Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[C:17]1(=[O:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.C(OCC)(=O)C>[C:7]([C:6]1[CH:15]=[CH:16][C:3]([CH2:2][N:18]2[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]2=[O:26])=[CH:4][CH:5]=1)(=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: O=C1N=Cc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1ccc(CN2Cc3ccccc3C2=O)cc1
Yield: 91 %

Procedure:
A mixture of 4-(bromomethyl)benzophenone (138 mg, 0.5 mmol), isoindolone (67 mg, 0.5 mmol), cesium carbonate (407 mg, 1.25 mmol), and 18-crown-6 (13 mg, 0.05 mmol) in acetone (10 mL) was stirred heating at reflux for 3 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-(4-benzoylbenzyl)-2,3-dihydroisoindol-1-one (149 mg, 91%). GC/MS gave: m/z (rel.int.) 327 (M+, 97), 250 (5), 222 (42), 196 (20) 165 (31), 146 (31), 133 (53), 119 (94), 105 (71), 91 (100), and 77 (98). 1H NMR (300 MHz, CDCl3): δ 4.33 (s, 2H), 4.89 (s, 2H), 7.42 (d, 2H), 7.45-7.59 (m, 6H), 7.77 (dd, 4H), 7.91 (dd, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)(=O)[CH3:2].C([O-])([O-])=O.[K+].[K+].ClCC[CH2:35][N:36]1[CH2:41][CH2:40][N:39]2[C:42]([C:45]([F:48])([F:47])[F:46])=[N:43][N:44]=[C:38]2[CH2:37]1>CN(C=O)C.O>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:1][CH2:2][CH2:35][N:36]4[CH2:41][CH2:40][N:39]5[C:42]([C:45]([F:48])([F:46])[F:47])=[N:43][N:44]=[C:38]5[CH2:37]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: FC(F)(F)c1nnc2n1CCN(CCCCl)C2
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCn2c(nnc2C(F)(F)F)C1
Temperature: 80 °C
Yield: 45.5 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate (0.62 g) and K2CO3 (0.35 g) in 10 mL of DMF was added 7-(3-chloropropyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.68 g) at rt. The reaction mixture was heated at 80° C. for 6 h, diluted with water and extracted with CH2Cl2. The combined organic phases were dried over anhydrous Na2SO4 for 1 h, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a white solid (0.43 g, 40.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 552.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.80 (m, 2H), 2.46 (t, J=4.2 Hz, 2H), 2.78 (t, J=3.6 Hz, 2H), 3.58 (s, 2H), 4.03 (s, 3H), 4.10 (t, J=4.2 Hz, 2H), 4.15 (t, J=3.6 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57 (m, 1H), 7.91 (m, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH3:3].C[Al](C)C.CCCCCC.C([O:25][C:26]([C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]2[CH:38]=1)=O)C.Cl>ClCCl>[CH2:10]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:26]([C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]2[CH:38]=1)=[O:25])[CH2:11][CH3:12]
Reactant: CCCN(CCC)CCCCN
Reactant: CCOC(=O)c1cn2cc(C#N)ccc2n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCN(CCC)CCCCNC(=O)c1cn2cc(C#N)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
The compound (263 mg) obtained in Example 1-2 was dissolved in dichloromethane (4.0 ml) and a 15% trimethyl aluminum/hexane solution (1.08 ml) was dropped thereto. The whole was stirred at room temperature for 15 minutes. The solution was added with the compound (300 mg) obtained in Example 19-1 and stirred for additional 20 hours. The resultant was heated to 40° C. and stirred for additional 7 hours, and then 1 mol/l hydrochloric acid was added to stop the reaction, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated saline solution and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (237 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7]C2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].C[C:36]1[N:41]=[C:40]([CH:42]=O)[CH:39]=[CH:38][CH:37]=1>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([CH3:42])[N:41]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: Cc1cccc(C=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1cccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)n1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 6-methylpicolinaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H), 7.03 (d, J=7.5 Hz, 1H), 4.83-4.77 (m, 1H), 4.13-4.08 (m, 2H), 3.99-3.95 (m, 1H), 3.72-3.69 (m, 1H), 3.62-3.54 (m, 2H), 3.42 (t, J=8.3 Hz, 1H), 3.06 (d, J=9.9 Hz, 1H), 2.85-2.83 (m, 1H), 2.64-2.57 (m, 1H), 2.55 (s, 3H), 2.44-2.29 (m, 3H), 2.08-2.03 (m, 1H), 1.91-1.82 (m, 2H), 1.20 (t, J=7.1 Hz, 3H). MS: (M+H m/z 409.1).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC.O>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: CC(=O)NN
Reactant: Fc1c(Br)ccc2c1CCC(=S)N2
Solvent: CCCCO
Solvent: O
Product: Cc1nnc2n1-c1ccc(Br)c(F)c1CC2
Temperature: 120 °C

Procedure:
To a stirred solution 6-bromo-5-fluoro-3,4-dihydroquinoline-2(1H)-thione (146-6; 0.25 g, 0.00096 mol) in n-butanol (10 mL) was added acetic hydrazide (0.177 g, 0.0024 mol). Reaction mass was heated at 120° C. and maintained for overnight. The reaction mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the title compound. 1H NMR (400 MHz, DMSO) δ 7.755-7.714 (t, J=8.4 Hz, 1H), 7.487-7.462 (dd, J=1.2 Hz, 1H), 3.034-3.008 (d, J=10.4 Hz, 4H), 2.640 (s, 3H) MS (M+1): 284.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:12])=[CH:4][CH:3]=1.[NH2:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>CCOC(C)=O>[NH2:25][C:26]1[N:31]=[C:30]([O:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=3[NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:15][CH:16]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Nc1nccc(Cl)n1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1nccc(Oc2ccc(NC(=O)c3ccccc3Nc3ccc(F)cc3)cc2)n1
Temperature: 150 °C

Procedure:
A mixture of 2-(4-fluorophenylamino)-N-(4-hydroxyphenyl)benzamide (157 mg, 486 μmol), 2-amino-4-chloropyrimidine (60 mg, 463 μmol), and cesium carbonate (302 mg, 926 μmol) in DMSO (2316 μl, 463 μmol) was placed in a microwave pressure vial, the vial was sealed, and the vial (reaction mixture) was heated in a Biotage Microwave to 150° C. for 12 minutes. LCMS analysis indicated that the reaction was complete. Reaction was diluted with EtOAc and washed with sat NaHCO3 (aq). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a brown color oil. The oil was taken up in minimal amount of DMSO and purified by Gilson HPLC {10-80% (0.1% TFA in CH3CN) in H2O over 20 min} to afford pure N-(4-(2-aminopyrimidin-4-yloxy)phenyl)-2-(4-fluorophenylamino)benzamide. MS Calcd for C23H18FN5O2=415. Found: [M+H]+=416.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9]
Reactant: O=Cc1cnccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCc1cnccc1Br

Procedure:
4-Bromo-pyridine-3-carbaldehyde (240 mg) in ethanol (10 mL) at 0° C. was treated with sodium borohydride (139 mg) for 30 min. The reaction mixture was then diluted with ethyl acetate and washed with aqueous ammonium chloride and brine to yield (4-bromo-pyridin-3-yl)-methanol as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[I:17](O)(=O)=O.II>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([I:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(-c2cccc(F)c2)n[nH]1
Reactant: [O-][I+2]([O-])O
Agent: II
Solvent: CCO
Product: CC(=O)Nc1[nH]nc(-c2cccc(F)c2)c1I
Temperature: 60 °C
Yield: 368.2 %

Procedure:
A suspension of N-[3-(3-fluorophenyl)-1H-pyrazol-5-yl]acetamide (7.6 g, 34.7 mmol), iodic acid (1.5 g, 8.5 mmol) and iodine (4.4 g, 17.3 mmol) in ethanol (200 mL) was heated at 60° C. for 1 h and cooled to room temperature. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 and 2 M Na2S2O3 aq. solution. The layers were separated and the organic washed with brine, dried (MgSO4), and concentrated in vacuo to provide the title compound as a solid (10.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[CH2:23]([O:30][CH2:31][C:32]#[C:33][CH2:34]O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][CH2:31][C:32]#[C:33][CH2:34][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:6]2[CH2:7][CH2:8][S:9][C:10]([CH3:12])([CH3:11])[CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: OCC#CCOCc1ccccc1
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCOCc3ccccc3)cc2)CCSC1(C)C
Yield: 41.9 %

Procedure:
According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 0.345 g (1.0 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 0.211 g (1.2 mmol) of 4-(benzyloxy)-2-butyn-1-ol provided 0.211 g (42%) of methyl 4-[(4-{[4-(benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylate as a pale yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[Cl:36][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH3:35])=[CH:32][CH:33]=1)[C@:17]1([C@H:16]([OH:37])[C@@H:15]([OH:38])[C@H:14]([OH:39])[C@@H:13]([CH2:12][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[O:18]1)[O:19][CH2:20]2
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: C1COCCN1
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN3CCOCC3)[C@@H](O)[C@H](O)[C@H]2O)cc1

Procedure:
((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (20 mg, 0.034 mmol) was dissolved in 1 mL of morpholine. Then the solution was allowed to reflux overnight. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 15 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.37 (s, 1H), 7.18 (s, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 5.17 (d, J=13.2 Hz, 1H), 5.11 (d, J=13.2 Hz, 1H), 4.65-4.60 (m, 2H), 4.18-4.00 (m, 4H), 3.82-3.50 (m, 7H), 3.31-3.25 (m, 1H), 3.08-2.99 (m, 2H), 2.61 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H); MS ESI (m/z) 490 (M+1)+, calc. 489.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:37])([F:36])[C:7]1[CH:8]=[C:9]([C@H:17]2[O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[C:33]([I:34])=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[C@H:18]2[CH3:35])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1>C(O)(=O)C.C([O-])(O)=O.[Na+]>[F:37][C:6]([F:5])([F:36])[C:7]1[CH:8]=[C:9]([C@H:17]2[O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[C:33]([I:34])=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]=4[N+:1]([O-:4])=[O:2])[CH:25]=3)[C@H:18]2[CH3:35])[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2ccccc2cc1I
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2cccc([N+](=O)[O-])c2cc1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Fuming nitric acid was added dropwise to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-iodo-2-naphthyl)methyl]-4-methyl-1,3-oxazolidin-2-one (synthesized from INTERMEDIATE 16 using a method analogous to that described in EXAMPLE 1, Step E) in acetic acid at room temperature. The reaction was stirred at room temperature for 3 h. The reaction was diluted with saturated NaHCO3 (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product as a mixture of product isomers. The main isomer was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-iodo-5-nitro-2-naphthyl)methyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.11 (20% EtOAc/hexanes). LCMS calc.=625.0; found=624.6 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 9.20 (s, 1H); 8.28 (dd, J=1.0, 7.7 Hz, 1H); 8.10 (d, J=8.2 Hz, 1H); 7.93 (s, 1H); 7.89 (s, 1H); 7.81 (s, 2H); 7.61 (t, J=7.9 Hz, 1H); 5.82 (d, J=7.9 Hz, 1H); 4.98 (d, J=15.9 Hz, 1H); 4.48 (d, J=15.9 Hz, 1H); 4.21-4.15 (m, 1H); 0.84 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:14]=[C:15]([CH:18]=O)[S:16][CH:17]=2)[CH:8]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:14]=[C:15]([CH:18]=[CH2:2])[S:16][CH:17]=2)[CH:8]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cc(-c2cc(Cl)ccn2)cs1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(-c2cc(Cl)ccn2)cs1
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (180 mg, 0.5 mmol) in THF (3 mL) was added n-BuLi (1.6 M, 0.34 mL) at 0° C. After the mixture was stirred for 30 minutes, a solution of 4-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (100 mg, 0.45 mmol) in THF (2 mL) was added. The resulting mixture was stirred at room temperature for 5 hours. Water was added and THF was removed. The water solution was extracted with EtOAc and organic layer was concentrated. The resulting residue was purified by silica gel column to yield 4-chloro-2-(5-vinyl-thiophen-3-yl)-pyridine.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](=[O:37])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([CH:29]1[C:28](=[O:37])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:15]=3)=[N:9][C:8]=2[CH:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: O=C1NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)nc2C(c2ccccc2)C1Cc1ccccc1
Yield: 57 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(3,5-bis(trifluoromethyl)phenyl)-1H-imidazol-5(4H)-one and trans-cinnamaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 21 as an off-white solid (88 mg, 57%). Analytical data for 21: 1H NMR (500 MHz, CDCl3) δ 9.16 (s, 1H), 8.15 (s, 2H), 7.80 (s, 1H), 7.40-7.26 (m, 6H), 7.15-7.06 (m, 2H), 7.00-6.96 (m, 2H), 4.11 (d, J=6.9 Hz, 1H), 3.63 (ddd, J=10.1, 6.8, 4.6 Hz, 1H), 3.37 (dd, J=14.8, 4.7 Hz, 1H), 2.44 (dd, J=14.8, 10.1 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.8, 149.4, 139.0, 137.7, 136.8, 132.4 (q, JCF=33.6 Hz), 131.2, 129.2, 129.0, 128.6, 128.4, 127.9, 126.8, 124.6 (d, JCF=4.0 Hz), 122.9 (d, JCF=273.0 Hz), 122.0, 112.1, 47.1, 38.5, 32.7; IR (film) cm−1 1780, 1641, 1618, 1528, 1401, 1361, 1279, 1186, 1133, 896, 730, 697, 682; LRMS (ESI): Mass calcd for [M+H]+ C27H19F6N2O2: 517.1. found 517.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 3% IPA/1% MeOH/hexanes 1.0 mL/min, 210 nm), Rt1 (minor)=17.2, Rt2 (major)=20.9 min; er=99:1.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:20]([C:23]([C:26]1[CH:30]=[C:29]([C:31]2[S:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:37]=3)=[CH:34][CH:35]=2)[N:28]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[Cl:52])[N:27]=1)([CH3:25])[CH3:24])=[N+]=[N-]>C1COCC1.O>[Cl:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[N:28]1[C:29]([C:31]2[S:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([CH3:45])(=[O:43])=[O:44])[CH:37]=3)=[CH:34][CH:35]=2)=[CH:30][C:26]([C:23]([NH2:20])([CH3:24])[CH3:25])=[N:27]1
Reactant: CC(C)(N=[N+]=[N-])c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(N)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Yield: 89 %

Procedure:
PPh3 (3.3 g, 12.58 mmol) was added at rt to a solution of the 3-(2-azidopropan-2-yl)-1-(2-chlorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H-pyrazole) (3.08 g, 6.185 mmol) in a mixture of THF—H2O (6:1, 70 mL), and the resulting mixture was stirred at it under N2 for 8d. The solvent was removed in vacuo, and the residue was partitioned between water and EtOAc. The two phases were separated, and the aqueous phase was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-60% 20% MeOH/DCM) to give the title compound as a light-yellow solid (2.43 g, 89%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.83-7.80 (m, 1H), 7.73-7.71 (m, 1H), 7.56-7.41 (m, 5H), 7.19 9d, 1H), 6.72 9d, 1H), 6.63 (s, 1H), 3.07 (s, 3H), 2.43 (brs, 2H), 1.61 (s, 6H). MS(ES) 455 (M-NH2).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20].O>CS(C)=O>[CH2:20]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH2:10]
Reactant: C=CCCCCCCCCCBr
Reactant: C1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCN1CCCCC1
Reaction time: 0.33 h
Yield: 262.8 %

Procedure:
This example illustrates a synthesis of N-(9,10-Oxidodecyl)piperidine (inventive compound no. 1619). Sodium hydride (95%) (864 mg, 36 mmol) was added to a solution of piperidine (2.554 g, 30 mmol) in dimethyl sulfoxide (75 mL). After 20 minutes of stirring, 1-bromundec-10-ene (6.99 g, 5 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing 100 mL of water and extracted with dichlormethane (5×75 mL). The organic extracts were combined, washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 5% methanol/dichloromethane eluant to yield 3.12 g (44% yield) N-(10-undecenyl)piperidine (inventive compound no. 1615).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)([CH2:16][CH2:17][N:30]3[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: O=C1CNCCN1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCNC(=O)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and piperazin-2-one following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.117 min, m/z=506; 1H NMR (CDCl3) 1.42 (d, 3H), 2.16-2.35 (m, 5H), 2.75-2.88 (m, 2H), 3.17-3.40 (m, 3H), 3.56-3.80 (m, 4H), 5.45 (m, 1H), 5.61-6.52 (s, 2H), 6.78 (d, 2H), 7.01-7.24 (m, 6H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]([NH:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])=[O:32])[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]([NH:33][CH2:34][C:35]1[CH:36]=[C:37]([NH:38]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:39]=[CH:40][CH:41]=1)=[O:32])[CH3:27]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C)CC(=O)NCc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-dimethylaminomethylcarbonylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.