Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[NH:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].I[CH2:29][CH3:30].Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[N:16]([CH2:29][CH3:30])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h

Procedure:
Methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (F) (5.30 g) was added to a stirred suspension of oil-free sodium hydride (0.424 g) in dry N,N-dimethylformamide (25 ml), under an atmosphere of nitrogen. The dark-red solution was stirred for 15 minutes, and iodoethane (3.04 g) was added. The mixture was stirred for 30 minutes, and was poured into 1M hydrochloric acid (75 ml). The mixture obtained was extracted wih ethyl acetate (2×50 ml). The combined extracts were washed with brine (25 ml), then dried (MgSO4), and evaporated. The yellow oil obtained was purified by flash chromatography on silica gel (600 ml), eluting with 70:30 v/v hexane:ethyl acetate, to give methyl 3-methoxy-4-(1-ethyl-5-nitroindol-3-ylmethyl)benzoate (G) as a yellow oil, which was crystallized from methylene chloride/hexane to give yellow needles (4.88 g, 82%); mp 129°-30° C.; 1.34(t, 3H, CH2CH3), 3.83(s, 3H, CO.OCH3), 3.92(s, 3H, OCH3), 4.11 (s, 2H, CH2Ar), 4.23(q, 2H, CH2CH3), 7.27(d, 1H), 7.48(m, 2H), 7.64(d, 1H), 7.99(dd, 1H, H6 -indole), 8.49(d, 1H, H4 -indole).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2cccc(F)c2)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.7 %

Procedure:
In 7 ml of N,N-dimethylformamide were dissolved 204 mg of 4-chloro-6-(3-fluorophenyl)pyrimidine and 82 mg of 2-butyn-1-ol, to which 47 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 151 mg of 4-(3-fluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (57)).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:23][CH:22]=1>>[C:1]1([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]4)=[CH:25][CH:26]=3)=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)NCc4ccccc4)cc3)cc2)CC1
Yield: 14.6 %

Procedure:
The title compound (7.1 mg, 15%) was prepared from (4-{[(phenylmethyl)amino]carbonyl}phenyl)boronic acid (25.5 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 487 (M+H).
Reaction SMILES: [N+:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])([O-:3])=[O:2].CC(O[C:17]([CH3:19])=O)=O>CCOCC>[CH:7]1[CH:8]=[CH:9][C:17](/[CH:19]=[C:4](/[N+:1]([O-:3])=[O:2])\[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])=[CH:4][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(C[N+](=O)[O-])c1ccccc1
Solvent: CCOCC
Product: O=C(/C(=C\c1ccccc1)[N+](=O)[O-])c1ccccc1

Procedure:
Condensation of α-nitroacetophenone (Compound 6) with N-methyl benzylidene imine (Compound 7) under the conditions detailed by Dornow et al., Ann., 588:40 (1954) (1.1 equiv. Ac2O, Et2O, reflux, 3 hours, 88 percent) provided (E)α-nitrochalcone (Compound 8) as the exclusive olefin isomer detected in the reaction mixture (Scheme 3). Treatment of Compound 8 with freshly cracked cyclopentadiene (9.0 equiv. 45° C., CH2Cl2 24 hours, 81 percent) provided a single predominant Diels-Alder adduct, Compound 9, derived from a [4+2] cycloaddition reaction through a transition state with the nitro substituent endo to the diene. Less than 1-3 percent of the diastereomeric exo adduct was detected. Notably, this Diels-Alder reaction proceeds almost exclusively to provide the sterically less favored adduct, Compound 9, presumably a consequence of a strong endo directing effect of the polarized nitro substituent. Use of cyclohexadiene in the place of cyclopentadiene provides the corresponding bicyclo[2.2.21]octane derivative.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7].[ClH:12].O1CCOCC1.C(=O)([O-])[O-].[NH4+:23].[NH4+]>C(O)C>[ClH:12].[C:6]([C:5]1[CH:8]=[CH:9][C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[NH:23])[NH2:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc(C(=N)N)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-methoxy-4-hydroxybenzonitrile (2.0 g, 13.4 mmol) were added ethanol (3 mL) and 4N hydrochloric acid/1,4-dioxane (27 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in ethanol (50 mL). Ammonium carbonate (6.4 g, 67 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, water was added and the mixture was freeze-dried to give the title compound (1.82 g).
Reaction SMILES: COC([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]2[C:16]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:20])=[CH:17][CH:18]=[C:7]2[CH2:6]1)=O.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][NH:21][C:19]([C:16]2[N:8]3[C:7]([CH2:6][NH:5][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9]3)=[CH:18][CH:17]=2)=[O:20])[CH:24]=1
Reactant: COC(=O)N1Cc2ccc(C(=O)NCc3cccnc3)n2Cc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10-(methoxycarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide (5 mmol) of Step B in methanol (50 mL) was treated with potassium carbonate and stirred at room temperature overnight. Water was then added to the solution and the pH adjusted to 6 with 6N hydrochloric acid. The solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate, and evaporated to dryness. The residual oil was triturated with ethyl acetate and hexane to yield the title compound as a powder.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:20](=[O:25])[C:21]([O:23]C)=[O:22])=[CH:15][N:16]3[CH3:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O.Cl>CO>[CH3:19][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:26])[F:27])=[CH:9][CH:8]=3)[CH:18]=2)[C:14]([C:20](=[O:25])[C:21]([OH:23])=[O:22])=[CH:15]1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cc(C(=O)C(=O)O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.4 %

Procedure:
The mixture of methyl 2-[6-(4-trifluoromethoxyphenyl)-1-methyl-1H-indol-3-yl]-2-oxoacetate (0.120 g, 0.318 mmol), and sodium hydroxide (1N, 1 mL, 1.0 mmol) in methanol (10 mL), was stirred at room temperature for 2.5 hours. The mixture was poured into excess water and acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The organic phase was evaporated to dryness and dried under vacuum at 55° C. for 12 hours to yield the title compound as a yellow solid (0.0686 g, 59.1%), mp: 233-235° C. (dec). Mass spectrum (+APCI, [M+H]+) m/z 364; 1HNMR (400 MHz, DMSO-d6): δ13.8-14.0 (br s, 1H), 8.55 (s, 1H), 8.25 (d, 1H, J=8.3 Hz), 7.95 (d, 1H, J=1.1 Hz), 7.85-7.95 (m, 2H), 7.65 (dd, 1H, J=8.2 and 1.6 Hz), 7.45 (dd, 2H, J=8.8 Hz and 0.88 Hz), add 4.0 ppm (s, 3H). Elemental Analysis for C19H14F3NO4: Calculated: C, 59.51; H, 3.33; N, 3.86. Found: C, 59.39; H, 3.38; N, 3.71.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:11])(=[NH:10])[CH2:6][CH2:7][CH2:8][CH3:9].[Cl:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[S:21])[CH:16]=[CH:17][CH:18]=1>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([NH:10][C:5](=[NH:11])[CH2:6][CH2:7][CH2:8][CH3:9])=[S:21])[CH:16]=[CH:17][CH:18]=1
Reactant: CCCCC(=N)N
Reactant: S=C=Nc1cccc(Cl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCC(=N)NC(=S)Nc1cccc(Cl)c1

Procedure:
To a stirred, ice bath chilled solution of 5.4 g. of sodium methoxide in 100 ml. of absolute ethyl alcohol was added slowly 13.69 g. of valeramidine hydrochloride. Stirring was continued for ten minutes and then 16.9 g. of 3-chlorophenyl isothiocyanate was added dropwise and stirring was continued an additional hour. The solvent was evaporated under reduced pressure, the resulting residue was taken up in 100 ml. of dry ether and the ether solution was extracted several times with water and the combined water wash was extracted with 50 ml. dry ether. The combined ether extract was dried and then acidified by addition of 50 ml. 2-N ethereal hydrogen chloride. The resulting precipitate was filtered to give, after recrystallization from acetonitrile, 9.6 g. of 1-(3-chlorophenyl)-3-(pentanimidoyl)-2-thiourea hydrochloride; m.p. 142°-145°C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.Br[CH2:32][CH2:33][CH2:34][O:35][CH3:36]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: COCCCBr
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Product: COCCCn1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc21

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 1, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and 1-bromo-3-methoxypropane. The desired product was obtained in a yield of 65% as light yellow foam. MS (m/e): 570.4 (M+H, 70%).
Reaction SMILES: CC[O-].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=O.[N:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N+]=[N-]>CCO>[Br:5][C:6]1[CH:7]=[C:8]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:16][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2
Reactant: COc1ccc(C=O)cc1Br
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Br)c(OC)cc2[nH]1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of sodium ethylate in ethanol (prepared from sodium (1.92 g; 83.70 mmol) and EtOH (40 mL)) was added dropwise to a cold (−10° C.) solution of 3-bromo-p-anisaldehyde (4 g; 18.60 mmol) and ethyl azidoacetate (ABCR, 27.80 ml; 46.50 mmol) in EtOH (60 mL). After the end of the addition, the reaction mixture was warmed up to 0° C. and stirred at RT for 5 hours. The heterogenous mixture was poured onto ice and stirred for 30 minutes. The solid was collected by filtration and dried under high vacuum. The solid was taken up in xylenes (60 mL) and heated to reflux for 3 hours. The solvent was evaporated and the residue was purified by silica column chromatography (c-Hexane/ethyl acetate, 80/20) to give the title compound as a pale yellow solid. 1H NMR (DMSO-d6) δ 11.87 (s, 1H), 7.89 (s, 1H), 7.05 (s, 1H), 6.98 (s, 1H), 4.31 (q, J=7 Hz, 2H), 3.85 (s, 3H), 1.32 (t, J=7 Hz, 3H). HPLC (Method A), Rt 4.28 min (Purity: 98.1%). LC/MS (Method B): 297.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: OCC1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1)N1CCC(CO)CC1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and piperidin-4-ylmethanol (59 mg, 0.51 mmol). The title compound was obtained as a solid (70 mg, 36% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 7.89 (1H, s), 4.50 (1H, m), 4.25 (2H, m), 3.24 (2H, m), 1.68 (3H, m), 1.09 (2H, m). MS m/z: 448.34, 450.34 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+]>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:10]([F:15])[F:14])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cnc(Cl)nc1
Yield: 39.7 %

Procedure:
2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium 2-chloro-2,2-difluoroacetate (3.50 g, 22.98 mmol) in N,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90° C. for 24 hours and concentrated in vacuo. The residue was purified by column chromatography (5-30% ethyl acetate/hexanes) to afford 2-chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7% yield) as a pale yellow oil. MS (LC/MS) R.T.=1.32; [M+H]+=181.14.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37]([Cl:49])=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51]CC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[Cl:49][C:37]1[C:38]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)=[CH:39][C:31]([C@H:12]2[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:50][OH:51])[O:11]2)=[C:32]2[C:36]=1[CH2:35][CH2:34][CH2:33]2
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCC3)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)CCC3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of compound 18 (0.87 g, 1.09 mmol) in THF/MeOH (8.9 mL/8.9 mL) were added Pd/C (10% Pd, 122 mg). The mixture was stirred at rt under hydrogen atmosphere for 15 h. The catalyst removed by filtration, and then the filtrate was concentrated in vacuo. The residue was purified by prep HPLC (reverse phase) to provide the compound E005 (0.11 g, 0.25 mmol, 23%).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19](Br)=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:24]([OH:26])=[O:25])([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.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:24]([OH:26])=[O:25])([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
Reactant: OB(O)c1cccs1
Reactant: O=C(O)c1cc2cc(Br)ccc2n1C(c1ccccc1)c1ccccc1
Product: O=C(O)c1cc2cc(-c3cccs3)ccc2n1C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 109 except that 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid and 2-thiopheneboronic acid were used.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C@H:43]2[CH2:48][CH2:47][C@H:46]([CH:49]=O)[CH2:45][CH2:44]2)=[CH:39][CH:38]=1)#[N:36]>C1COCC1>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[CH:49][C@H:46]1[CH2:47][CH2:48][C@H:43]([C:40]2[CH:39]=[CH:38][C:37]([C:35]#[N:36])=[CH:42][CH:41]=2)[CH2:44][CH2:45]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](C=CCC3OCCCO3)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2-(1,3-dioxan-2-yl)ethyl)triphenylphosphonium bromide (17.4 g, 38.0 millimols) with THF (100 ml) was cooled down to -20° C., followed by adding t-BuOK (4.5 g, 39.9 millimols) to the mixture, stirring for 30 minutes, dropwise adding to the mixture, a THF (35 ml) solution of trans-4-(4-cyanophenyl)cyclohexanecarbaldehyde (7.7 g, 36.1 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 3, to obtain raw 4-(trans-4-(3-(1,3-dioxan-2-yl)propenyl)cyclohexyl)benzonitrile (10.3 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.[N:16]1([CH:21]([CH3:26])[C:22](OC)=[O:23])[CH:20]=[N:19][CH:18]=[N:17]1>O1CCCC1>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:22]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:11])[F:12])=[CH:9][CH:8]=2)([OH:23])[CH:21]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH3:26])=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: COC(=O)C(C)n1cncn1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(n1cncn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 4-trifluoromethoxybromobenzene (9.3 g) in dry tetrahydrofuran (40 cm3)was added dropwise to a stirred mixture of magnesium turnings (0.93 g), dry tetrahydrofuran (15 cm3) and a crystal of iodine under a nitrogen atmosphere and at the ambient temperature. The reaction was observed to have commenced after 4 cm3 of the solution had been added. After the addition was complete the mixture was stirred for a further 2 hours. A solution of methyl 2-(1,2,4-1H-triazol-1-yl)propionate (3.0 g) in dry tetrahydrofuran (5.0 cm3) was added dropwise to the mixture and after stirring for a further two hours at the ambient temperature the mixture was warmed to 40° C. for 3 hours. The mixture was then quenched with water, acidified with dilute hydrochloric acid and extracted with diethyl ether. The ethereal extract was washed with water (three times) and dried over anhydrous magnesium sulphate. The residual oil remaining after removal of the solvent by evaporation under reduced pressure was subjected to purification by hplc using a silica gel column eluted with a mixture of dichloromethane (3 parts by volume) and ethyl acetate (2 parts by volume) to give 1,1-bis(4-trifluoromethoxyphenyl)-2-(1,2,4-1H-triazol-1-yl)propanol (1.0 l g) as a solid residue.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([CH2:25]Br)[C:22]([C:27]#[N:28])=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C>[C:27]([C:22]1[CH:21]=[CH:20][CH:19]=[CH:24][C:23]=1[CH2:25][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2])#[N:28]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: N#Cc1ccccc1CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2C#N)CCCC1=O
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
40% Methanolic Triton B (2.18 mL, 4.8 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at 25° C. After 10 minutes, a-bromo-o-tolunitrile (1.0 g, 5.0 mM) was added and the resultant mixture stirred at room temperature for 30 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was triturated with diethyl ether and methylene chloride, then dried in vacuo to afford 1.31 g (91%) of the 9-[(2-cyanophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.75 (dd, 1H, J=1 and 8 Hz), 7.5-7.2 (m, 5H), 6.6 (d, 1H, J=8 Hz), 5.55 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.25 (m, 2H). IR (KBr, cm−1) 2222, 1711, and 1650. MS (ES) m/e 357, 359.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[N:32]([CH2:12][C@H:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1C=Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Reaction time: 0.08 h
Yield: 88.5 %

Procedure:
A solution of (R)-(8-(2,6-dichlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate prepared in Example 57, step 7 (500 mg, 1.0 mmol) and sodium azide (340 mg, 5.2 mmol) in anhydrous DMF (20 mL) was heated at 90° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (20 mL) and the resulting suspension stirred vigorously for 5 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography on silica gel with 10–25% ethyl acetate in hexanes afforded 310 mg (85%) of (R)-2-azidomethyl-8-(2,6-dichloro-phenyl)-6-fluoro-2H-chromene as a yellow oil. [α]D25=+282.1° (c=2.7 mg/0.7 MeOH); MS (EI) m/z 349. (M+).