Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH3:20].C([Li])CCC.[CH3:26][O:27][CH2:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>C1COCC1.C(OCC)(=O)C.O>[CH3:20][C:3]1[CH:4]=[C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:17]=[C:18]([CH3:19])[C:2]=1[CH:34]([C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:28][O:27][CH3:26])=[CH:37][CH:36]=1)[OH:35]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Br
Reactant: COCOc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (4-bromo-3,5-dimethyl-phenoxy)triisopropylsilane (8.0 g, 23.30 mmol) in THF (50 mL) was added a solution of n-butyllithium (2.5 M in THF, 90 mL) at −78° C. The heterogeneous mixture was stirred at −78° C. for 1 h A solution of 4-methoxymethoxy-benzaldehyde (3.09 g, 18.58 mmol) in THF (5 mL) was added and the mixture was stirred at −78° C. for 1 h then warmed up to r.t. The reaction was then diluted with ethyl acetate and water, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated to afford crude (2,6-dimethyl-4-triisopropylsilanyloxyphenyl)-(4-methoxymethoxyphenyl)methanol. Carried on to the next step without further purification.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1CCCC([Cl:25])C1=O)(C)(C)C>>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([Cl:25])[C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Reactant: O=C1CCCCC1Cc1ccccc1
Product: O=C1C(Cl)CCCC1Cc1ccccc1

Procedure:
The chlorination of 2-benzylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C([O-])(=O)C.BrBr.S(=O)(=O)(O)O.[Br:24]([O-])(=O)=O.[K+].S(=O)(O)[O-].[Na+]>O>[Br:24][C:7]1[C:2]([Cl:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=[C:5]([F:9])[C:6]=1[Cl:8]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1Cl
Agent: BrBr
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(Cl)c(Br)c1Cl
Reaction time: 8 h
Yield: 91.9 %

Procedure:
96.6 g of 2,4-dichloro-5-fluoronitrobenzene (0.46 mol) was stirred with 1150 ml of glacial acetate acid containing 9.7 ml of bromine. Then, a solution consisting of 690 ml of concentrated sulfuric acid and 464 ml of water was added thereto. To the resultant was added 67.5 g of potassium bromate seven times (9.65 g each) at 40° C. over around 2 hours. The reaction was ceased after 8 hours. The reacting mixture was slowly poured into 3000 ml of water containing 46.0 g of sodium bisulfite, and kept overnight. The resultant was filtered, and washed with warm water (about 30° C.) from three to four times, and dried to give a primrose crystal of 3-bromo-2,4-dichloro-5-fluoronitrobenzene, 122.1 g (0.423 mol), mp 51-53.5° C., in 91.9% yield.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>O1CCCC1.C(#N)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)CNC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), methyl 2-aminoacetate hydrochloride (19.35 mg, 0.154 mmol), and TEA (0.050 mL, 0.356 mmol) in tetrahydrofuran (1 mL) and acetonitrile (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction was stirred at 60° C. for 2 h. The mixture was added 1M HCl and purified by HPLC to give the title compound. LCMS m/z=409.1 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.8 Hz, 0.3H), 1.46 (d, J=6.5 Hz, 2.7H), 1.70-1.82 (m, 1H), 2.01-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.56 (t, J=7.7 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 3.07-3.21 (m, 4H), 3.36-3.47 (m, 1H), 3.49-3.61 (m, 1H), 3.69 (s, 3H), 3.73-3.83 (m, 1H), 3.90 (d, 6.0 Hz, 2H), 6.80 (s, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[C@@H:10]([O:11]P(OP(OC[C@H]2O[C@@H](N3C(=O)NC(=O)C=C3)[C@H](O)[C@@H]2O)(O)=O)(O)=O)[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@@H:6]1[OH:39])=[O:3].CC([O-])=O.[Na+]>>[OH:11][CH:10]1[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@H:6]([OH:39])[C@H:5]1[NH:4][C:2]([CH3:1])=[O:3]
Reactant: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
MAPTP-G-CSF solution (540 ug) was concentrated and exchanged with 1M MES buffer (pH 6.0) and adjusted to 50 ul. Then UDP-GalNAc (100 ug, 0.15 umol, 5 eq), GalNAcT2 (5.0 U/ml, 5 ul) and 100 mM MnCl2 (5 ul) was added. The resulting mixture was rocked at RT overnight. Then CMP-SA-PEG (20K) (2.16 mg, 0.108 umol) and St6GalNAcI (1.0 U/ml, 50 ul) were added. The solution was rocked at rt for 60 h. Additional CMP-SA-PEG(20K) (2.16 mg, 0.108 umol) and St6GalNAcI (1.0 U/ml, 50 ul) were added, followed by slow rotation at rt for 24 h. Reaction mixture was exchanged with buffer A (25 mM NaOAc, 0.005% polysorbate 80, pH 4.5), then purified on an Amersham SP-FF (5 mL) column with an isocratic elution of 100% A for 10 minutes followed by a linear gradient of 100% A to 20% B over 20 minutes at a flow rate of 3 mL min−1, where B=25 mM NaOAc, 2 M NaCl 0.005% polysorbate 80, pH 4.5. The peak at retention time 17 mins was pooled and concentrated to 0.5 ml, which was further purified on an Amersham HiLoad Superdex 200 (16×600 mm, 34 μm) with phosphate buffered saline, pH 5.0, 0.005% Tween80, at a flow rate of 0.4 mL min−1. Product fractions at retention time 160 mins was pooled, concentrated to provide 30 ug of MAPT-G-CSF(GalNAc-SA-PEG(20K))2(BCA). The yield was not optimized.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1CC1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc(O)cc1CC1CCCCC1

Procedure:
A solution of (4-benzyloxy-2-cyclohexylmethylphenoxy)acetic acid ethyl ester (1.77 mmol) in ethanol (15 mL) was treated with 5% Pd/C (70 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: C([O:4][C@H:5]([C:14]([F:33])(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C.[I-].[Sm+2].[I-].O1CCCC1.[Cl-].[NH4+].[Mg]>CO>[F:33][CH2:14][C@@H:5]([OH:4])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)O[C@@H](C=Cc1ccccc1)C(F)(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [I-]
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H](/C=C/c1ccccc1)CF
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 5 ml round-bottomed flask provided with a stirrer, MeOH (10 ml) was added to the (3S)-3-acetoxy-4-fluoro-1-phenyl-4,4-bis(phenylsulfonyl)-1-but ene (200 mg, 0.41 mmol, 94% ee) prepared in Reference Example 4, and the resultant mixture was cooled to −40° C. Then, samarium(II) iodide/tetrahydrofuran (0.1 M, 41 ml) was slowly added dropwise, and the mixture was stirred for 6 hours. Then, a saturated ammonium chloride aqueous solution was added. The aqueous layer was extracted with dichloromethane. A sodium thiosulfate aqueous solution was added to the organic layer, and the mixture was extracted. Then, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation using an evaporator, and then complete removal of the salt was carried out by silica gel column chromatography (ethyl acetate). Next, a magnesium ribbon (164 mg, 6.73 mmol) was activated by a heat gun in a nitrogen atmosphere, then left to cool at room temperature. Then, the magnesium ribbon was cooled to 0° C., and MeOH (0.5 ml) was added. Then, a solution of the crude product, which had been dried, in MeOH (2.0 ml) was added to the mixture, and then the mixture was stirred. After 1 hour, a saturated ammonium chloride aqueous solution was added. The aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation using an evaporator, and then the product was purified by preparative thin-layer chromatography (dichloromethane:methanol=95:5) to obtain the target (3S)-(E)-4-fluoro-3-hydroxy-1-phenyl-1-butene. However, the isolated yield was low, at 30% (20.4 mg, 93% ee).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1.N1C=CN=C1.[C:29]([Si:33]([CH3:36])([CH3:35])Cl)([CH3:32])([CH3:31])[CH3:30].C(OCC)(=O)C>CN(C=O)C>[Si:33]([O:1][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
To a solution of 2.34 g (7.45 mmol) of the product of Step J in DMF (30 mL) were added imidazole (609 mg, 8.94 mmol) and tertbutyldimethyl-chlorosilane (1.35 g, 8.94 mmol) at 0° C. The solution was stirred at room temperature for 18 hours, and was then poured into 100 mL of ethyl acetate and washed with H2O (2×). The water layer was extracted with ethyl acetate (2×). The combined organic layer was washed with H2O (3×) and brine, and was dried over anhydrous MgSO4. After concentration the mixture was purified by flash chromatography (hexane: EtOAc=10:1) to give 1.96 g of the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][O:23][CH3:24])=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[O:23][CH3:24])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(CCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 86 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[2-(4-fluorophenyl)-ethyl]-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (86% yield): mp 106-107° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 2.95 (2H, m, CH2), 3.72 (3H, s, OCH3), 3.87 (2H, m, NCH2), 6.38 (1H, broad s, CH), 6.99 (2H, m, aromatics), 7.20 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.39; H, 5.43; N, 4.13.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:5]=1[O:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH4+].[OH-]>CO>[Cl:3][C:4]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:5]=1[O:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)c(Cl)c1
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(OCCN2CCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Add sodium borohydride (0.58 g, 15.26 mmol) to a solution of 1-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-pyrrolidine (0.83 g, 3.07 mmol) and NiCl2.6H2O (1.45 g, 6.12 mmol) in MeOH (20 mL). Stir at room temperature for 2 h and add 10% NH4OH solution. Extract with CH2Cl2 and then EtOAc, combine the organics, dry, and concentrate. Purify by flash chromatography using 0-10% 2N NH3/MeOH in CH2Cl2, to give the title compound (0.5 g, 69%). MS (ES+) 241.2 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 6.78 (d, 1H, J=8.4 Hz), 6.72 (d, 1H, J=3.1 Hz), 6.51 (dd, 1H, J=8.4, 3.1 Hz), 4.07 (t, 2H, J=6.2 Hz), 3.47 (s, 2H), 2.90 (t, 2H, J=6.2 Hz), 2.64 (m, 4H), 1.79 (m, 4H).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:21][C:20]3[CH:22]=[C:23]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=5)=[CH:32][CH:31]=4)[C:24]4[C:29]([C:19]=3[CH:18]=[CH:17]2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:12][CH:11]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:21][C:20]3[CH:22]=[C:23]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][C:39]([O:42][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:38][CH:37]=5)=[CH:32][CH:31]=4)[C:24]4[C:29]([C:19]=3[CH:18]=[CH:17]2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:12][CH:11]=1
Reactant: CCCCCC(=O)Cl
Reactant: Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(F)cc3)O4)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(F)cc3)O4)cc2)cc1
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
Hexanoyl chloride (5.01 g, 37 mmol) was added dropwise to a solution of 3-(4-fluorophenyl)-6-(4′-hydroxybiphen-4-yl)-3-phenyl-3H-naphtho[2,1-b]pyran (19.37 g, 37 mmol) in DCM (100 mL) containing pyridine (20 mL) at 0° C. After ½ h additional hexanoyl chloride (5.01 g, 37 mmol) was added. Stirring was continued for a further ½ h more, the solution was poured into HCl (2 M, 400 mL), separated and extracted with DCM (2×100 mL), the combined organic phases were washed with water saturated sodium bicarbonate (200 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (50% in hexanes) as eluent. The solvent was removed under reduced and the residue triturated alternately with hexanes and methanol twice. The residue was dried under vacuum to give the title compound (16.51 g, 72%) as a yellow foam, mp 64-65° C.
Reaction SMILES: [H-].[Na+].CC([CH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([Br:16])[C:10]=2[S:9](=[O:18])(=[O:17])[N:8]1[C:19]([O-])=O)(C)C.Br.[CH2:23]([N:25]([CH2:28]CBr)[CH2:26][CH3:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:16][C:15]1[C:10]2[S:9](=[O:17])(=[O:18])[N:8]([CH2:19][CH2:28][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH2:7][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)C1c2cccc(Br)c2S(=O)(=O)N1C(=O)[O-]
Reactant: CCN(CC)CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCN(CC)CCN1Cc2cccc(Br)c2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To sodium hydride (90 mg, 2.3 mmol) in tetrahydrofuran (10 mL) at 0°C. was added 1,1-dimethylethyl-7-bromo-1,2-benzisothiazole-2(3H)-carboxylate 1,1-dioxide (0.36 g, 1.5 mmol). The reaction was stirred for 20 min and treated with N,N-diethylaminoethyl bromide hydrobromide (0.39 g, 1.5 mmol) and potassium carbonate (0.62 g, 4.5 mmol). The resulting mixture was stirred at ambient temperature over 18 h, poured into ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by a flush chromatography (methanol/methylene chloride, 1:9) to afford 7-bromo-N,N-diethyl-1,2-benzisothiazole-2(3H)-ethanamine 1,1-dioxide (0.48 g, 93%). LRMS (ES+): 348.0 (M+H)+.
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([NH:13]C(=O)C)[CH:11]=2)[N:6]([CH3:20])[C:5]1=[O:21])([CH3:3])[CH3:2].Cl>CC(O)C>[NH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[N+:17]([O-:19])=[O:18])[N:6]([CH3:20])[C:5](=[O:21])[CH:4]2[CH:1]([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)C2C(C)C
Agent: Cl
Solvent: CC(C)O
Product: CC(C)C1C(=O)N(C)c2cc([N+](=O)[O-])c(N)cc21
Yield: 73.1 %

Procedure:
(rac)-N-(3-Isopropyl-1-methyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (686 mg) is dissolved in 2-propanol (4 ml) and hydrochloric acid (6 N; 6 ml) and heated for 1 h at 100° C. After a typical aqueous work-up the crude material is purified by flash chromatography on silica gel eluting with light petroleum/EtOAc (1:1) to give the title compound (429 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:28])=[CH:13][O:14][C:15](=[O:27])[CH2:16][CH2:17][C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C([BH3-])#N.[Na+]>CO.Cl.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:28])=[CH:13][O:14][C:15](=[O:27])[CH2:16][CH2:17][CH:18]([OH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCC(=O)CCC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCCCCCCC(O)CCC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Yield: 100.2 %

Procedure:
A solution of 10.00 g 4-oxo-undecanoic acid 3-(4-tert-butyl-phenyl)-2-methyl-propenyl ester was dissolved in 60 ml methanol and a trace of bromocresol green was added. When 1.63 g sodium cyanoborohydride was added, the color changed immediately from yellow to deep blue. Several drops of 2N HCl/methanol solution turned the color of the reaction back to yellow. The reaction was stirred for 2½ hours, with occasional addition of acid to maintain the yellow color. The reaction mixture was evaporated to dryness and water was added to the residue. This solution was extracted with ether and washed with water. The solution was dried, filtered and evaporated to dryness to yield 10.07 g of a colorless oil.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=2)O1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+]>O1CCOCC1.O.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Yield: 81.6 %

Procedure:
To a 200 mL round bottomed flask equipped with a magnetic stir bar was added 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) (3.45 g, 11.2 mmol), and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (C2) (3.71 g, 13.4 mmol). These reagents were diluted with dioxane (45.0 mL) and water (11.3 mL) and the resulting solution was sparged with nitrogen gas for 10 minutes. Tri-tert-butylphosphonium tetrafluoroborate (0.325 g, 1.12 mmol), palladium(II) acetate (0.126 g, 0.560 mmol) and cesium fluoride (3.40 g, 22.4 mmol) were added as solids. The flask was sealed and placed under nitrogen atmosphere. The reaction mixture was heated to an internal temperature of 60° C. The reaction mixture was allowed to cool to room temperature, and was poured into a brine solution and the layers were partitioned. The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified via flash column chromatography using 0-10% ethyl acetate/hexanes as eluent to afford the title compound as an off-white solid (3.45 g, 82%): 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.11-8.04 (m, 4H), 7.63 (ddt, J=7.9, 2.1, 1.1 Hz, 2H), 7.48-7.36 (m, 2H), 3.77 (s, 2H), 3.64 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −57.02; ESIMS m/z 378 ([M+H]+).
Reaction SMILES: [CH:1]1([C:7]#[N:8])[CH2:4][CH2:3][CH:2]1[C:5]#[N:6].[OH:9][CH2:10][C:11](N)([CH3:14])[CH2:12][OH:13]>Cl[Cu]>[CH3:14][C:11]1([CH2:12][OH:13])[CH2:10][O:9][C:5]([CH:2]2[CH2:3][CH2:4][CH:1]2[C:7]2[O:9][CH2:10][C:11]([CH2:12][OH:13])([CH3:14])[N:8]=2)=[N:6]1
Reactant: CC(N)(CO)CO
Reactant: N#CC1CCC1C#N
Agent: Cl[Cu]
Product: CC1(CO)COC(C2CCC2C2=NC(C)(CO)CO2)=N1

Procedure:
53 g of cyclobutane-1,2-dinitrile were heated for 3.5 hours to 100°C with 150 g of 2-hydroxymethyl-2-amino-1-propanol in the presence of 0.5 g of CuCl. Distillation of the reaction mixture in the same way as described in Example 15 gave 175 g of distillate boiling at 142° - 200°C/0.6 Torr which, when subsequently fractionated in a Vigreux column, gave 117 g (83% of the theoretical) of 1,2-bis-(4-methyl-4-hydroxymethyl oxazolin-2-yl)-cyclobutane boiling at 198° - 204°C/0.05 Torr.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:14][C:13]=2[OH:29])=[O:10])=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[OH:29][C:13]1[CH:14]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:16]=[CH:17][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:37]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cc1ccc(Br)cc1)Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1O
Reactant: COc1cccc(B(O)O)c1
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: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2ccc(CC(=O)Nc3ccc(Oc4ccc(C(F)(F)F)cc4)cc3O)cc2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To 120 mg (0.1 mmol) of above resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(4-trifluoromethyl-phenoxy)-phenyl]-acetamide in 2.0 mL of DME were added 46.0 mg (0.3 mmol) of 3-methoxyphenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% methylene chloride) to give 25 mg (50%) of the title compound. LC/MS (m/z) 494 (M+1)+.