Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: BrCc1ccccc1
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
The N-Boc p-hydroxy phenyl glycine methyl ester from step (300a) (123.0 g, 440 mmol) was combined with benzyl bromide (90.3 g, 528 mmol), potassium carbonate (182 g, 1.3 mol) and acetone (800 mL) under a nitrogen atmosphere. The reaction was heated to reflux for 5 h, allowed to cool to rt, diluted with ethyl acetate (800 mL) filtered to remove the solids and concentrated in vacuo to give a semisolid residue. The product was crystallized from ethyl ether to give the N-Boc p-benzyloxy phenyl glycine methyl ester (106.7 g, 65%) as a white powder. MS (M+H)+=372, (M+NH4)+=389.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1>C(O)(=O)C.ClCCl>[Br:1][C:12]1[S:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:13]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Temperature: 2 °C
Reaction time: 0.75 h

Procedure:
Bromine (1 ml) was added dropwise to a solution of 2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene (5.3 g) in acetic acid (53 ml) and dichloromethane (53 ml) at 2° C. The mixture was stirred at 2° C. for 45 minutes and concentrated to dryness. The residue was collected and washed with water and ethanol to give dark green crystals of 5-bromo-2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene (6.5 g).
Reaction SMILES: [C:1](/[C:3](=[C:7]1/[C:8]2[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18](OCCC)=[O:19])[CH:15]=[CH:14][C:13]/1=2)/[CH2:4][CH2:5][CH3:6])#[N:2].C(/C(=C1\C2C=CC=CC=2OCC2C=C(C(OCCC)=O)C=CC\1=2)/CCC)#N.C(C1(/C=C2\C3C=CC=CC=3OCC3C=C(C(OCCC)=O)C=CC\2=3)CC1)#N>>[OH:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2/[C:7](=[C:3](/[CH2:4][CH2:5][CH3:6])\[C:1]#[N:2])/[C:8]3[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=3[O:10][CH2:11][C:12]=2[CH:17]=1
Reactant: CCCOC(=O)c1ccc2c(c1)COc1ccccc1/C2=C(/C#N)CCC
Agent: CCCOC(=O)c1ccc2c(c1)COc1ccccc1/C2=C(\C#N)CCC
Agent: CCCOC(=O)c1ccc2c(c1)COc1ccccc1/C2=C\C1(C#N)CC1
Product: CCC/C(C#N)=C1/c2ccc(CO)cc2COc2ccccc21
Yield: 41 %

Procedure:
[step 1] Using pentanenitrile (2.7 mL, 25.9 mol) instead of cyclopropylacetonitrile, and in the same manner as in Reference Example B9, step 1, (E)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentanenitrile and (Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentanenitrile (1.90 g, 51%) were obtained. [step 2] Using (E)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentanenitrile and (Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentanenitrile (1.9 g, 5.37 mmol) obtained in Reference Example B11, step 1, instead of (E)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylacetonitrile and (Z)-2-(8-bromo-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)cyclopropylacetonitrile, and in the same manner as in Reference Example B9, step 2, propyl(E)-11-(1-cyanobutylidene)-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate and propyl(Z)-11-(1-cyanobutylidene)-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate (1.05 g, 54%) were obtained. [step 3] Using propyl(E)-11-(1-cyanobutylidene)-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate and propyl(Z)-11-(1-cyanobutylidene)-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate (1.05 g, 2.91 mmol) instead of propyl(E)-11-(1-cyanocyclopropylmethylene)-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate and propyl(Z)-11-(1-cyanocyclopropylmethylene)-6,11-dihydrodibenzo[b,e]oxepine-8-carboxylate, and in the same manner as in Example B9, step 3, (E)-2-(8-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)pentanenitrile (0.370 g, 41%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:31])[CH2:4][N:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26](OC)=[O:27])=[C:19]3[N:18]=2)[C:6]1=[O:30].[OH-].[Li+].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C1COCC1.CO.CN(C=O)C>[F:11][C:9]1[CH:8]=[C:7]2[C:6](=[O:30])[N:5]([CH:10]=1)[CH2:4][C@H:3]([CH3:31])[CH2:2][NH:1][C:26](=[O:27])[C:25]1=[C:19]3[N:18]=[C:17]([CH:22]=[CH:21][N:20]3[N:23]=[CH:24]1)[N:13]1[C@@H:12]2[CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(C[C@H](C)CN)c3=O)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CNC(=O)c2cnn3ccc(nc23)N2CCC[C@@H]2c2cc(F)cn(c2=O)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 10.1 %

Procedure:
To a solution of methyl 5-((R)-2-(1-((R)-3-amino-2-methylpropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (65 mg, 0.15 mmol) in THF/MeOH (6 mL/2 mL) was added lithium hydroxide (455 μL, 0.91 mmol). The reaction was stirred at 70° C. for 3 hours, then quenched with hydrogen chloride (910 μL, 0.91 mmol). The solvent was removed under reduced pressure and the residue was dried under high vacuum. To the resulting crude residue was added DMF (10 mL), HATU (115 mg, 0.30 mmol) and N-ethyl-N-isopropylpropan-2-amine (78 mg, 0.61 mmol). The reaction was stirred for 3 hours, and the solvent was removed under reduced pressure. The residue was purified by silica column chromatography, eluting with 10% MeOH/EtOAc to afford the title compound (6.0 mg, 10% yield). MS (apci) m/z=397.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=3)[N:16]=[C:15]([C:29]([F:32])([F:31])[F:30])[CH:14]=2)=[CH:9][C:8]=1[CH3:33])(=[O:5])=[O:4].[Cl:36]N1C(=O)CCC1=O.O>CN(C=O)C>[F:35][C:2]([F:1])([F:34])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[C:20]([F:28])[CH:19]=3)[N:16]=[C:15]([C:29]([F:30])([F:31])[F:32])[C:14]=2[Cl:36])=[CH:9][C:8]=1[CH3:33])(=[O:5])=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1OS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2c(Cl)c(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.4 %

Procedure:
To a stirred solution of 2-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl trifluoromethanesulfonate (0.185 g, 0.339 mmol) in DMF (2 mL) was added N-chlorosuccinimide (0.227 g, 1.70 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 72 hours. The reaction mixture was added water (20 mL) and extracted with ethyl acetate/hexane/ether=2/1/1 (20 mL×2). The organic layer was washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (4/1) to give the subtitle compound (0.117 g, 59.7% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:23][C@H:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:25][C:26](O)=[O:27])(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:26](=[O:27])[CH2:25][C@H:24]([O:23][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCC
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CI
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCC
Yield: 90.9 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-heptanoyloxytetradecanoic acid (780 mg, 2.2 mmol) in the presence of EDC MeI (745 mg, 2.5 mmol) in CH2Cl2 to afford 0.97 g (91%) of N-[(R)-3-heptanoyloxytetradecanoyl]-L-serine benzyl ester: mp 46-48° C.; 1H NMR (CDCl3) δ 0.88 (t, 6 H, J=6.9 Hz), 1.1-1.7 (m, 28 H), 2.30 (t, 2 H, J=7.7 Hz), 2.50 (d, 2 H, J=5.8 Hz), 2.62 (t, 1 H, J=6.0 Hz), 3.97 (m, 2 H), 4.65 (m, 1 H), 5.19 (m, 3 H), 6.61 (d, 1 H, J=6.9 Hz), 7.35 (br s, 5 H).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:23].[H][H]>CO.O.[Pd]>[ClH:23].[ClH:23].[N:18]1([CH:16]2[CH2:17][NH:14][CH2:15]2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1ccc(C(c2ccccc2)N2CC(n3ccnc3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: c1cn(C2CNC2)cn1

Procedure:
3.20 g of 1-benzhydryl-3-(1-imidazolyl)azetidine [prepared as described in step (a) above] were dissolved in 30 ml of methanol, and 8.90 ml of a 10% w/v solution of hydrogen chloride in methanol were added to the resulting solution. 1.60 g of a 20% w/w palladium hydroxide-on-carbon catalyst were then added to the mixture, after which the mixture was hydrogenated at 50° C. for 40 minutes in an atmosphere of hydrogen. The catalyst was then removed by filtration and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was washed with diethyl ether and dried under reduced pressure, to obtain 2.03 mg of the title compound, as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1.O>CC(C)=O>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-hydroxy-5-nitrobenzoate (0.685 g, 3.5 mmol) was dissolved in acetone (75 mL). Potassium carbonate (1.43 g, 10.4 mmol) and 2-bromomethylnaphthalene (0.77 g, 3.5 mmol) were added, and the whole was stirred under reflux for 5 h. Mixture was cooled to room temperature and poured into basic (NaOH, pH 10-11) water. After 1 h, precipitated solid was filtered, washed with water (3×25 mL), and air-dried. Off-white crystals, yield 0.970 g (82%). 1H NMR (DMSO-d6, 400 MHz), δ: 8.24 (s, 1H); 8.14 (s, 1H); 8.05 (s, 1H); 7.99-7.90 (m, 4H); 7.63 (d, J=7.5 Hz, 1H); 7.57-7.50 (m, 2H); 5.51 (s, 2H); 3.92 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([NH:14]C(=O)C(C)(C)C)=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1>Cl.O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[C:5]([NH2:14])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1c(-c2ncccn2)cc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: Nc1c(-c2ncccn2)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A suspension of N-(4-bromo-2-nitro-6-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propionamide (29.9 grams, 78.8 mmoles) in conc. HCl (200 mL) was refluxed for 8 hours. The partially homogeneous crude reaction was then cooled to room temperature, diluted with water (500 mL), and the resulting precipitate was stirred for 1 hour. The solids were then filtered, washed with water, and vacuum dried at 50° C. to afford the title compound (21.1 grams, 91% yield) as an orange powder.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>>[CH:12](=[C:5]1[C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc2c(n1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2c(n1)C(=Cc1ccccc1)CCC2
Temperature: 25 °C

Procedure:
A solution of Intermediate 200A1 (27.5 g, 187 mmol), benzaldehyde (18.4 mL, 181 mmol) and acetic anhydride (32.5 mL, 290 mmol) was heated at 155° C. for 4 h. The mixture was cooled to room temperature, mixed with crushed ice, basified with 2M NaOH to pH>8. The aqueous layer was extracted with hexane/ethyl acetate. The pooled organic layers were dried over MgSO4, filtered, evaporated and purified by chromatography on SiO2 to give 8-benzylidene-2-methyl-5,6,7,8-tetrahydro-quinoline (Intermediate 200A2) as the major product. This material was carried onto the next step. Note: 2-styryl-5,6,7,8-tetrahydro-quinoline (removed by chromatography on SiO2 with 1.5% acetone in hexanes) and 8-benzylidene-2-styryl-5,6,7,8-tetrahydro-quinoline were also produced as side products.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[N:18]=[C:19]([CH:21]([OH:30])C(O)C3C=CC=CC=3)[O:20][C:14]=2[CH2:13]1)=[O:11])[CH3:8].CO>C1COCC1.O>[CH2:7]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[N:18]=[C:19]([CH:21]=[O:30])[O:20][C:14]=2[CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)N1CCc2nc(C(O)C(O)c3ccccc3)oc2C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2nc(C=O)oc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
Sodium periodate (1.7 g, 7.8 mmol) was added to a stirred solution of 2-(1,2-dihydroxy-2-phenylethyl)-6,7-dihydro-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (1.7 g, 5.2 mmol) in a mixture of THF (34 mL), MeOH (17 mL) and H2O (8.5 mL). The mixture was stirred at room temperature for 2 hours, diluted with H2O and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 2-formyl-6,7-dihydro-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (1.2 g, 99% yield) as a dark oil that was used in the next step without further purification. C10H12N2O4 LCMS: Rt 1.13, m/z 243 [M+H2O+H]+ (using method, LC-MS Method 3).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:20][CH3:21])=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([CH2:1][NH:25][CH3:24])[C:4]=2[O:20][CH3:21])[CH:14]=1
Reactant: COc1ccc(C#N)c(Oc2cccc(C=O)c2OC)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(OC)ccc2C#N)c1OC
Yield: 60.5 %

Procedure:
2-(3-Formyl-2-methoxy-phenoxy)-4-methoxy-benzonitrile (0.38 g, 1.3 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (10 mg, 1.8 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 17 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.15 g, 1.3 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-methoxy-2-(2-methoxy-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (326 mg, 58%) as an off-white solid.
Reaction SMILES: C(C1[O:9][CH2:8][C:7]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:10])[CH2:6][O:5]1)(C)C.[OH-].[Na+]>CO>[CH2:13]([O:12][CH2:11][C:7]([CH3:10])([CH2:8][OH:9])[CH2:6][OH:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C1OCC(C)(COCc2ccccc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CO)(CO)COCc1ccccc1
Yield: 32.5 %

Procedure:
A 2 L 3-neck, round-bottom flask, equipped with a reflux condenser, a thermometer, and magnetic stir bar, was charged with 2-isopropyl-5-benzyloxymethyl-5-methyl-1,3-dioxane (48.5 g, 0.183 mol), IN HCI (330 mL), and methanol (600 mL). The mixture was heated to reflux for 3 h, then neutralized with 1N NaOH (~330 mL). The mixture was extracted with CH2Cl2 (600 mL), and the organic layer was separated. The aqueous layer was extracted with 250 mL of CH2 Cl2. The combined organic layer was washed with brine (300 ML), and dried over MgSO4. After removing MgSO4, the solution was concentrated using a rotary evaporator under reduced pressure. The residual oily mixture was purified by column chromatography. It was applied to a column of Silica gel and eluted with 5:1 and 2:3 Hexanes:EtOAc to give 12.5 g of white crystals after removing solvent and drying in vacuo (33% of theory). m.p. (DSC): 54.5° C.; IR (neat): 3280, 2930, 2860, 2840, 1448, 1403, 1354, 1296, 1200, 1150, 1108, 1050, 1021, 990, 962, 892, 727, 688 cm-1 ; 1H NMR (CDC13, 300 Mhz) δ0.84 (s, 3H), 2.92 (s, 2H), 3.45(s, 2H), 3.57 (d, 2H), 3.69 (d, 2H), 4.51 (s, 2H), 7.32 (m, 5H); 13C NMR (CDC13, 75 MHz) δ17.09, 40,77, 67.71, 73.56, 75.49, 127.47, 127.72, 128.43, 137.87.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cn2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
To a solution of 1-(t-butyloxycarbonyl)-4-piperidinol (600 mg) in dry DMF (20 mL) was added sodium hydride (0.24 g, 50% dispersion in oil) and stirred under argon for 1 hour. 2-Chloro,5-cyanopyridine (0.44 g) was added and the mixture was heated at 70° C. overnight. The reaction was quenched by pouring into water and extracted with diethyl ether. The extract was washed with water, brine, dried (MgSO4) and evaporated. The residue was then chromatographed on silica gel eluting with a mixture of dichloromethane (25%) in isohexane increasing to dichloromethane. The residue was recrystallised from isohexane to afford 1-(t-butyloxycarbonyl),4-(5-cyano,2-pyridyloxy)piperidine (400 mg) as a colourless crystalline solid; NMR: (CDCl3) 1.46 (s,9H), 164-182 (m,2H), 1.92-2.09 (m,2H), 3.21-3.36 (m,2H), 3.70-3.84 (m,2H), 5.28 (m,1H), 6.78 (d,1H), 7.77 (dd,1H): MS: m/z 304 (MH)+.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:38])[CH2:35][CH2:36][CH3:37]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 62 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, butyryl chloride (0.24 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}butanamide (0.41 g, 62%) as a white solid: mp 121-123° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.44 (t, J=5.55 Hz, 1H), 7.87-7.66 (m, 3H), 5.19-5.12 (dd, J=5.1 and 12.4 Hz, 1H), 4.72 (d, J=5.6 Hz, 2H), 2.96-2.85 (m, 1H), 2.63-2.51 (m, 2H), 2.17 (t, J=7.2. Hz, 2H), 2.08-2.04 (m, 1H), 1.63-1.51 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); 13C NMR (DMSO-d6) δ 172.71, 172.47, 169.77, 167.46, 166.92, 139.53, 134.68, 133.11, 131.49, 127.04, 12.1.77, 48.84, 37.55, 37.16, 30.91, 21,96, 18.60, 13.63; Anal. Calcd. For C18H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C, 60.46; H, 5.36; N, 11.59.
Reaction SMILES: CS[C:3]1[C:8]2=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)[CH:10]=[CH:11][N:7]2[N:6]=[CH:5][N:4]=1.C(O)(C(F)(F)F)=O.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([F:46])[CH:40]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>ClCCl.C1COCC1>[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:3]2[C:8]3=[C:9]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]4)[CH:10]=[CH:11][N:7]3[N:6]=[CH:5][N:4]=2)=[C:41]([F:46])[CH:40]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: CSc1ncnn2ccc(CN3CCC(O)CC3)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Oc2ncnn3ccc(CN4CCC(O)CC4)c23)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
To 1-((4-(methylthio)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-4-ol (188 mg, 0.675 mmol) in dichloromethane (7 mL) at 0° C. was added TFA (78 μL, 1.01 mmol) followed by m-CPBA (166 mg, 0.675 mmol, ˜70% pure). After stirring at 0° C. for 1 h, the mixture was concentrated in vacuo. Ether (20 mL) was added and then decanted off to remove the benzoic acid. The resulting crude sulfoxide was dried under high vacuum. 4-Amino-2-fluorophenol (343 mg, 2.7 mmol) was dissolved in THF (10 mL), cooled to −78° C., and charged with NaHMDS (2.7 mL, 2.7 mmol, 1 M in THF). After stirring at 0° C. for 5 min, the crude sulfoxide in THF (3 mL) was added. The reaction was stirred at 0° C. for 30 min and was then concentrated in vacuo. The residue was suspended in EtOAc (20 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by reverse phase prep HPLC and the appropriate fractions were concentrated in vacuo to remove methanol. The resulting aqueous solution was made basic with 5% aqueous sodium bicarbonate solution and extracted with EtOAc (3×10 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give 36 mg (15%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 8.04 (s, 1H), 8.00 (d, 1H, J=2.8 Hz), 7.02 (t, 1H, J=8.8 Hz), 6.88 (d, 1H, J=2.8 Hz), 6.51 (dd, 1H, J=12.8, 2.8 Hz), 6.46–6.42 (m, 1H), 5.45 (br s, 2H), 3.83 (s, 2H), 3.18 (m, 1H), 2.76–2.71 (m, 2H), 2.12–2.06 (m, 2H), 1.72–1.67 (m, 2H), 1.41–1.38 (m, 2H); MS(ESI+) m/z 358.4 (M+H)+.