Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:25][C:22]1[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3)c2cc1OC
Temperature: 170 °C
Reaction time: 0.83 h
Yield: 169.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.84 g) and commercially available 4-nitrophenol (3.42 g) was mixed and stirred at 170° C. for 50 minutes. After cooling to room temperature in air, aqueous sodium hydrogen carbonate was added to the reaction mixture, and the admixture was extracted 3 times with ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol to obtain 4.54 g of the title compound (yield: 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]2[N:14]=[C:15]([SH:17])[N:16]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25](I)([F:27])[F:26].C(=O)=O>CN(C)C=O.C(Cl)Cl.C(OCC)(=O)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]2[N:14]=[C:15]([S:17][C:25]([F:27])([F:26])[F:24])[N:16]=[C:4]2[N:3]=1
Reactant: Cc1cc(-c2ccccc2)n2nc(S)nc2n1
Reactant: FC(F)(F)I
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)n2nc(SC(F)(F)F)nc2n1
Temperature: 30 °C

Procedure:
To 1.5 g (6.2 mmol) of 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidin-2-thiol and 1.5 g (10.9 mmol) of powdered potassium carbonate stirring in 20 ml of dimethylformamide, 3 ml of condensed trifluoromethyl iodide was added dropwise at ambient temperature. Keeping the dry ice condenser on from the addition, the stirred mixture was warmed to 30° C. At three separate times during a 2 h period, 2.0 ml portions of trifluoromethyliodide were added. Excess water was added and the aqueous mixture was extracted with a 1:1 mixture of ethyl acetate/diethyl ether (200 ml) and the organic layer was washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and evaporated in vacuo to give an oil. Silica gel column chromatography (methylene chloride followed by 1:1 methylene chloride/ethyl acetate) afforded 0.4 g of the title compound (main component present), m.p. 91°-93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[F:22][C:23]([F:28])([F:27])[C:24](O)=[O:25]>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]([F:28])([F:27])[F:22])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)C(F)(F)F)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reaction time: 72 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (30 mg, 0.11 mmol) and trifluoroacetic acid (28.5 mg, 0.25 mmol) were mixed in THF (3 ml). Carbodiimde resin (295 mg, 0.31 mmol) was added and shaking continued for 72 h. The reaction was filtered, the resin washed with THF and methanol and the combined filtrate and washings filtered through an SPE (SCX), to give, after evaporation of the solvent under vacuum, N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)trifluoracetamide. NMR; δH [2H6]—DMSO 11.25,(1H, s), 8.62,(1H, t), 7.92,(2H, d), 7.60,(1H, dd), 7.55,(1H, d), 7.43,(2H, d), 7.34,(1H, d), 3.16,(2H, t), 2.21,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.29 min, MH+377.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:21]=3)(=[O:17])=[O:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Yield: 77 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with [[3-(3,4-dichlorophenyl)phenyl]sulfonyl chloride (17.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 77% yield (17.2 mg). MS (ESI+) calcd mass for C19H13Cl2N5O2S 445.016701, found 445.016851.
Reaction SMILES: [C:1]([S:20][CH:21]1[NH:24][C:23](=[O:25])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH3:27].O.[C:34]([OH:38])(=[O:37])[CH:35]=[O:36]>O1CCCC1.C(Cl)Cl>[CH2:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH3:27].[C:34]([CH:35]([N:24]1[CH:21]([S:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][C:23]1=[O:25])[OH:36])([OH:38])=[O:37]
Reactant: O=CC(=O)O
Reactant: O=C1CC(SC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)C(O)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4-tritylthio-2-azetidinone (3.5 g, 10.15 mmol) in tetrahydrofuran (8 ml) was added triethylamine (1.42 ml, 10.15 mmol) and glyoxylic acid hydrate (1.02 g, 10.15 mmol). The mixture was stirred at room temperature with 4A mol sieves* (volume of 8 ml) for 1 h and allowed to stand at room temperature overnight. The solidified mixture was diluted with methylene chloride and filtered; the filtrate was evaporated and the residue crystallized from pentane to give 5.18 g (98%) of title compound as a white solid mp (112°-5° C.; ir νmax : 3100-3600, and 1755 cm-1 ; 1Hmr (CDCl3) δ: 7.3 (15H, m), 4.92 and 5.10 (1H, 2s), 4.50 (1H, dd, J=8 Hz, J=3Hz), 3.0 (1H, dd, J=15 Hz, J=7 Hz), 3.1 (6H, q, J=7 Hz), 2.70 (1H, dd, J=15 Hz, J=3Hz), 2.0-3.5 (2H, m) and 1.21 ppm (9H, t, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:3]3[C:2]([F:1])=[CH:7][C:6]([OH:8])=[CH:5][C:4]=3[F:9])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: Oc1cc(F)c(-c2ccc3cc(O)ccc3c2)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Oc1cc(F)c(-c2ccc3c(Cl)c(O)ccc3c2)c(F)c1

Procedure:
The title compound was prepared by reacting 6-(2,6-difluoro-4-hydroxyphenyl)-2-naphthol (510 mg, 1.86 mmol) and NCS (301 mg, 2.25 mmol) in THF (30 mL) according to Method C to yield 440 mg (77%) of yellowish solid: mp 213–214° C.; 1H NMR (acetone-d6): δ 6.71–6.78 (2H, m), 7.47 (1H, d, J=8.85 Hz), 7.76 (1H, dd, J=8.12 Hz, J=1.52 Hz), 7.97 (1H, d, J=8.90 Hz), 8.04 (1H, s), 8.29 (1H, d, J=8.80 Hz), 9.26 (1H, s), 9.60 (1H, s); MS (ESI) m/z 305/307 (M−H)−; HRMS: calcd for C16H9ClF2O2, 306.0259; found (ESI−), 306.01991 Anal. for C16H9ClF2O2.0.25 H2O:
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C@@H:14]3[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[F:23].[F:24][C:25]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:26]=1[NH2:27].O1CCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(OC(C)C)(=O)C>C(Cl)Cl.O>[CH3:19][C:16]1([CH3:20])[O:15][C@H:14]([CH2:13][N:9]2[C:10](=[O:12])[C:11]3[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([I:32])=[CH:31][C:25]=4[F:24])=[C:3]([F:23])[C:4](=[O:22])[N:5]([CH3:21])[C:6]=3[N:7]=[CH:8]2)[CH2:18][O:17]1
Reactant: Cn1c(=O)c(F)c(Cl)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Temperature: 25 °C

Procedure:
Combine (R)-5-chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (4.00 g, 11.6 mmol), 2-fluoro-4-iodoaniline (2.76 g, 11.6 mmol) and tetrahydrofuran (16.0 mL, 197 mmol). Cool to 0° C. to 5° C. in an ice bath, add 1.0 M lithium hexamethyldisilazide in tetrahydrofuran (23.3 mL, 23.3 mmol) while keeping the temperature below 10° C. Agitate in an ice bath for no less than 30 min and then warm to ambient temperature and stir overnight. Add water (20.0 mL) and methylene chloride (40.0 mL) and agitate, then separate the phases. Combine the organic phase and 40 mL of water, adjust the pH to 7 with 2 N HCl. Separate the organic phase extract with water (20 mL), dry over MgSO4, concentrate to 20 mL to give a solid. Add isopropyl acetate (40.0 mL, 342 mmol) to the suspension, stir at ambient temperature for no less than 2 hours, collect the solid by filtration, rinse with isopropyl acetate (20 mL), and dry overnight at 30° C. under vacuum to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].O(C1C=C(C=CC=1)CBr)C1C=CC=CC=1.[OH-].[Na+].CCOCC>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C@H:10]([C:11]([OH:13])=[O:12])[CH:14]([CH3:16])[CH3:15]
Reactant: Cc1ccc(NC(C(=O)O)C(C)C)c(F)c1
Agent: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(N[C@H](C(=O)O)C(C)C)c(F)c1

Procedure:
To a mixture of 5.15 mmole of α-(2-fluoro-4-methylphenylamino)isovaleric acid, potassium carbonate (6.44 mmole), 4 ml of HMPT and 3 ml of THF, stirred, is added 5.13 mmole of m-phenoxybenzyl bromide. The reaction is stirred overnight at RT. The reaction is poured into 5% sodium hydroxide/ether, extracted with water (2×) and then washed with water (2×), dried over sodium sulfate and rotoevaporated under vacuum. The crude product is subjected to preparatory TLC eluting with 10% ether/hexane to give m-phenoxybenzyl ester of N-(2-fluoro-4-methylphenyl)valine.
Reaction SMILES: [Si]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)(O)[CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)C>CO>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH:13]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=3)[O:16][CH:15]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(C2(O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3OCC2c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CO
Product: COc1ccc(C2C(c3ccc(O)cc3)=COc3cc(O)ccc32)cc1
Reaction time: 8 h

Procedure:
7-(tert-Butyldimethylsilyloxy)-3-(4 (tert-butyldimethylsilyloxy)phenyl)-4-(4-methoxyphenyl)chroman-4-ol (42 g), pTsOH (435 g), boiling chips and 2.5 L of ethanol win, combined in a 2-neck SL round bottom flask with condenser attached. The reaction was heated at reflux for 3 hours. The solvent was concentrated in vacuo to ˜1000 ml before being poured into chilled, stirred water (700 ml). The mixture was then extracted with ethyl acetate, the combined organic layers washed with water (3×2 L) brine (1×500 ml), dried over anhydrous magnesium sulphate and filtered and solvent removed in vacuo to give red/brown oil. The oil was dissolved in methanol (˜100 ml) ad put in freezer overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[C:3]=1[N+:16]([O-])=O>[Pd].CCO.C1COCC1>[NH2:16][C:3]1[C:4](=[O:15])[N:5]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccn(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccn(Cc2ccccc2)c(=O)c1N
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A solution of 4-amino-1-benzyl-3-nitro-1H-pyridin-2-one (1.10 g, 4.49 mmol) in 1:3 EtOH/THF (20 mL) was hydrogenated over 10% Pd/C (0.48 g, 0.45 mmol) at room temperature. After 1 h, the catalyst was removed by filtration, rinsing with MeOH. The filtrate was concentrated to provide 3,4-diamino-1-benzyl-1H-pyridin-2-one (0.90 g, 93% yield). 1H-NMR (DMSO): δ 7.32 (m, 2H), 7.23 (m, 3H), 6.98 (d, 1H, J=7.6 Hz), 5.80 (d, 1H, J=7.2 Hz), 5.22 (m, 2H), 5.0 (s, 2H), 4.11 (m, 2H). MS: calculated for C12H13N3O+H 216.1; found: 216.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][C@@H:17]3[CH2:19][C@H:14]1[CH2:15][N:16]3[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=O)=[CH:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][N:13]1[CH2:18][C@@H:17]3[CH2:19][C@H:14]1[CH2:15][N:16]3[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[CH:5]2
Reactant: O=C(c1cc2cc(F)ccc2[nH]1)N1C[C@@H]2C[C@H]1CN2c1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc2[nH]c(CN3C[C@@H]4C[C@H]3CN4c3ccccn3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 15C in THF solution (30 mL) was treated with LAH (5.50 mmol) and stirred at room temperature for 2 hours. The mixture was treated with Na2SO4 decahydrate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (10% MeOH/CH2Cl2) to provide the title compound. The maleate salt was formed and recrystallization from ethanol/diethyl ether. 1H NMR (CD3OD, 300 MHz) δ 2.22-2.36 (m, 2H), 3.45-3.62 (m, 2H), 3.70 (s, 2H), 4.45-4.58 (m, 3H), 4.95 (s, 1H), 6.23 (s, 1H), 6.62-6.65 (m, 1H), 6.70 (t, J=3.0 Hz, 1H), 6.95 (dt, J=2.0, 6.0 Hz, 1H), 7.22 (dd, J=2.0, 8.0 Hz, 1H), 7.40-7.45 (m, 1H), 7.60 (t, J=2.0 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 322 (M+H)+. Mp 211-214° C. Anal. Calcd for C19H19N4F.1.3 C4H4O4: C, 61.82;H, 5.36; N, 11.38. Found: C, 61.88;H, 4.99; N, 11.28.
Reaction SMILES: C[O:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[N:23]2CC2C=CC(OC)=CC=2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][C:13]([CH3:21])=[CH:14][C:15](=[O:20])[O:16]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[NH:23]2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][C:13]([CH3:21])=[CH:14][C:15](=[O:20])[O:16]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Agent: C/C1=C/C(=O)O[C@@H]2C[C@@H](CCC/C=C/CC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C/CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Product: CC1=CC(=O)O[C@@H]2C[C@@H](CCCC=CCC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2

Procedure:
Application of the method shown in Example 46, with the modification that (R)-4-((1R,4Z,8E,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCO[C:42]2[CH:50]=[C:49]3[C:45]([C:46](C4C=CC=CC=4)=C(Br)C3=O)=[CH:44][CH:43]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:42]2[CH:50]=[CH:49][C:45]([CH3:46])=[CH:44][CH:43]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCC4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Yield: 66 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[1-(methylsulfonyl)piperidin-4-yl]ethoxy}-1H-inden-1-one obtained in Step 3 of Example 100 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, p-tolylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/hexanes=2:1) to obtain the title compound (66%).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.C([O-])(=O)C.[NH4+].C(O)(=O)C.[N+:21]([CH3:24])([O-:23])=[O:22]>>[N+:21](/[CH:24]=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]2[O:11][CH2:1][O:2][C:3]=2[CH:4]=1)([O-:23])=[O:22]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
3,4-methylenedioxybenzaldehyde (15.55 Kg) was treated sequentially with ammonium acetate (13.4 Kg,), acetic acid (45.2 Kg) and nitromethane (18.4 Kg), warmed to 70° C., stirred for 30 minutes, warmed to 80° C., stirred for 10 hours, cooled to 10° C. and filtered. The filtrant was washed with acetic acid (2×8 Kg) and water (2×90 Kg) and dried under a nitrogen stream then in under vacuum at 50 ° C. for 2 days.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[CH2:21]([O:23][C:24](=[O:30])[CH2:25][CH:26]([CH3:29])[CH2:27]Br)[CH3:22]>CN(C=O)C>[CH3:27][CH:26]([CH2:29][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1)[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:30]
Reactant: CCOC(=O)CC(C)CBr
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (1.02 g) in dry DMF (10 ml) was added solution hydride (60% dispersion in mineral oil, 0.16 g) and the mixture stirred for 1 hour at room temperature. To the resulting solution was added ethyl-4-bromo-3-methylbutyrate and the mixture stirred for 16 hours. Solvent was evaporated and the residue partitioned between water and dichloromethane. Insoluble material was removed by centrifugation. The organic layer was filtered through phase separating paper (Whatman IPS) and the residue was purified by flash chromatography on silica gel by elution with methanol/dichloromethane/concentrated ammonia (50/950/5) to give ethyl 3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate (0.27 g) which was hydrolysed in methanol (3 ml) and aqueous sodium hydroxide (1N, 2 ml) for 2 hours at room temperature. The solution was evaporated and the residue purified by reverse phase h.p.l.c (water/acetonitrile/0.1% TFA gradient) to give a glass which crystallised on trituration with ether to give the title compound (0.08 g): m.p. 169°-171° C.; NMR (d6DMSO) δ 13.45(1H,br), 12.07 (1H,br), 8.27(2H,d), 7.28(2H,d), 6.9(4H,m), 3.80(6H,m), 3.16(4H,t), 2.45(1H,m), 2.37(1H,m), 2.12(1H,m), 1.0(3H,d); m/e 356(M+H)+ ; calculated for C22 H25N3O4F3. 0.5 H2O: C, 55.2; H, 5.6; N, 8.9 Found: C, 55.3; H, 5.6; N, 8.7%.
Reaction SMILES: [NH2:1][NH2:2].[F:3][CH:4]([C:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]#[N:6]>C(O)C>[C:8]([C:7]1[C:4]([F:3])=[C:5]([NH2:6])[NH:2][N:1]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: NN
Reactant: CC(C)(C)C(=O)C(F)C#N
Solvent: CCO
Product: CC(C)(C)c1n[nH]c(N)c1F
Yield: 54.3 %

Procedure:
Hydrazine (1.29 g, 2.4 equiv) was added to a solution of 2-fluoro-4,4-dimethyl-3-oxopentanenitrile (2.40 g, 1 equiv) in ethanol (EtOH) (50 mL), and the reaction was heated at reflux overnight. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (DCM) and washed with water. The organic solution was dried over sodium sulfate and concentrated in vacuo to provide the title compound (1.43 g, 54% yield) which was used in the next reaction without purification.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:23]([O:25][CH3:26])=[O:24])=[CH:14][CH:13]=1)([O-])=O>O.CCO>[NH2:9][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:23]([O:25][CH3:26])=[O:24])=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccn1-c1ccc([N+](=O)[O-])cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccn1-c1ccc(N)cc1
Yield: 54.7 %

Procedure:
Sodium hydrosulphite (2.08 g, 10.15 mmoll) in water (7.5 mL) was added to a refluxing solution of (i) (1 g, 4.06 mmol) in EtOH (15 mL). After 5 minutes another solution of sodium hydrosulphite (2.08 g, 10.15 mmoll) in water (7.5 mL) was added. The mixture refluxed for 5 min After that time the mixture was poured onto water. The reaction mixture was extracted with EtOAc and DCM/iPrOH. The organic fractions were dried (MgSO4), filtered and concentrated in vacuo to give a residue that was purified by flash chromatography on silica gel, eluting with a MeOH gradient in DCM to afford the desired product (ii) (480 mg). 1H NMR (400 MHz, DMSO) δ 7.06 (dd, J=2.5, 1.9 Hz, 1H), 6.96-6.90 (m, 3H), 6.59-6.53 (m, 2H), 6.22 (dd, J=3.9, 2.6 Hz, 1H), 5.25 (s, 2H), 3.60 (s, 3H).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:25]=[C:24]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=2[F:39])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:39][C:32]1[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=1[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[N:25][C:24]=1[CH2:26][C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2CC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
To a solution of 6-((tert-butyldiphenylsilyloxy)methyl)-3-(2-fluoro-5-methoxyphenyl)-2-neopentylpyridine (10.0 g) in THF (50 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in THF (55.0 mL), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.00 g) as a white amorphous solid.