Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[F:16][C:17]([F:37])([F:36])[C:18]1[C:27]([C:28](Cl)=[O:29])=[C:26]([OH:31])[C:25]2[C:20](=[C:21]([C:32]([F:35])([F:34])[F:33])[CH:22]=[CH:23][CH:24]=2)[N:19]=1>C(OCC)(=O)C.[OH-].[Na+]>[F:36][C:17]([F:16])([F:37])[C:18]1[C:27]([C:28]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)=[O:29])=[C:26]([OH:31])[C:25]2[C:20](=[C:21]([C:32]([F:35])([F:33])[F:34])[CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Cl)c1)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A solution of 4.083 g of m-chloroaniline, 9.71 g of triethylamine and 65 ml of ethyl acetate was poured over 15 minutes at 8° C.-10° C. into a solution of 11.96 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride in 130 ml of ethyl acetate with violent stirring and the temperature was allowed to return to room temperature. The mixture was refluxed for one hour and was cooled and vacuum filtered. The filtrate was washed with water, was dried and evaporated to dryness at 40° C. under reduced pressure to obtain 17.14 g of a triethylamine salt. The residue was dissolved in 2 N sodium hydroxide solution which was then heated to reflux and cooled to room temperature. The mixture was vacuum filtered and the recovered product was dissolved in water. The solution was adjusted to a pH of 1 by addition of 20% hydrochloric acid and the mixture was vacuum filtered. The recovered product was crystallized from benzene to obtain 7.599 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(3-chlorophenyl)-3-quinolinecarboxamide melting at 152° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=O.C1(P(=[N:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO[CH:39]=[CH:40][C:41]([O:43][Si](C)(C)C)=[CH2:42]>C1C=CC=CC=1>[O:43]=[C:41]1[CH:40]=[CH:39][N:26]([C:27]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:36])[CH:2]([C:1]([O:5][CH3:6])=[O:4])[CH2:42]1
Reactant: COC(=O)C=O
Reactant: C=C(C=COC)O[Si](C)(C)C
Reactant: O=C(N=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: c1ccccc1
Product: COC(=O)C1CC(=O)C=CN1C(=O)OCc1ccccc1
Yield: 70.4 %

Procedure:
A solution of methyl glyoxylate (1.92 g) and (phenylmethyl) (triphenylphosphoranylidene)carbamate (6.00 g) in benzene (100 ml), was stirred at reflux under nitrogen, for 1 h. A solution of 1-methoxy-3-trimethylsilyloxybutadiene (5.00 g) in benzene (40 ml) was added and the resulting solution stirred at reflux, under nitrogen, for 18 h. The benzene was evaporated in vacuo, and the residue dissolved in tetrahydrofuran (100 ml), treated with 1M hydrochloric acid (10 ml) and stirred at 22° for 1 h. The solution was diluted with ethyl acetate (100 ml), water (40 ml) and the aqueous phase separated. The organic phase was washed with saturated aqueous sodium chloride, dried and evaporated. The residue was purified by chromatography eluting with ethyl acetate-hexane (1:1) to give the title compound as an oil (2.97 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[N:24]O)[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:26]=1>[Ni].C(O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]([NH2:24])[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:26]=1
Reactant: COc1ccc2nc(-c3cccc4c3-c3ccccc3C4=NO)[nH]c2c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2nc(-c3cccc4c3-c3ccccc3C4N)[nH]c2c1
Yield: 73.1 %

Procedure:
Carry out the procedure as in Example 6, starting from 900 mg of 4-(6-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the preceding stage, and 1.55 mg of Raney Nickel in 50 ml of ethanol and 50 ml of tetrahydrofuran for 16 hours at 60° C. under a hydrogen pressure of 1 bar. After purification by making a paste in diisopropyl ether, we obtain 631 mg of 4-(6-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a brown powder, with the following characteristics:
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][CH2:10][CH2:9]1)=[O:6])[CH3:4].P(=O)(O)(O)[OH:31].[OH-].[Na+].O>C(#N)C>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:31])[CH2:9]1)=[O:6])[CH3:4]
Reactant: O=P(O)(O)O
Reactant: CC[C@H](C)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Reaction time: 0.83 h

Procedure:
Analysis of the starting compactin by HPLC using a Waters column RP-18 (5 m, 2.1×150 mm) with a mobile phase of (a) 0.1% phosphoric acid and the pH adjusted with 25% NaOH and (b) a mixture of distilled water and acetonitrile (1:9). The column was run for 50 min at 40° C. using a detection wavelength of 240 nm. The amount of compactin was determined using a standardized solution of 10 mg of compactin and 10 mg compactin ammonium salt.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C@H:36]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[F:59])=[CH:48][CH:47]=1)[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:58][C:56]1[CH:55]=[CH:54][C:53]([F:59])=[C:52]([C:49]2[CH:48]=[CH:47][C:46]([CH2:45][C@@H:36]([NH:35][C:8]([C:6]3[O:5][N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=3)=[O:10])[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40])=[CH:51][CH:50]=2)[CH:57]=1
Reactant: CCc1cc(C(=O)O)on1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
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: CN(C)C=O
Product: CCc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.4 %

Procedure:
3-Ethylisoxazole-5-carboxylic acid (8 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (3.6 mg). MS m/z [M+H]+ calc'd for C25H26ClFN2O5, 489.15. found 490.2.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[C:20][CH2:21][CH3:22])[CH:12]=O.C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[C:20][CH2:21][CH3:22]
Reactant: CCC#CCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCC#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 59.9 %

Procedure:
Piperidine (0.22 mL, 2.2 mmol) was added to a suspension of 3-methoxy-4-(pent-2-ynyl)oxybenzaldehyde (0.50 g, 2.3 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.49 g, 2.2 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-[[3-(3-Methoxy-4-(pent-2-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.50 g, 60%) was obtained as a colourless crystalline solid; mp 185.5-186.5° C.; δH (400 MHz, DMSO-d6) 1.05 (t, J=7.4 Hz, 2H, CH2CH3), 2.20 (q, J=7.4 Hz, 3H, CH2CH3), 3.84 (s, 3H, OCH3), 4.78 (s, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 7.03 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5 8.0 Hz, 1H, H4), 7.24 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.39 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.53 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.7, 13.5, 56.6, 56.4, 74.7, 89.3, 110.7, 113.3, 116.6, 120.2, 120.3, 122.2, 122.7, 127.9, 131.1, 134.0, 141.0, 141.5, 148.5, 149.2, 164.1, 169.5; HRMS (ESI) calculated for C22H21NO6 [M+Na]+ 402.1312. found 402.1317; vmax 747, 1001, 1253, 1508, 1583, 1661, 2980, 3246, 3523 cm−1.
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.C(N)C.CO[C:17]1[C:21]([NH:22][CH2:23][CH3:24])=[N:20][S:19](=[O:26])(=[O:25])[N:18]=1.[CH3:27][N:28]([CH2:30][C:31]1[O:35][C:34]([CH2:36][S:37][CH2:38][CH2:39][NH2:40])=[CH:33][CH:32]=1)[CH3:29]>>[CH3:29][N:28]([CH2:30][C:31]1[O:35][C:34]([CH2:36][S:37][CH2:38][CH2:39][NH:40][C:17]2[C:21]([NH:22][CH2:23][CH3:24])=[N:20][S:19](=[O:26])(=[O:25])[N:18]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CCNC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: CCN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CCNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with one equivalent of ethylamine and treatment of the resultant 3-methoxy-4-ethylamino-1,2,5-thiadiazole 1,1-dioxide with one equivalent of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine yields the title compound, which is identical to the product prepared in Example 12.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[Cl:13].C([Mg]Br)(C)C.CN(C)[CH:21]=[O:22]>O1CCCC1>[Cl:13][C:3]1[CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:7]([Cl:8])[C:2]=1[CH:21]=[O:22]
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-3,5-dichlorobenzotrifluoride (1 g, 3.4 mmol) in 1.2 mL tetrahydrofurane was slowly added to isopropylmagnesium bromide (15% in THF, 3.3 g, 3.4 mmol) at max. −10° C. After complete addition the reaction mixture was stirred for 30 min at −10° C. Dimethylformamide (0.275 g, 3.7 mmol) was added and the mixture was slowly warmed up. The mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product was used without any further purification, brown oil (741 mg, 89%).
Reaction SMILES: [C:1]1([CH:7]([NH2:19])[CH2:8][Se:9][CH2:10][CH:11]([NH2:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([Se:26][Se:27]C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.C1COCC1.[PH2](O)=O>CCOCC.C1COCC1>[C:1]1([CH:7]([NH2:19])[CH2:8][Se:9][CH2:10][CH:11]([NH2:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[SeH-:26]=[Se:27]
Reactant: c1ccc([Se][Se]c2ccccc2)cc1
Agent: NC(C[Se]CC(N)c1ccccc1)c1ccccc1
Agent: O=[PH2]O
Solvent: CCOCC
Solvent: C1CCOC1
Product: [Se]=[SeH-]

Procedure:
A preferred compound is phenyl-2-aminoethyl selenide and salts thereof. Phenyl-2-aminoethyl selenide (PAESe) was synthesized by employing the following procedure. Diphenyl diselenide, 24.707 g (79.16 mmol) was dissolved into 100 ml of tetrahydrofuran THF) with steam heating. To the intensely dark red THF solution was added 9.84 ml (95 mmol, 1.2 eq.) of 50% hypophosphorous acid and the reaction was refluxed under argon for 6 hours, cooled, and diluted with 200 ml of Et2O and washed with 200 ml of 0.127 M NaOAc buffer pH 5.0 to remove the phosphoric acid by-product. Both the Et2O and the buffer were deoxygenated by bubbling argon through fritted glass for over 1 hour in order to prevent reoxidation of phenylselenol to diphenyl diselenide. The washed organic phase was then concentrated to yield a yellow oil (diselenide contaminant) with residual salt-containing water pockets The crude product was pumped down to remove residual solvent prior to distillation which yielded the desired phenylselenol (12.6g, 51% yield). pNMR (CDCl3) (s,1H) 1.54 d (m,5H) 7.35 d. Yields as high as 70% have been obtained for this reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.N.O1CCOCC1.C([N:37](C(C)C)CC)(C)C>S(Cl)(Cl)=O.CCOC(C)=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:37])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
4-Methyl-3-(1-morpholinophthalazin-6-yl)benzoic acid (86 mg, 0.25 mmol) was dissolved in thionyl chloride (3.6 mL) and heated to 70° C. for 2 h. The reaction mixture was concentrated in vacuo before ammonia, 0.5 M in 1,4-dioxane (10 mL, 4.9 mmol) and diisopropylethylamine (0.2 mL, 1.2 mmol) were added. The reaction mixture was heated to 50° C. for 5 h and stirred overnight at RT. The reaction was diluted with 100 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layers were washed 3 times 75 mL of sodium bicarbonate (saturated, aqueous), combined, dried over sodium sulfate, and concentrated via rotovap to give a crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 349(M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH2:11]([N:13]1[C:17]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH:26]([NH2:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:20][CH2:19]2)=[CH:16][C:15]([CH3:34])=[N:14]1)[CH3:12].CCN(CC)CC>C(Cl)Cl>[ClH:10].[CH2:11]([N:13]1[C:17]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH:26]([NH:33][S:7]([C:5]3[S:6][C:2]([Br:1])=[CH:3][CH:4]=3)(=[O:9])=[O:8])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:20][CH2:19]2)=[CH:16][C:15]([CH3:34])=[N:14]1)[CH3:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CCn1nc(C)cc1C1CCN(CCC(N)c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1nc(C)cc1C1CCN(CCC(NS(=O)(=O)c2ccc(Br)s2)c2ccccc2)CC1
Product: Cl
Reaction time: 3 h
Yield: 10 %

Procedure:
(5-Bromothien-2-yl)sulfonylchloride (34 mg, 0.13 mmol) was added dropwise to a stirred solution of 3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-piperidin-1-yl]-1-phenyl-propylamine (see Example 8 (48 mg, 0.15 mmol) and Et3N (20 μL, 0.14 mmol) in CH2Cl2 (2 mL) at RT under N2 and the mixture was stirred for 3 hours. The solution was diluted with CH2Cl2 (20 mL) and then washed with NaHCO3 solution (20 mL), and the organic layer separated. The aqueous phase was re-extracted with CH2Cl2 (20 mL) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 5% MeOH/CH2Cl2 as eluent. The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was taken up in Et2O (5 mL) and a solution of HCl in Et2O was added. The resultant solid was purified by trituration to isolate the title compound (8 mg, 10%) as a colourless solid. 1H NMR (d6-DMSO, 400 MHz) δ 10.32 (1H, s), 8.85 (1H, d, J=9.1 Hz), 7.24–7.19 (5H, m), 7.09 (1H, d, J=4.0 Hz), 7.06 (1H, d, J=4.0 Hz), 5.80 (1H, s), 4.46–4.40 (1H, m), 3.99 (2H, q, J=7.2 Hz), 3.51–3.41 (2H, m), 3.15–2.87 (5H, m), 2.42–2.00 (5H, m), 1.98–1.80 (4H, m), 1.28 (3H, t, J=7.2 Hz). MS (ES+) C24H31BrN4O2S2 requires: 550, found: 551/553 (1:1, M+H+).
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[C:10](OC)=[C:9]([C:19]#[CH:20])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.[CH2:22]([O:29][C:30](=[O:40])[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)C1C=CC=CC=1.C(N(CC)CC)C.[C:48](OCC)(=[O:50])C>CCCCCC.[Cu]I.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>[CH3:22][O:29][C:30](=[O:40])/[CH:31]=[CH:32]/[C:33]1[CH:34]=[CH:35][C:36]([C:20]#[C:19][C:9]2[CH:8]=[C:7]([O:50][CH3:48])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=3[CH:10]=2)=[CH:37][CH:38]=1
Reactant: CCOC(C)=O
Reactant: O=C(C=Cc1ccc(O)cc1)OCc1ccccc1
Reactant: C#Cc1ccc2c(c1OC)C(C)(C)CCC2N(C)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.095 g, 0.336 mmol), methyl-4-iodocinnamate (Reagent 4, 0.097 g, 0.336 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 5–15% ethyl acetate in hexane as the eluent, the title compound was obtained as a white solid (0.12 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH3:14]I>CN(C)C=O.O>[CH3:14][O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: OCc1ccc(Br)cc1
Reactant: [H][H]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(Br)cc1
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
4-Bromobenzyl alcohol (1.87 g) was added over 10 minutes to a stirred suspension of sodium hydride (0.24 g--used directly in the form of 0.48 g of a 50% dispersion in oil) in dry N,N-dimethylformamide (10 cm3) under an atmosphere of nitrogen. Afer evolution of hydrogen had ceased (20 minutes), methyl iodide (1.42 g) was added and the reaction mixture was stirred for a further 10 minutes. The mixture was poured into water and the organic layer separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulphate, and concentrated by evaporation under reduced pressure. The residual, crude product was purified by column chromatography on a silica gel support, eluting with n-hexane containing 12.5% by volume ethyl acetate, to give 4-bromobenzyl methyl ether (1.6 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[BrH:16]>>[NH:7]1[CH:8]=[C:4]([CH2:3][CH2:2][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:5]=[CH:6]1.[OH2:1].[BrH:16].[BrH:16]
Reactant: Sc1ccccn1
Reactant: OCCc1c[nH]cn1
Agent: Br
Product: O
Product: c1ccc(SCCc2c[nH]cn2)nc1

Procedure:
0.5 g (4.4 mmol) of 4-(2-hydroxyethyl)-1H-imidazole and 0.49 g (44.4 mmol) of 2-mercaptopyridine are brought to reflux in 5 ml of 47% aqueous HBr for 24 h. The solvent is removed azeotropically with isopropanol under reduced pressure to provide the title compound in the form of a dihydrobromide monohydrate salt which, after crystallization from isopropanol, melts at 189°-190° C.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13]C1C=C2C(C=CN=C2)=CC=1.CO.[C:26]1([CH3:39])[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:27]=1[S:34]([O:37]N)(=[O:36])=[O:35]>C(Cl)Cl.CCOCC>[CH3:33][C:28]1[CH:29]=[C:30]([CH3:32])[CH:31]=[C:26]([CH3:39])[C:27]=1[S:34]([O-:37])(=[O:36])=[O:35].[NH2:2][N+:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Oc1ccc2ccncc2c1
Reactant: N[n+]1ccc2ccccc2c1
Agent: [I-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1ccc2ccc(O)cc2c1
Temperature: 0 °C
Yield: 60.5 %

Procedure:
O-mesitylene sulfonyl hydroxylamine (MSH) (3) was used to prepare the N-amino salt as an aminating agent as described by Tamura et al., (1972) Tetrahedron Letter. 40: 4133, incorporated herein by reference in its entirety. An ice cooled solution of 7-hydroxyisoquinoline (2.0 g, 13.78 mmol) in 30 mL of dry methylene chloride, and 15 ml of dry methanol was added drop wise to O-mesitylenesulfonylhydroxylamine (2.97 g, 13.78 mmol) in 10 mL of dry methylene chloride over 5 min with stirring. The reaction stirred at 0° C. for 6 h. 70 mL of ether was added and the suspension filtered. The precipitate was recrystallized from ethyl acetate to give 2-amino-7-hydroxyisoquinolinium 2,4,6-trimethylbenzenesulfonate (6) in 60.5% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:21](OCC)=[O:22].CC[O-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21][OH:22])[C:14](=[O:20])[CH2:15]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A solution of 0.27 g (0.9 mmol) of 9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one in 2.0 mL of THF was stirred at rt and 0.70 mL (8.7 mmol) of ethyl formate was added followed by 1.0 mL of EtOH and 0.78 mL of a 21 wt % solution of NaOEt in EtOH. The reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was concentrated by rotary evaporation, quenched with sat. aq. NH4Cl and extracted with CHCl3. The organic layer was dried over MgSO4, filtered and concentrated to afford 0.25 g (86%) of 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one as an orange solid. 1H NMR (300 MHz, CDCl3) δ 14.11 (s, 1H), 8.24 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 4.85 (s, 1H), 4.32 (m, 1H), 2.58 (dd, J=19.8, 7.7 Hz, 1H), 2.17 (d, J=19.8 Hz, 1H), 2.00-1.76 (m, 2H), 1.61 (m, 5H).