Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]#[CH:33]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:10][N:11]([CH2:33][C:32]#[CH:31])[C:12]=2[C:13]([F:15])([F:16])[F:14])=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: CSc1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1nc(-c2ccc(SC)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 21.1 %

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylthio)phenyl]-5-(trifluoromethyl)-1H-pyrazole (0.15 g) from step 1 was added to potassium carbonate (0.14 g) and propargyl bromide (0.45 g) in 5 mL of DMF. HPLC purification gave 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-1-propargyl-5-(trifluoromethyl)pyrazole (35 mg, 22%) in the first fraction (mp 144.5°-146° C.) and 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-1-propargyl-3-(trifluoromethyl)-1H-pyrazole in the second fraction (87 mg, 56%, mp 135.5°-138.5° C.) .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH3:12])([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:19]([C:18]3[CH:21]=[CH:22][C:15]([N:14]([CH3:23])[CH3:13])=[CH:16][CH:17]=3)[O:20][C:9]([CH3:11])([CH3:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)N=C1c1cccc(Cl)c1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: C1COCCO1
Product: CN(C)c1ccc(C2OC(C)(C)N=C2c2cccc(Cl)c2)cc1

Procedure:
3 g of 3-(m-chlorophenyl)-2,2-dimethyl-2H-azirine and 2.4 g of p-(dimethylamino)benzaldehyde were exposed to light for 2 hours in 350 ml of 1,4-dioxane (with the light source described in Example 2). After removing the solvent in a water-jet vacuum, the residue was chromatographed twice on aluminum oxide (neutral, activity 1), the elution was carried out in both cases with n-hexane/ether (9:1). Crystallization from n-hexane gave 4-(m-chlorophenyl)-5-[p-(dimethylamino)phenyl]-2,2-dimethyl-3-oxazoline which melted at 96°-97° C. after drying for 5 hours at 60° C. and 13 Torr.
Reaction SMILES: [O:1]1C2C(=CC=CC=2)C(=O)C(C2C=CC=CC=2)=[CH:2]1.[CH:18]1[C:23]([C:24]2[C:33](=[O:34])[C:32]3[C:31](O)=[CH:30][C:29]([OH:36])=[CH:28][C:27]=3[O:26][CH:25]=2)=[CH:22][CH:21]=[C:20]([OH:37])[CH:19]=1.C1C(C2C(=O)C3C=CC(O)=CC=3OC=2)=CC=C(O)C=1>>[CH3:2][O:1][C:30]1[CH:31]=[C:32]2[C:33](=[O:34])[C:24]([C:23]3[CH:18]=[CH:19][C:20]([OH:37])=[CH:21][CH:22]=3)=[CH:25][O:26][C:27]2=[CH:28][C:29]=1[OH:36]
Reactant: O=c1c(-c2ccccc2)coc2ccccc12
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Agent: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Product: COc1cc2c(=O)c(-c3ccc(O)cc3)coc2cc1O
Yield: 4 %

Procedure:
A dried aglucone isoflavone material weighing 7.3 g and containing 49% genistein, 19% daidzein, and 4% glycitein is obtained.
Reaction SMILES: [F:1][C:2]([F:44])([CH2:40][CH2:41][CH2:42][CH3:43])[C:3](=[O:39])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@H:7]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32])=[O:28].C(O)(=O)C.O>C1COCC1>[F:1][C:2]([F:44])([CH2:40][CH2:41][CH2:42][CH3:43])[C:3](=[O:39])[CH2:4][CH2:5][C@H:6]1[C@H:10]([OH:11])[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:32])=[O:28]
Reactant: CCCCC(F)(F)C(=O)CC[C@@H]1[C@H](C/C=C\CCCCCC(=O)OCC(=O)c2ccccc2)C(=O)C[C@H]1OC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
The compound (16-a)(0.514 g) was dissolved in the solvent mixture (acetic acid:water:THF=4:2:1)(30 ml), and the solution was maintained overnight at room temperature. The titled compound (16-b) was obtained by purifying the crude product on silica gel column [yield:0.272 g(61%)].
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[N:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[CH:52][N:51]=1.[NH2:60][C:61]1[CH:62]=[C:63]([C:73]2[N:78]=[C:77]([C:79]3([OH:83])[CH2:82][CH2:81][CH2:80]3)[CH:76]=[CH:75][CH:74]=2)[CH:64]=[C:65]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)[CH:66]=1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:67]1([C:65]2[CH:64]=[C:63]([C:73]3[N:78]=[C:77]([C:79]4([OH:83])[CH2:82][CH2:81][CH2:80]4)[CH:76]=[CH:75][CH:74]=3)[CH:62]=[C:61]([NH:60][C:50]3[N:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[CH:52][N:51]=3)[CH:66]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1cc(-c2cccc(C3(O)CCC3)n2)cc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: OC1(c2cccc(-c3cc(Nc4nccc(C(F)(F)F)n4)cc(N4CCOCC4)c3)n2)CCC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Xantphos (93 mg, 0.161 mmol), palladium(II) acetate (24.2 mg, 0.108 mmol), and cesium carbonate (350 mg, 1.08 mmol) were added to a degassed solution of 2-chloro-4-(trifluoromethyl)pyrimidine (103 mg, 0.565 mmol), 1-{6-[3-amino-5-(morpholin-4-yl)phenyl]pyridin-2-yl}cyclobutanol (175 mg, 0.538 mmol) in dioxane (45.3 mL) and the reaction mixture was heated to 100° C. for 2 hours and then for 5 hours at 115° C. Then, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate:hexanes) to afford 1-{6-[3-(morpholin-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]pyridin-2-yl}cyclobutanol as an off-white solid. MS APCI calc'd for C24H25F3N5O2 [M+H]+ 472. found 472. 1H NMR (NMR Hz 400 MHz, Acetone-d6): δ 9.26 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.16 (s, 1H), 7.90 (t, J=7.8 Hz, 1H), 7.84-7.77 (m, 2H), 7.66 (d, J=7.8 Hz, 1H), 7.53 (s, 1H), 7.23 (d, J=4.9 Hz, 1H), 3.86 (t, J=4.4 Hz, 4H), 3.30 (t, J=4.4 Hz, 4H), 2.74-2.63 (m, 2H), 2.43 (m, 2H), 2.04 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.N1C2C(=CC=CN=2)C=C1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].O1CCCC1>C(=O)([O-])[O-].[K+].[K+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[CH:5]=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cnc3[nH]ccc3c2)cc1OC
Temperature: 120 °C
Yield: 40.9 %

Procedure:
In a microwave safe tube, 5-bromo-7-azaindole (81, 392 mg, 1.99 mmol), prepared from 7-azaindole following the published procedure (Marie-Claude, Viaud, Heterocycles, 1999, 50, 1065-1080), 3,4-dimethoxyphenyl boronic acid (905 mg, 4.97 mmol), and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.099 mol) were mixed in 1.0 M of potassium carbonate (6.0 mL) and tetrahydrofuran (9.5 mL, 0.12 mol). The resulting mixture was heated at 120° C. in a CEM Discover microwave unit for 10 minutes. Ethyl acetate and water were added, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded the crude material, which was purified by column chromatography (40-70% ethyl acetate:hexanes) to yield the desired product as a light yellow solid (82, 207 mg, 41%). MS(ESI) [M+H+]+=255.2.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C@@H:3]([N:5]([CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=O)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[CH3:26][C:27]([S@:30]([NH2:32])=[O:31])([CH3:29])[CH3:28]>C1COCC1.[Cl-].[Na+].O>[C:27]([S@:30](/[N:32]=[C:15](/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)\[CH2:14][CH2:13][N:5]([C@H:3]([C:2]([CH3:25])([CH3:24])[CH3:1])[CH3:4])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:31])([CH3:29])([CH3:28])[CH3:26]
Reactant: C[C@H](N(CCC(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C)C(C)(C)C
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](N(CC/C(=N\[S@](=O)C(C)(C)C)c1ccc(F)cc1)C(=O)OC(C)(C)C)C(C)(C)C
Yield: 41.2 %

Procedure:
To a solution of (S)-tert-butyl 3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (1.50 g, 4.27 mmol) in dry THF (20 mL) was added Ti(Oi-Prl)4 (2.46 g, 8.55 mmol) and (R)-2-methylpropane-2-sulfinamide (1.03 g, 8.55 mmol) under N2, and the mixture was refluxed overnight. After the reaction was over, the solution was poured into 20 mL brine and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by chromatography to afford tert-butyl (E)-3-((R)-tert-butylsulfinylimino)-3-(4-fluorophenyl)propyl((S)-3,3-dimethylbutan-2-yl)carbamate (800 mg, 42%). 1H NMR (CDCl3): 0.75 (s, 9H), 1.26 (m, 12H), 1.47 (s, 8H), 3.27 (m, 2H), 3.49 (m, 2H), 3.91 (m, 1H), 7.14 (m, 2H), 7.89 (m, 1H), 8.25 (m, 1H).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C[O:36][B:37](OC)[O:38]C.S([O-])(O)(=O)=O.[K+]>O1CCCC1.[Cl-].[NH4+].C(OCC)C>[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])=[CH:24][CH:25]=2)[CH:20]=[C:19]1[B:37]([OH:38])[OH:36])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)n1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyllithium in pentane (1.7 M, 20.7 mL, 35.2 mmol, 1.20 equiv) was added to a solution of 5-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester (1-5, 10.2 g, 29.3 mmol, 1 equiv) in tetrahydrofuran (100 mL) at −78° C. The resulting light-brown solution was stirred at −78° C. for 30 min, then trimethylborate (6.67 mL, 58.7 mmol, 2.00 equiv) was added. The resulting mixture was warmed to 0° C., then diluted with saturated aqueous ammonium chloride solution (100 mL) and ethyl ether (200 mL). The aqueous layer was made acidic with aqueous 10% potassium hydrogensulfate solution. The organic layer was separated, then washed with brine, dried over magnesium sulfate, and concentrated. The residual yellow solid was triturated with hexanes to give 1-(tert-butoxycarbonyl)-5-{[tert-butyl(dimethyl)silyl]oxy}-1H-indol-2-ylboronic acid (1-6) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ7.84 (d, 1H, J=8.9 Hz), 7.37 (s, 1H), 7.01 (d, 1H, J=2.4 Hz), 6.97 (br s, 2H), 6.88 (dd, 1H, J=9.0, 2.4 Hz), 1.73 (s, 9H), 1.00 (s,9H), 0.20 (s,6H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][Si:11]([CH3:27])([CH3:26])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C:17]1=[O:25].Br[CH2:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1COCC1>[N+:39]([C:36]1[CH:35]=[C:31]2[C:30]([CH2:29][C:18]3([C:32]2=[O:33])[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:27])([CH3:26])[CH3:10])[C:17]3=[O:25])=[CH:38][CH:37]=1)([O-:41])=[O:40]
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Diisopropylethylamine (3.64 mL, 22 mmol) is added to a stirred solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (prepared according to the procedures described in WO2008/020902) (2.64 g, 10 mmol) in THF (75 mL) at ambient temperature. To the stirred mixture is added dropwise a solution of 2-(bromomethyl)-5-nitrobenzoyl chloride (3.06 g, 11 mmol) [Pifferi et al. (1966) Tetrahedron 22, 2107] in THF (75 mL) and the mixture is then stirred at ambient temperature for 18 h. The mixture is then partitioned between EtOAc and saturated aqueous NaHCO3. The layers are separated and the aqueous layer further extracted with EtOAc. The combined organic extracts are washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][N:5]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[O:14])[C:6]1=[O:25].[Li+].[OH-]>C1COCC1.O>[C:15]1([C:13]([NH:12][CH:7]2[CH2:8][CH:9]=[CH:10][CH2:11][N:5]([CH2:4][C:3]([OH:26])=[O:2])[C:6]2=[O:25])=[O:14])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of {3-[(isoquinolin-1-carbonyl)amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl} acetic acid methyl ester, 4, (330 mg, 0.9 mmol) in 3:1 THF/H2O is treated with excess LiOH (360 mg, 8.6 mmol) and stirred for 2.5 hours at room temperature. The solution is then acidified and the aqueous layer extracted with EtOAc. The EtOAc layer is dried (MgSO4) and concentrated in vacuo to afford the desired product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:20])(=[O:19])[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[CH2:21]=[O:22].[Li][Li].Cl>O1CCCC1>[OH:22][CH2:21][CH:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]([OH:20])=[O:19]
Reactant: CC(C)CCC(=O)O
Reactant: C=O
Agent: Cl
Agent: [Li]CCCC
Agent: [Li][Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)CC(CO)C(=O)O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
Diisopropylamine (20.6 g) is dissolved in 80 ml of dry tetrahydrofuran. This solution is cooled to -30° C. n-Butyllithium (77 ml of 2.6 M in hexane) is added dropwise in a nitrogen atmosphere at a rate that maintains the reaction at -30° to -20° C. This solution is stirred at -20° C. for 30 minutes. Isocaproic acid (11.6 g) in 10 ml of tetrahydrofuran is added dropwise at -20° to -10° C., then stirred at -10° C. for 30 minutes. In a separate flask, paraformaldehyde (28 g) is heated to about 200° C. and the vapors are carried in a stream of nitrogen over the surface of the tetrahydrofuran solution of the dilithium salt of isocaproic acid. During this procedure the temperature is kept between -10° and +10° C. After all of the paraformaldehyde has vaporized the reaction mixture is cooled to 0° C. and 10% hydrochloric acid is added dropwise until the reaction mixture becomes acidic. Product is extracted with 2 portions of ether (400 ml each). The ether is dried with magnesium sulfate, filtered and concentrated in vacuo to yield 13.2 g of crude material. Product is vacuum distilled to yield 9.0 g, boiling point 135°-142° C./9 mm of Hg.
Reaction SMILES: [C:1]([CH:3]1[NH:7][CH:6]=[N:5][C:4]1=[N:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].C([O-])(=O)C.[Na+].C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+].Cl>CO.C(O)(=O)C>[C:1]([C:3]1[NH:7][CH:6]=[N:5][C:4]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2]
Reactant: N#CC1NC=NC1=NCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1[nH]cnc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 30.3 %

Procedure:
To a stirred solution of 5-cyano-4-phenylmethylimino-1H-imidazole (0.7 g, 0.004 mole) in 10 ml of methanol was added 5 ml of a 1M sodium acetate/acetic acid buffer (pH=6), followed by sodium cyanoborohydride (0.5 g, 0.008 mole). The pH of the reaction mixture was adjusted to 6 by the dropwise addition of acetic acid. The reaction mixture was stirred at ambient temperature for 17 hours, and the pH was adjusted to 10 with aqueous 5% sodium hydroxide. The pH of the reaction mixture was readjusted to 6 with aqueous 2N hydrochloric acid and the mixture extracted with four 50 ml portions of diethyl ether. The combined yellow extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was chromatographed on a column using silica gel as the stationary phase and diethyl ether as the eluant, to give 5-cyano-4-phenylmethylamino-1H-imidazole (0.24 g; mp, 95°-97° ).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].F[B-](F)(F)F.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[C:3]([CH2:9][C:10]([NH2:12])=[O:11])[CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: NC(=O)Cc1cc(F)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(F)cc1CC(N)=O
Temperature: 65 °C
Reaction time: 16 h

Procedure:
Under inert conditions a suspension of 2-(2-bromo-5-fluorophenyl)acetamide (A33) (0.242 g, 1.04 mmol), PdCl2(PPh3)2 (0.037 g, 0.052 mmol), t-Bu3PH.BF4 (0.015 g, 0.052 mmol), CuI (0.010 g, 0.052 mmol) and (trimethylsilyl)acetylene (0.177 mL, 1.25 mmol) in anhydrous DMF (9 mL) was degassed with nitrogen for 10 minutes. Et3N (3 mL) was added and the resulting mixture was stirred at 65° C. under nitrogen for 16 hours. The volatiles were removed under reduced pressure, then the residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A34 as a tan coloured solid (0.242 g, 93%); 1H NMR (400 MHz, d6-DMSO) δ 7.46 (dd, J=8.6, 5.9 Hz, 1H), 7.38 (s, 1H), 7.15 (dd, J=10.0, 2.7 Hz, 1H), 7.08 (td, J=8.6, 2.7 Hz, 1H), 6.99 (s, 1H), 3.60 (s, 2H), 0.23 (s, 9H).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14])[C:10](=[O:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li].[Li+].CC([N-]C(C)C)C.[CH:32]([C:34]1[N:35]=[CH:36][O:37][CH:38]=1)=[O:33].Cl>C1COCC1>[OH:33][CH:32]([C:34]1[N:35]=[CH:36][O:37][CH:38]=1)[CH2:11][C:10](=[O:12])[CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:13]([O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:17])[CH3:18])[CH3:14]
Reactant: O=Cc1cocn1
Reactant: CC(=O)C(O[Si](C)(C)C(C)(C)C)C(C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)C(=O)CC(O)c1cocn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 3,4-di)t-butyldimethylsilyloxy)pentan-2-one (4, 2.8 g, 8 mmol,) in THF (10 mL) was added to -70° C. solution of litium diisopropylaminde (LDA, 8 mmol) in THF (20 mL). After 10 minutes at -70° C., a solution of 4-formyloxazole (1.0 g, 8 mmol--Preparation 15) in THF (5 mL) was added and the resulting mixture allowed to warm to 0° C. Aqueous HCl was added and the mixture extracted with ether. The organic layer was washed with water and brine, dried over MgSO4, evaporated and the residue purified by medium pressure chromatography (0-50% hexane-ethyl acetate gradient) to yield 4-[1-hydroxy-4,5-di-(t-butyldimethylsilyloxy)-3-oxohexyl]oxazole (5).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: OC1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCC(O)CC2)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 78.2 %

Procedure:
To a round bottom flask was added azepan-4-ol (300 mg, 2.60 mmol), 1-fluoro-4-nitrobenzene (368 mg, 2.60 mmol), Cs2CO3 (1018 mg, 3.13 mmol) and DMF (5 mL). The reaction was stirred at 100° C. for 10 hrs. The reaction was diluted with EtOAc (50 ml), washed with water (4×20 ml) and saturated aqueous NaCl (25 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/He) to give the product, 1-(4-nitrophenyl)azepan-4-ol (480 mg, 2.032 mmol, 78% yield) as a light yellow solid. Anal. Calcd. for C12H16N2O3 m/z 236.2, found: 237.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.18-8.03 (m, 2H), 6.71-6.57 (m, 2H), 4.00 (br. s., 1H), 3.74-3.60 (m, 1H), 3.60-3.41 (m, 3H), 2.22-2.01 (m, 2H), 1.95-1.72 (m, 4H); 13C NMR (101 MHz, CDCl3) δ ppm 153.41, 136.89, 126.38, 110.02, 69.88, 49.24, 44.00, 35.87, 34.96, 21.59.
Reaction SMILES: C([O:5][C:6](=[O:16])[C@@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:50][C:51]1[C:52]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][C:53]=2[S:54][C:55]=1[C:56](O)=[O:57].C(O)(C(F)(F)F)=O>ClCCl>[Cl:50][C:51]1[C:52]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][C:53]=2[S:54][C:55]=1[C:56]([NH:8][C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([OH:5])=[O:16])=[O:57]
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Reactant: Cc1ccc2c(Cl)c(C(=O)O)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(Cl)c(C(=O)N[C@H](Cc3ccccc3)C(=O)O)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general method B, to a solution of A1 (110.65 mg, 0.5 mmol) in dry dichloromethane (3 mL) was added HATU (171.09 mg, 0.45 mmol), DIPEA (0.174 mL, 1 mmol) and 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid (113.34 mg, 0.50 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure gave an yellow oil. Then the oil was dissolved in 2 mL of CH2Cl2 and 2 mL TFA was add under argon. The reaction mixture was stirred at room temperature for 12 h (TLC monitor). The solvent was removed under reduce pressure and the crude compound was purified by flash chromatography on silica gel, using HOAc/ethyl acetate (1:100) as the eluent, gave 2a; (178.51 mg, 95.5%). [α]D25: −31.7 (c=0.36, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.80-7.75 (m, 3H), 7.41-7.24 (m, 6H), 5.03-4.97 (m, 1H), 3.44-3.26 (m, 2H), 2.50 (s, 3H); 13C NMR (300 MHz, acetone-d6): δ 171.57, 159.83, 138.30, 138.05, 136.67, 134.65, 131.57, 129.50, 128.39, 127.54, 126.87, 122.57, 122.51, 118.78, 54.03, 36.85, 20.73; HRMS (ESI): calcd for: C19H16ClNO3S [M−H]−=372.0467, obsd [M−H]−=472.0484.