Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCCC1C=CC(O)=CC=1.NCCC1C=CC(O)=C(O)C=1.COC1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.[CH3:46][N:47]1[CH:56]([CH2:57][C:58]2[CH:59]=[CH:60][C:61]([O:65]C)=[C:62]([OH:64])[CH:63]=2)[C:55]2[CH:54]=[C:53](O)[C:52]([O:68]C)=[CH:51][C:50]=2[CH2:49][CH2:48]1.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1>>[CH:59]1[C:58]2[CH2:57][C@H:56]3[N:47]([CH2:48][CH2:49][C@@:50]45[C@H:55]3[CH:54]=[CH:53][C@H:52]([OH:68])[C@@H:51]4[O:64][C:62]([C:63]=25)=[C:61]([OH:65])[CH:60]=1)[CH3:46]
Reactant: COc1ccc(CC2c3cc(O)c(OC)cc3CCN2C)cc1O
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Agent: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: NCCc1ccc(O)c(O)c1
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5

Procedure:
To examine the tyramine to dopamine step, dopamine (DA) levels in ganglia and hemolymph were examined before and after tyramine addition followed by CYP2D6 inhibition by quinidine. Tyramine injection significantly increased ganglionic (4.98±0.27 μg/g to 9.17±1.21 μg/g wet weight; P<0.01) and hemolymph (10.13±1.24 μg/mL to 16.47±1.28 μg/mL, P<0.05) DA levels (FIGS. 19 and 20). The ganglionic and hemolymph DA level increases were blocked by quinidine exposure, demonstrating that the CYP2D6 enzyme was mediating this step. Ganglia were also exposed to THP, reticuline, DA, or codeine. Each resulted in significantly enhanced morphine levels, a phenomenon that was also significantly blocked by quinidine exposure, again demonstrating a role for CYP2D6 in the second part of the morphine biosynthetic pathway (FIGS. 15 and 20).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][C:23]([NH2:30])=[N:24][C:25]=2Cl)[C@H:9]([O:11][Si](C(C)(C)C)(C)C)[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=[O:34]>O>[NH2:30][C:23]1[NH:24][C:25](=[O:34])[C:26]2[N:27]=[CH:28][N:20]([CH2:19][C@H:8]([C@H:9]([OH:11])[CH3:10])[CH2:7][OH:6])[C:21]=2[N:22]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1cnc2c(Cl)nc(N)nc21
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@@H](O)[C@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 48 h
Yield: 70 %

Procedure:
A solution of 36 (1.8 g, 3.6 mmol) in a mixture of TFA (60 ml) and water (20 ml) was kept at room temperature for 2 days until almost no starting material was found by HPLC analysis. The reaction was concentrated, co-evaporated with water (3×100 ml) and re-dissolved in ˜5 ml of acetonitrile. Ethyl ether (˜50 ml) was added to precipitate 0.84 g of 37 as a TFA salt. The salt was dissolved in ˜7 ml of ethanol, treated with 0.5 ml of triethylamine and allowed to crystallize at −20° C. for 2 hrs. The crystals were collected by filtration, washed with ethyl ether and dried in vacuo to afford 0.64 g (70%) of 37 as a white solid. 1H NMR (DMSO-d6): δ 10.55 (s, 1H), 7.63 (s, 1H), 6.46 (s, 2H), 4.63 (d, J=5 Hz, 1H), 4.55 (t, J=5 Hz, 1H), 3.97 (d, J=7.5 Hz, 2H), 3.64 (m, 1H), 3.41 (m, 2H), 1.92 (m, 1H), 1.10 (d, J=6.3 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:11][N:12]=[C:13]([C:39]2[N:40]=[C:41]([NH:44]C=O)[S:42][CH:43]=2)[C:14]([NH:16][C@@H:17]2[C:37](=[O:38])[N:19]3[C:20]([C:34]([O-:36])=[O:35])=[C:21]([CH2:24][N+:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][CH:26]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[CH2:10][CH2:9]1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[NH2:44][C:41]1[S:42][CH:43]=[C:39]([C:13](=[N:12][O:11][CH:8]2[CH2:9][CH2:10]2)[C:14]([NH:16][C@@H:17]2[C:37](=[O:38])[N:19]3[C:20]([C:34]([O-:36])=[O:35])=[C:21]([CH2:24][N+:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][CH:26]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[N:40]=1
Reactant: NC(=O)c1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(NC=O)n4)[C@H]3SC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NC(=O)c1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(N)n4)[C@H]3SC2)cc1
Temperature: 0 °C
Yield: 11.8 %

Procedure:
A mixture of trifluoroacetic acid salt of 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-carbamoyl-l-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (1.6 g) and concentrated hydrochloric acid (0.76 ml) in a mixture of methanol (16 ml) and tetrahydrofuran (5 ml) was warmed at 33° to 35° C. for 1.5 hours. The mixture was poured into ice-water, adjusted to pH 2.5 with saturated aqueous solution of sodium bicarbonate and washed with ethyl acetate. The aqueous solution was subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (30 ml). After the column was washed with water (300 ml), 1% isopropyl alcohol (60 ml), and 3% isopropyl alcohol (60 ml) successively, the elution was carried out with 5% isopropyl alcohol (250 ml) and 10% isopropyl alcohol (150 ml) successively. The fractions containing the object compound were collected, combined, concentrated in vacuo to about 100 ml and lyophylized to give 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (180 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([N+:19]([O-])=O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:12]([CH2:15][C:16](=[O:17])[NH:19]3)=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Yield: 69.3 %

Procedure:
3′-Methoxy-3-nitrobiphenyl-4-acetic acid (5.2 g) was dissolved in methanol and hydrogenated over 0.8 g 10% palladium on carbon for 3 hours at room temperature. The catalyst was removed by filtration, washed with methanol and the filtrates combined and concentrated to give a brown solid. The solid was chromatographed on silica gel in ethyl acetate:hexane:acetic acid 33:66:1 to give 3.0 g (75 % yield based on 4-fluoro-3′-methoxy-3-nitrobiphenyl) of 6-(3-methoxypheny)-2-oxindole as a pink solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=1)[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.CO.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.CCCCCC.[Cl-].[Na+].O.CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=1)[CH:7]=[O:8]
Reactant: CCOC(=O)C(CCCCCl)c1cccc(-c2cccnc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=CC(CCCCCl)c1cccc(-c2cccnc2)c1
Reaction time: 0.08 h

Procedure:
To a solution of 0.54 g (1.6 mmol) ethyl 6-chloro-2-[m-(3-pyridyl)-phenyl]-hexanoate in 10 ml methylene chloride at -78° is added slowly 2.2 ml (3.4 mmol) of a 1.5M solution of diisobutylaluminium hydride in hexane. The reaction mixture is stirred at -78° for 5 min and 1.6 ml methanol is added followed by 50 ml ether. The mixture is warmed to 0° and 1.6 ml brine and 1.11 g finely powdered sodium sulfate are added. The mixture is stirred and then filtered. The filter cake is washed with methylene chloride and combined organic layer is evaporated to give 6-chloro-2-[m-(3-pyridyl)-phenyl]-hexanal as an oil; IR (CH2Cl2): 1724, 1682 cm-1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:30])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[CH:18][C:11]3=[N:12][C:13]=2[N:14]([O:16][CH3:17])[CH:15]=1)=[O:5])C.CS(O)(=O)=O>C(O)C.O.[OH-].[K+].C(OC(C)C)(C)C>[F:22][C:20]1[C:19]([N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)=[CH:18][C:11]2=[N:12][C:13]3[N:14]([O:16][CH3:17])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:30])[C:8]=3[CH:9]=[C:10]2[CH:21]=1
Reactant: CCOC(=O)c1cn(OC)c2nc3cc(N4CCN(C)CC4)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CCO
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)CC4)cc3nc21
Yield: 32.8 %

Procedure:
A suspension of 0.98 g of 3-ethoxycarbonyl-7-fluoro-1-methoxy-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 15 cm3 of ethanol, 9 cm3 water and 6 cm3 of 2 N aqueous potassium hydroxide solution is stirred at a temperature close to 20° C. for 1 hour 6 cm3 of 2 N methanesulphonic acid are added to the solution obtained and the mixture is extracted with 3 times 10 cm3 of trichloromethane. The combined organic extracts are washed with 3 times 5 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The dry extract obtained is taken up in 5 cm3 of diisopropyl ether, drained and washed with twice 2 cm3 of the same solvent. After recrystallizing once from 30 cm3 of dimethylformamide containing 30% of ethanol, 0.3 g of 7-fluoro-1-methoxy-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]-naphthyridine-3-carboxylic acid is obtained in the form of a brown solid melting at 270° C.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[CH2:34](OC(C1(SC2SC(N)=NC=2)CCC1)=O)C.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:33][C@H:30]1[CH2:29][CH2:28][C@H:27]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]3([C:3]([OH:5])=[O:4])[CH2:1][CH2:34][CH2:6]3)=[CH:9][N:10]=2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)C1(Sc2cnc(N)s2)CCC1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCc2ccccc2)C(=O)Nc2ncc(SC3(C(=O)O)CCC3)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-Methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-amino-thiazol-5-ylsulfanyl)cyclobutanecarboxylic acid ethyl ester prepared using the procedure for the preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:6][CH2:5]2)(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Agent: Cl
Product: COc1ccc(S(=O)(=O)NC2CCN(CCCC(=O)c3ccccc3)CC2)cc1

Procedure:
Using an analogous procedure to Example 2 4-amino-1-(4-phenyl-4-oxobutyl)piperidine dihydrochloride may be reacted with p-methoxybenzenesulphonyl chloride to give the title compound.
Reaction SMILES: C(O)=O.[CH2:4]([NH2:6])[CH3:5].[F:7][C:8]([F:21])([F:20])[S:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17](=O)[CH3:18])[CH:13]=[CH:14][CH:15]=1.Cl>O>[F:7][C:8]([F:21])([F:20])[S:9][C:10]1[CH:11]=[C:12]([CH2:16][CH:17]([NH:6][CH2:4][CH3:5])[CH3:18])[CH:13]=[CH:14][CH:15]=1
Reactant: CCN
Reactant: CC(=O)Cc1cccc(SC(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: O=CO
Product: CCNC(C)Cc1cccc(SC(F)(F)F)c1

Procedure:
1.85 g (40 mmols) of formic acid are introduced into a 50 ml. two-necked flask equipped with an air condenser and a dropping funnel. The flask is cooled on an ice bath and 2 ml. of ethylamine are added dropwise. The reaction mixture is allowed to return to ambient temperature and 2.85 g. (10 mmols) of 1-(3'-trifluoromethylthio-phenyl)-2-propanone are added. The contents of the flask are heated for 14 hours at 160°-170°C., 2 ml. of concentrated hydrochloric acid and 2 ml. of water are added, and the mixture is heated for 3 hours at the reflux temperature. A further 2 ml. of concentrated hydrochloric acid are added and the mixture is heated again at the reflux temperature for 2 hours. The mixture is allowed to cool, water is added and the product is extracted once with 50 ml. of diethyl ether. The aqueous layer is rendered alkaline with sodium hydroxide solution and extracted three times in succession with 50 ml. of diethyl ether each time. The combined ether extracts are washed several times with water, dried over sodium sulphate, and filtered. The ether is evaporated from the filtrate in vacuo on a water bath. The 1.4 g of oily residue are dissolved in anhydrous diethyl ether and a solution of hydrogen chloride in diethyl ether is added until precipitation has ended.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>O.CC(C)=O.[OH-].[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)Cl)c2)C1
Reactant: NCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)NCCCC(=O)O)c2)C1
Temperature: 25 °C

Procedure:
2-Chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoyl chloride (1.75 g.) is added to a solution of 4-aminobutyric acid (0.54 g.) in water (30 ml.), acetone (30 ml.) and 1 N sodium hydroxide (10 ml.). After stirring at room temperature for a half hour, the acetone is removed by evaporation, and the aqueous solution is acidified with concentrated hydrochloric acid. The precipitate is dissolved in 50 ml. of hot acetone-methanol (1:1) and concentrated to half volume. Hexane is added to crystallize the product, m.p. 193-°195° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CCOCC>[CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCO)cc2)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Product: CC1(C)OC[C@@H](COc2ccc(CCCOS(C)(=O)=O)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To (3-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-propan-1-ol (12.2 g, 46 mmol) in dry ether (150 ml) is added TEA (12.8 ml, 92 mmol). The mixture is cooled to 0° C. and treated dropwise with methanesulfonyl chloride (5.3 ml, 69 mmol). The reaction mixture is allowed to warm to room temperature and then stirring continued for 3 hours. The resulting mixture is washed with water (2×100 ml), saturated aqueous sodium hydrogencarbonate, brine, dried (MgSO4) and concentrated in vacuo to give Methanesulfonic acid 3-[4-((R)-2,2-dimethyl[1,3]dioxolan-4-ylmethoxy)-phenyl]-propylester as a white solid; 1H NMR (CDCl3): 1.39 (3H, s), 1.43 (3H, s), 2.02 (2H, pent, J=6.9 Hz), 2.63 (2H, tr, J=6.9 Hz), 3.00 (3H, s), 3.90 (2H, m), 4.05 (1H, m), 4.14 (3 h, m), 4.46 (1H, pent, J=6.8 Hz), 6.82 (2H, d, J=7.4 Hz), 7.10 (2H, d, J=7.4 Hz).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].O[N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[O:14]=[C:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[O:5][C:1](=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.8 %

Procedure:
35 mg of butanoic acid was dissolved in 0.5 mL of 1,4-dioxane, to which 46 mg of N-hydroxysuccinimide and 82 mg of N,N′-dicyclohexylcarbodiimide were added, and stirred at room temperature for 1 hour. The deposit was filtered off, and the solvent was evaporated to obtain 94 mg of butanoic acid 2,5-dioxopyrrolidin-1-yl ester crude product. The crude product was used in the next reaction without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH2:25]([CH2:27][NH2:28])[OH:26]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:28][CH2:27][CH2:25][OH:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: NCCO
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(CNCCO)ccc1-2

Procedure:
Following the procedure for 212, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde and ethanolamine were reacted to give 285 isolated as a pale yellow solid (131 mg, 47%). LCMS: RT=6.85 min, [M+H]+=386. 1H NMR δ (ppm) (CDCl3): 8.31 (1 H, d, J=8.11 Hz), 7.89 (1 H, s), 7.12 (1 H, d, J=8.19 Hz), 7.02 (1 H, s), 5.93-5.82 (1 H, m), 4.37 (2 H, t, J=5.06 Hz), 3.81 (2 H, s), 3.66 (2 H, t, J=5.12 Hz), 3.38 (2 H, t, J=5.06 Hz), 2.81 (2 H, t, J=5.11 Hz), 1.60 (6 H, d, J=6.63 Hz). 2 Exchangeable protons not seen.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:28]([CH2:32][CH2:33][OH:34])[CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][OH:34])[C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:20]
Reactant: OCCNCCO
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N(CCO)CCO

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to diethanolamine via General Procedure B. The product was purified via reverse phase HPLC to give 15.8 mg of 258. MS (Q1) 468.8 (M)+.
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Si:13]([O:20][CH2:21][CH:22]1[CH2:24][N:23]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[Si:13]([O:20][CH2:21][C@@H:22]([NH:23][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][NH:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC1CO[Si](C)(C)C(C)(C)C
Reactant: NCC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNCC12CC3CC(CC(C3)C1)C2)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
To a solution of (1-adamantylmethyl)amine (15 g, 52 mmol) in anhydrous CH2Cl2 (50 mL) was added tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)aziridine-1-carboxylate (13 g, 78.3 mmol). The mixture was stirred for 10 min, the solvent was removed in vacuo and the residue was stirred at 40° C. for 5 h. The mixture was diluted with EtOAc (500 mL) and washed with water (100 mL),1N aq HCl (50 mL), satd aq NaHCO3 (50 ml) and brine (50 mL), and dried over MgSO4. The solution was concentrated to give a residue, which was purified by chromatography on silica gel to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-((1-adamantylmethyl)amino)propan-2-ylcarbamate (10 g, 24%). 1H NMR: (CDCl3, 400 MHz): δ=0.041 (s, 6H), 0.882 (s, 9H), 1.44 (s, 9H), 1.49 (s, 6H), 1.65 (m, 6H), 1.94 (s, 3H), 2.23 (s, 2H), 2.62-2.81 (m, 2H), 3.67 (m, 3H), 5.30 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[C:10]2[CH2:16][CH:15]3[NH:17][CH:12]([CH2:13][CH2:14]3)[CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(OC)(OC)OC.C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[C:10]2[CH2:11][CH:12]3[N:17]([CH2:23][C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[CH3:26])[CH:15]([CH2:14][CH2:13]3)[CH2:16]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=C2CC3CCC(C2)N3)c2ccsc2)c1
Reactant: Cc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: COc1cccc(C(=C2CC3CCC(C2)N3Cc2ccccc2C)c2ccsc2)c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 99.7 %

Procedure:
To 100 mg (321 μmol) of 3-[(3-Methoxy-phenyl)-thiophen-3-yl-methylene]-8-aza-bicyclo[3.2.1]octane in 1 mL of trimethyl orthoformate was added 56 μL (482 μmol) of 2-methylbenzaldehyde, 156 mg (739 μmol) of sodium triacetoxyborohydride, 34 μL of glacial acetic acid at room temperature. The reaction mixture was allowed to stir 10 days at room temperature. After 10 days, the crude was diluted with 1 mL of DCM and 0.5 mL of MeOH. The diluted solution was filtered and washed with 1 mL of DCM. The combined filtrates were concentrated. The concentrated sample was purified using Biotage NH2-silica column using a gradient of 5% ethyl acetate/hexane to 40% ethyl acetate/hexane. The eluent was evaporated to yield 133 mg of the title compound as a white solid; MS m/z (MH+) 416.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([OH:37])=[C:13]2[C:18](=[CH:19][N:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16](=[O:28])[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[CH:14]2)=[O:10])C.[OH-].[Na+].CO>C1COCC1>[CH2:21]([N:17]1[C:18]2[C:13](=[C:12]([OH:37])[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:10])=[N:20][CH:19]=2)[CH:14]=[C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)[C:16]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(-c2cc3c(O)c(C(=O)NCCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
A mixture of 4-{[1-benzyl-5-hydroxy-3-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carbonyl]-amino}-butyric acid ethyl ester (38 mg, 0.074 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washes several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 24 mg of the title compound as a yellow solid. MS: (+) m/z 488.40 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13](I)=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[CH:15]([B-](F)(F)F)=[CH2:16].[K+].CCOC(C)=O>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:1][CH2:2][CH2:3][C:4]1[C:13]([CH:15]=[CH2:16])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: O=C1OCc2cc(CCO)c(I)cc21
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=Cc1cc2c(cc1CCO)COC2=O
Temperature: 100 °C

Procedure:
To a 500 ml flask containing a stir bar was added 5-(2-hydroxyethyl)-6-iodo-2-benzofuran-1(3H)-one (5 g, 16.4 mmol), Potassium vinyltrifluoroborate (3.3 g, 24.7 mmol), Pd(dppf)Cl2 (0.6 g, 0.822 mmol) and TEA (2.3 mL). The mixture was then dissolved in EtOH (50 mL) and heated at 100° C. in a silicon oil bath for 2 h; TLC showed complete reaction. The flask was cooled to room temperature, treated with EtOAc (150 mL) and poured into a separatory funnel and washed with brine (2×100 mL). The organic layer was then separated, dried (Na2SO4), filtered and concentrated to dryness. The resulting organic residue was dissolved in DCM and absorbed into silica gel and purified by MPLC (hexanes/EtOAc; 1/1 eluent) to provide 5-(2-Hydroxyethyl)-6-vinyl-2-benzofuran-1(3H)-one.