Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH3:38][S:39]([CH:42]=[CH2:43])(=[O:41])=[O:40]>CC(N(C)C)=O>[CH:26]([O:25][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][CH2:43][CH2:42][S:39]([CH3:38])(=[O:41])=[O:40])=[N:13][N:14]=2)=[CH:24][C:21]=1[C:22]#[N:23])([CH3:28])[CH3:27]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: C=CS(C)(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NCCS(C)(=O)=O)s2)cc1C#N
Temperature: 90 °C
Yield: 31.1 %

Procedure:
To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (25 mg, 0.06 mmol) and DIEA (32 mg, 0.24 mmol) in DMA (1 mL) was added (methylsulfonyl)ethene (20 mg, 0.18 mmol). The reaction mixture was heated at 90° C. for 24 h. The solvent was evaporated and the product purified by preparative HPLC to afford 9 mg (31%) of (S)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)benzonitrile 31 as half-white solid. LCMS-ESI (m/z) calculated for. C24H26N4O3S2: 482.1; found 483.1 [M+H]+, tR=2.49 min.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].Br[CH2:19][CH2:20][OH:21]>CN(C=O)C.CCOC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:17][CH2:19][CH2:20][OH:21]
Reactant: OCCBr
Reactant: COc1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(OCCO)cc1OC
Temperature: 120 °C
Yield: 60 %

Procedure:
K2CO3 (1.07 g, 7.78 mmol) was added to a solution of 3,4,dimethoxyphenol (1.0 g, 6.48 mmol) in dry DMF (15 ml). 2-Bromoethanol (0.81 g, 6.48 mmol) was added, and the mixture was heated overnight at 120° C. The mixture was cooled, taken up in EtOAc, extracted with water (20 ml), saturated NaCl (4×20 ml), dried over MgSO4, and evaporated under reduced pressure. The product was purified by column chromatography on silica (Hexane:EtOAc 3:1) to give the desired product in 60% yield. B. Synthesis of 4-(2-bromo-ethoxy)-1,2-dimethoxy benzene
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C@@H:4]([NH:9]C(=O)OC(C)(C)C)[C:5]([CH3:8])([CH3:7])[CH3:6].Cl.CCN(CC)CC.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([N:39]=[C:40]=[S:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>O1CCOCC1>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:32]=[C:31]([NH:39][C:40](=[S:41])[NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([N:2]([CH3:18])[CH3:1])=[O:17])[CH:30]=[C:29]([C:28]([F:42])([F:27])[F:43])[CH:34]=1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reactant: CN(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H](NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
A 50-mL round-bottomed flask was charged with (S)-tert-butyl 1-(dimethylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (6c) (860 mg, 2.0 mmol, 1.0 equiv) and 4N HCl in dioxane (5.0 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure and maintained at ˜1 torr for 1 h. The resulting white, foamy solid was dissolved in CH2Cl2 (10 mL). Et3N (562 μL, 4.0 mmol, 2.0 equiv) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (596 mg, 2.2 mmol, 1.1 equiv) were added sequentially via syringe. The flask was capped with a plastic stopper, and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to purification by flash column chromatography on silica gel (gradient elution, 3:1 hexanes/Et2O→1:1 hexanes/Et2O) to provide the product (4a) as a white solid (613 mg, 1.43 mmol, 71% yield over two steps). [α]D25=−32.8° (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.06 (1H, s), 7.90 (2H, s), 7.77 (1H, d, J=9 Hz), 7.56 (1H, s), 5.68 (1H, d, J=9 Hz), 3.35 (3H, s), 2.97 (3H, s), 1.12 (9H, s). 13C {1H}NMR (100 MHz, CDCl3): δ 181.8, 174.0, 140.3, 131.7 (q, JC-F=33 Hz), 123.7 (m), 123.3 (q, JC-F=272 Hz), 118.1 (m), 60.9, 39.1, 36.2, 36.0, 27.2. IR (cm−1): 3322 (br m), 2972 (m), 1611 (m), 1532 (s), 1474 (m), 1385 (m), 1274 (s), 1174 (m), 1126 (s), 963 (m), 883 (m), 848 (w), 700 (m), 680 (m). LRMS (ESI): 452.1 (60%) [M+Na]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:17]=1)[NH2:14].C(N(CC)CC)C>C1COCC1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:14][C:13]1[CH:15]=[C:16]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH:17]=[C:11]([F:10])[CH:12]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cc(F)cc(N2CCOCC2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)cc(N2CCOCC2)c1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
2,2,2-Trichloroethyl chloroformate (1.05 mL, 7.65 mmol) was added to an ice cold solution of 3-fluoro-5-morpholin-4-ylaniline (reference procedure see EP1102743; 1.0 g, 5.10 mmol) and triethylamine (1.77 mL, 10.2 mmol) in THF (25 mL). The reaction mixture was stirred at RT for 1.5 h, then quenched with water. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (1.89 g, 99%) as a clear oil. LCMS (Method 3): Rt 3.75 min, m/z 371, 373 [MH+].
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9](OCC)=O)[CH:6]=CC=CC=1.C(O[CH:17]1[CH2:21][CH2:20][CH:19]([O:22][CH2:23][CH3:24])[O:18]1)C>C(O)(=O)C>[N:7]1([CH:20]([C:21]2[CH:17]=[CH:17][CH:21]=[CH:20][CH:19]=2)[C:19]([O:22][CH2:23][CH3:24])=[O:18])[CH:1]=[CH:6][CH:9]=[CH:8]1
Reactant: CCOC1CCC(OCC)O1
Reactant: CCOC(=O)CNc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(c1ccccc1)n1cccc1

Procedure:
52.8 g (0.24 mole) of ethyl phenylglycinate were dissolved in 136 ml of glacial acetic acid. Thereafter 39 g (0.24 mole) of 2,5-diethoxytetrahydrofuran were added over 10-15 minutes with stirring. The mixture was heated under reflux for one hour. After this time had elapsed, the mixture was allowed to cool and the major portion of the acetic acid was drawn off under reduced pressure. Finally, the residue was distilled under vacuum and the fraction distilling out at 115°-118° C. at 0.2 mm Hg was collected. The product obtained was first a colourless oil which crystallised on cooling, adopting a waxy aspect and weighing 46.5 g (70%). M.p. 51°-53° C. Centesimal composition: 73.31% C.; 6.08% N; 6.53% H. The IR spectrum in 0.5% KBr is illustrated in FIG. 1.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23](O)=[O:24])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][O:27][CH2:28][CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:33]([O:32][C:31]([NH:30][CH2:29][CH2:28][O:27][NH:26][C:23]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]([NH:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][N:14]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:24])=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NOCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1C(=O)NOCCNC(=O)OCc1ccccc1
Yield: 100 %

Procedure:
(2S,5R)-5-((Benzyloxy)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1.879 g, 5.362 mmol) described in Example 99 or 100, benzyl 2-(aminooxy)ethylcarbamate (1.41 g, 6.707 mmol) of Reference Example 11 and 1-hydroxybenzotriazole.monohydrate (220 mg) were dissolved in methylene chloride (20 mL), followed by stirring under ice cold. To this was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.29 g), and a temperature was elevated to room temperature, followed by stirring overnight. The mixture was diluted with methylene chloride (20 mL), and washed with water, 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine sequentially, and then dried over magnesium sulfate. The solvent was concentrated under reduced pressure to afford 2.91 g of the title compound (quantitative).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH2:6]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1C=CC=CC=1>[CH3:1][N:2]([CH3:20])[C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH2:6]1)=[S:30]
Reactant: CN(C)C(=O)C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CN(C)C(=S)C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Yield: 137.4 %

Procedure:
A mixture of 0.43 g of N,N-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide, 0.33 g of Lawesson's reagent, and 2 ml of benzene was heated under reflux for 30 minutes. The reaction product was purified by silica gel column chromatography (CH2Cl2) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 0.33 g of N,N-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:25](=[O:27])[CH3:26])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(C)=O
Yield: 91 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.10 gm, 0.29 mmoles), acetic anhydride (0.5 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 100 mg (91%) of 2-(p-methoxy-benzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran, mp. 119°-120° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.[Sn](C)(C)(C)[CH3:18]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:18])[C:5]([CH:9]=[O:10])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: C[Sn](C)(C)C
Reactant: CCCCCNc1nc(N)nc(Cl)c1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1C=O
Temperature: 100 °C

Procedure:
To the product from step (i) (20 g) in DMF (200 ml), Pd(PPh3)4 (2 g) was added followed by SnMe4 (20 ml) and the mixture heated at 100° C. for 16 h. The solvent was evaporated and the residue partitoned between EtOAc and brine, the organics were dried and solvent removed. The product was purified by silica chromatography to give the subtitle compound, 14.4 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]3[C:20](=O)[NH:19]C(=O)C3(CCC)C=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:20][NH2:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC12C=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C1C(=O)NC2=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Temperature: 25 °C

Procedure:
To a solution of 20.24 g (54.34 mM) of 3-(1-tert-butoxycarbonyl-4-piperidyl)-1-propylphthalimide in 350 ml of ethanol was added 7.9 ml (163 mM) of hydrazine monohydrate and the mixture was refluxed for one hour. After cooling to room temperature, the resulting precipitate (phthalide) was filtered off and washed with a small amount of ethanol. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The residue was extracted with chloroform and the organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide the title compound. Light-yellow oil. Yield 13.08 g (99%)
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].Cl.[NH2:18][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20]>C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:18][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
3-Acetylthio-2-benzylpropanoyl chloride and (L)-alanine, methyl ester, hydrochloride are reacted in the presence of triethylamine according to the procedure of Example 25 to give (±)-N-[2-(acetyl-thiomethyl) -1-oxo-3-phenylpropyl]-L-alanine, methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)c(Br)c(C)c1
Temperature: 65 °C
Yield: 98.6 %

Procedure:
To a mixture of 4-bromo-3,5-dimethyl-phenol (40.2 g, 0.200 mol) and potassium carbonate (55.2 g, 0.400 mol) in acetone (200 mL) was added methyl iodide (24.9 mL, 0.600 mol) at room temperature under N2. The reaction mixture was then refluxed at 65° C. for 8 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The resulting clear liquid was distilled under reduced pressure (70° C./0.1 Torr) to give 42.4 g (99%) of title compound as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 6.663 (s, 2H), 3.778 (s, 3H), 2.402 (s, 61-1); 13C NMR (100 MHz, CDCl3): δ 158.165, 139.203, 118.357, 113.953, 55.520, 24.319. MS (EI): m/z 214 [M+, 79Br 100], 216 [M+, 79Br, 96].
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][Li].C>C1COCC1.CCOCC>[OH:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1O
Reactant: [Li]C
Agent: C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C(F)(F)F)c1O
Temperature: 10 °C
Yield: 99 %

Procedure:
A solution of Example 42B (14.1 g, 68.4 mmol) in THF (70 mL) was cooled to 5° C. and methyllithium (133 mL of a 1.6M solution in Et2O, 212 mmol) was added, keeping the temperature ≦20° C. (slow addition, methane generation). The cooling bath was removed and after 10 min, the reaction mixture was complete by LCMS. The reaction was cooled to 10° C. and EtOAc (140 mL) and 2N HCl (140 mL) were added. The layers were partitioned and the organic portion was washed with water (70 mL) and brine (28 mL). The organic portion was dried (Na2SO4), filtered, and concentrated, to give the title compound (14.0 g, 68.6 mmol, 99%) as an orange oil that was used without further purification. MS (DCI/NH3) m/z 222 (M+NH4)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][OH:12].[OH-].[Na+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.ClCCl>O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:12][CH2:11][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: OCCc1nc2ccccc2o1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: BrCCCCCCOCCc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-benzoxazoleethanol (1.46 g), 50% sodium hydroxide (3 ml), 1,6-dibromohexane (3 ml), TAB (100 mg) and dichloromethane (2 ml) was vigorously stirred at room temperature for 22 h, diluted with water (15 ml) and extracted with ether (40 ml). The organic phase was washed with brine (10 ml), dried and evaporated in vacuo. The residual oil was purified by FCC. Elution with hexane and hexane-ether (19:1) followed by hexane-ether (2:1) and ether gave the title compound as a pale yellow oil (1.60 g) which solidified on refrigeration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=[O:13])[CH2:7][CH2:6]2.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:16][N:17](/[CH:19]=[C:9]1/[C:8](=[O:13])[CH2:7][CH2:6][C:5]2[C:10]/1=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc2c(c1)CCC(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1ccc2c(c1)CCC(=O)/C2=C/N(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
6-methoxy-3,4-dihydronaphthalen-2(1H)-one (460 mg, 2.61 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (8 mL, 26.1 mmol) at room temperature. Within 5 minutes the solution had turned dark green in color. Next, p-toluenesulfonic acid (10 mg, 0.053 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum to afford the title compound as a dark red oil. LC/MS M+1=232.2. The material was used for subsequent reactions without further purification.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.[C:29]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]([C:29](=[O:36])[CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2
Reactant: O=C1CCCC(=O)O1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Product: O=C(O)CCCC(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1

Procedure:
The title compound was prepared from N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide and glutaric anhydride following a procedure analogous to that described in Example 90. LC-MS Method 5 tR=2.034 min, m/z=494.3; 1H NMR (CD3OD) δ=1.52-1.69 (m, 4H), 1.79-2.04 (m, 16H), 2.41 (m, 2H), 2.62 (m, 2H), 3.16-3.27 (m, 2H), 3.86 (m, 2H), 3.98 (m, 3H), 7.15-7.39 (m, 3H), 7.41 (d, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](=[N:9][OH:10])[NH2:8].[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17](Cl)=O>>[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[O:10][N:9]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1
Reactant: NC(=NO)c1cnccn1
Reactant: O=C(Cl)c1sccc1Cl
Product: Clc1ccsc1-c1nc(-c2cnccn2)no1

Procedure:
The title compound was prepared from pyrazine-2-amidoxime (42.2 mg, 0.306 mmol) and 3-chloro-thiophene-2-carbonyl chloride (55 mg, 0.30 mmol) similar to Example 16, and yielded 67.4 mg (84%) of white solid. 1H NMR (CDCl3): 9.45 (d, J=1.37 Hz, 1H), 8.81 (dd, J=2.48, 1.65 Hz, 1H), 8.77 (d, J=2.47 Hz, 1H), 7.66 (d, J=4.95 Hz, 1H), 7.16 (d, J=5.50 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>O>[C:16]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:8])[CH3:9])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
A solution of methyl 3-amino-5-tert-butylthiophene-2-carboxylate (20.0 g, 93.9 mmol), benzyl chloroformate (80.4 mL, 563 mmol), Na2CO3 (1.10 g, 9.93 mmol), toluene (400 mL) and water (50 mL) was heated at the reflux temp. for 18 h. Volatiles were removed under reduced pressure. The resulting oil was dissolved in EtOAc, washed with water and a concentrated NaCl solution, dried (MgSO4) and concentrated under reduced pressure to afford methyl 3-(N-carbobenzyloxyamino)-5-tert-butylthiophene-2-carboxylate as a crude oil in quantitative yield.
Reaction SMILES: Br[C@@H:2](C)[C:3](OC)(OC)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.[C:21]([O-:24])(=[O:23])C.[K+].CN(C)C=O>O>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([C@H:3]([CH3:2])[C:21]([OH:24])=[O:23])[CH:13]=[CH:12]2
Reactant: COc1ccc2cc(C(OC)(OC)[C@H](C)Br)ccc2c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 97 %

Procedure:
A mixture of (+)(S)2-bromo-1,1-dimethoxy-1-(6-methoxy-2-naphthyl)-propane (3.39 g; 10 mmol), potassium acetate (1.2 g; 12 mmol), N,N-dimethylformamide (14 ml) and of water (8 ml) is heated at 100° C. under stirring. The reaction mixture is worked up as described in example 1 to provide (+)(S)2-(6-methoxy-2-naphthyl)-propionic acid (2.23 g; 9.7 mmol; yield 97%), m.p. 155°-157° C.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].Cl.CO.[NH3:16].[CH3:17][S:18]([OH:21])(=[O:20])=[O:19]>CO>[CH3:17][S:18]([OH:21])(=[O:20])=[O:19].[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)(=[NH:16])[NH2:2]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: N
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CO
Product: N=C(N)c1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
2-Cyano-6-hydroxybenzothiazole, (White, E. H.; McCapra, F.; Field, G. F. The structures and synthesis of firefly luciferin. J. Am. Chem. Soc. 1963, 85, 337-342; 0.8 g, 4.54 mmol) was added to a cooled, saturated methanol-HCl solution (15 mL) and the mixture was stirred for 24 h at ambient temperature. The reaction mixture was concentrated in vacuo to give a solid. The solid was suspended in anhydrous methanol (40 mL) and gaseous NH3 was introduced into the mixture at ambient temperature for 1 h and then at 50° C. for 2 h to give a homogenous solution. The solvent was evaporated in vacuo, and the resulting brown solid was suspended in methanol (15 mL) and then treated with a saturated solution of NaHCO3 (50 mL). The precipitate was collected by filtration, washed with water (2×10 mL) and then dried in open air for 3 h. The solid (0.94 g) was suspended in 3 mL of methanol and then treated with methanesulfonic acid (0.45 g, 4.69 mmol). The precipitated material was recrystallized from methanol to give 0.75 g (57%) of 2-amidino-6-hydroxybenzothiazole methanesulfonate as a yellow solid, mp 276-278° C.