Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][N:37]2C(=O)C3=CC=CC=C3C2=O)=[O:10])=[CH:5][CH:4]=1.O.NN>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][NH2:37])=[O:10])=[CH:48][CH:49]=1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN)cc1
Yield: 77.8 %

Procedure:
To a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-phthalimidomethyl-4-tritylthiopyrrolidine (752 mg: 1.124 mmole) in a mixture of dichloromethane (3 ml) and methanol (12 ml), hydrazine hydrate (109 μl: 2 eq.) is added. The mixture is heated for 5 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in dichloromethane (5 ml) and the solid is filtered off. The filtrate is washed with water and concentrated in vacuo. The residue is recrystallized from a mixture of dichloromethane and methanol to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-aminomethyl-4-tritylthiopyrrolidine (471 mg). Yield: 78%. mp. 165° to 167° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH2:35][CH2:36][C@@H:37]([OH:39])[CH3:38]>O1CCOCC1>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH2:36][C@@H:37]([OH:39])[CH3:38])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Reactant: C[C@H](O)CN
Solvent: C1COCCO1
Product: C[C@H](O)CNc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), (S)-(+)-1-amino-2-propanol (79 mg, 1.056 mmol) in 1,4-dioxane (2 mL), the title compound was obtained as a white foam (44 mg, 0.075 mmol, 35.4%). 1H NMR (400 MHz, DMSO-d6) ppm 1.05 (d, J=6.32 Hz, 3H), 1.75 (qd, J=12.13, 4.04 Hz, 2H), 1.99-2.09 (m, 2H), 2.98-3.24 (m, 2H), 3.29 (tt, J=11.49, 3.92 Hz, 1H), 3.39-3.53 (m, 2H), 3.78 (dt, J=11.31, 5.84 Hz, 1H), 3.93 (dd, J=11.49, 2.15 Hz, 2H), 4.69 (brs., 1H), 5.94 (d, J=1.26 Hz, 1H), 6.66 (d, J=1.01 Hz, 1H), 7.13 (t, J=5.81 Hz, 1H), 7.23-7.39 (m, 2H) 7.46 (t, J=6.95 Hz, 1H), 7.82 (t, J=1.77 Hz, 1H), 8.08 (d, J=5.05 Hz, 1H), 8.28 (s, 1H), 10.32 (s, 1H); MS (ESI): 560.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:22]=[CH:21][C:11]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C1C(=O)N([Cl:30])C(=O)C1>C(Cl)Cl>[Cl:30][C:22]1[CH:21]=[C:11]([CH:10]=[CH:9][C:8]=1[N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCN(c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1
Solvent: ClCCl
Product: CN1CCN(c2ccc(CNC(=O)OC(C)(C)C)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Step F (2): To a solution of tert-butyl 4-(4-methylpiperazin-1-yl)benzylcarbamate (30 mg, 0.1 mmol) from step F (1) in CH2Cl2 (1.0 mL) was added NCS (14 mg, 0.1 mmol). The mixture was stirred at rt for 4 h, and then the mixture was concentrated to give tert-butyl 3-chloro-4-(4-methylpiperazin-1-yl)benzylcarbamate which was used without purification in the next step. LC-MS (M+H)+=340.29 1H-NMR (500 MHz, CD3OD) δ 7.30 (s, 1 H), 7.18 (d, J=8.24 Hz, 1 H), 7.10 (d, J=8.24 Hz, 1 H), 4.16 (s, 2 H), 3.00-3.15 (m, 4 H), 2.62-2.81 (m, 7 H), 1.50(s, 9 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])=[CH:10][N:11]=1)[C:5]([O:7]C)=[O:6].O1CCC[CH2:14]1.C[Al](C)C.[Cl-].[NH4+]>CCOC(C)=O.CCOC(C)=O.CCCCCC>[F:12][C:9]1[C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]([CH3:14])=[N:11][CH:10]=1
Reactant: COC(=O)c1cc(Br)ncc1F
Reactant: C1CCOC1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)c(F)cn1
Reaction time: 0.17 h
Yield: 374.8 %

Procedure:
To a solution of methyl 2-bromo-5-fluoroisonicotinate (1.0 g, 4.27 mmol) in tetrahydrofuran (25 ml) tetrakis(triphenylphosphine)palladium (495.0 mg, 0.43 mmol) was added. The mixture was stirred for 10 min, and then trimethylaluminum (5.13 ml, 1.00 M in heptane, 5.13 mmol) was added. The mixture was refluxed for 4 h, and the reaction was monitored by TLC (10% EtOAc-Hexane). Then, the reaction was diluted with EtOAc (75 ml) and a few drops of saturated. ammonium chloride were added. The mixture was filtered through a small silica gel pad, followed by removal of the solvent. The crude product was re-dissolved in 5N NaOH solution in water and stirred at room temperature for 2 hours. The crude product was purified on Flashmaster II to afford 250 mg of 5-fluoro-2-methylisonicotinic acid.
Reaction SMILES: [C:1]([C:5]1[C:6]([Cl:34])=[C:7]([C:11]2[NH:33][C:14]3[C:15]([O:29][CH2:30][CH:31]=[O:32])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([OH:39])CCC.CC(=CC)C.O.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[Na+].[OH-].[Na+]>>[C:1]([C:5]1[C:6]([Cl:34])=[C:7]([C:11]2[NH:33][C:14]3[C:15]([O:29][CH2:30][C:31]([OH:39])=[O:32])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCO
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCC=O)c2[nH]1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCC(=O)O)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of [2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy]-acetaldehyde (30.0 mg, 0.0610 mmol, prepared as described in the previous step) in 5:5:2 tart-BuOH/2-methyl-2-butene/H2O (1.2 mL) was added sodium chlorite (11.6 mg, 0.128 mmol) followed by sodium dihydrogen phosphate (17.8 mg, 0.183 mmol). After stirring at room temperature for 16 h, the resulting mixture was treated with 1N NaOH (2 mL) and concentrated in vacuo. The resulting residue was treated with H2O (20 mL) and washed with EtOAc (2×10 mL). The aqueous phase was acidified to pH 5 by adding HOAc and then extracted with EtOAc (3×15 mL). The combined organic layers were washed with H2O (15 mL), brine (15 mL) and then dried with Na2SO4. Removal of the solvent in vacuo yielded [2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy]-acetic acid as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ: 7.13-8.04 (m, 5H), 5.10 (s, 2H), 4.06 (s, 3H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C23H21ClF3N5O3: 508.1 (M+H), Measured: 508.1.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH:28]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]3[CH:35]=[CH:34][C:33]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[CH:41][CH:40]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(-c2cccnc2)cc1

Procedure:
The title compound, off-white solid (98 mg, 77%), MS (ISP) m/z=508.4 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-pyridin-3-yl-benzoic acid.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH3:17][C:18](=[O:21])[C:19]#[CH:20].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][CH:20]=[C:19]([C:18](=[O:21])[CH3:17])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C#CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)C1=CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (9.76 g, 0.041 mol) in CH2Cl2 (40 mL) at 0° C., was added dropwise over a 5 minutes period but-3-yn-2-one (2.0 g, 0.029 mol) followed by trifluoroacetic acid (0.22 mL, 0.003 mol) (very exothermic reaction). The ice bath was removed after 30 minutes, and the solution was stirred at 25° C. for an additional 2 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/Heptane 1:1) afforded 2.90 g (49%) of the title compound as a yellow oil. ES-MS m/e: 202.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[C:5](=O)[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][NH:8]2>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][NH:8]2
Reactant: CCOC(=O)c1c[nH]c2c(OC)ccc(OC)c2c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CNc2c(OC)ccc(OC)c2C1
Yield: 2.6 %

Procedure:
Ethyl 5,8-dimethoxy-3-quinolinecarboxylate was formed as described in the literature (E. H. Erickson, C. F. Hainline, L. S. Lenon, et al. J. Med. Chem. 1979, 22, 816). 2,5-Dimethoxyaniline and diethyl ethoxymethylenemalonate condense and then cyclise at high temperature (250° ) in diphenyl ether to form ethyl 1,4-dihydro-5,8-dimethoxy-4-oxo-3-quinolinecarboxylate which is chlorinated at the 4-position with phosphorus oxychloride to give ethyl 4-chloro-5,8-dimethoxy-3-quinolinecarboxylate. The dehalogenation of this quinoline (20.34 g, 0.069 mol) in 150 ml of absolute ethanol with 1 g of 5% Pd/C and 22.53 ml of triethylamine (0.156 mol) was done with a Parr hydrogenator apparatus which gave the correct product, ethyl 5,8-dimethoxy-3-quinolinecarboxylate, as well as the 1,4-dihydro and the 1,2,3,4-tetrahydro quinoline products. This result of further reduction to the 1,4-dihydro product was indicated in the article listed above on page 817, but the formation of the 1,2,3,4-tetrahydro product had not been mentioned there. These three quinoline products were separated on a silica gel column which was eluted with hexane, followed by hexane:ethyl acetate/4:1 and 1:1, giving 0.46 g (2.6% yield) of the title compound, NMR: CDCl3 δ1.23 (tr, 3, CH2Me), 2.94 (br-m, 2, CH2), 3.2-3.6 (m, 3, CH2, CH), 3.76 (s, 6, (OMe)2), 4.21 (quartet, 2, CH2Me), 4.2 (br, 1, NH), 6.12 (d, 1, Ar), 6.57 (d, 1, Ar); 3.31 g of the 1,4-dihydro quinoline product (18.5%), NMR: CDCl3 δ 1.28 (tr, 3, CH2Me), 3.61 (s, 2, CH2), 3.73 (s, 6, (OMe)2), 4.19 (quartet, 2, CH2Me), 6.2-6.7 (br, 1, NH), 6.29 (d, 1, Ar), 6.60 (d, 1, Ar), 7.32 (d, 1, pyr-H); and 2.04 g (11%) of the ethyl 5,8-dimethoxy-3-quinolinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccccn1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1-c1ccccn1
Reaction time: 12 h

Procedure:
A suspension of Pd/C (0.25 g of 10%) in MeOH (5 mL) was mixed with a solution of 2-(2-methoxy-4-nitrophenyl)pyridine (0.5 g, 2.17 mmol) in MeOH (5 mL). The resulting reaction mixture was stirred vigorously for 12 h under an atmosphere of hydrogen, filtered through a pad of celite, and the filtrate was concentrated and purified by flash column chromatography on silica gel with EtOAc:hexanes (1:9 to 3:2) to afford 3-methoxy-4-pyridin-2-ylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)#[N:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: N#Cc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-cyanobenzene-1-sulfonyl chloride.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([N:13]2[C:17]([SH:18])=[N:16][N:15]=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22](=[O:23])[O:21]1>CN(C)C=O>[C:7]1([N:13]2[C:17]([S:18][C:20]3([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:22](=[O:23])[O:21]3)=[N:16][N:15]=[N:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2Cl)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OC(Sc2nnnn2-c2ccccc2)(c2ccc(Cl)cc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 300 ml of dried dimethylformamide, was added 5.6 g (0.05 mol.) of potassium tert-butoxide and 8.9 g (0.05 mol.) of 1-phenyl-5-mercaptotetrazole. The mixture was stirred for 20 minutes at room temperature. Thereafter, to the mixture which was cooled to 5° C. and kept there, was added gradually dropwise a solution prepared by adding 13 g (0.04 mol.) of 3-chloro-3-(2,4-dichlorophenyl)phthalide in 75 ml of dried dimethylformamide. After dropwise addition, the cooling bath was removed, and the mixture was stirred for 5 hours at room temperature. Thereto, 300 ml of a saturated aqueous solution of ammonium chloride was added. The reaction mixture was extracted with ethyl acetate repeatedly. The extract was washed with water, and the resulting organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was filtered off with suction, and the filtrate was concentrated to yield 23.5 g of oily substance. This oily substance was separated and purified by flash column chromatography (silica gel: 800 g, eluate: hexane-ethyl acetate (3:1 by volume) mixture). Thus, the intended compound, 3-(1-phenyl-tetrazole-5-ylthio)-3-(2,4-dichlorophenyl)phthalide (3), was obtained in a form of white crystals. Yield 7.8 g, Melting Point 148° to 149° C.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16]SC2SC3C=CC=C(C)C=3N=2)[N:14]([CH:28]([C:47]([CH3:49])=[CH2:48])[C:29]([O:31][CH2:32][C:33]2[C:38]([Cl:39])=[C:37]([O:40][CH3:41])[C:36]([O:42][CH3:43])=[C:35]([O:44][CH3:45])[C:34]=2[Cl:46])=[O:30])[C:13]1=[O:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:51]1([S:57](C#N)(=[O:59])=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:57]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)(=[O:59])=[O:58])[N:14]([CH:28]([C:47]([CH3:49])=[CH2:48])[C:29]([O:31][CH2:32][C:33]2[C:34]([Cl:46])=[C:35]([O:44][CH3:45])[C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[C:38]=2[Cl:39])=[O:30])[C:13]1=[O:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCc1c(Cl)c(OC)c(OC)c(OC)c1Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2c(C)cccc2s1
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1c(Cl)c(OC)c(OC)c(OC)c1Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 85 %

Procedure:
A 268 mg quantity of 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-[3-phenoxyacetamido-4-(4-methylbenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 69 mg of benzenesulfonyl cyanide were dissolved in 3 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 5 was followed, producing 3,4,5-trimethoxy-2,6 dichlorobenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 85%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. The NMR spectrum data are shown below in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH3:23].C(O)(=O)C(O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCI
Reactant: OC1(c2cc(F)cc(Cl)c2)CCNC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(O)(c2cc(F)cc(Cl)c2)C1

Procedure:
Preparation according to Example 8: 3-(3-chloro-5-fluorophenyl)pyrrolidin-3-ol (0.30 g, 1.4 mmol), acetonitrile (20 mL), sodium carbonate (0.19 g, 3.5 mmol), iodoethane (0.22 g, 1.4 mmol). Yield: 0.17 g. The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 169-170° C.; MS m/z (relative intensity, 70 eV) 243 (M+, 8), 228 (7), 157 (7), 129 (7), 72 (30), 71 (bp).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([C:30](=[O:42])[NH:31][C:32]3[S:33][C:34]4[C:39]([N:40]=3)=[CH:38][CH:37]=[C:36](Br)[N:35]=4)[CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([C:30](=[O:42])[NH:31][C:32]3[S:33][C:34]4[C:39]([N:40]=3)=[CH:38][CH:37]=[C:36]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[N:35]=4)[CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)Nc3nc4ccc(Br)nc4s3)cc2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)Nc3nc4ccc(N5CCOCC5)nc4s3)cc2)CC1
Temperature: 160 °C

Procedure:
To title compound F, 4-{4-[1-(5-Bromo-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-2-cyclopentyl-ethyl]-benzenesulfonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.148 mmol) in a microwave vial was added Pd2 dba3 (0.013 g, 0.0148 mmol), Xanphos (0.011 g, 0.0295 mmol), sodium t-butoxide (0.028 g, 0.295 mmol), morpholine (0.019 g, 0.222 mmol), 2 mL toluene and 1 mL t-butanol. The sealed container was heated to 160° C. for 5 minutes in a microwave reactor. Workup entailed quenching into water and extraction with ethyl acetate. The combined organic layer was dried over MgSO4, filtered and evaporated to afford a yellow oil. Purification on silica (EtOAc/hexane) afforded the product as an oil. 1H NMR (400 MHz, CDCl3) δ 1.12 (m, 2H) 1.39 (s, 9H) 1.48 (m, 2H) 1.62 (m, 3H) 1.73 (m, 2H) 1.90 (m, 1H) 2.24 (m, 1H) 3.01 (s, 4H) 3.51 (s, 4H) 3.54-3.58 (m, 4H) 3.65 (m, 1H) 3.80-3.87 (m, 4H) 6.73 (s, 1H) 7.50 (d, J=8.34 Hz, 2H) 7.73 (d, J=8.08 Hz, 3H) MS 685.3 [M+1]+.
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C:10]=3[C:9]1=[CH:8][CH2:7][C:6]2=[O:24])[CH:2]([CH3:4])[CH3:3].[H][H]>[Pd].C1C=CC=CC=1>[CH2:1]([C@:5]12[CH2:13][CH2:12][C:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C:10]=3[C@@H:9]1[CH2:8][CH2:7][C:6]2=[O:24])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)C(=O)CC=C12
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
To a pre-reduced suspension of 2% palladium on calcium carbonate catalyst (7.0 g) in benzene (30 cc) add a solution of 13β-isobutyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (20.0 g) in benzene (500 cc) and hydrogenate the mixture at atmospheric pressure until one mole equivalent of hydrogen is consumed. After the catalyst is removed by filtration, evaporate the solvent to obtain a gum which on crystallization from ethanol affords the title product (17.1 g.; 71%), m.p. 117°-119°; ultraviolet absorption peak at 278 mμ (ε14,560).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C:15]1[C:24]([NH2:25])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:14][C:15]1[C:24]([NH:25][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:13])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1
Reactant: Nc1cc2ccccc2cc1N
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc2ccccc2cc1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 24.1 %

Procedure:
A solution of 5-chloroindole-2-carboxylic acid (247 mg), 2,3-diaminonaphthalene (200 mg), 1-hydroxybenzotriazole hydrate (221 mg), 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (315 mg) and triethylamine (447 mg) in N,N-dimethylformamide was stirred under nitrogen at room temperature for 3 h. The reaction mixture was diluted with water before extraction with ethyl acetate (three times). The combined organic extracts were washed sequentially with saturated aqueous ammonium chloride solution, water and saturated aqueous sodium bicarbonate solution (three times each), dried over anhydrous magnesium sulfate and evaporated under vacuum to yield a solid. The solid was triturated with chloroform and then dried under vacuum to obtain the title compound as a tan solid (102 mg).
Reaction SMILES: CS([C:5]1[N:10]=[C:9](S(C)(=O)=O)[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=O)=O.[H-].[Na+].[OH:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[N:36]1[CH:37]=[CH:38][C:33]([O:32][C:5]2[N:10]=[C:9]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[C:8]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:6]=2)=[CH:34][CH:35]=1
Reactant: Oc1ccncc1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(-c2c(Oc3ccncc3)nc(Oc3ccncc3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2,4-Bis-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Reference Example 5 (500 mg, 1.02 mmol) was reacted with 1.1 equivalents each of sodium hydride (60% in oil, 45 mg, 1.12 mmol) and 4-hydroxy-pyridine (106.4 mg, 1.12 mmol) by the general procedure described in Example 16 to afford the title compound: 1H-NMR 400 MHz (CDCl3): δ 6.38 (d, J=8 Hz, 2H), 7.17-7.21 (m, 4H), 7.25-7.31 (m, 4H), 7.42 (d, J=2 Hz, 1H), 8.53 (d, J=8 Hz, 2H), 8.75 (d, J=5 Hz, 2H).