Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.O.C(=O)(O)[O-].[Na+].Cl[CH2:16][CH:17]=O>[Na+].[Cl-].CCO>[N:1]1[CH:16]=[CH:17][N:3]2[C:4]([NH2:8])=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Nc1cccc(N)n1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2nccn12
Temperature: 70 °C
Yield: 36 %

Procedure:
To a solution of 2,6-diaminopyridine (5.00 g, 45.8 mmol) in 1:1 H2O:EtOH (10 mL) were added sodium bicarbonate (5.00 g, 59.5 mmol) and chloroacetaldehyde (4.31 g, 27.5 mmol). The reaction mixture was heated to 70° C. overnight, then cooled to rt, diluted with saturated aqueous NaCl (100 mL), and extracted with n-butanol (3×200 mL). The organic layers were combined, dried (MgSO4), and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give imidazo[1,2-a]pyridin-5-ylamine (1.32 g, 22%). MS (ESI+): calcd for C7H7N3 m/z 133.06, found 134.1 (M+H)+. 1H NMR (d6-DMSO): 8.23-8.21 (m, 1H), 7.91 (d, J=1.3, 1H), 7.50 (dd, J=8.8, 7.4, 1H), 7.22 (d, J=8.8, 1H), 6.97 (br s, 2H), 6.37 (dd, J=7.4, 0.9, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:11]1
Reactant: O=Cc1ccccn1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccccn2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.4 %

Procedure:
To a solution of 2-pyridinecarboxaldehyde (1.1 g, 9.9 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.5 g, 11.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.2 mL, 1.2 mM). The reaction solution was stirred at room temperature for 2 days. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The residue was purified by chromatography (silica gel, pet. ether/ethyl acetate) to yield yellow crystals (1.6 g, 75% yield), m.p. 87.5°-89.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:24])[NH:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:38][C@@H:39]1[C@@H:44]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:43]([O:52][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[C@@H:42]([CH2:59][O:60][C:61](=[O:66])[C:62]([CH3:65])([CH3:64])[CH3:63])[O:41][C@@H:40]1Br)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:40]3[O:41][C@H:42]([CH2:59][O:60][C:61](=[O:66])[C:62]([CH3:65])([CH3:64])[CH3:63])[C@@H:43]([O:52][C:53](=[O:58])[C:54]([CH3:55])([CH3:56])[CH3:57])[C@H:44]([O:45][C:46](=[O:51])[C:47]([CH3:48])([CH3:49])[CH3:50])[C@H:39]3[O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCc2ccccc2)cc1OC1CCOCC1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccc(OCc2ccccc2)cc1OC1CCOCC1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-{[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH2:8]([N:10]([CH2:13][CH3:14])[CH:11]=[O:12])[CH3:9]>C(N(CC)CC)C>[CH2:8]([N:10]([CH2:13][CH3:14])[C:11](=[O:12])[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[O:4])[CH3:9]
Reactant: CCN(C=O)CC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)C(=O)C(Cl)(Cl)Cl

Procedure:
The procedure of Example 1 was followed using 27g (0.15 mole) of trichloracetyl chloride and 45g (0.45 mole) of diethyl-formamide and 15g (0.15 mole) of triethylamine. Obtained following distillation was 14g 0f pure N,N-diethyl 3,3,3-trichloropyruvamide as a clear, colorless liquid: Bp 94°-96° (0.15 mm); ir (λmax, film) 5.7 (s), 6.1 (s), 6.8 (s), 6.9 (s), 9.4 (s), 12.1 (s) microns.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([CH3:32])([CH3:31])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:21][N:20]=3)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:35]1[N:44]=[CH:43][C:42]2[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=2)[C:36]1=[O:50])(=O)C.[OH-].[Na+].C(Cl)Cl>O1CCOCC1.O>[C:45]([C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([F:49])[CH:39]=1)[C:36](=[O:50])[N:35]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([CH3:31])([CH3:32])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:21][N:20]=4)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:44]=[CH:43]2)([CH3:46])([CH3:47])[CH3:48]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(OC(C)(C)CN(C)C)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)CC(C)(C)Oc1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 26.1 %

Procedure:
To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-benzyl acetate (292 mg, 0.43 mmol) in dioxane (1.5 ml) was added a solution of 2N sodium hydroxide (2.5 ml, 5 mmol). The flask was heated at 50° C. (oil bath) with vigorous stirring under argon atmosphere for 3 hours. The material was cooled to ambient and the contents were taken up in water (25 ml) and methylene chloride (50 ml) and transferred to a reparatory funnel and shaken. The organic phase was collected and washed with a solution of 50% diluted brine (25 ml). The aqueous phases were back extracted with methylene chloride (2×40 ml) and the organic phases combined, dried (magnesium sulfate), filtered and stripped. The remainder was purified by preparative thin layer chromatography (3 plates), eluting with 6% methanol/dichloromethane and then re-developing the plates with first 8% and then 11% methanol/dichloromethane. The product band was collected providing the desired product as a light yellow-white solid (72 mg). MP=136-144° C.; (M+H)+=642 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 6H) 1.42 (s, 9H) 2.40 (s, 6H) 2.51 (s, 2H) 3.90 (s, 3H) 4.42 (s, 2H) 6.90 (d, J=9.06 Hz, 1H) 7.33 (dd, J=8.69, 3.02 Hz, 1H) 7.41-7.72 (m, 5H) 8.09 (d, J=3.02 Hz, 1H) 8.20-8.35 (m, 2H) 8.53 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([Cl:9])=[C:6]([F:8])[CH:7]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[F:18][C:19]([F:25])([F:24])[C:20](OC)=[O:21]>C1COCC1>[Cl:9][C:5]1[C:4]([F:10])=[CH:3][C:2]([C:20](=[O:21])[C:19]([F:25])([F:24])[F:18])=[CH:7][C:6]=1[F:8]
Reactant: COC(=O)C(F)(F)F
Reactant: Fc1cc(Br)cc(F)c1Cl
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cc(F)c(Cl)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-bromo-2-chloro-1,3-difluorobenzene (2000 mg, 8.2 mmol) was stirred at room temperature in THF under N2 and the isopropylmagnesium chloride/LiCl reagent (1310 mg, 9.02 mmol, 6.94 mL) was added over about 1 minute—very slight exotherm noticed to ˜30° C. Reaction was stirred at room temperature for 30 minutes followed by the addition of methyl trifluoroacetate (1580 mg, 12.3 mmol, 1.24 mL) over about 1 minute—slight exotherm to ˜40° C. Solvents were evaporated under reduced pressure to provide the desired product. 1H NMR (CDCl3) δ ppm: 8.05 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)(Cl)Cl)=[CH:4][CH:3]=1.Cl.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:21][C:15]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Reactant: Nc1cc(Cl)ccc1O
Agent: Cl
Product: Clc1ccc(-c2nc3cc(Cl)ccc3o2)cc1

Procedure:
Compound XIV was prepared as in Example 12 at 180° C from p-chlorobenzotrichloride and 2-amino-4-chlorophenol hydrochloride, and purified through a preheated aluminum trioxide column: 16 g of raw product, M.P. 178°-183° C (61% of the theory). Upon recrystallization from benzene: M.P. 190°-192° C.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:3]1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][N:4]1[CH2:3][CH:2]([OH:1])[C:6]2([CH2:7][CH2:8]2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCN1CC(O)C2(CC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propanol (1.14 g, 6.67 mmol) and Et3N (1.35 g, 13.34 mmol) in CH2Cl2 (20 mL) was added methanesulfonyl chloride (1.15 g, 10 mmol) dropwise at 0° C. The reaction was then stirred at 0° C. for 3 hrs. The reaction mixture was washed with cold water (10 mL) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound as orange oil. The crude product was used for the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Se](=O)=O.[OH2:25].C.[O:27]1CCO[CH2:29][CH2:28]1>>[CH2:15]([O:14][C:7]1[C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[C:4]([CH:1]([OH:3])[CH:2]([O:27][CH2:28][CH3:29])[OH:25])=[CH:5][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)oc12
Reactant: C1COCCO1
Reactant: O
Agent: O=[Se]=O
Product: CCOC(O)C(O)c1ccc(OCc2ccccc2)c2[nH]c(=O)oc12

Procedure:
49.5 g (175 mmol) 7-acetyl-4-benzyloxy-3H-benzoxazol-2-one and 19.6 g (177 mmol) selenium dioxide are refluxed for 8 hours in 200 mL dioxane and 8 mL water in the presence of activated charcoal. The insoluble constituents are suction filtered, the solvent is distilled off and the residue is combined with 150 mL ethanol. The mixture is refluxed for 30 minutes and then filtered through activated charcoal. After the addition of a crystallisation aid the product is precipitated out of the cooled solution. It is suction filtered and washed with ethanol and diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].I[CH3:13].[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH:8][CH3:13])=[N:6][CH:7]=1
Reactant: CI
Reactant: Cc1cc(Br)cnc1N
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1ncc(Br)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 5-bromo-3-methylpyridin-2-amine (B-4-1) (3.7 g, 0.02 mol) in THF (50 mL) was added portionwise NaH (0.8 g, 0.02 mol) at 0° C. After the addition, the mixture was stirred at room temperature for about 0.5 hr, and cooled to 0° C. again. Iodomethane (2.8 g, 0.02 mol) was added slowly. The resulting mixture was allowed to rise to room temperature and stirred for 1 hr. TLC (EtOAc: Petroleum ether=1:4) showed that the reaction was complete. Saturated aqueous NaCl (10 mL) and EtOAc (10 mL) were added. The organic layer was concentrated and the residue was purified via a silica gel column eluted with EtOAc/Petroleum ether (1:8) to give 5-bromo-N,3-dimethylpyridin-2-amine (B-4-2) (2.3 g, 57.8%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@@H:12]([NH:18][C:19](=[O:35])[C@@H:20]([NH:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:13][CH2:14]C(O)=O)[CH2:6][CH2:5]2.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:55](CC)CC)C.[N-:60]=[C:61]=[O:62].C(=O)(O)N.[N-]=[N+]=[N-]>CC(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@@H:12]([NH:18][C:19]([C@@H:20]([NH:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:35])[CH2:13][CH2:14][NH:60][C:61]([NH2:55])=[O:62])[CH2:6][CH2:5]2
Reactant: [N-]=C=O
Reactant: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)CN2CCc3cc(F)ccc32)c1
Reactant: CCN(CC)CC
Agent: NC(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [N-]=[N+]=[N-]
Solvent: CC(C)(C)O
Product: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCNC(N)=O)CN2CCc3cc(F)ccc32)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
The title compound of Example 43 (58.8 mg, 121 μmol) was treated with tBuOH (2 mL), diphenylphosphoryl azide (70 mg, 254 μmol) and triethylamine (60 mg, 592 mmol). The reaction was heated at 90° C. for 3 hours and cooled to rt. HPLC-MS analysis indicated that the Curtius rearrangement had occurred, but that the intermediate isocyanate had been hydrolyzed to the carbamic acid and activated as the azide rather than being intercepted by the alcohol. The solvent was removed and the reaction was extractively worked up with ethyl acetate and water, dried over MgSO4 and rotary evaporated. The residue was treated with concentrated ammonia and allowed to stir overnight. The reaction was again extractively worked up and then chromatographed on silica gel using DCM an MeOH as eluent to afford the title material (12 mg, 20%); 1H NMR (CDCl3, 400 MHz) δ 0.88 (d, 3H, J=6.3), 0.91 (d, 3H, J=6.3), 1.55-1.80 (m, 4H), 1.85-1.95 (m, 1H), 2.37 (s, 3H), 2.90-3.03 (m, 3H), 3.06-3.26 (m, 2H), 3.37 (dd, 1H, J1=8.7, J2=17.1), 3.48-3.61 (m, 2H), 4.01-4.26 (m, 1H), 4.26-4.38 (m, 1H), 4.50 (dd, 1H, J1=7.7, J2=15.0), 6.00-6.20 (m, 1H), 6.49 (dd, 1H, J1=4.0, J2=8.4), 6.74 (ddd, 1H, J1=2.5, J2=J3=8.9), 6.78-6.83 (m, 1H), 7.16-7.20 (m, 1H), 7.23-7.37 (m, 3H), 7.50-7.57 (m, 2H).
Reaction SMILES: ClC1C=CC([CH:8]2[CH:12](C3C=CC(Cl)=CC=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3C=CC(C(C)(C)COC)=CC=3OCC)=[N:9]2)=CC=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45]N1CCNCC1)(=[O:43])=[O:42]>>[CH3:40][S:41]([CH2:44][CH2:45][N:9]1[CH2:8][CH2:12][N:11]([CH:20]=[O:21])[CH2:10][CH2:23]1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)COC)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CS(=O)(=O)CCN1CCN(C=O)CC1
Yield: 300.4 %

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (60 mg, 0.107 mmol, example 153) was reacted with 1-(2-methanesulfonyl-ethyl)piperazine dihydrochloride (42.5 mg, 0.161 mmol, example 17) using the procedure described in example 25 to give 4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone (70.8 mg) as white solids. The enantiomers were separated by chiral chromatography (Diacel ChiralPak OD, eluting with 40/60 hexane/ethanol). The first peak coming off the column is the desired {(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone (32.1 mg, white solids). HR-MS (ES, m/z): observed 715.2485, calculated for C36H45Cl2N4O5S [(M+H)+] 715.2482.
Reaction SMILES: [CH3:1][C:2](CC(CC(O)=O)=O)=[O:3].[CH3:11][C@@:12]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@@H:16]1[CH2:22][CH:23]=[C:24]3[CH2:29][C@@H:28]([OH:30])[CH2:27][CH2:26][C@:25]3([CH3:31])[C@H:15]1[CH2:14][CH2:13]2.CC[O:34]CC>N1C=CC=CC=1.C([O-])(=O)C.[Ag+]>[C:2]([C@H:29]1[C@@H:28]([OH:30])[CH2:27][CH2:26][C@@:25]2([CH3:31])[C:24]1=[CH:23][CH2:22][C@@H:16]1[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:11])[C@H:17]1[CH2:18][C@@H:19]([OH:34])[C@@H:20]2[OH:21])(=[O:3])[CH3:1]
Reactant: CC(=O)CC(=O)CC(=O)O
Reactant: CCOCC
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(=O)[C@@H]1C2=CC[C@H]3[C@@H]4C[C@@H](O)[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC[C@@H]1O
Reaction time: 0.5 h

Procedure:
Compound 6 was dissolved in 30 mL of anhydrous ether and 10 mL of anhydrous pyridine. A solution of silver acetate (1.03 g, 1(914 mg, 2.98 mmol) in 5 mL of anhydrous pyridine was added. The reaction mixture was stirred under dark for 0.5 hr. A heavy greenish precipitate was deposited. Ether (50 mL) was added and precipitate was filtered off. The filtrate was under vacuum to dryness. The residue was purified by flash chromatograph on silica gel eluted with 50:50 ethyl acetate:hexanes to afford the title compound 7 (124 mg) as a white solid. Selected 1H NMR data: (CD3OD, 300 MHz): δ 5.78 (d, 1H, J=2.2 Hz), 5.34 (br, 1H), 4.02 (t, 1H, J=4.5 Hz), 3.52 (dt, 1H, J=7.7 Hz, 3.0 Hz), 3.37 (d, 1H, J=4.9 Hz), 2.03 (s, 3H), (1.12 (s, 3H), 0.75 (s, 3H). Melting Point: 152-153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1.[OH-:24].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:24])=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)CC(=O)c1cc(C(C)C(N)=O)ccc1S2
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CC(=O)c1cc(C(C)C(=O)O)ccc1S2
Temperature: 0 °C
Yield: 34.9 %

Procedure:
A mixture of 0.1 g of 2-(10,11-dihydro-8-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 1.0 g of sodium hydroxide, 10 ml of water and 20 ml of ethanol was refluxed for 3 hours. After the completion of the reaction, the solvent was removed by distillation to obtain a residue, to which was added ice water, and the mixture was acidified with hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, which was chromatographed over silica gel and eluted with chloroform/benzene (4/1), thereby obtaining a solid substance. This substance was recrystallized from benzene-n-hexane to give 35 mg (yield: 35%) of 2-(10,11-dihydro-8-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a powder having a melting point of 152°-153° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:3]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([CH3:23])[CH:16]=1.[C:24](O)(=[O:27])[CH2:25][SH:26]>C(#N)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[S:26][CH2:25][C:24](=[O:27])[NH:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[C:5]2=3)=[C:17]([CH3:23])[CH:16]=1
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: O=C(O)CS
Reactant: Cn1nc(-c2ccccn2)cc1N
Solvent: CC#N
Product: Cc1cc(Cl)ccc1C1SCC(=O)Nc2c1c(-c1ccccn1)nn2C
Temperature: 150 °C
Yield: 47.6 %

Procedure:
A mixture of 2-methyl-5-(2-pyridyl)pyrazol-3-amine (1.1 g, 6.3 mmol, Example #2, step B), 4-chloro-2-methylbenzaldehyde (1.0 g, 6.5 mmol, Fluorochem), and thioglycolic acid (2.4 g, 26 mmol) in acetonitrile (20 mL) was heated, in a sealed microwave vessel, for about 20 min, at about 150° C., in a microwave. After cooling to rt the precipitated solid was collected by filtration and washed with acetonitrile (2 mL) to afford 4-(4-chloro-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one (1.16 g, 3.0 mmol, 48%), which was used as such: 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.50 (3 H, s); 3.07 (1 H, d, J=12 Hz); 3.50 (1 H, d, J=12 Hz); 3.84 (3 H, s); 6.59 (1 H, s); 6.86 (1 H, d, J=8 Hz); 6.98 (1 H, m); 7.1-7.2 (2 H, m); 7.68 (1 H, m), 7.76 (1 H, d, J=6 Hz); 8.4 (1 H, s); 10.2 (1 H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[S:10][C:5]=2[C:4](=[O:21])[NH:3]1.[NH3:23].CO>O1CCOCC1>[NH2:23][C:13]1[N:12]=[C:11]([C:9]2[S:10][C:5]3[C:4](=[O:21])[NH:3][C:2]([CH3:22])([CH3:1])[NH:7][C:6]=3[CH:8]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CC1(C)NC(=O)c2sc(-c3ccnc(S(C)(=O)=O)n3)cc2N1
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)NC(=O)c2sc(-c3ccnc(N)n3)cc2N1
Yield: 53 %

Procedure:
A mixture of 2,2-dimethyl-6-[2-(methylsulfonyl)pyrimidin-4-yl]-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.044 g, 0.13 mmol) and 7 M ammonia in methanol (2.0 mL, 14 mmol) in 1,4-dioxane (8 mL) was microwave-irradiated at 120° C. for 75 min. Then, the reaction mixture was cooled, and concentrated with silica gel, and the residue was purified twice by flash chromatography (Combiflash, silica gel, ethyl acetate to 90:10 ethyl acetate/methanol) to give the title compound (0.019 g, 53%) as a yellow solid:
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[N:14]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C.[N+]1([O-:39])C=CC=CC=1>>[CH3:31][C:25]([CH3:32])([CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:13][NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:6][N+:8]=2[O-:39])=[CH:19][CH:20]=1)[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CC(C)(C)Cc1ccc(OCCc2cccc(NC(=O)OC(C)(C)C)n2)cc1
Reactant: [O-][n+]1ccccc1
Product: COC(=O)CC(C)(C)Cc1ccc(OCCCNc2cccc[n+]2[O-])cc1

Procedure:
The procedure for the preparation of the product of STEP 7, EXAMPLE 4 was repeated using 2-[3-hydroxy-1-propyl)amino]pyridine-N-oxide (Ref: WO 98/30542) in the place of the product of STEP 6, EXAMPLE 4 to provide the above product as a colorless gum.
Reaction SMILES: [CH3:1][N:2]([CH3:5])C=O.CN1[C:11]([OH:12])=[CH:10][CH:9]=[N:8]1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:5]1[N:2]([CH3:1])[N:8]=[CH:9][C:10]=1[CH:11]=[O:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1nccc1O
Reactant: CN(C)C=O
Product: Cn1ncc(C=O)c1Cl
Temperature: 80 °C
Yield: 77 %

Procedure:
N,N-Dimethyl formamide (2980 mg, 40.8 mmol) was added to 1-methyl-1H-pyrazol-5-ol (1000 mg, 10.19 mmol). Phosphorus oxychloride (7.46 ml, 81.5 mmol) was then added dropwise over 10 minutes. The reaction was then heated to 80° C. for 6 hours. The reaction was concentrated in vacuo and crude material neutralised with saturated aqueous NaHCO3 solution. The product was then extracted with ethyl acetate (2×25 ml), the combined organics were washed with brine (20 ml) dried over Na2SO4, filtered and concentrated in vacuo to give the title product as a brown oil which formed a crystalline solid upon standing (1130 mg, 77% yield). 1H NMR (400 MHz, CD3OD) 3.84-3.87 (3H s) 7.95-7.97 (1H d) 9.76-9.78 (1H d).