Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:11][CH:12](Br)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]1([N:21]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:22](=[O:25])[CH2:23][CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1CCCCC1>[C:1]1([O:11][CH:12]([N:29]2[CH2:28][CH2:27][CH:26]([N:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:31][CH2:30]2)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: CC(Br)Oc1cccc2ccccc12
Solvent: C1CCCCC1
Product: CCC(=O)N(c1ccccc1)C1CCN(C(C)Oc2cccc3ccccc23)CC1

Procedure:
Using the procedure of Example I step B and starting from (α-naphtoxyethyl) bromide and 4(N-phenyl N-propionylamino) piperidine, N(α-naphtoxyethyl) 4-(N'-phenyl-N'-propionylamino) piperidine is obtained melting at 110°-112° (cyclohexane).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][Si](C)(C)C)=[CH:24][C:21]=1[C:22]#[N:23]>O1CCCC1.C(Cl)Cl>[C:28]([C:25]1[CH:26]=[CH:27][C:20]([F:19])=[C:21]([CH:24]=1)[C:22]#[N:23])#[CH:29]
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1ccc(F)c(C#N)c1
Reaction time: 0.33 h

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 70 mL) was added to a solution of Example 62A (5.05 g, 23.2 mmol) in tetrahydrofuran (50 mL) and allowed to stir for 20 minutes. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.13 (dd, J=6.27, 2.20 Hz, 1H) 7.82-7.95 (m, 1H) 7.56 (t, J=8.99 Hz, 1H) 4.40 (s, 1H).
Reaction SMILES: C(C[O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)#N.[NH3:21]>O1CCCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([NH2:21])=[O:4])=[CH:12]1
Reactant: N
Reactant: N#CCOC(=O)CCCCCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Product: NC(=O)CCCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 40 h
Yield: 98 %

Procedure:
A solution of 6-(1H-Indol-3-yl)hexanoic acid cyanomethyl ester (5.72 g, 21.16 mmol) in tetrahydrofuran (160 ml) was added to a 25 percent strength ammonia solution (125 ml) and the mixture was stirred at RT for 40 h. Working up of the mixture was carried out by phase separation and extraction of the aqueous phase with THF (2×40 ml). The organic extracts were combined and washed with saturated NaCl solution (50 ml). After drying and concentration of the organic phase, the product was isolated as a colourless solid in a yield of 98% (4.75 g) with an m.p. of
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].Cl.[CH3:19][NH2:20]>CCO>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:20][CH3:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NC)c([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 99.3 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.125 g, 0.521 mmol), methylamine hydrochloride (0.035 g, 0.521 mmol) in 80% aq. EtOH (3 mL) was heated at 85° C. for 4 hours. Usual work-up provided the title compound (0.130 g, 100%) which was used without further purification. MS (ESI) (M+H)+=252.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:15]=[CH:16][C:17]3[S:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[C:18]=3[CH:19]=2)=[N:10][CH:11]=1)=[O:5].C[OH:27]>O>[CH2:2]([O:3][C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:19]=[C:18]3[C:17](=[CH:16][CH:15]=2)[S:23](=[O:27])[CH2:22][CH2:21][C:20]3([CH3:24])[CH3:25])=[N:10][CH:11]=1)[CH3:1]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)nc1
Reactant: CO
Solvent: O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3=O)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of tazarotene (10.0 g, 28.5 mmol) in methanol (300 mL) was chilled in an ice water bath to <10° C., and then charged with the dropwise addition of a solution of NaIO4 (9.13 g, 42.7 mmol) in water (100 mL) over 30 minutes. The reaction was allowed to warm to room temperature while stirring for 18 hours, and was then concentrated under reduced pressure to remove as much methanol as possible. The reaction was then diluted with DCM (500 mL) and water (150 mL). The two layers were then separated, and the aqueous layer was extracted with DCM (2×100 mL aliquots). The organic fractions were pooled, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude sulfoxide product was then chromatographed using a DCM:EtOAc solvent system. Yield: 9.00 g (86%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:8]=2[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=[N:3]1.O.C1COCC1>[Cl-].[NH4+].[Zn]>[CH3:1][N:2]1[C:6]([C:7]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:8]=2[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 214.7 %

Procedure:
To a solution of 4-{2-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-morpholine (1.913 g, 2.88 mmole), in saturated ammonium chloride solution (6 mL), water (6 mL) and THF (12 mL) was added zinc dust (1.123 g, 6 eq) at 0° C. The mixture was stirred at room temp for 1 hour and then filtered off through celite. The solution was dried in vacuo to give title compound as a yellow gummy solid (1.87 g, 99%). Exact mass calculated for C16H22N4O2302.2, found 303.4 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[CH2:20]([NH:21][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12)[CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCN
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Product: CCCCCNc1c(C(=O)OCC)cnc2cn[nH]c12

Procedure:
The above compound was prepared from ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate and n-amylamine in an analogous manner to the preparation of Example 2 giving a pale yellow solid, m.p. 153°-155° C.
Reaction SMILES: [Cl-].[S-:2][C:3]#[N:4].[K+].[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)[N:11]=1.[OH2:22]>O1CCOCC1>[CH2:10]([CH:12]([CH2:13][CH2:14][CH2:19][CH3:18])[C:21]([NH:4][C:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)[N:11]=1)=[S:2])=[O:22])[CH3:9]
Reactant: O
Reactant: N#C[S-]
Reactant: Nc1nc(-c2ccc3c(c2)CCCC3)cs1
Agent: [Cl-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCC(CC)C(=O)NC(=S)Nc1nc(-c2ccc3c(c2)CCCC3)cs1
Reaction time: 4 h
Yield: 58.1 %

Procedure:
2-Ethylexanoyl chloride (0.43 g) was added to a solution of potassium thiocyanate (0.506 g) in dioxane (10 ml), followed by stirring at 55° to 60° C. for 4 hours. Then, 2-amino-4-(5,6,7,8-tetrahydro-2-naphthyl)thiazole (0.5 g) was added to the solution, which was stirred at 55° to 60° C. for 3 hours. The reaction mixture was poured into water, and the crystals which separated out were recovered by filtration, washed with water and isopropyl ether, successively, and recrystallized from dichloromethane-isopropyl ether to give 1-(2-ethylhexanoyl) 3-[4-(5,6,7,8-tetrahydro-2-naphthyl)-2-thiazolyl]thiourea (0.438 g, 58.1%) in the form of colorless needles. m.p. 178°-179° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][N:8]1[C:7]2[C:2]([CH3:1])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[CH:4]=[CH:5][C:6]=2[S:10][C:9]1=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2sc(=O)[nH]c2c1C
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc2sc(=O)n(C)c2c1C
Yield: 84.3 %

Procedure:
A solution of 11.38 g (51 mmol) of methyl 4-methylbenzo-thiazol-2-one-5-carboxylate in 400 ml of acetone was admixed with 14.18 g of potassium carbonate. 5.1 ml (54 mmol) of dimethyl sulfate were then added dropwise with stirring, and the mixture was stirred at 23° C. for 78 hours. The precipitated solid was filtered off and the solvent was removed under reduced pressure. Recrystallization from ether gave, in a yield of 84%, 10.15 g (43 mmol) of methyl 3,4-dimethylbenzothiazol-2-one-5-carboxylate of m.p. 97° C.-100° C.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:53]=[CH:54][C:55]=1[Cl:56])[CH2:40][N:41]([CH3:52])[C:42]([C:44]1[CH2:45]N(C)[C:47](=[O:50])[C:48]=1[OH:49])=[O:43]>>[Cl:36][C:37]1[CH:38]=[C:39]([CH:53]=[CH:54][C:55]=1[Cl:56])[CH2:40][N:41]([CH3:52])[C:42]([C:44]1[CH2:45][N:23]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([S:32](=[O:33])(=[O:34])[NH2:35])=[CH:30][CH:31]=2)[C:47](=[O:50])[C:48]=1[OH:49])=[O:43]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCc2ccc(S(N)(=O)=O)cc2)C1
Yield: 19 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 4-(2-amino-ethyl)benzenesulfonamide as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (47.9 mg, 19% yield). Decomposition point=110–113° C. 1H NMR (500 MHz, DMSO) δ: 10.97 (s, 1H), 7.72, (m, 2H), 7.61 (d, 1H, J=8.54), 7.51 (s, 1H), 7.42 (m, 2H), 7.29 (m, 2H), 7.25, (m, 1H), 4.56, (s, 2H), 4.04, (s, 2H), 3.67 (m, 2H), 3.34 (m, 2H), 2.95 (d, 3H, J=6.41). HRMS (M−H) calcd for C21H20SN3Cl2O5: 496.0500. found: 496.0503.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=2)[CH:17]([CH2:30][O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:16]1)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH2:30][CH:17]2[CH2:16][NH:15][CH2:20][CH2:19][N:18]2[C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=2)[CH:33]=1
Reactant: COC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1csc(N2CCNCC2COc2cccnc2)n1
Reaction time: 8 h
Yield: 17 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of methyl 2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylate (32 mg, 0.074 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The material was dissolved in H2O (20 mL), and the pH was adjusted to ˜2 with concentrated HCl. This was washed with Et2O (3×5 mL, discarded). The aqueous layer was adjusted to pH ˜12 with 1 N NaOH and was extracted with EtOAc (3×20 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 5.0 mg (17%) of the title compound. LC-MS: RT=3.41 min, (M+H)+=335.4.
Reaction SMILES: [N:1]1([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:31]3[CH2:32][CH2:33][N:28]([C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[CH3:20])[CH2:29][CH2:30]3)=[O:16])=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(-n4cnc5ccccc54)cc3)CC2)c(C)c1
Yield: 55.6 %

Procedure:
Using methyl 4-(benzimidazol-1-yl)benzoate (126 mg) and 1-(2,4-dimethylphenyl)piperazine (95 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (114 mg) was obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1.[C:17]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[C:24](O)=[O:25])([CH3:20])([CH3:19])[CH3:18].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[C:30]([C:28]1[CH:27]=[C:23]([CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:29]=1)[C:24]([NH:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1)=[O:25])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCN(CC)CCSc1nnc(N)s1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1nnc(NC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.1 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole (2.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 3,5-Di-tert-butylbenzoic acid (2.3 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.5 g of the aimed compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=1)[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([CH3:37])([CH3:36])[CH2:19][CH2:20][C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]#[N:23])[CH2:14][CH2:13]1.C[O:42]B(OC)OC.C[N+]1([O-])CCOCC1>O1CCCC1>[NH3:15].[OH:42][C:7]1[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=1)[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([CH3:37])([CH3:36])[CH2:19][CH2:20][C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]#[N:23])[CH2:14][CH2:13]1
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CCC(OCc2cccc(Br)c2)CC1
Reactant: COB(OC)OC
Agent: C[N+]1([O-])CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CCC(OCc2cccc(O)c2)CC1
Product: N
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (2.5M in hexanes, 0.18 mL, 0.45 mmol) was added dropwise to a solution of the product of example 87 (200 mg, 0.38 mmol) in tetrahydrofuran (5 mL), cooled to −78° C., and the mixture was stirred for 15 minutes. Trimethylborate (0.13 mL, 1.13 mmol) was added and the mixture was stirred at −78° C. for 30 minutes and at room temperature for 2 hours. 4-methylmorpholine N-oxide (132 mg, 1.13 mmol) was added and the mixture was heated under reflux for 4 hours and stirred at room temperature for 18 hours. The reaction mixture was then partitioned between ethyl acetate (30 mL) and water (30 mL) and the organic layer was separated and washed with water (20 mL). The organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1. The appropriate fractions were evaporated under reduced pressure and the residue was further purified by preparative tlc, eluting with dichloromethane:methanol:0.88 ammonia, 90:10:1, to afford the title compound as a gum in 3% yield, 5 mg.
Reaction SMILES: [I-:1].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH3:9].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(N(C(C)C)CC)(C)C>C(#N)C>[I-:1].[N:10]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=2[CH3:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[n+]1ccccc1-n1ccnc1

Procedure:
2-Chloro-1-methylpyridinium iodide (9.43 g), imidazole (2.45 g) and diisopropylethylamine (4.77 g) were added to acetonitrile (150 ml) and the mixture refluxed for 2 hours. The product was filtered off from the chilled solution and dried. Yield, 6 g.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:31]C(=O)OC(C)(C)C)([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:21]=[C:20](/[CH:22]=[CH:23]/[C:24]5[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=5)[O:19][N:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:4][O:3]1.C(=O)(OC1(C2OC3C=CC(C4N=C(C5C=CC(OCCC)=C(Cl)C=5)ON=4)=CC=3C=2)COC(C)(C)OC1C(C)(C)C)N>>[NH2:31][C:5]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]=[C:20](/[CH:22]=[CH:23]/[C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[O:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: Cc1ccc(/C=C/c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(OC(N)=O)COC(C)(C)OC5C(C)(C)C)cc4c3)no2)cc1Cl
Product: Cc1ccc(/C=C/c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cc1
Yield: 48 %

Procedure:
When the product of Step C was substituted for tert-butyl5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-yl carbamate in Example 36, Step E, the similar procedure afforded the title compound in 48% yield, as colourless solid. 1H-NMR (DMSO-d6) 8.23 (b, 1H); 7.9-7.85 (m, 2H); 7.72-7.64 (m, 3H); 7.33 (d, 1H, J=16.2 Hz); 7.25 (d, 2H, J=6.3 Hz); 6.87 (s, 1H); 4.77 (b, 2H); 3.63 (b, 2H); 3.56 (b, 2H); 2.32 (s, 3H); 1.95 (b, 2H).
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]=O)[N:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:22]1[CH2:28][C:26](=[O:27])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:23]1=[S:24].[Cl-].[NH4+].N>C(O)C>[C:8]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]=[C:28]3[S:22][C:23](=[S:24])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:26]3=[O:27])[N:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(NC(c2ccccc2)c2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(NC(c3ccccc3)c3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.95 g of 2-diphenylmethylaminothiazole-4-carbaldehyde. 1.32 g of rhodanine-3-acetic acid, 0.4 g of ammonium chloride, 0.4 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a reddish-brown powder having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[O:10][CH2:9]2)=[CH:6][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[ClH:1].[Cl:1][C:2]1[C:7]([CH:8]([OH:10])[CH2:9][NH:30][CH:27]([CH3:29])[CH3:28])=[CH:6][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1
Reactant: CC(C)N
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1C1CO1
Product: CC(C)NCC(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cc1Cl
Product: Cl

Procedure:
Following the procedures of Example 6, 6-chloro-3,4-dibenzyloxystyrene oxide is refluxed with isopropylamine to give 6-chloro-α-(isopropylaminomethyl)-3,4-dibenzyloxybenzyl alcohol hydrochloride, m.p. 154°-163°C., which is hydrogenated to yield 6-chloro-α-(isopropylaminomethyl)-3,4-dihydroxybenzyl alcohol hydrochloride, m.p. 171°-172°
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:29](OS(C)(=O)=O)[CH3:30])[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[C:13](=[O:36])[C@H:12]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:49](N(CC)CC)C>C(Cl)(Cl)Cl>[C:5]1([CH3:49])[C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:29]=[CH2:30])[C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:17])[C:13](=[O:36])[C@H:12]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)(=[O:8])=[O:9])=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: CCN(CC)CC
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Product: C=C=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccccc1C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of 4-nitrobenzyl 2-[(3R,4R)-4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methanesulfonyloxy-2-butenoate (XXc, 0.0714 g, 0.00010 mole) in chloroform (1 mL) was treated with triethylamine (0.014 mL, 0.00010 mole) at room temperature. After a period of 1 h, reverse-phase C-18 HPLC indicated consumption of the starting material with formation of a single new peak (65% acetonitrile and 0.01M phosphate pH 6.5 buffer). Dilute hydrochloric acid (chilled at 0° C.) and ethyl acetate were added. The organic layer was washed with cold water, dried (sodium sulfate) and concentrated to give 0.0615 g (ca 100%) of the title compound as a foam. The product was characterized by its 1H-NMR spectrum.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([NH2:12])[CH:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([NH2:12])[CH:3]=1
Reactant: Nc1cc(Cl)c2ccccc2n1
Reactant: c1ccc2c(c1)CCNC2
Product: Nc1cc(N2CCc3ccccc3C2)c2ccccc2n1

Procedure:
The title compound, MS: m/e=276.3 (M+H+), was prepared from 4-chloro-quinolin-2-ylamine and 1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH3:44])[CH:26]=[C:27]2[C:31]=1[CH:30]([NH:32][C:33]1[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=1)[CH2:29][CH2:28]2>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH3:44])[CH:26]=[C:27]2[C:31]=1[CH:30]([NH:32][C:33]1[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH:43][C:1]([NH:20][CH:17]4[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]4)=[O:2])[CH:39]=3)[N:34]=1)[CH2:29][CH2:28]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C)cc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cc(C)cc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-methyl-piperidin-4-ylamine and rac-N2-(7-methoxy-5-methyl-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=460.8 (M+H+).