Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[Cl-].[CH3:3][C:4]([CH3:25])=[CH:5][CH2:6]C1C(O)=CC(O)=CC=1C1OC2C=C(O)C=CC=2C=1.CC(C)=CC[C:30]1[CH:31]=[C:32]([C:37]2O[C:46]3[CH:45]=[C:44]([OH:48])[CH:43]=[C:42]([OH:49])[C:41]=3[C:39](=[O:40])[C:38]=2O)[CH:33]=[CH:34][C:35]=1[OH:36]>CO>[CH3:3][C:4]([CH3:25])=[CH:5][CH2:6][C:45]1[CH:46]=[C:41]([C:39](/[CH:38]=[CH:37]/[C:32]2[CH:33]=[CH:34][C:35]([OH:36])=[CH:30][CH:31]=2)=[O:40])[C:42]([OH:49])=[CH:43][C:44]=1[OH:48]
Reactant: CC(C)=CCc1cc(-c2oc3cc(O)cc(O)c3c(=O)c2O)ccc1O
Reactant: CC(C)=CCc1c(O)cc(O)cc1-c1cc2ccc(O)cc2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCc1cc(C(=O)/C=C/c2ccc(O)cc2)c(O)cc1O

Procedure:
Yellow powder; mp 157-158° C.; UV (MeOH) λmax (log ε) 373 (4.23), 205 (4.43) nm; IR (NaCl) γmax 3350, 2923, 1645, 1558, 1508 cm−1; 1H NMR (CD3OD, 500 MHz) δ 1.75 (3H, s, H-4″), 1.76 (3H, s, H-5″), 3.27 (2H, d, J=7.2 Hz, H-1″), 5.34 (1H, m, H-2″), 6.29 (1H, s, H-3′), 6.85 (2H, d, J=8.5 Hz, H-3), 7.54 (1H, d, J=15.4 Hz, H-a), 7.59 (2H, d, J=8.5 Hz, H-2), 7.72 (1H, s, H-6′), 7.76 (1H, d, J=15.3 Hz, H-β); 13C NMR (CD3OD, 125 MHz) δ 17.8 (C-4″), 26.0 (C-5″), 28.9 (C-1″), 103.4 (C-3′), 114.4 (C-1′), 117.0 (C-3), 118.6 (C-o), 122.2 (C-5′), 124.2 (C-2″), 127.4 (C-1), 131.9 (C-2), 132.4 (C-6′), 133.1 (C-3″), 145.4 (C-β), 161.5 (C-4), 164.6 (C-4′), 165.5 (C-2′), 193.4 (CO); EIMS m/z 324 (M+, 100), 231 (10), 205 (77), 147 (12).
Reaction SMILES: [SH:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21].CC(C)=O>O>[C:7]1([C:4]2[N:3]=[C:2]([S:1][CH2:21][C:20]#[CH:19])[O:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1nc(-c2ccccc2)no1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#CCSc1nc(-c2ccccc2)no1
Yield: 74 %

Procedure:
A mixture of 5-mercapto-3-phenyl-1,2,4-oxadiazole (100 parts), potassium carbonate (39 parts), propargyl bromide (66 parts) and dry acetone (500 parts) was heated at reflux for one hour. The solution was cooled, poured into water and extracted with chloroform. The extract was washed and dried and the solvent evaporated off to give 3-phenyl-5-propargylthio-1,2,4-oxadiazole (90 parts, 74% yield), melting point 39.40° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:13]2[C:9]([CH3:21])([C:10]([CH:14]([CH3:20])[CH2:15][CH:16]([Cl:19])[CH2:17]O)=[CH:11][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O.[Br-:34].[Li+]>ClCCl.N1C=CC=CC=1>[C:1]([O:4][CH:5]1[CH:13]2[C:9]([CH3:21])([C:10]([CH:14]([CH3:20])[CH2:15][CH:16]([Cl:19])[CH2:17][Br:34])=[CH:11][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCCC2(C)C(C(C)CC(Cl)CO)=CCC12
Reactant: [Br-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC1CCCC2(C)C(C(C)CC(Cl)CBr)=CCC12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 1.50 g (4.76 mmol) of [3aS-[3(βS*,δR*),3aα,7β,7aβ]]-7-(acetyloxy)-β-chloro-3a,4,5,6,7,7a-hexahydro-δ,3a-dimethyl-1H-indene-3-butanol in 20 mL of dichloromethane and 20 mL of pyridine was treated at 0° C. and under argon with 4.50 g (23.60 mmol) of p-toluenesulfonyl chloride and then stirred overnight at 0° C. Water (8 mL) was then added and, after stirring the resulting mixture for 1 hour at room temperature, the solvents were removed in vacuo and the residue diluted with water and extracted with ethyl acetate. The combined organic extracts were subsequently washed with 1N hydrochloric acid, water, 2N aqueous potassium bicarbonate solution and brine and dried. The residue obtained after evaporation of the ethyl acetate (weighing 2.10 g) was dissolved in 40 mL of N,N-dimethylformamide and heated under argon at 50° C. with 4.00 g (46.06 mmol) of anhydrous lithium bromide for 17 hours. After cooling, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The combined organic extracts were washed several times with water, dried and evaporated to dryness to give 1.62 g (90% overall yield) of the title compound. 1H NMR (60 MHz, CDCl3) δ0.88 (s, 3H), 1.07 (d, J=6.4 Hz, 3H), 2.03 (s, 3H), 3.60 (br AB q, J=10.2 Hz, Δγ=14.0 Hz, 2H), 5.00 br m, 1H), 5.33 (br s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([O:22]C)[CH:16]=[C:15]([O:24]C)[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33].Cl.N1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([OH:22])[CH:16]=[C:15]([OH:24])[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc([N+](=O)[O-])cc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccc([N+](=O)[O-])cc4Br)oc23)[C@@H]1CO

Procedure:
Compound of example 41 (0.3 g, 0.6 mmol) was demethylated using pyridine hydrochloride (3 g, 26 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].C[C@H]1CCCN[C@H]1CN1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)=[O:11]
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Agent: C[C@H]1CCCN[C@H]1CN1C(=O)c2ccccc2C1=O
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in Example A13 using 2-(((2R,3S)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione. MS (ESI) 348 (M+H).
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:1][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[OH:11]
Reactant: II
Reactant: COc1cccc(O)c1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(I)c(O)c1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
I2 (40.9 g, 161.1 mmol) was dissolved in CHCl3 (850 mL) with stirring over 1 hour. The solution was added slowly into a reaction mixture of 3-methoxyphenol 5-A (20 g, 161.1 mmol) and silver trifluoroacetate in 200 mL CHCl3 over 1.5 hours. The reaction was stirred at room temperature for 16 hours. Solids were removed by filtration. The filtrate was washed with 5% Na2S2O3(500 mL), saturated NaHCO3, brine, dried over MgSO4 and concentrated. The crude mixture was triturated with carbon tetrachloride to give 2-iodo-5-methoxyphenol 5-B (13.6 g) as a white solid. The remaining crude products were purified by silica gel column chromatography eluted with CH2Cl2 to give 28.2 g of compound 5-B.
Reaction SMILES: Br.Br[CH2:3][C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH2:11][CH3:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH2:11]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]=1[CH2:3][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1)[CH3:12]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1cncc(F)c1CBr
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cncc(F)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
A mixture of 4-(bromomethyl)-3-ethyl-5-fluoropyridine hydrobromide (9.7 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (1.7 g, 12 mmol), and triethylamine (3.5 mL, 25 mmol) in absolute ethanol (100 mL) was stirred at overnight room temperature. The mixture was evaporated. Water (100 mL) and EtOAc (100 mL) were added. The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude mixture was purified by flash chromatography (0-5% MeOH/CH2Cl2), affording the title compound (250 mg, 9% yield); 1H NMR (500 MHz, DMSO-d6): δ 1.21 (t, 3H, J=7.5 Hz), 2.23 (s, 3H), 2.83 (q, 2H, J=7.5 Hz), 4.51 (s, 2H), 6.07 (s, 1H), 8.33 (s, 1H), 8.41 (s, 1H); M+280.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:28](=[O:82])[NH:29][CH2:30][CH2:31][CH2:32][NH:33][C@@H:34]([C@H:42]([CH:44]1[C@@H:48]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C@@H:47]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[C@H:46]([N:65]2[CH:70]=[CH:69][C:68](=[O:71])[N:67]([CH2:72][C:73]3[CH:78]=[CH:77][C:76]([O:79][CH3:80])=[CH:75][CH:74]=3)[C:66]2=[O:81])[O:45]1)[OH:43])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(=O)OCC1C=CC=CC=1)=O)C1C=CC=CC=1>CO.[Pd]>[Si:50]([O:49][C@H:48]1[C@@H:47]([O:57][Si:58]([C:61]([CH3:64])([CH3:62])[CH3:63])([CH3:60])[CH3:59])[C@H:46]([N:65]2[CH:70]=[CH:69][C:68](=[O:71])[N:67]([CH2:72][C:73]3[CH:74]=[CH:75][C:76]([O:79][CH3:80])=[CH:77][CH:78]=3)[C:66]2=[O:81])[O:45][CH:44]1[C@H:42]([OH:43])[C@H:34]([NH:33][CH2:32][CH2:31][CH2:30][NH:29][C:28](=[O:82])[C@@H:12]([NH2:11])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([C:53]([CH3:54])([CH3:55])[CH3:56])([CH3:51])[CH3:52]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](N)CCCCN)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 91.8 %

Procedure:
By using an analogous procedure to that described for Example 2, tert-butyl (9S,16S)-9-{[(benzyloxy)carbonyl]amino}-16-[(R)-[(3R,4R,5R)-3,4-bis{[tert-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-3,10-dioxo-1-phenyl-2-oxa-4,11,15-triazaheptadecan-17-oate (70 mg, 0.06 mmol, obtained from Example 18) was hydrogenated in methanol (2 ml) using 10% palladium on carbon (17 mg) to provide tert-butyl (2S,3R)-3-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-2-[(3-{[(2S)-2,6-diaminohexanoyl]amino}propyl) amino]-3-hydroxypropanoate (50 mg, 92%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[F:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:16][CH2:17][C:18]([OH:20])=O>ClCCl>[F:12][C:13]1[CH:14]=[C:15]2[C:21](=[CH:22][C:23]=1[F:24])[C:18](=[O:20])[CH2:17][CH2:16]2
Reactant: O=C(O)CCc1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
Oxalyl chloride (1.12 mL) and DMF (78.2 mg) were added to a solution of 3,4-difluorohydrocinnamic acid (2.00 g) in dichloromethane (3.0 mL) at 0° C., and the reaction solution was stirred at room temperature overnight. After confirming that the raw materials disappeared, the reaction solution was concentrated under reduced pressure. Next, a solution of the resulting residue in dichloromethane (10 mL) was added to a solution of aluminum chloride (2.13 g) in dichloromethane (20 mL) at −30° C. The reaction solution was stirred at room temperature for 1.5 hours. After confirming that the raw materials disappeared, the reaction solution was poured into ice water. The solution was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system) to obtain 535 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: O1CCOCC1.[C:7]1([C@H:17]([N:19]([CH2:27][C@@H:28]2[C@@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:31][NH:30][CH2:29]2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:48]=[CH:49][C:50]=1[NH:51][C:52](OC1C=CC([N+]([O-])=O)=CC=1)=[O:53])[C:44]([O:46][CH3:47])=[O:45]>C(N(CC)CC)C>[C:22]([O:21][C:20]([N:19]([CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:31][N:30]([C:52]([NH:51][C:50]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=2[O:40][CH3:39])=[O:53])[CH2:29]1)[C@@H:17]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:18])=[O:26])([CH3:24])([CH3:25])[CH3:23]
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(OC)c1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A 1,4-dioxane solution of 250 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate was mixed, under ice-cooling, with 0.13 ml of triethylamine and 250 mg of methyl 3-methoxy-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate and stirred overnight at 80° C. The solvent was evaporated under a reduced pressure, and the residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 245 mg of methyl 4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)-3-methoxybenzoate as a colorless amorphous substance.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]12[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=[C:15]1[C:14]1[C:9](=[CH:10][C:11]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[C:12]([Cl:22])[C:13]=1[Cl:21])[CH2:8]2)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:41]([CH3:46])([CH3:45])[C:42]([OH:44])=[O:43]>O1CCCC1>[C:1]([O:4][CH2:5][CH2:6][C:7]12[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=[C:15]1[C:14]1[C:9](=[CH:10][C:11]([O:23][CH2:24][C:25]([O:27][C:41]([C:42]([OH:44])=[O:43])([CH3:46])[CH3:45])=[O:26])=[C:12]([Cl:22])[C:13]=1[Cl:21])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reactant: CC(C)(O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)OCCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC(C)(C)C(=O)O)c(Cl)c1Cl)C2
Temperature: 20 °C

Procedure:
{[9a-(Acetoxyethyl)-5,6-dichloro-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl]oxy}acetic acid (4.13 g, 10 mMole) is dissolved in dry tetrahydrofuran (20 ml). 1,1'-Carbonyldiimidazole (3.2 g, 10 mMole) is added and the mixture stirred at 20° C. for an hour. 2-Hydroxy-2-methylpropionic acid (1.05 g, 10 mMole) is added and the mixture stirred for 18 hours at 20° C. The solvent is removed by evaporation in vacuo. The residue is dissolved in methylene chloride, washed with water and dried over MgSO4. The solvent is removed by evaporation in vacuo and the residue purified by chromatography using a silica gel column with methylene chloride/tetrahydrofuran/acetic acid 100/2/1 (V.V.V.) as the eluent. Selecting the appropriate cuts gave the desired compound upon evaporation of the solvent in vacuo.
Reaction SMILES: C([O-])(O)=O.[Na+].Cl.[OH:7][CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[NH2:10].[CH2:19]([O:26][CH2:27][C:28](Cl)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][CH2:27][C:28]([NH:10][C@H:9]1[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][CH:8]1[OH:7])=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(COCc1ccccc1)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 68 %

Procedure:
To a round-bottom flask containing sat. NaHCO3 (9 mL) was added mannosamine hydrochloride (500 mg, 2.30 mmol). The solution was stirred for 1 h under N2, at which point benzyloxyacetyl chloride (0.44 mL, 2.8 mmol) was added dropwise via syringe. The biphasic mixture was stirred vigorously for 4 h resulting in a clear light yellow solution. The solution was concentrated and the residue was purified by silica gel chromatography eluting with a gradient of 20:1 to 10:1 CHCl3/MeOH to afford 512 mg (68%) of a viscous oil. IR (thin film): 3331, 2918, 2356, 1652, 1524 cm−1. 1H NMR (400 MHz, D2O): δ 3.26 (s, 1H), 3.33 (app t, 1H, J=6.7), 3.45 (app t, 1H, J=9.7), 3.54-3.66 (m, 1H), 3.69 (app d, 1H, J=4.8), 3.72 (d, 1H, J=2.0), 3.74-3.86 (m, 2H), 3.98 (dd, 1H, J=4.5, 9.8), 4.06 (s, 2H), 4.10 (s, 1H), 4.24-4.27 (m, 1H), 4.38-4.40 (m, 1H), 4.55 (s, 2H), 4.57 (d, 1H, J=4.3), 4.97 (s, 1H), 4.99 (s, 1H), 7.32-7.36 (m, 10H), 7.49 (d, 1H, J=10.7), 7.58 (d, 1H, J=9.6). 13C NMR (100 MHz, D2O): δ 52.9, 60.4, 66.8, 68.5, 68.7, 72.0, 73.5, 76.5, 89.3, 92.8, 128.5, 128.6, 128.7, 128.8. HRMS (FAB) m/z 328.1396 (MH+C15H22NO7 requires 328.1396).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27](O)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:28])[CH3:23]
Reactant: CCOC(=O)CC(=O)O
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CCOC(=O)CC(=O)N[C@@H]1C(=O)N(CCOC)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-Amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless, viscous oil (>98%). MS: m/e=397(M+H+).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[CH3:40][S:37]([NH:36][C:33]1[CH:32]=[CH:31][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:35][CH:34]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Nc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (200 mg, 0.51 mmol) is coupled to aryl bromide 201 (134 mg, 0.54 mmol) using Method A to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[NH:4][C:3](=[O:15])[CH:2]=1.[Cl:16]Cl>C(O)(=O)C>[Cl:16][C:2]1[C:3](=[O:15])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[CH:1]=1
Reactant: O=c1ccc2c([nH]1)CCc1ccccc1-2
Reactant: ClCl
Solvent: CC(=O)O
Product: O=c1[nH]c2c(cc1Cl)-c1ccccc1CC2

Procedure:
Add 19.7 gm of 5,6-dihydrobenzo[f]quinolin-3(4H)-one to 300 ml of acetic acid. Bubble chlorine into the reaction solution for 4 hours at 100°. Cool the system and collect the product as a precipate. Dissolve the solid into water and neutralize the solution with 1N NaOH. Extract the product with chloroform. Dry the chloroform over anhydrous magnesium sulfate and filter the solution. Remove the solvent by stripping to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].C([O:18][C:19](=[O:22])[CH:20]=[CH2:21])C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:7]([C:6]1[CH:9]=[C:2](/[CH:21]=[CH:20]/[C:19]([OH:22])=[O:18])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1)#[N:8]
Reactant: C=CC(=O)OCC
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(/C=C/C(=O)O)cc2C#N)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a DMF (10 mL) solution of 5-bromo-2-(4-methyl-1H-imidazol-1-yl)benzonitrile (700 mg) and acrylic acid ethyl ester (362 mg), palladium acetate (31 mg), tri-ortho-tolylphosphine (85 mg) and TEA (2 mL) were added, and the reaction solution was agitated at 80° C. under nitrogen-atmosphere overnight. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate system), fractions of the object substance were combined, and concentrated under reduced pressure. The obtained substance was dissolved by SN sodium hydroxide solution (5 mL) and ethanol (30 mL), and the reaction mixture was agitated at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and was made neutral with 5N hydrochloric acid. Insoluble matter consequently deposited was separated by filtering, washed with ether, and 498 mg of the title compound was obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[C:6]2[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([O:16][CH3:17])[C:5]=2[CH2:4][CH2:3]1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[CH2:10]([N:7]1[C:8](=[O:9])[CH:2]([N:1]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:3][CH2:4][C:5]2[C:15]([O:16][CH3:17])=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=[CH:12][C:6]1=2)[CH3:11]
Reactant: BrCCOCCBr
Reactant: CCN1C(=O)C(N)CCc2c1ccc([N+](=O)[O-])c2OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCN1C(=O)C(N2CCOCC2)CCc2c1ccc([N+](=O)[O-])c2OC
Yield: 33.4 %

Procedure:
Combine 3-Amino-1-ethyl-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.8 g), 1-Bromo-2-(2-bromo-ethoxy)-ethane (797 mg) and Potassium carbonate (879 mg) in Acetonitrile (37 mL), heat to 85° C., After 2 days, added another eq of Potassium carbonate and 0.5 eq of 1-Bromo-2-(2-bromo-ethoxy)-ethane and continue heating. Diluted with CH2Cl2, filter, the material was concentrated onto Celite and purified by ISCO chromatography (120 g, SiO2, gradient elution 0% MeOH/DCM/to 10% MEOH/DCM) to give 1-ethyl-6-methoxy-3-morpholin-4-yl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as an orange solid (334 mgs). 1H-NMR (CDCl3): 7.86 (d, J=8.8 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 4.32-4.22 (m, 1H), 3.96 (s, 3H), 3.73-3.60 (m, 5H), 3.27-3.23 (m, 1H), 2.97-2.92 (m, 1H), 2.72-2.55 (m, 4H), 2.54-2.45 (m, 1H), 2.39-2.23 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl.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>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])=[CH:3][N:4]=1
Reactant: Brc1cncc2ccccc12
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCC#Cc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
In an inert atmosphere, 0.268 g of bis(triphenylphosphine)palladium dichloride and 0.072 g of cuprous iodide was added with stirring to a deoxygenated solution of 5 g of 4-bromoisoquinoline, 3.02 g of 3-butyn-1-ol and 10 mL of triethylamine in 20 mL of dichloromethane. The reaction was stirred at room temperature for 1 hour and then at reflux for 18 hours. The cooled mixture was filtered and the filtrate was washed with water. The dried (Na2SO4) organic phase was concentrated in vacuo and the residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 3.4 g of 4-(4-isoquinolinyl)-3-butyn-1-ol as an oil.