Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.CCCCCC.C(O)C.C(NCC)C>>[CH3:1][C:2]1[O:3][C:4]2[C:13]3[C@H:12]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCC(=O)NCCC1CCc2ccc3nc(C)oc3c21
Solvent: CCNCC
Solvent: CCCCCC
Solvent: CCO
Product: CCC(=O)NCC[C@@H]1CCc2ccc3nc(C)oc3c21
Yield: 47.8 %

Procedure:
Racemic N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propionamide (96 mg, 0.353 mmol) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AS (50 mmID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=94/6/0.1, flow rate: 60 mL/min, column temperature: 30° C., sample concentration: 1.61 mg/mL, injection weight: 48 mg). A fraction containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was added again, and the mixture was concentrated to dryness to give the title compound (46 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AS (4.6 mmID×250 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=95/5/0.1, flow rate: 0.5 mL/min, column temperature: 30° C., sample concentration: 0.62 mg/mL (hexane/ethanol), injection volume: 10 μL).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:9])[CH:15]=2)[CH:7]=1
Reactant: Brc1ccnc(Br)c1
Reactant: OB(O)c1cccc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cc(Br)ccn2)c1
Temperature: 110 °C

Procedure:
A mixture of 2,4-dibromopyridine (3.30 g, 13.9 mmol), 3-bromophenylboronic acid (3.69 g, 16.7 mmol), tetrakis(triphenylphosphine) palladium (0) (643 mg, 0.557 mmol), 2 M Na2CO3(aq) (12 cm3), EtOH (12 cm3) and toluene (40 cm3) was degassed and then heated at reflux with a bath temperature of 110° C. under argon for 3.5 days. The reaction was allowed to cool and the two phases were separated. The aqueous layer was extracted with ether (3×13 cm3). The organic layer and the ether extracts were combined, washed with brine (1×30 cm3) and dried over anhydrous sodium sulfate. The solvents were completely removed to leave a black brown oil. The oil was purified by column chromatography over silica gel using DCM-light petroleum (0:1 to 1:10) as eluent to give 1.03 g (24%) of A-6 as a white solid; δH (200 MHz; CDCl3) 7.36 (1 H, m, ArH), 7.45 (1 H, m, PyH), 7.58 (1 H, m, ArH), 7.89 (2 H, m, PyH & ArH), 8.16 (1 H, m, ArH), and 8.52 (1 H, m, PyH); m/z [APCI+] 311, 314, 316 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Mg]Br>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: Br[Mg]c1ccccn1
Reactant: O=Cc1cccc(Br)c1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC(c1ccccn1)c1cccc(Br)c1F
Temperature: -78 °C
Yield: 22.4 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (0.250 g, 1.231 mmol) in THF (5.35 mL) cooled to −78° C. was added pyridin-2-ylmagnesium bromide (5.91 mL, 1.478 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, then allowed to warm to room temperature slowly over 2 hr. The reaction quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2. Layers were separated. The aqueous phase was extracted with CH2Cl2 (2×). The organics were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount CH2Cl2 and chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 1-40% EtOAc in hexanes over 25 min, tr=16 min) gave the title compound (78 mg, 0.276 mmol, 22.45% yield) as a yellow residue.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14].[BH3-]C#N.[Na+].N#N.[OH-].[Na+]>CC(O)=O>[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C)C1=NCCc2c(I)cccc21
Agent: N#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(C)C1NCCc2c(I)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
A mixture of methyl 2-(5-iodo-3,4-dihydroisoquinolin-1-yl)propanoate (1.15 g, 3.35 mmol) in glacial AcOH (12 mL) was treated with NaBH3CN (421 mg, 6.70 mmol) at RTunder N2. The mixture was stirred at RT for 16 h, and then poured onto H2O. The mixture was rendered basic with a 50% aqueous solution of NaOH and extracted with AcOEt. The combined org. phases were then dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.17 g) that was used as it is. UPLC-MS: MS 346.1 (M+H+); UPLC rt 0.65 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].Cl.Cl.[NH2:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19].NC1C=C(C=CC=1)C(C1CCN(C)CC1)=O.C(N(CC)CC)C>C(OCC)(=O)C.[OH-].[Na+].O1CCCC1.C(Cl)Cl.CO.[OH-].[NH4+]>[ClH:6].[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[C:18]([CH:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])=[O:5]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
2,4 difluorobenzoyl chloride (100 μl, 0.82 mmol) was added to a mixture of 4-[3-aminobenzoyl]-1-methylpiperidine dihydrochloride (200 mg, 0.69 mmol), tetrahydrofuran (5 ml) and 1N sodium hydroxide solution (2.4 ml). The reaction mixture was stirred 24 h at room temperature. The reaction mixture was diluted with ethyl acetate and 1N sodium hydroxide solution then extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, then dried over sodium sulfate. Solvent was removed under reduced pressure to give 220 mg. This mixture contained product and unreacted 4-[3-aminobenzoyl]-1-methylpiperidine. This mixture was dissolved in tetrahydrofuran and triethylamine (144 μl, 1.03 mmol) was added to the solution followed by 2,4 difluorobenzoyl chloride (100 μl, 0.82 mmol). The resulting mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with ethyl acetate and 1N sodium hydroxide solution then extracted with ethyl acetate. The ethyl acetate extracts were washed with 1N sodium hydroxide solution, water, brine, then dried over sodium sulfate. Solvent was removed under reduced pressure to give an oil. The oil was dissolved in methylene chloride:methanol:ammonium hydroxide (100:5:0.5) and the resulting precipitate was filtered and discarded. Purification by radial chromatography (silica gel, 1000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:5:0.5) gave 200 mg (81%) of a clear colorless oil. Crystallization as the hydrochloric acid salt from ethyl acetate/ethanol provided 185 mg of a white powder.
Reaction SMILES: [ClH:1].[CH:2]1([CH2:5][N:6]2[CH2:15][CH2:14][C@@:13]3([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=4)[C@@H:8]([CH2:9][CH2:10][C:11](=O)[CH2:12]3)[CH2:7]2)[CH2:4][CH2:3]1.[CH2:25]([N:27]([CH2:42][CH3:43])[C:28](=[O:41])[C:29](=[N:33]NC1C=CC=CC=1)[C:30](=O)[CH3:31])[CH3:26].CC(O[Na])=O>[Zn].C(O)(=O)C>[ClH:1].[CH:2]1([CH2:5][N:6]2[CH2:15][CH2:14][C@:13]3([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=4)[C@H:8]([CH2:9][C:10]4[C:30]([CH3:31])=[C:29]([C:28]([N:27]([CH2:42][CH3:43])[CH2:25][CH3:26])=[O:41])[NH:33][C:11]=4[CH2:12]3)[CH2:7]2)[CH2:4][CH2:3]1
Reactant: COc1cccc([C@]23CCN(CC4CC4)C[C@@H]2CCC(=O)C3)c1
Reactant: CCN(CC)C(=O)C(=NNc1ccccc1)C(C)=O
Agent: CC(=O)O[Na]
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@H]1CN(CC3CC3)CC[C@@]1(c1cccc(OC)c1)C2
Yield: 57.9 %

Procedure:
0.28 g (0.80 mmol) of (±)-trans-2-cyclopropylmethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.56 g (2.14 mmol) of N,N-diethyl-2-phenylhydrazono-3-oxobutyramide, 0.131 g (1.6 mmol) of CH3COONa, 0.402 g (6.16 mmol) of zinc dust and 10 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography ((i-Pr)2O/MeOH/conc. NH4OH 90:10:0.5). The product was dissolved in acetone and the solution brought to acidic pH with Et2O/HCl . The solid was filtered, washed and dried yielding 0.225 g of the title compound. M.p.=190°-195° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=3)[CH2:5]1.Br[C:47]1[NH:51][C:50]([C@@H:52]2[CH2:56][CH2:55][CH2:54][N:53]2[C:57](=[O:67])[C@@H:58]([NH:62][C:63](=[O:66])[O:64][CH3:65])[CH:59]([CH3:61])[CH3:60])=[N:49][CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:65][O:64][C:63]([NH:62][C@@H:58]([CH:59]([CH3:61])[CH3:60])[C:57]([N:53]1[CH2:54][CH2:55][CH2:56][C@H:52]1[C:50]1[NH:51][C:47]([C:32]2[CH:33]=[C:34]3[CH2:35][O:36][C:23]4[CH:22]=[C:21]5[C:26]([CH:27]=[CH:28][C:18]6[N:17]=[C:16]([C@@H:6]7[CH2:5][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]7[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[NH:20][C:19]=65)=[CH:25][C:24]=4[C:29]3=[CH:30][CH:31]=2)=[CH:48][N:49]=1)=[O:67])=[O:66]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)C(C)C
Reactant: COC[C@@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COC[C@@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 44.6 %

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (299 mg, 0.49 mmol), methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (217 mg, 0.58 mmol), tetrakis(triphenylphosphine) palladium(0) (28 mg, 0.02 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (35 mg, 0.04 mmol) in a mixture of 1,2-dimethoxyethane (4.3 mL) and dimethylformamide (0.75 mL) was added a solution of potassium carbonate (2M in water, 0.73 mL, 1.46 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield (2S,4R)-tert-butyl 2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (170 mg, 45%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:12])[CH:3]=1.CN(C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21].[Br-]>O1CCOCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:20](=[O:21])[CH2:19][Br:18])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: O=C(Br)CBr
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1cc(F)c(F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 4,5-difluoro-2-aminobenzoic acid (20.0 g, 115.5 mmol) in a mixture of anhydrous DMF (50 mL) and anhydrous dioxane (50 mL) was cooled to 0° C. under N2 using an ice-bath. Bromoacetyl bromide (23.3 g, 10.1 mL, 115.5 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 3/4 h period. After the addition of bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 200 mL of ice-water. The resulting precipitate was filtered, washed with water, and then dried in a vacuum desiccator overnight to afford 31.24 g (92%) of the title compound as a white solid, mp 177°-180° C.: 1H NMR (DMSO-d6) δ14.17 (bs, 1H), 11.66 (s, 1H), 8.47 (dd, J=13.6, J=7.6, 1H), 7.97 (dd, J=11.2, J=9.2, 1H), 4.28 (s, 2H); 13C NMR (DMSO-d6) δ167.55, 165.45, 151.99 (dd, J=249, J=12.9), 144.53 (dd, J=242, J=12.9), 137.58 (dd, J=7.5, 1=3), 119.75 (d, J=18.9), 114.18 (t, J=3), 108.96 (d, J=23.5), 30.43; MS (EI m/z) 293 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Br:8].[CH2:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[CH2:11][CH3:12].O>C(NCC)C.[Cu](I)I>[F:1][C:2]1[CH:3]=[C:4]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: Fc1cc(I)ccc1Br
Reactant: C#Cc1ccc(CCC)cc1
Agent: I[Cu]I
Solvent: O
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2ccc(Br)c(F)c2)cc1
Yield: 100 %

Procedure:
To a solution of 33 mmol of 3-fluoro-4-bromo iodobenzene, 0.6 mmol of copper iodide and 1.1 mmol of dichlorobistriphenylphosphine palladium in 100 ml of diethylamine were added dropwise 33 mmol of 4-propyl phenylacetylene under an argon stream while stirring. After completion of the addition, the solution was stirred at room temperature for a further 2 hours and placed into water. The solution was extracted with heptane, washed with water and concentrated under reduced pressure to afford a brown oily product. The product was isolated and purified by a silica gel column chromatography to afford 33 mmol of 2-fluoro-4-[2-(4-propylphenyl)ethynyl]bromobenzene as a pale yellow oily product.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:24]>>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:24])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Reactant: N
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Temperature: 100 °C
Yield: 39.2 %

Procedure:
6′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 27 Step 3, 57 mg, 0.14 mmol) in ammonia (7 M in MeOH) (1.5 mL, 10.5 mmol) was heated in a microwave reactor for 40 min at 100° C. The mixture was concentrated, re-dissolved in ammonia (7 M in MeOH) (1.5 mL, 10.5 mmol) and heated with MW for 40 min at 100° C. The mixture was concentrated. Purification of the crude product by flash chromatography using a gradient of CHCl3/MeOH 40:1-30:1-20:1 gave the title compound (21 mg, 39% yield): 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.15-1.29 (m, 1 H), 1.47 (m, 2 H), 1.61-1.73 (m, 1 H), 1.73-1.97 (m, 4 H), 2.18 (s, 3 H), 2.98 (d, 1 H), 3.08 (d, 1 H), 6.67 (m, 3 H), 7.26 (d, 1 H), 7.37 (dd, 1 H); MS (ES+) m/z 382 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[N:10]2[CH:5]([CH2:6][CH:7]=[CH:8][C:9]2=[O:11])[CH2:4][CH2:3]1.[N:13]([Si](C)(C)C)=[N+:14]=[N-:15].CC(O)=O.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:13]([C:7]1[CH:6]=[C:5]2[N:10]([C:2]([CH3:12])([CH3:1])[CH2:3][CH2:4]2)[C:9](=[O:11])[CH:8]=1)=[N+:14]=[N-:15]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC1(C)CCC2CC=CC(=O)N21
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC1(C)CCc2cc(N=[N+]=[N-])cc(=O)n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 2,3,8,8a-tetrahydro-3,3-dimethylindolizin-5(1H)-one (0.3 g, 1.8 mmol) in 10 ml of toluene was taken a 25 ml RB flask. To the above flask azido-trimethylsilane (2.42 ml, 18.2 mmol), AcOH (1.2 ml, 20 mmol) and DBU (0.27 ml, 1.8 mmol) were added. The reaction mixture was stirred at room temperature for overnight. Volatiles were removed under vacuum and the crude reaction mixture was purified by column chromatography. The product was obtained as colorless oil in 85% yield (0.32 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[CH2:16][CH:17]([OH:19])[CH3:18].BrC(C)CO.C(N(CC)CC)C>C(#N)C>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:16][CH:17]([OH:19])[CH3:18])[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(O)CBr
Agent: CC(Br)CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 70 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (2.0 g, 10.0 mmol), 1-bromopropan-2-ol (2.8 g, 20.0 mmol, commercial product which also contained 30% of the regioisomer 2-bromopropan-1-ol), triethylamine (4.2 mL, 30.0 mmol), and acetonitrile (15 mL) were combined in a microwave vial and heated to 70° C. for 4 hours. The reaction mixture was concentrated to dryness. The crude product was partitioned between ethyl acetate/water. The aqueous phase was re-extracted 2× with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The product was purified by flash chromatography on silica gel eluting with a gradient of 20-30% methanol in dichloromethane to give 1.7 g of the desired product as an oil.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[I-].[CH3:15][S+](C)(C)=O.O>CS(C)=O>[O:1]1[C:5]2[C:6]([CH:10]3[CH2:15][O:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: C[S+](C)(C)=O
Reactant: O=Cc1cccc2ccoc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1cc(C2CO2)c2occc2c1

Procedure:
A solution of benzofuran-7-carboxaldehyde (4.4 g) in dry dimethylsulphoxide was added dropwise to a stirred solution of sodium hydride (60% dispersion in oil, 2.5 g) and trimethylsulphoxonium iodide (7.6 g) in dimethylsulphoxide (50 ml) at room temperature. After 1 hour iced water was added and extracted with diethylether. The extracts were washed with water, dried, filtered and evaporated to a yellow oil. Chromatography on silica eluting with 10:1:90 ether:triethylamine:hexane gave 7-benzofuranyl oxirane as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.CC(OC)(C)C.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.CCCCCCC.C(OCC)(=O)C.CCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](/[C:8](=[N:18]/[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])/[CH3:9])[CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(Br)ccc1F
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)ccc1F
Temperature: 75 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Commercially available 1-(5-bromo-2-fluorophenyl)ethanone (140 g, 645 mmol, Eq: 1.0) [CAS No. 477-89-3], (R)-2-methylpropane-2-sulfinamide (78.2, 645 mmol, Eq: 1.0) and titanium(IV) ethoxide (221 g, 204 ml, 968 mmol, Eq: 1.5) were dissolved in tetrahydrofuran (1.19 l) and the mixture heated to 75° C. and stirred at this temperature overnight. The mixture was cooled to 50° C., sat. potassium sodium tartrate solution (1.17 l, 2.58 mol, Eq: 4) was added and the mixture stirred at this temperature for 1.5 hours. The mixture was diluted with TBME, the layers separated, the organic layer washed with sulfuric acid (0.05 M, 2.36 l, 118 mmol, Eq: 0.183), sat. Na2CO3-solution (645 ml, 645 mmol, Eq: 1.00) and brine, dried over Na2SO4 and the solvent evaporated leaving an dark orange solid, which was purified by trituration with n-heptane to give the first batch (144.7 g) as an off-white solid. From the mother liquor another batch (23.0 g) was obtained by trituration with pentane, yet another batch was obtained by silica gel column chromatography with n-heptane/ethyl acetate. Total yield of (R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (180.7 g, 564 mmol, 87.5% yield) as an off-white solid. MS (ISP): m/z=320.3 [M+H]+ and 322.0 [M+2+H]+.
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15]([OH:17])=O)([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([NH:38][NH2:39])=[O:37])=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:24]([O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([NH:38][NH:39][C:15]([C:10]23[CH2:9][CH2:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([CH2:14][CH2:13]2)[CH2:12][CH2:11]3)=[O:17])=[O:37])=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NNC(=O)c1ccc(OCc2ccccc2)cc1C(F)(F)F
Reactant: O=C(O)C12CCC(c3ccccc3)(CC1)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)C12CCC(c3ccccc3)(CC1)CC2)c1ccc(OCc2ccccc2)cc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a magnetically stirred solution of 4-phenylbicyclo[2.2.2]octane-1-carboxylic acid (8-A) (70 mg, 0.30 mmol) in methylene chloride (1 mL) at room temperature was added 2 M oxalyl chloride in methylene chloride (0.61 mL, 1.22 mmol). Two drops of catalytic DMF were added to catalyze the reaction. The reaction was stirred for 30 min and solvent and reagent removed in vacuo. Methylene chloride (1 mL) was added to the residue, followed by 4-(benzyloxy)-2-(trifluoromethyl)benzoic hydrazide (8-B) (141 mg, 0.46 mmol) and triethylamine (0.07 mL, 0.46 mmol). The reaction was stirred at room temperature overnight to afford intermediate 8-C, N′-[4-(benzyloxy)-2-(trifluoromethyl)benzoyl]-4-phenylbicyclo[2.2.2]octane-1-carbohydrazide, which was not isolated. To the crude product (8-C) were then added 2-chloro-1,3-dimethylimidazolinium chloride (257 mg, 1.52 mmol), more triethylamine (0.42 mL, 3.04 mmol), and methylene chloride (2 mL). The reaction was stirred at room temperature for 4 h. The reaction mixture was then diluted with methylene chloride (30 mL) and washed with water (30 mL) two times and with brine (30 mL) once. The combined aqueous layers were extracted with methylene chloride (25 mL) once. The combined organic layers were dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed on silica with 10% ethyl acetate in hexanes as eluant to give 2-[4-(benzyloxy)-2-(trifluoromethyl)pheny ]-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole (8-D). MS: m/z 505 (M+1).