Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.I[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:7]=1
Reactant: FC(F)(F)c1cc(I)ccn1
Reactant: OB(O)c1cc(F)ccc1O
Product: Oc1ccc(F)cc1-c1ccnc(C(F)(F)F)c1

Procedure:
(5-Fluoro-2-hydroxyphenyl)boronic acid and 4-iodo-2-(trifluoromethyl)pyridine were reacted under Suzuki conditions to produce 4-fluoro-2-[2-(trifluoromethyl)pyridin-4-yl]phenol.
Reaction SMILES: [F:1][C:2]([F:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].Br([O-])(=O)=[O:29].[Na+].S(=O)(=O)(O)[O-].[Na+].O>C(#N)C>[F:27][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:29])=[O:24])=[CH:25][CH:26]=3)=[N:15]2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Yield: 95.1 %

Procedure:
A solution of 4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (1.7 g, 4.4 mmol), sodium bromate (2.1 g, 13.9 mmol) and sodium bisulfate (0.53 g, 4.5 mmol) in acetonitrile (50 mL) was heated to reflux for 5 h, during which time a voluminous precipitate formed. The solution was then cooled and poured into water (100 mL), filtered, and dried to furnish the acid (1.67 g) as a white solid: mp 225° C.; 1H NMR (300 MHz, CDCl3) δ 10.1 (s, 1H), 8.63 (s, 1H), 8.35 (d, J=8.4 Hz, 2H), 8.5 (d, J=8.4 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 7.43 (d, J=9 Hz, 2H); ESIMS m/z 399.2 (M+H+).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O:14][C:15]1(OC)[CH2:19][CH2:18][CH2:17][CH:16]1[O:20][C:21](=[O:38])[C@@H:22]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C(=O)([O-])O.[Na+]>CC(C)=O>[O:14]=[C:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[O:20][C:21](=[O:38])[C@@H:22]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[C:15]1(=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC1(OC)CCCC1OC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OC1CCCC1=O
Product: O=C1CCCC1
Reaction time: 72 h

Procedure:
4-Toluenesulphonic acid monohydrate (1.7 g, 9.2 mmol) was added to a stirred solution of (2S)-2-tert-butoxycarbonylamino-3-phenylpropionic acid 2,2-dimethoxycyclopentyl ester (36 g, 91.6 mmol) in acetone (450 ml) at ambient temperature. The solution was stirred for 3 days then water (600 ml) and saturated aqueous sodium hydrogen carbonate solution (200 ml) were added, then the product was extracted into ethyl acetate (600 ml). The aqueous phase was extracted with ethyl acetate (2×400 ml), then the combined ethyl acetate solutions were washed with saturated aqueous sodium chloride solution (2×150 ml), dried (Na2SO4) and the solvent removed in vacua. The residue (18.05 g) was purified by flash chromatography over silica gel eluting with a gradient of heptane:ethyl acetate 3:1→2:1. Appropriate fractions were combined and the solvents removed in vacuo to leave (2S)-2-tert-butoxycarbonylamino-3-phenylpropionic acid 2-oxocyclopentyl ester as a colourless oil (18.05 g, 40% from cyclopentanone). TLC (single UV spot, Rf=0.25, heptane:ethyl acetate 7:3), analytical HPLC with main broad peak Rt=17.9-19.2 mins, HPLC-MS (main broad UV peak with Rt=9.04-9.24 mins, 248.1 [M−Boc+2H]+, 370.2 [M+Na]+, 717.3 [2M+Na]+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[N:17]=1>>[CH3:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:23])=[CH:20][CH:19]=2)[N:17]=1
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)cs1
Reactant: Nc1ccc2cccnc2c1
Product: Cc1nc(-c2ccc(C(=O)Nc3ccc4cccnc4c3)cc2)cs1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (27 mg, 0.19 mmol) and 4-(2-methylthiazol-4-yl)-benzoic acid (D87) (50 mg, 0.23 mmol) as a solid. MS(ES): MH+ 346, M-H+ 344
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37]>CC#N>[Br-:23].[O:37]=[C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35](=[O:36])[N:27]1[CH2:26][CH2:25][CH2:24][N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 80.2 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0861 g, 0.293 mmol) and 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (0.118 g, 0.440 mmol) in 2 CH3CN/3 CHCl3 (5.0 mL) were reacted to give the desired product (0.1319 g, 82.4%). EI-MS m/z 481 (M+) Rt (1.90 min).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].Cl[C:13]1[N:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:16]([N+:29]([O-:31])=[O:30])=[CH:15][CH:14]=1>C(#N)C>[CH2:7]([NH:11][C:13]1[N:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:16]([N+:29]([O-:31])=[O:30])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCCCN1CCCCC1
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCNc1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)n1
Temperature: 25 °C
Yield: 98 %

Procedure:
Potassium carbonate (930 mg, 2 eq) and a solution of 1-butylamine (300 mg, 1.2 eq) in acetonitrile (2 ml) are added successively to a solution of 6-chloro-3-nitro-N-(3-piperidin-1-ylpropyl)pyridin-2-amine (1 g, 1 eq; prepared according to Example A2) in acetonitrile (80 ml). The mixture is heated to reflux for 15 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (90 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue obtained, by flash chromatography on silica gel (eluent: heptane/ethyl acetate 9:1 to 100% ethyl acetate), produces the expected compound (1.1 g; 98% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=O.CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc(F)cnc1Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)cnc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
A suspension of crude compound 3 (65 g, 372.4 mmol) and Et3N (114 mL, 819.2 mmol) in DCM (700 mL) was cooled to 0° C. and TFAA (57 mL, 409.6 mmol) was added dropwise. The resulting yellow solution was stirred for 90 minutes at 0° C., diluted with DCM, washed with sat. aq. NaHCO3 and brine, and dried (Na2SO4). The mixture was filtered and concentrated. Kugel Rohr distillation of the residue (˜70° C./1 mbar) gave 50 g (86%) of compound 4 as a beige solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)CC1CCN(OC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CON1CCC(CCO)CC1
Temperature: 25 °C

Procedure:
A solution of (1-methoxy-piperidin-4-yl)-acetic acid ethyl ester (16.7 g, 83 mmol) in 50 ml of THF was added dropwise to a suspension of lithium aluminum hydride (6.3 g, 166 mmol) in 150 ml of THF at 0° C. under nitrogen. After the addition, the mixture was warmed to room temperature for 2 h. Then, the resulting mixture was poured into 500 ml of ice water and extracted with CH2Cl2 three times. The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel. Yield: 12.0 g of 2-(1-methoxy-piperidin-4-yl)-ethanol as an oil.
Reaction SMILES: [CH3:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH3:7].B1C2CCCC1CCC2.B(O)O.Br[C:21]1[CH:54]=[CH:53][C:24]([CH2:25][C:26]2[N:27]([C:39]3[CH:40]=[C:41]([N:45]4[S:49](=[O:51])(=[O:50])[NH:48][C:47](=[O:52])[CH2:46]4)[CH:42]=[CH:43][CH:44]=3)[CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])[N:30]=2)=[CH:23][CH:22]=1>C1COCC1>[Cl:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[C:29]1[N:30]=[C:26]([CH2:25][C:24]2[CH:53]=[CH:54][C:21]([C:2]([CH3:1])=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:22][CH:23]=2)[N:27]([C:39]2[CH:40]=[C:41]([N:45]3[S:49](=[O:50])(=[O:51])[NH:48][C:47](=[O:52])[CH2:46]3)[CH:42]=[CH:43][CH:44]=2)[CH:28]=1
Reactant: CC#CCCCC
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Agent: B1C2CCCC1CCC2
Agent: OBO
Solvent: C1CCOC1
Product: CCCCC=C(C)c1ccc(Cc2nc(-c3ccc(Cl)cc3Cl)cn2-c2cccc(N3CC(=O)NS3(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-heptyne (129 μL, 1 mmol) in 2 mL dry THF at 0° C. was added 2 mL 0.5 M 9-BBN solution in THF. The resulting solution was stirred at room temperature under nitrogen for 4 hr. Then it was condensed under vacuum and used as boronic acid derivative according to general procedure G, reacting with 5-{3-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(1-methyl-hex-1-enyl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[C:15]([C:18]3[N:19]=[CH:20][N:21]4[CH:25]=[CH:24][S:23][C:22]=34)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[C:15]([C:18]3[N:19]=[CH:20][N:21]4[CH:25]=[CH:24][S:23][C:22]=34)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10]
Reactant: C=CCOC(=O)C1=C(c2ncn3ccsc23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(c2ncn3ccsc23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
To a solution of 460 mg of allyl (1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 14 ml of THF were added 860 μl and 3.76 ml of a 1 M tetra-n-butylammonium fluoride in THF, and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with 120 ml of ethy acetate, washed with 30 ml of semi-saturated aqueous saline, and then with 30 ml of a mixed solution of semi-saturated aqueous saline and a saturated aqueous sodium hydrogen carbonate solution (1:1), dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=97:3-95:5) to give 286 mg of allyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([CH2:10][S:11](/[CH:14]=[CH:15]/[C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])(=[O:13])=[O:12])=[CH:5][N:4]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:8]([NH:9][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:7][C:6]([CH2:10][S:11](/[CH:14]=[CH:15]/[C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])(=[O:13])=[O:12])=[CH:5][N:4]=1
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(N)c2)c(OC)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)cnc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (E)-2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-amine (28 mg, 0.072 mmol) in DMF (5 mL), ethyl bromoacetate (0.110 mL, 1 mmol) and potassium carbonate (138 mg, 1 mmol) were added. The mixture was stirred at 60° C. overnight. The mixture was diluted with H2O (20 mL) and extracted (2×20 mL ethyl acetate). The combined extracts were washed with brine, dried on MgSO4, and filtered. The residue was further purified by silica gel chromatography, eluting with PE/EtOAc (2:3, v/v) to afford pure product as a white solid (24.2 mg, 70%). 1H-NMR (CDCl3): δ 3.85 (s, 6H, 2×OCH3), 3.87 (s, 3H, OCH3), 3.90 (d, 2H, J=2.8 Hz, CH2), 4.00 (s, 3H, OCH3), 4.15 (s, 2H, CH2), 4.27 (q, 2H, CH2), 6.10 (s, 2H, Ph-H), 6.74 (d, 1H, J=2.0 Hz, Py-H), 7.04 (d, 1H, J=15.6 Hz, CH), 7.44 (d, 1H, J=2.0 Hz, Py-H), 7.811 (d, 1H, J=15.6 Hz, CH); HR-MS (ESI+) m/z: 481.1364 [M+H]+; C22H28N2O8S requires 480.1566,
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]3[O:38][C:37]([C:39]([O:41]C)=[O:40])=[CH:36][C:35]=3[CH:43]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]3[O:38][C:37]([C:39]([OH:41])=[O:40])=[CH:36][C:35]=3[CH:43]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3oc(C(=O)O)cc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A solution of chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylate (80.7 mg, 0.126 mmol) in THF (6 ml) was reacted with LITHIUM HYDROXIDE MONOHYDRATE (222.3 mg, 0.531 mmol) in water (3 ml) and stirred at rt for 3 hrs. The reaction treated with 1 N HCl (pH 3-4) and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried with sodium sulfate, filtered and lyophilized to give chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylic acid (74.3 mg, 94.1%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 626.13. found: 626.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH:17](O)(C)C>>[O:14]1[CH2:15][CH2:16][N:11]([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([O:7][CH3:17])=[O:6])[CH2:12][CH2:13]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CC(C)O
Product: COC(=O)c1ccnc(N2CCOCC2)c1
Temperature: 150 °C
Reaction time: 27 h

Procedure:
A 5.0 g portion of 2-chloroisonicotinic acid and 6.91 g of morpholine were suspended in 16 ml of isopropanol and stirred at 150° C. for 27 hours in a sealed tube. The solvent was evaporated and then the residue was mixed with 70 ml of methanol and 5 ml of concentrated sulfuric acid and heated under reflux for 6.5 hours. The solvent was evaporated and the residue was dissolved in chloroform and washed with saturated aqueous sodium bicarbonate. After evaporation of the solvent, the resulting mixture was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (4:1, v/v) to obtain 4.42 g of crystals of the title compound.
Reaction SMILES: [C:1]([O:10]CC)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:18]([CH2:20][C:21](OCC)=[O:22])=[O:19].[O-]CC.[Na+]>C1(C)C(C)=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:18]([C:20]1[C:21](=[O:22])[NH:4][C:3]2[C:2]([C:1]=1[OH:10])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:19]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)c1ccccc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1ccc(C(=O)c2c(O)c3ccccc3[nH]c2=O)cc1OC
Yield: 17.6 %

Procedure:
Ethyl anthranilate (1.44 grams) and 2.2 grams of ethyl 3,4-dimethoxybenzoylacetate are dissolved in 100 ml of xylene and heated to reflux for five hours with 200 mg of sodium ethoxide. After cooling, crystals are separated out and collected by filtration and recrystallized from methanol to give 0.5 grams of 3-(3,4-dimethoxybenzoyl)-4-hydroxy-2-quinolone, pale yellow needles, melting point 235° to 236° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.CCO.[OH2:21].Cl.[NH2:23]O.[OH-].[Na+]>CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:23][OH:21])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: NO
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: ON=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 25 %

Procedure:
4-(3-Fluoro-benzyloxy)-benzaldehyde (which may be prepared as described in Brabanti, E. et al. WO 2007147491 or may be purchased from Matrix Scientific, Columbia, S.C. 29224-5067; 24 g, 78.2 mmol) was taken up in 9:1 EtOH/H2O (200 mL) and hydroxylamine hydrochloride (8.15 g, 117.3 mmol) was added. A solution of NaOH (7.51 g, 187.6 mmol) in 9:1 EtOH/H2O was added dropwise by addition funnel over 30 min. The mixture was heated at reflux for 4 h, then allowed to cool and acidified to pH 5 by adding glacial AcOH (17 mL). The solid was filtered off and dissolved in EtOAc. The organic solution was dried over Na2SO4, filtered, and evaporated to give 4-(3-fluoro-benzyloxy)-benzaldehyde oxime (6.6 g, 25%).
Reaction SMILES: [H-].[Na+].C([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C=C.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.O1C[CH2:28][CH2:27][CH2:26]1>>[CH2:28]([C:8]1[C:7]([OH:6])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[CH2:21][C:20]1[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=1)[CH:27]=[CH2:26]
Reactant: Fc1ccc(CBr)cc1
Reactant: C=CCOc1ccc2[nH]ccc2c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: C=CCc1c(O)ccc2c1ccn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium hydride (60%, 140 mg, 3.47 mmol) in 4 mL tetrahydrofuran (THF) was added 5-allyloxyindole (Step A; 0.5 g, 2.89 mmol) in 1 mL and the mixture was stirred for 1 hour at ambient temperature. 4-fluorobenzyl bromide (0.43 mL, 3.32 mmol) was added and the reaction stirred 18 hours. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered through a short pad of silica and used directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@H:13]2[C@H:17]([O:18][Si](C(C)(C)C)(C)C)[C@H:16]([O:26][Si](C(C)(C)C)(C)C)[C@@H:15]([CH2:34][O:35][CH3:36])[O:14]2)=[C:6]([NH:37][CH2:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][CH2:2][CH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:26])[C@@H:15]([CH2:34][O:35][CH3:36])[O:14]2)=[C:6]([NH:37][CH2:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:5]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.2 %

Procedure:
N-{2-(2-Aminoethyl)-9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-9H-purin-6-yl}-N-(2,2-diphenylethyl)amine (1.07 g, 1.46 mmol) (preparation 18) was dissolved in dry tetrahydrofuran (4 ml), a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (6 ml, 6 mmol) added and the mixture stirred at room temperature for 2.5 hr. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The solvent was again removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (90:10:1), to give the product as a foam (760 mg). MS: 505 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=O)[CH3:11])[CH:3]=1.[H-].[Na+].Cl.[CH2:16]([O:23][CH2:24][CH2:25][N:26](C)[CH2:27]CCl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:23][CH2:24][CH2:25][N:26]([CH2:11][CH2:10][NH:9][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1cc(C)cc(C)n1
Reactant: CN(CCCl)CCOCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(NCCN(C)CCOCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To 24.5 g (0.149 mole) of N-(4,6-dimethyl-2-pyridyl)acetamide dissolved in 350 ml of dimethylformamide is added sodium hydride in mineral oil (50%) (7.2 g., 0.15 mole) in two portions with stirring, at room temperature. When reaction ceases, N-(2-benzyloxyethyl)-N-(2-chloroethyl)methylamine hydrochloride (24.5 g., 0.149 mole) is added in 2 portions. After bubbling ceases, the mixture is stirred at 50°-55° for 45 minutes and than heated on a steam bath for two hours. The mixture is cooled and concentrated under vacuum after 25 ml of acetic acid is added. The residue is taken up in dilute hydrochloric acid and extracted with hexane. The aqueous is made alkaline with 10 N sodium hydroxide and extracted with ether, then methylene chloride. The combined organic extracts are backwashed with brine, dried (sodium sulfate) and vacuum concentrated. The residue is distilled, the fraction boiling at 205°-215°/0.5 mm collected and this then refluxed in 5 N sodium hydroxide until hydrolysis is complete. On cooling, the mixture is extracted with toluene and then with methylene chloride. The combined organic extracts are washed with brine, dried and vacuum concentrated to obtain the product as an oil, weight 35 g.