Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][N:22]=C[CH:20]=1)[C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]#[N:17].ClC1C=CC([N+:36]([O-])=O)=C2C=1C=CC=C2C#N.N1C=CC=C(N)N=1>>[CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[N:36][CH:20]=1)[C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]#[N:17]
Reactant: N#Cc1cccc2c(Cl)ccc([N+](=O)[O-])c12
Reactant: CN(Cc1ccncc1)c1ccc([N+](=O)[O-])c2c(C#N)cccc12
Agent: Nc1cccnn1
Product: CN(Cc1ccnnc1)c1ccc([N+](=O)[O-])c2c(C#N)cccc12
Yield: 24 %

Procedure:
5-(Methyl-pyridazin-4-ylmethyl-amino)-8-nitro-naphthalene-1-carbonitrile (24) was prepared in a manner analogous to that described above for the preparation of compound (10), except that compound (9) and pyridazyl amine compound (48) were used as starting materials. Compound (24) (24% yield) was isolated as a yellow foam by flash chromatography on silica, eluting CH2Cl2 :MeOH (25:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11]C(=O)C[Cl:14])([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>C(O)C>[ClH:14].[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:11])([CH3:9])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)CCl)c1cccc(Br)c1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(N)c1cccc(Br)c1
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of N-(2-(3-bromophenyl)propan-2-yl)-2-chloroacetamide (20.3 g) in ethanol (120 mL) was added acetic acid (20 mL). The reaction mixture was stirred at reflux for 18 h. The solution was cooled to room temperature and the precipitate was filtered off on a celite pad. The filtrate was concentrated and the residue was dissolved in EtOAc. The organic layer was treated with aqueous NaOH [1.0M] solution, dried over Na2SO4 and concentrated. The crude material was treated with a solution of HCl/dioxane [4M]. The intermediate 2-(3-bromophenyl)propan-2-amine hydrochloride was triturated in ether and used as is for the next step (7.50 g, 43%). 1H NMR (400 MHz, CD3OD) δ 7.69 (q, J=1.8 Hz, 1H), 7.55 (ddd, J=1.0, 1.8, 7.9 Hz, 1H), 7.49 (ddd, J=1.0, 2.0, 8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 1.71 (s, 6H) ppm.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=1)[CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[S:4]
Reactant: CC(C)C(=O)NCCC1C=CC=CC1=O
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)C(=O)NCC(=NNC(N)=S)c1ccccc1
Yield: 60.7 %

Procedure:
Thiosemicarbazide (2.22 g, 24.4 mmol) was added to a solution of N-(2-oxo-phenyl-ethyl)-2-methyl-propanamide (5.0 g, 24.4 mmol), prepared in the previous step, in 70 ml of methanol plus 6.75 ml of 1N HCl plus 6.25 ml of water and the reaction stirred at room temperature overnight. The solid formed was collected by filtration, rinsed with isopropyl alcohol and hexane, and then dried to give 4.12 g of a white solid. Recrystallization of this solid from isopropyl alcohol gave the title compound (3.15 g, 46%) as a white solid, mp 183-185° C.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22](I)=[CH:23][C:17]=4[S:16](=[O:26])(=[O:25])[N:15]=3)=[C:10]([OH:27])[C:9]3=[CH:28][CH:29]=[CH:30][N:8]23)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]1[S:39](=[O:44])(=[O:43])[CH2:40][CH2:41][CH:42]=1)CCC>CN(C)C=O.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>[O:43]=[S:39]1(=[O:44])[CH2:40][CH2:41][CH:42]=[C:38]1[C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:14]([C:11]3[C:12](=[O:13])[N:7]([CH2:6][C:5]4[CH:31]=[CH:32][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]4[CH:30]=[CH:29][CH:28]=[C:9]4[C:10]=3[OH:27])=[N:15][S:16](=[O:26])(=[O:25])[C:17]=2[CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCS1(=O)=O
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
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: O=c1c(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Temperature: 90 °C
Yield: 48.5 %

Procedure:
1-(4-Fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (Example 9b, 0.207 g, 0.371 mmol), tributyl-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-stannane (Example 11a, 0.181 g, 0.442 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.020 mmol) were dissolved in N,N-dimethylformamide (8 mL) at 25° C. The mixture was heated to 90° C. for 24 h, then was allowed to cool to 25° C. and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→7% methanol in dichloromethane) to afford a brown solid. This material was re-chromatographed (Merck silica gel 60, 40-63 μm, 40→100% ethyl acetate in hexanes, followed by 100% ethyl acetate, followed by 0→7% methanol in dichloromethane) to afford the desired product, 3-[7-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (0.100 g, 0.180 mmol, 48.6% yield). LC-MS (ESI) calcd for C25H19FN4O6S2 554.07. found 555.00 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4].O[CH2:26][CH2:27][N:28]([CH3:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)[Cl:53]>>[ClH:53].[CH3:23][C:8]1[NH:7][C:6]([CH3:24])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]=1[C:20]([O:22][CH2:26][CH2:27][N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:36])=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CN(CCO)Cc1ccccc1
Reactant: ClC(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Product: Cl
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A mixture of 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid (3.32 g, 0.01 mole), N-(2-hydroxyethyl)-N-benzyl-methylamine (4.98 g) and N,N'-dicyclohexylcarbodiimide (DCC) (2.05 g) is stirred at 60°-80° C. for 1 hour. To the reaction mixture chloroform (16 ml) is added and the mixture is washed with water (3×50 ml). Then the organic layer is washed with a 10% aqueous solution of HCl (16 ml) and water (3×10 ml). The organic layer is dried with anhydrous Na2SO4 and the solvent is evaporated in vacuo. The oily residue is dissolved in ethyl acetate (18 ml) and stirred at 0° C. for 2 hours. The precipitate, which separates, is filtered off, dried in vacuo and recrystallized from acetone. Thus, there is obtained the title compound nicardipine hydrochloride (4.4 g, 85.4%).
Reaction SMILES: [CH3:1][N:2]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:1][N:2]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
A mixture of ethyl 7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxylate (2.50 g), 1N aqueous sodium hydroxide solution (10 mL), ethanol (10 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 1.5 hr. 1N Hydrochloric acid (10 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (2.30 g, yield 98%) as colorless crystals. The crystals were recrystallized from acetone-hexane to give colorless prism crystals. melting point 207-208° C.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([O:22][C:23]2[CH:45]=[CH:44][C:26]3[C:27]4[N:31]([CH2:32][CH2:33][O:34][C:25]=3[CH:24]=2)[CH:30]=[C:29]([C:35]2[N:36]([CH:41]([CH3:43])[CH3:42])[N:37]=[C:38]([CH3:40])[N:39]=2)[N:28]=4)[C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.CO.[CH3:48]CN(C(C)C)C(C)C.C(Cl)(=O)C>[Pd].CC(C)=O>[F:21][C:18]([F:19])([F:20])[CH:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH3:48])[CH2:12][CH2:13]1)[O:22][C:23]1[CH:45]=[CH:44][C:26]2[C:27]3[N:31]([CH:30]=[C:29]([C:35]4[N:36]([CH:41]([CH3:43])[CH3:42])[N:37]=[C:38]([CH3:40])[N:39]=4)[N:28]=3)[CH2:32][CH2:33][O:34][C:25]=2[CH:24]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C4CCN(C(=O)OCc5ccccc5)CC4)C(F)(F)F)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Solvent: CO
Solvent: CC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(C(Oc2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.3 %

Procedure:
To a solution of 4-{2,2,2-trifluoro-1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}piperidine-1-carboxylic acid benzyl ester from Example 5 (210 mg, 0.34 mmol) in a 1:10 mixture MeOH:acetone (11 mL), was added 10% Pd/C (200 mg). The reaction mixture was stirred at RT under a hydrogen atmosphere for 18 h. The suspension was then filtered through a pad of Celite® and to the filtrate fresh 10% Pd/C (200 mg) was added. The reaction mixture was stirred at RT under a hydrogen atmosphere for 48 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resulting residue was treated with DIPEA (0.79 mL, 4.42 mmol) and acetyl chloride (0.23 mL, 4.08 mmol) and stirred at RT for 18 h. The crude material was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90% 0.1% HCO2H in acetonitrile/water) affording 179 (15 mg, 8%). LCMS: RT 4.23 min [M+H]+ 533.2. 1H NMR (CDCl3, 400 MHz): δ 8.47 (1H, d, J=8.99 Hz), 7.61 (1H, s), 6.80 (1H, dd, J=9.00, 2.62 Hz), 6.64 (1H, d, J=2.49 Hz), 5.92-5.85 (1H, m), 4.78-4.69 (1H, m), 4.50-4.47 (2H, m), 4.46-4.35 (3H, m), 3.93-3.85 (1H, m), 3.16-3.02 (1H, m), 2.64-2.51 (1H, m), 2.42 (3H, s), 2.27-2.15 (1H, m), 2.10 (3H, d, J=2.36 Hz), 2.05-1.93 (1H, m), 1.89-1.75 (1H, m), 1.64-1.44 (8H, m)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:12].C([Li])CCC.CN(C)[CH:20]=[O:21]>C1COCC1.[Cl-].[NH4+]>[Cl:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:20]=[O:21])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
To a solution of 6-bromo-4-chloro-quinoline (3.0 g, 12.37 mmol) in THF (60 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (5.95 mL, 14.84 mmol, 1.1 equiv.) at −70° C. During the addition, the color of the solution was turned to red and it was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (1.91 mL, 24.74 mmol) in THF (10 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude brown solid which was purified by using a Biotage silica gel column chromatography to obtain 0.6 g (25% yield) of 4-chloro-quinoline-6-carbaldehyde as a white solid: EI-HRMS m/e calcd for C10H6ClNO (M+) 187.0633, found 187.0638.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl:25]CCCl>>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[Cl:25])=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: ClCCCl
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of nicotinoyl chloride (0.500 g, 2.84 mmol) in 15 mL of 1,2-dichloroethane was added 4-chloroaniline (0.432 g, 3.41 mmol) and triethylamine (0.400 mL, 2.84 mmol), respectively. The reaction mixture was stirred at room temperature for 1 h before it was washed with water (2×), brine (1×), dried over Na2SO4, and the solvent removed in vacuo. The crude material was purified by chromatography over silica, using an eluent of 2% (2 M NH3 in methanol) in chloroform, to afford the amide (0.758 g, 100%).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[C:16](OC(=O)C)(=[O:18])[CH3:17].S(=O)(=O)(O)O>>[C:16]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])(=[O:18])[CH3:17]
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-Hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (5 grams), 25 milliliters of acetic anhydride and 0.1 milliliter of sulfuric acid were mixed with stirring at 25° C. for 15 minutes. The reaction mixture was then heated to reflux and refluxed for one-half hour, poured into ice with stirring, stirred for ten minutes and filtered. Filtration yielded the desired 1-acetoxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product as a solid. It was taken up in ether, dried over magnesium sulfate, and the ether evaporated. The product then melted at 103°-04° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:16](COCC[Si](C)(C)C)[CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[N:19]=2)=[O:14])OCC[O:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[C:18]1[NH:19][C:15]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:3])[CH3:1])=[N:16][CH:17]=1
Reactant: CC1(CCCCCCC(=O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)CCCCCCC(=O)c1ncc(-c2ccc3ccccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The ketone E3 was dissolved in TFA/DCM (1:1) and stirred for 4 hr at RT. After evaporation of the solvent under reduced pressure, the crude product was purified by preparative RP-HPLC (column: C18), using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents. The desired fractions were lyophilized to afford E4 as a white solid. 1H NMR (300 MHz, DMSO) δ: 8.17 (1H, s), 7.92-7.79 (3H, m), 7.76-7.64 (2H, m), 7.55-7.45 (2H, m), 3.15 (2H, t, J=7.4 Hz), 2.44 (2H, t, J=7.4 Hz), 2.15 (3H, s), 1.74 (2H, m), 1.58 (2H, m), 1.37 (4H, m). MS (ES) C22H24N2O2 requires: 348, found: 349 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccc4ccccc4c3)cc2)ccc1Cl
Yield: 34.1 %

Procedure:
2-(4-Aminophenylthio)naphthalene (4.2 mmoles, 1.06 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (4.2 mmoles, 0.93 g) were reacted according to procedure A to yield of the title compound 0.7 g, 34%. Mass Spec (FD) 489. Calculated for C24H16ClF3 N2S2 : C, ; H, N, . Found: C, ; H, ; N, .
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:20]([OH:23])[CH2:21]Br)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:24])[CH:3]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CO.Cl>C(Cl)Cl>[O:23]=[C:20]1[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[N:5]2[C:4](=[O:24])[CH:3]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:2]2[S:1][CH2:21]1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate prepared by the method of Example 4.-III (2) (70 mg) in a mixture of methylene chloride (2 ml), methanol (2 ml), and 10% hydrochloric acid (0.3 ml) is stirred at room temperature for 2 hours. The reaction mixture is poured into ice water, and is extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl 3-oxo-7-phenoxyacetamidocepham-4-carboxylate (44.5 mg), identical with the product of Example 4.-III (3). Yield: 74%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridyl)benzoic acid (40 mg, 0.1017 mmol) and morpholine (18 mg, 0.2608 mmol) were dissolved in methylene chloride (3 ml), then WSC-HCl (49 mg, 0.2556 mmol) was added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (methylene chloride:methanol=95:5) to give the title compound (32 mg, 0.0692 mmol, 68%).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:34]5[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=5)=[CH:3][C:4]([C:25]([F:27])([F:28])[F:26])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c2[nH]1

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 4-(trifluoromethyl)phenylboronic acid (47 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 515 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N([CH2:21][CH3:22])CC)C.[C:23](=[S:25])=[S:24].C(I)C>O.C(O)C>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([S:25][CH2:21][CH3:22])=[S:24]
Reactant: S=C=S
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: O
Solvent: CCI
Product: CCSC(=S)N1Cc2[nH]c3ccccc3c2C[C@H]1CO

Procedure:
In the same manner as described in Example 2 by using (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (2.02 g), triethylamine (1.52 g), CS2 (1.14 g), ethyl iodide (2.34 g), ethanol (25 ml) and water (5 ml), there is prepared the title compound (2.0 g, 65%) as colorless needles, m.p. 74°-76° C. (recrystallized from ethanol), [α]D20 +146.0° (c=1, methanol). NMR (CDCl3, δ): 1.35 (t, J=7.5 Hz, 3H, CSSCH2CH3), 3.36 (q, J=7.5 Hz, 2H, CSSCH2CH3), Mass m/e: 306 (M+), 244 (M+ -thioethanol).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH:44][CH2:45][CH3:46])=[CH:38][CH:37]=1>>[Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:44]([CH2:43][CH2:42][C:39]1[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][CH:40]=1)[CH2:45][CH3:46])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCNCCc1ccc(Cl)cc1
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: Cl
Product: CCN(CCc1ccc(Cl)cc1)C(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Yield: 43 %

Procedure:
The title compound was prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) and [2-(4-chloro-phenyl)-ethyl]-ethyl-amine hydrochloride (preparation 81), using a similar method to that of preparation 109, as a white solid in 43% yield. 1H NMR (400 MHz, CD3OD) 7.90-6.90 (10H, m), 6.72 (1H, d), 4.69 (1H, m), 4.63 (2H, m), 3.70 (1H, m), 3.61 (1H, m), 3.49 (1H, m), 3.10 (1H, m), 3.03-2.58 (6H, m), 1.29-1.26, 1.07-1.01 (9H, 2×m), 0.82 (9H, s), 0.01 (3H, s), -0.18 (3H, s) ppm; LRMS APCI m/z 639 [M+H]+