Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([OH:21])([CH3:20])[CH3:19])[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([OH:21])([CH3:19])[CH3:20])[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: CC(C)(O)c1ccc(C(=O)OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)O)cc1F
Yield: 93.5 %

Procedure:
To a solution of 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (9.1 g, 45.7 mmol) in DMF (40 mL) was added cesium carbonate (22.3 g, 68.5 mmol) followed by benzyl bromide (11.7 g, 8.1 mL, 68.5 mmol) and reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed sequentially with H2O (3×10 mL), brine solution. The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography eluting with 10-20% EtOAc-hexanes to provide benzyl 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoate (2.8 g, 21%) ESI-MS m/z calc. 288.2. Found 289.3 (M+1)+; Retention time: 1.79 min (3 min run). To a solution of benzyl 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoate (2.8 g, 9.71 mmol) in MeOH (50 mL) was added palladium on carbon (100 mg, 0.09 mmol) and the reaction mixture was subjected to an atmosphere of hydrogen for 16 hours. The catalyst was removed via filtration over Celite® and the solvent removed in vacuo to provide 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (1.8 g, 96%) as a white solid. ESI-MS m/z calc. 198.2. Found 199.9 (M+1)+; Retention time: 0.91 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:24]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:38][CH2:37][CH:36]2[C:39]([O-])=[O:40])[CH2:31][CH2:30]1)=[O:28])[CH3:25].[Li+]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C@H:11]2[CH2:15][N:14]([C:39]([CH:36]3[CH2:37][CH2:38][N:35]3[CH:32]3[CH2:31][CH2:30][N:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:34][CH2:33]3)=[O:40])[C@H:13]([C:16](=[O:17])[NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)[CH2:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Cl)c3)CN2)CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3cccc(Cl)c3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(3-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7F and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(3-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (64%). MS ISP (m/e): 592.4/594.3 (100/41) [(M+H)]+.
Reaction SMILES: O[C@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C@@H:3]([NH:5][C:6](=[O:15])[O:7]CC1C=CC=CC=1)[CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[C:46]1[CH:47]=[C:48]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:56][C:55]=2[CH3:64])[CH:49]=[CH:50][C:51]=1[O:52][CH3:53]>CC(N(C)C)=O.C1COCC1>[CH3:53][O:52][C:51]1[CH:50]=[CH:49][C:48]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:56][C:55]=2[CH3:64])=[CH:47][C:46]=1[C:37]1[CH:38]=[CH:39][C:40]([C:42]([F:45])([F:43])[F:44])=[CH:41][C:36]=1[CH2:35][N:5]1[C@@H:3]([CH3:4])[C@@H:2]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[O:7][C:6]1=[O:15]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Reactant: COc1cccc([C@@H](O)[C@H](C)NC(=O)OCc2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cccc(OC)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of benzyl [(1S,2R)-2-hydroxy-2-(3-methoxyphenyl)-1-methylethyl]carbamate (40 mg, 0.126 mmol) in DMA (1.5 mL) was added NaHMDS (0.246 mL of a 1M solution in THF, 0.246 mmol). After 5 minutes, a solution of methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (68 mg, 0.138 mmol) in DMA (2.5 mL) was added via cannula. After 5 minutes, the reaction was quenched with saturated NH4Cl solution (10 mL), diluted with EtOAc (20 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% acetone/hexanes), followed by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA) afforded methyl 4′-methoxy-2″-{[(4S,5R)-5-(3-methoxyphenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS=644.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.94-7.86 (m, 2H), 7.71-7.62 (m, 2H), 7.43-7.36 (m, 2H), 7.31-7.22 (m, 2H), 7.3 (m, 1H), 7.08-7.05 (m, 1H), 6.85-6.83 (m, 1H), 6.75-6.68 (m, 2H), 5.45 (d, J=8.0 Hz), 5.23 (d, J=8.0 Hz), 4.89 (d, J=16.0 Hz), 4.82 (d, J=16.0 Hz), 4.20 (d, J=15.8 Hz), 3.96 (d, J=15.8 Hz), 3.91 (s, 3H), 3.85 (s, 3H), 3.77-3.75 (m, 3H), 3.72-3.69 (m, 1H), 2.31 (s), 2.08 (s), 0.54 (d, J=6.4 Hz), 0.44 (d, J=6.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:36]([NH:24][C:3]1[CH:4]=[C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)[CH:6]=[CH:7][C:2]=1[F:1])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a solution of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (105 mg, 0.32 mmol) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (83 mg, 0.64 mmol) followed by benzoyl chloride (49 mg, 0.35 mmol) at 0° C. under nitrogen. The reaction mixture was then stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to afford methyl 2-(3-benzamido-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate 130 mg (94%) as a pale yellow solid. MS (ESI+APCI) M+1=433.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:24]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)([CH3:26])[CH3:25]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:28]4[C@H:27]([CH:24]([CH3:26])[CH3:25])[CH2:31][O:30][C:29]4=[O:32])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)C)cc3)CC2)c(C)c1
Yield: 36.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (567 mg) described in Preparation Example 77 and (R)-4-isopropyloxazolidin-2-one (192 mg), the title compound (210 mg) was obtained.
Reaction SMILES: O[N:2]([CH:9]=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](OC=C)(=O)[CH3:12]>>[CH:9]([N:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:12]=[CH:11]1)=[O:10]
Reactant: O=CN(O)c1ccccc1
Reactant: C=COC(C)=O
Product: O=Cn1ccc2ccccc21

Procedure:
In a manner analogous to that of Example 1, 3.1 g of N-hydroxy-N-formylaniline, 200 mg of Li2PdCl4 and 60 ml of vinyl acetate are reacted at 55° C. for 6 hours, and, after further processing, N-formylindole is obtained; IR spectrum (CHCl3): 1660 (CO): NMR spectrum (100 MHz, CDCl3): 6.54 (broad d, J=5 Hz, CH); 7.0-7.3 (m, 4H); 8.02 (broad d, J=6 Hz, CH); 8.68 (s, H--CO) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:18][CH3:19])=[O:9])=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1ccc(O)cc1

Procedure:
A mixture of 10 g 4-hydroxycinnamic acid, 100 ml ethanol and 0.5 ml concentrated sulphuric acid was heated under gentle reflux for 96 hours. The reaction mixture was poured onto water, the resultant precipitate filtered off, washed with portions of water and then dried. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent and recrystallisation from acetonitrile to yield 9.2 g of ethyl (E)-4-hydroxycinnamate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH3:11])=[CH:3][CH:2]=1.[ClH:19]>>[ClH:19].[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C)CCCc1ccncc1
Agent: Cl
Product: CN(CCCc1ccncc1)CCC(=O)O

Procedure:
The ethyl 3-{N-[3-(pyrid-4-yl)propyl]-N-methyl-amino}-propionate obtained is refluxed for 24 hours with 600 ml of 4-n hydrochloric acid. The reaction mixture is evaporated to complete dryness, and the crystalline residue formed is separated, washed with water and dried yielding 3-{N-[3-(pyrid-4-yl)propyl]-N-methyl-amino}-propionic acid hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].N1C=CC=CC=1.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>O1CCCC1>[C:22]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:25])[CH:23]=[CH2:24]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: C=CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
12-Hydroxydodecanoic acid (5.0 g, 0.023 mol) dissolved in tetrahydrofuran (100 ml) and pyridine (2.16 g, 0,027 mol) was cooled to 0° C. Acryloyl chloride (3.15 g, 0.023 mol) in tetrahydrofuran (75 ml) was then added dropwise to the solution. The mixture was stirred for 5 hours at 0° C. then stirred overnight at room temperature. The precipitated pyridinium salt was filtered off and the solvent removed under vacuum. The resulting liquid was purified by flash chromatography (silica gel/chloroform) to give 2.5 g (40%) of the title compound. 1H NMR (60 MHz, CDCl3): δ1.20 (s, 18H, CH2), 2.15 (m, 2H, CH2COOH), 4.0 (m, 2H, COOCH2), 5.7-6.0 (m, 3H, CH2 =and =CH).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[NH:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN1C(=O)CCC1>[N:28]1([CH2:27][CH:23]2[CH2:24][CH2:25][CH2:26][N:22]2[C:2]2[N:15]=[CH:14][C:13]3[C:12]4[N:8]([CH:9]=[C:10]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=5)[N:11]=4)[CH2:7][CH2:6][O:5][C:4]=3[CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCN(CC2CCCN2)CC1
Reactant: Clc1cc2c(cn1)-c1nc(-c3ccccn3)cn1CCO2
Solvent: CN1CCCC1=O
Product: c1ccc(-c2cn3c(n2)-c2cnc(N4CCCC4CN4CCCCC4)cc2OCC3)nc1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
To a solution of 12-chloro-4-(pyridin-2-yl)-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (200 mg, 0.671 mmol) in NMP (10 mL) was added TEA (10 mL) and 1-(pyrrolidin-2-ylmethyl)piperidine (135 mg, 0.804 mmol). The reaction mixture was stirred at 160° C. for 24 h. After cooling to room temperature, the reaction mixture was purified by Combi-flash eluting with a 5-95% gradient of CH3CN in 0.3% NH4HCO3 to give 129 which was further purified by chiral HPLC (AS-H column, 10% EtOH isocratic) to separate 15.9 mg of one enantiomer and 7 mg of the other (8% total yield). LCMS (ESI): RT=4.55 min, m/z: 431.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.50-8.49 (d, J=4.0 Hz, 1H), 7.97-7.95 (d, J=8.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.22-7.19 (m, 1H), 5.95 (s, 1H), 4.49-4.44 (m, 4H), 4.17 (m, 1H), 3.46-3.44 (m, 1H), 3.28-3.25 (m, 1H), 2.54 (m, 1H), 2.45-2.33 (m, 3H), 2.21-2.16 (m, 1H), 2.01-1.97 (m, 2H), 1.94-1.86 (m, 2H), 1.53-1.50 (m, 4H), 1.39-1.38 (m, 2H)
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:19])([F:18])[C:11]1[N:12]=[CH:13][NH:14][C:15](=[O:17])[CH:16]=1>C(#N)C>[I:1][C:16]1[C:15](=[O:17])[NH:14][CH:13]=[N:12][C:11]=1[C:10]([F:9])([F:18])[F:19]
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(C(F)(F)F)nc[nH]1
Solvent: CC#N
Product: O=c1[nH]cnc(C(F)(F)F)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
N-Iodosuccinimide (2.75 g) was added to a stirred suspension of 4-trifluoromethylpyrimidin-6-one (1 g) in dry acetonitrile (13 ml). The reaction mixture was stirred at the ambient temperature for 2 hours, and then heated under reflux for 10 hours. After cooling, removal of the solvent under reduced pressure gave a brown solid which was recrystallised from water to give 5-iodo-4-trifluoromethylpyrimidin-6-one as a pale orange solid (150 mg);
Reaction SMILES: C(=N[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)C(C)C.Cl.[OH2:21]>C1(C)C=CC=CC=1>[O:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH:6]=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O
Reactant: CC(C)C=NCc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1cccc(Oc2ccccc2)c1
Yield: 91 %

Procedure:
80 g (0.316 mol) of N-isobutylidene-3-phenoxybenzylamine is dissolved in 80 ml of toluene; to the solution is then added 4 g (0.036 mol) of potassium-tert-butylate, and the mixture is refluxed for 4 hours. After cooling of the reaction mixture, 35 g of 37% hydrochloric acid (about 0.35 mol) and 50 ml of water are added, and the toluene phase is separated. The toluene is distilled off to leave 57 g (0.288 mol) of 3-phenoxybenzaldehyde, corresponding to a yield of 91% of theory.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([O:9][CH3:10])=[O:8].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(#N)C>[CH2:24]([N:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1)[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 71 °C
Yield: 65.6 %

Procedure:
To a dry 100 ml one necked round bottom flask equipped with a stirring bar was added 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (5 g, 20.5 mmol) under N2 (FIG. 1). Anhydrous acetonitrile (60 mL) was added followed by the additions of BnBr (2.7 mL, 22.5 mmol) and triethylamine (8.5 ml, 61.5 mmol). A condenser was then put on to the flask and the reaction mixture was heated at 71° C. for 45 minutes. The reaction mixture was allowed to come to room temperature and concentrated under reduced pressure. It was then diluted with dichloromethane and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified with flash column (PE: EA=8:1) to yield 4.5 g (66%) of 111a. MS: [M+H]+: 335
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15].C(N(CC)CC)C.Cl>CCOC(C)=O>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[F:7]
Reactant: Oc1cccc(F)c1F
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Step M (1): Ethyl chloroformate (16.6 g, 153 mmol) was added to a solution of 2,3-difluorophenol (20 g, 153 mmol) and triethylamine (20.7 mL, 146 mmol) in EtOAc (200 mL). The resulting mixture was stirred at rt for 2 h. The crude reaction was poured into 1 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (5% EtOAc/hexane) to afford 2,3-difluorophenyl ethyl carbonate (20 g, 64% yield).
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][N+:24]#[C-:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[C-]#N.[K+]>CCO>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]2[O:7][CH:25]=[N:24][CH:23]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:26])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(C=O)cc(OC)c1Br
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: COc1cc(C2OC=NC2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To an oven-dried flask under argon was added 4-bromo-3,5-dimethoxybenzaldehyde (1.0 g, 4.08 mmol), absolute EtOH (34 mL), p-toluenesulfonylmethyl isocyanide (0.78 g, 4.0 mmol) and KCN (0.035 g, 0.54 mmol). The mixture was stirred for 19 hours at room temperature then concentrated in vacuo to give 5-(4-bromo-3,5-dimethoxyphenyl)-4-tosyl-4,5-dihydrooxazole which was used in the next synthetic step without purification.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCCCCOc2ccccc2)cc1

Procedure:
A mixture 100 grams (0.438 mole) of 4-phenoxybutyl bromide, 59.5 grams (0.438 mole) of p-hydroxyacetophenone, and 60.4 grams (0.438 mole) of potassium carbonate in approximately 200 milliliters of dry dimethylformamide, is stirred at its reflux temperature for a period of about 4 hours. The reaction mixture is cooled, water added, and the reaction product removed by filtration. The product is washed with a solution of 2 N sodium hydroxide, washed with water, and recrystallized twice from isopropyl alcohol to yield the desired p-(4-phenoxybutoxy) acetophenone having a m.p. of 104°-6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1>C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)cc3ccoc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NS(=O)(=O)c3ccccc3Cl)cc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
tert-Butyl 4-(5-amino-1-benzofuran-7-yl)piperazine-1-carboxylate (0.59 g, 1.87 mmol; Intermediate 10) was dissolved in DCM. 2-Chlorobenzenesulfonyl chloride (0.59 g, 2.8 mmol) was added followed by pyridine (0.45 mL, 5.6 mmol). The reaction mixture was stirred at room temperature overnight. Filtration through a silica plug afforded 0.66 g (72%) of the title product. HPLC purity 92%, RT=2.56 min (System A; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 3.07-3.21 (m, 4H) 3.51-3.65 (m, 4H) 6.51 (d, J=2.0 Hz, 1H) 6.62 (d, J=2.3 Hz, 1H) 6.93 (d, J=2.0 Hz, 1H) 7.00 (s, 1H) 7.18-7.31 (m, 2H) 7.36-7.47 (m, 1H) 7.47-7.57 (m, 2H) 7.90 (dd, J=7.9, 1.6 Hz, 1H). MS (ESI+) m/z 492.2 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:37][C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][C:39]=1[CH2:48][CH2:49][CH3:50]>CS(C)=O.C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][C:39]=3[CH2:48][CH2:49][CH3:50])[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)Cc2ccc3c(c2)OCO3)cc1
Reactant: CCCc1cc(C(=O)OC)ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCc1cc(C(=O)OC)ccc1CC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 0.531 g (1.47 mmol) of the product of Example 1 dissolved in 2.0 mL of DMSO was added 4.40 mL of a 1.0M solution of lithium bis(trimethylsilyl)amide in THF under a nitrogen atmosphere at a temperature just warm enough to prevent the DMSO from solidifying (approximately 18° C.). During the addition of the base, the reaction mixture was further cooled to 0°-50° C. with an ice-water bath. When the addition was complete, the reaction mixture was stirred for 1 hour at 0°-5° C., then a solution of 0.496 g (1.84 mmol) of the product of Step E dissolved in 2.0 mL of THF was added via syringe. The ice-water bath was then removed and the reaction mixture was stirred at room temperature for an additional hour. The mixture was next partitioned between EtOAc and 10% aqueous NaHSO4, and extracted. The organic layer was separated, washed with saturated brine, dried (MgSO4), filtered, and evaporated. The residue was partially purified on a silica gel flash chromatography column eluted with 1% MeOH--CHCl3. After evaporation of the product containing fractions the residue was rechromatographed on a silica gel flash chromatography column eluted with 5% EtOAc--CHCl3. Evaporation of the product containing fractions and drying in vacuo afforded 0.284 (36%) of the title compound as an amorphous white solid.