0.5 mm.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([O:26][C:27](=[O:28])[C:5]=2[CH:4]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1)=[O:15])[CH2:10]3.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([O:26][C:27](=[O:28])[C:5]=2[CH:4]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1)=[O:15])[CH2:10]3
Reactant: COc1ccc2c(c1)C(=O)OC21CCN(C(=O)C2(c3ccc(C)cc3)CC2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2(C(=O)N3CCC4(C3)OC(=O)c3cc(O)ccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methoxy-1′-{[1-(4-methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (40 mg, 0.0001 mol) in tetrahydrofuran (2 mL, 0.02 mol) was added. L-Selectride® in tetrahydrofuran (1.0 M, 0.53 mL) and the resulting solution was heated to 120° C. for 50 minutes using microwave irradiation. To the reaction mixture was added a few drops of water to quench the reaction. Then the reaction mixture was concentrated and about. 3 mL of concentrated HCl aqueous solution was added to dissolve the residue. The resulting solution was stirred at rt for 2 h. The crude product was purified using prep-HPLC. LCMS: m/z 364.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.C[O:16][B:17](OC)[O:18]C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([B:17]([OH:18])[OH:16])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Clc1ccc(Br)cc1I
Agent: CC(C)[Mg]Cl
Product: OB(O)c1cc(Br)ccc1Cl
Yield: 36 %

Procedure:
Following the method described in Example 81, 4-bromo-1-chloro-2-iodo-benzene, isopropylmagnesium chloride and trimethylborate provided 5-bromo-2-chloro-phenylboronic acid (36% yield).