Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH:17]=1.O.[OH-].[Na+]>CN1CCCC1=O>[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:23]=[C:24]([NH:25][C:5]3[CH:6]=[CH:7][C:8]([N:10]4[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH:26]=[CH:27][CH:28]=2)[CH:17]=1
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: O=[N+]([O-])c1cc(-n2cccc2)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cc(-n2cccc2)ccc1Nc1cccc(-c2cccnc2)c1
Temperature: 127.5 °C

Procedure:
A mixture of 1a (0.5g, 2.4mmol) and 2a (0.41g, 2.4mmol) in N-methyl-2-pyrrolidone (2.5ml) is heated to 120-135° C. for 2 days. After cooling water and diluted sodium hydroxide is added and the mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate, and the solvent is evaporated to leave crude 3a. This crude product is purified by column-chromatography on silica gel using dichloromethane and subsequently a mixture of dichloromethane and methanol (9:1) as the eluents to yield pure 3a (0.61g, 71%) as an oil.
Reaction SMILES: [CH2:1](I)I.[O:4]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:21]>CCOCC>[CH:12]12[CH2:1][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2
Reactant: O=C1CCCCCC=CCCCCCCCCO1
Reactant: ICI
Solvent: CCOCC
Product: O=C1CCCCCCC2CC2CCCCCCCO1
Reaction time: 4 h

Procedure:
To a dry 500 ml multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 8 g of ZnCu, 26 g of CH2I2, 100 ml of Et2O and 2 crystals of 12, were added and stirred. 12 g of oxacycloheptadec-8-en-2-one were added to the mixture and the mixture was heated to reflux. In 4 hours, first sample was taken at 35° C. The mixture was left to age overnight. Next morning, the mixture was quenched with saturated NH4Cl, aqueous layer separated and the organic layer washed with NaHCO3. The organic layer was then dried over anhydrous MgSO4. The gas chromatography test indicated that 8.1% of the starting alkene lactone converted to the cyclopropanated lactone.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]([OH:18])[C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:3].COC.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:25]O.O1CCCC1>CS(O)(=O)=O.CN(C)C(=N)N(C)C.CCCCCC>[CH3:17][N:15]([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:7]2[CH:19]=[CH:20][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[O:18][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Reactant: CCOC(=O)CO
Agent: CN(C)C(=N)N(C)C
Agent: COC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)COC(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1

Procedure:
A solution of 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether (11.0 g, 0.039 mole), ethyl glycolate 4.04 g, 0.039 mole), 70 ml of tetrahydrofuran, 230 ml of n-hexane and one drop of methanesulfonic acid was refluxed for 2 hours. On completion of the reaction, 2 drops of tetramethylguanidine was added to discharge the blue color. The reaction mixture was filtered hot and the filtrate was cooled. An oily layer formed which was removed and stripped free of solvent; the remaining filtrate was also stripped, leaving an oil. Both samples of oil were combined and chilled. A waxy solid formed which, on repeated trituration with petroleum ether, gave a white solid. Recrystallization from a mixture of petroleum ether/acetone gave a white solid, mp 63°-67.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C1(C)C=CC=CC=1.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.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:40]1[CH:41]=[CH:42][C:37]([CH3:36])=[CH:38][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
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: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(C)cc2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A mixture of methyl 6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (9.24 g, 18 mmol), 4-methylphenylboronic acid (2.94 g, 21.6 mmol) and sodium carbonate (2.86 g, 27 mmol) in toluene (50 ml)-methanol (10 ml)-water (10 ml) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (1.04 g, 1 mmol) and the mixture was refluxed under heating under an argon, atmosphere for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (6.91 g, 84.4%) as crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Mg].II.CN([CH:15]=[O:16])C>C1COCC1>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][CH:15]=[O:16]
Reactant: CN(C)C=O
Reactant: BrCCC1OCCO1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=CCCC1OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To the solution of 2-(2-bromoethyl)-1,3-dioxolane (10 g, 55.2 mmol) in THF (50 mL) was added magnesium (1.6 g, 66.3 mmol) and trace amount of I2 as initiator. The reaction mixture was stirred at rt for 2 hrs. After cooling to −78° C., the mixture was quenched with dry DMF (1.39 g, 66.3 mmol) and kept at −78° C. for 2 hrs. After dilution with H2O the reaction mixture was extracted with CH2Cl2 (2×), followed by distillation (45-55° C.@8 mmHg) to afford 2 g (28%) of the title compound. MS (DCI/NH4+) m/z 131 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl-].[CH2:17](N(CC)CC)[CH3:18].C=C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCC>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[CH:17]=[CH2:18]
Reactant: CCN(CC)CC
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCCCC
Product: C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 94.5 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)-1-bromobenzene (75 g, 0.256 mol), tetiabutylammonium chloride (71.4 g, 0.256 mol), triethylamine (71.3 mL, 0.97 mol) and palladium(II) acetate (113 mg) in acetonitrile (360 mL) was deoxygenated with a vigorous flow of nitrogen. The reaction was pressurized with ethylene (950 psi) and heated to 80° C. for 36 hours. Pentane (400 mL) was added and after 3 water washes (200 mL) the organic layer was dried over Na2SO4 and the solvent was removed in vacuo to afford 3,5-bis(trifluoromethyl)styrene as a pale yellow oil (58.2 g, 0.242 mol, 95% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[S:25])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: S=C=Nc1ccccc1
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=S)Nc2ccccc2)[C@@H]1O
Yield: 86.1 %

Procedure:
A suspension of (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med. Chem; 1983, 26, p. 1582 and J. Med. Chem., 1986, 29, p. 2194) (1.0 g, 4.6 mmol) in ethanol (4 ml) under argon was treated with phenylisothiocyanate (0.62 g, 4.6 mmol) and the reaction was heated at reflux for 4 hours. The reaction was then concentrated in vacuo and the residue was triturated with isopropylether to give the title compound as a colorless solid (1.4 g, 85%), m.p. 183°-185° C.; 1H NMR (CDCl3) δ8.5 (s, 1H), 7.4 (m, 7H), 6.83 (d, J=8.0 Hz, 1H), 6.1 (s, 1H), 6.0 (s, 1H), 4.0 (s, 1H), 3.67 (d, J=10.0 Hz, 1H), 1.5 (s, 3H), 1.3 (s, 3H); 13C NMR (CDCl3) 182.5, 156.8, 133.3, 131.9, 130.4, 128.2, 126.0, 125.8, 122.2, 118.8, 118.6, 104.0, 80.5, 75.8, 50.0, 26.3, 18.6; IR (KBr) 1070, 1265, 1491, 1531, 2226, 2978, 3312, 3362 cm--1.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([CH3:16])[C:13]([Cl:15])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Cl:15][C:13]1[C:12]([CH3:16])=[CH:11][C:9]2=[N:10][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=3)([C:3]#[N:4])[CH3:17])[N:7]=[C:8]2[CH:14]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: Cc1cc2nn(CC(C)(N)C#N)nc2cc1Cl
Product: Cc1cc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc2cc1Cl

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-6-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (90 mg, described in Example 9) and 4-trifluoromethylthiobenzoyl chloride (0.1 mL), the title compound was isolated as a white solid (152 mg, 93%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=454. 1H NMR: (400 MHz, DMSO-d6): 1.73 (s, 3H), 2.46 (s, 3H), 5.38 (d, J=13.4 Hz, 1H), 5.45 (d, J=13.4 Hz, 1H), 7.87 (d, J=8.5 Hz, 2H), 7.91 (d, J=8.6 Hz, 2H), 7.96 (s, 1H), 8.13 (s, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.93 (s, 3F).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[CH:11]1[N:16]2[N:17]=[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[C:15]2[C:14](=[O:28])[NH:13][CH2:12]1>C(Cl)Cl>[F:7][CH:11]1[N:16]2[N:17]=[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[C:15]2[C:14](=[O:28])[NH:13][CH2:12]1
Reactant: O=C1NCC(O)n2nc(COc3ccccc3)cc21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1NCC(F)n2nc(COc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.7 %

Procedure:
DAST (0.035 mL, 0.29 mmol) was added to a solution of (rac)-7-hydroxy-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.19 mmol) in DCM (0.5 mL) at −10° C. The mixture was stirred at room temperature for 15 minutes. Then quenched with a 1N solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield (rac)-7-fluoro-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (51 mg, quantitative) as light brown solid that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ncccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3ncccc3F)sc2N)c1N1CC[C@@H](F)[C@@H](N)CC1
Yield: 74 %

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxylic acid gave 388 as an off-white solid (120 mg, 74% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.42 (s, 1H), 7.85 (t, J=9.8 Hz, 1H), 7.64 (s, 1H), 7.50-7.44 (m, 1H), 4.85 (d, J=47.3 Hz, 1H), 3.64 (s, 3H), 3.40-3.22 (m, 3H), 3.23-2.83 (m, 2H), 2.31-2.01 (m, 1H), 2.04-1.66 (m, 2H), 1.92-1.48 (m, 1H). Exchangeable NH2 (×2) and NH not observed. LCMS (ES+) m/z 449 (M+1)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.C([O-])([O-])=O.[Na+].[Na+].[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][N:18]=1>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>[Cl:8][C:7]1[C:2]([C:20]2[CH:19]=[N:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Clc1cccnc1Cl
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
Solvent: O
Product: Cc1ccc(-c2ncccc2Cl)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of 0.5 g (3.6 mmol) 2,3-dichloropyridine in 20 mL 1,2-dimethoxyethane and 20 mL distilled water were added 2.2 g (21.1 mmol) Na2CO3, 0.41 g (3.0 mmol) 2-methylpyridine-5-boronic acid and 50 mg Pd(PPh3)4, followed by stirring for 18 hours in a heat flux condition. After being cooled to room temperature, the solution was 50% concentrated in a vacuum condition. The aqueous layer was washed with ethyl acetate. Thereafter, the organic layer was dried over magnesium sulfate and vacuum concentrated. The concentrate was separated using column chromatography (developing solvent: ethyl acetate/hexane=1/10) to produce 0.56 g of 3-chloro-2-(6-methylpyridin-3-yl)pyridine (yield 80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:14])[C:4](=O)[CH2:3]1.C([O-])(=O)C.[Na+].Cl.[CH3:23][O:24][NH2:25]>CO>[CH3:23][O:24]/[N:25]=[C:4]1/[C:5](=[O:14])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([CH3:16])([CH3:1])[CH2:3]/1
Reactant: CON
Reactant: CC1(C)CC(=O)C(=O)N1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CO/N=C1\CC(C)(C)N(Cc2ccccc2)C1=O
Reaction time: 8 h
Yield: 102.3 %

Procedure:
To a solution of 5,5-dimethyl-1-(phenylmethyl)-2,3-pyrrolidinedione (3.9036 g, 17.97 mmol) in MeOH (90 mL) was added sodium acetate (1.81 g, 21.54 mmol) and methoxyamine hydrochloride (1.80 g, 21.55 mmol). The solution was stirred overnight and the solvent was then removed in vacuo. The residue was partitioned between DCM (200 mL), sat. aq. NaHCO3, and water. The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to provide crude (3E)-5,5-dimethyl-1-(phenylmethyl)-2,3-pyrrolidinedione 3-(O-methyloxime) (4.5282 g, >100% crude yield) as a yellow/orange oil. LCMS: (M+H)+: 247.1.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:34])[C:19]([S:22]([CH2:25][CH:26]2[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]2)(=[O:24])=[O:23])([CH3:21])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOCC>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:34])[C:19]([S:22]([CH2:25][CH:26]2[CH2:27][CH2:28][CH:29]([O:32][CH3:33])[CH2:30][CH2:31]2)(=[O:24])=[O:23])([CH3:21])[CH3:20])[O:14][N:13]=1)([CH3:1])[CH3:11]
Reactant: COC1CCC(CS(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)COC3CCCCO3)no2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC1CCC(CS(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)CO)no2)CC1
Yield: 37.9 %

Procedure:
A solution of 1.3 g (2.6 mmol) of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-(4-methoxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide in DCM/methanol (1/1, 20 mL) is treated with 1.58 g (5.2 mmol) of MP-TsOH resin (loading 3.3 mmol/g) at room temperature for 36 h. The resin is removed by filtration and washed alternating with DCM (10 mL) and methanol (10 mL) twice. The combined filtrates are concentrated under reduced pressure and the resulting residue is purified by column chromatography (Isolute SCX-2, eluent: DCM, 10% ethyl acetate) to yield 0.41 g of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-(4-methoxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide. Yield 38%; ES-MS: m/z 417 [M+H].
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Br)[CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[Br:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: BrCc1cccc(CBr)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOCc1cccc(CBr)c1
Temperature: 0 °C
Yield: 74.6 %

Procedure:
Sodium hydride (125 mg, 60% dispersion in mineral oil, 3.13 mmol) was added portionwise to an ice-cooled solution of tert-butyl 2-hydroxyethylcarbamate (500 mg, 3.10 mmol), and 1,3-bis(bromomethyl)benzene (8.2 g, 31.0 mmol) in tetrahydrofuran (15 ml), and the reaction stirred at 0° C. for an hour under a nitrogen atmosphere, then allowed to warm to room temperature. Saturated ammonium chloride solution (10 ml) was added, and the mixture partitioned between water and ethyl acetate, and the layers separated. The organic phase was then dried over MgSO4, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (15:85 to 75:25) to give the title compound as a colourless oil, (796 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].CO.[BH4-].[Na+].Cl>C1COCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:8]=[CH:7][C:4]=1[CH2:5][OH:6]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=O)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(CO)c(OC)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Methoxy-4-(2′,2′,2′-tris(octadecyloxymethyl)ethoxy)benzaldehyde (288 mg, 280 μmol) was dissolved in THF (3 ml), methanol (0.3 ml) and sodium borohydride (31.8 mg, 841 μmol) were added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (5 ml) and chloroform (5 ml) were added, and the mixture was stirred. The aqueous layer was removed, and the organic layer was further washed twice with purified water (5 ml). The organic layer was evaporated under reduced pressure, and the residue was azeotropically distilled with acetonitrile and dried in vacuo to give 2-methoxy-4-(2′,2′,2′-tris(octadecyloxymethyl)ethoxy)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.C1(=O)C=CC(=O)C=C1.[OH-].[Na+]>C1COCC1.CC#N.CC#N.Cl[Pd]Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:13][C:12](=[O:14])[C:11]3[C:10]([CH:9]=2)=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[CH:15]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(/C=C/c2cccc(Cl)c2)c(C(=O)O)c1
Agent: Cl[Pd]Cl
Agent: O=C1C=CC(=O)C=C1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc2cc(-c3cccc(Cl)c3)oc(=O)c2c1
Yield: 73.6 %

Procedure:
A solution of (E)-2-[2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid (15.00 g, 51.95 mmol) in anhydrous THF (520 mL) was sparged with argon for 5 min. p-Benzoquinone (6.18 g, 57.20 mmol) was added followed by bis(acetonitrile)dichloropalladium(II) (674 mg, 2.60 mmol) and the resultant mixture stirred at ambient temperature for 17 h. 1 N NaOH (aq.) (375 mL) was added and the resultant brown solid washed with chloroform (4×200 mL) to provide 3-(3-chlorophenyl)-7-methoxyisochromen-1-one (10.96 g, 38.23 mmol, 74%) as pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@@:3]([OH:21])([CH2:8][C:9]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].Br[C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:19]1[C:20]2[C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][C@@:3]([CH2:2][NH:1][C:23]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]4[C:24]=3[CH:25]=[N:26][N:27]4[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([OH:21])[C:4]([F:6])([F:7])[F:5])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: Cc1cc(Br)c2cnn(-c3ccccc3)c2c1
Reactant: CC(C)(C[C@](O)(CN)C(F)(F)F)c1cccc2c1OCC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(NC[C@@](O)(CC(C)(C)c2cccc3c2OCC3)C(F)(F)F)c2cnn(-c3ccccc3)c2c1
Temperature: 120 °C
Yield: 28.1 %

Procedure:
To a mixture of (2S)-2-(aminomethyl)-4-(2,3-dihydro-1-benzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-pentanol (Intermediate 31, 87 mg, 0.3 mmol) and 4-bromo-6-methyl-1-phenyl-1H-indazole (Intermediate 33, 92 mg, 0.32 mmol) in toluene (3.5 mL) were added tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.04 mmol), racemic-BINAP (28 mg, 0.04 mmol) and sodium tert-butoxide (45 mg, 0.47 mmol). The mixture was heated in a microwave at 120° C. for 15 min and then cooled and partitioned between ethyl acetate (30 mL) and water (20 mL). The organic layer was separated, washed with water (20 mL), passed through a hydrophobic frit and evaporated. The residue was purified by two sequential SPE cartridge purifications eluting with a gradient of ethyl acetate:petroleum:ether (1:6 to 1:4) to give the title compound as a yellow foam (43 mg).
Reaction SMILES: CC([O-:5])(C)C.[K+].[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Cl)[C:13]=1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1>O1CCOCC1>[Cl:7][C:8]1[C:13]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:12]([OH:5])[CH:11]=[N:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Clc1cncc(Cl)c1COC1CCCCO1
Agent: [K+]
Solvent: C1COCCO1
Product: Oc1cncc(Cl)c1COC1CCCCO1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
Potassium tert-butylate (1.77 g, 15.80 mmol) was added to a stirred solution of 3,5-dichloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (825 mg, 3.16 mmol) in dioxane. After stirring for 3 d at 100° C. the solvent was removed in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 243.8 [M+H+].