Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=N1.[CH2:31]([NH:33][NH2:34])[CH3:32]>>[CH2:31]([N:33]1[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[CH:6]=[N:34]1)[CH3:32]
Reactant: CCNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CCn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting ethyl hydrazine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 2H), 8.23 (d, J=8.3 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1 H), 7.85 (d, J=7.4 Hz, 1H), 7.83 (s, 1 H), 7.74 (m, 2 H), 7.57 (t, J=7.9 Hz, 1H), 7.21 (d, J=8.7 Hz, 2 H), 7.14 (d, J=9.1 Hz, 2 H), 7.04 (m, 2H) 5.42 (s, 2H), 4.03 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.5 Hz, 3H); MS: (M+H m/z=407.3).
Reaction SMILES: Cl.[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2+:12][CH3:13])([OH:4])=[O:3].Cl[Si](C)(C)C.C(N(CC)CC)C.C([O:29][C:30]1[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:32](Cl)=[O:33])(=O)C.C(O)(=O)C1C(=CC=CC=1)O>ClCCl>[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([N:12]([CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[O:33]
Reactant: C[NH2+]CCCCCCCC(=O)O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=C(O)c1ccccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCCCCCC(=O)O)C(=O)c1ccccc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 100 ml round bottomed flask fitted with argon purge, magnetic stir bar and condenser was added (7-carboxy-heptyl)-methylammonium hydrochloride (3.25 g, 0.0155 mol, 1.0 eq) and dichloromethane (DCM, 50 ml). Chlorotrimethylsilane (3.37 g, 0.0310 mol, 2.0 eq) was added and the resulting mixture was brought to reflux for approximately 2 h. The flask was removed from the heating mantle and placed in an ice water bath. Once the reaction was cooled to 0° C., triethylamine (3.92 g, 0.0388 mol, 2.5 eq) was added and a white vapor formed over the reaction mixture. The reaction was allowed to stir for approximately 10 min at 0° C. In a separate flask, acetylsalicyloyl chloride (ASCC, 3.08 g, 0.0155 mol, 1.0 eq) was dissolved in DCM (20 ml). The ASCC solution was added dropwise to the reaction mixture, the ice bath was removed, and the reaction mixture was allowed to stir and warm to ambient temperature overnight. The DCM was removed under reduced pressure and aqueous 2N NaOH (20 ml) was added to the residue. The aqueous mixture was allowed to stir at ambient temperature for several hours and was then acidified with aqueous 2N HCl. The aqueous mixture became cloudy and a brow oil separated out. The aqueous mixture was extracted with EtOAc (3×100 ml). The combined EtOAc extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The resulting brown oil was further dried under high vacuum to yield a brown solid. HPLC at this point indicated the solid consisted of two components (rt 2.8 min, salicylic acid and rt 4.0 min, desired product). This mixture was stirred in warm water (40-50° C.) to dissolve the salicylic acid. The remaining solid was filtered off, HPLC indicated this is predominantly desired product, crude yield 3.99 g (0.0136 mol, 87.7%). This material was treated in warm water (40-50° C.) and filtered two more times to produce pure 8-[(2-Hydroxy-benzoyl)-methyl-amino]-octanoic acid. (HPLC rt 4.0 min; NMR consistent with desired product; Elemental analysis Theoretical: C=65.31, H=7.82, N=4.76 Found: C=65.32, H=7.72, N=4.73) This application incorporates by reference in its entirety International Publication No. WO 03/072195, which is also attached as an appendix A to this application.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[CH2:12]([C:19]1([NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[ClH:31].[C:32]([N:40]1[CH2:45][CH2:44][CH2:43][C:42]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=2)([CH2:46][CH2:47][CH2:48]N2CCC(C(N3CCCC3)=O)CC2)[CH2:41]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH2:8].[ClH:68].[C:32]([N:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH2:46][CH2:47][CH2:48][N:22]2[CH2:21][CH2:20][C:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23]2)([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=2)[CH2:41]1)(=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1.[C:32]([N:40]1[CH2:45][CH2:44][CH2:43][C:42]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=2)([CH2:46][CH2:47][CH2:48][N:22]2[CH2:21][CH2:20][C:19]([NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:24][CH2:23]2)[CH2:41]1)(=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1.[ClH:31]
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCOC(=O)NC1(Cc2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Product: O
Yield: 83.5 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 7, starting from 0.5 g of 4-benzyl-4-(ethoxycarbonylamino)piperidine p-toluene-sulfonate, 0.5 g of the compound obtained in step B of EXAMPLE 1 and 0.52 g of K2CO3 in 5 ml of DMF. This gives 0.32 g of the expected product, m.p.=142° C. (dec.).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:17])([F:16])[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(Cl)(Cl)Cl>[C:22]1([O:21][C:19](=[O:20])[NH:15][C:12]2[CH:11]=[N:10][C:9]([C:8]([F:7])([F:16])[F:17])=[CH:14][CH:13]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C(F)(F)F)nc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (2.9 mL) was added to a solution of 2-trifluoromethyl-5-aminopyridine (1.95 g) in chloroform (15 mL), the mixture was cooled in ice, and phenyl chloroformate (1.8 mL) was added thereto. The resulting mixture was stirred at room temperature overnight, and the reaction mixture was concentrated under reduced pressure. The residue was washed with isopropyl ether to afford phenyl[6-(trifluoromethyl)pyridin-3-yl]carbamate (2.16 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][S:12][CH3:13])[CH:6]=[CH:5][C:4]=1[NH:14][C:15]([C@@H:17]1[NH:21][C@@H:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@:19]2([C:34]3[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=3)[NH:28][C:27]2=[O:36])[C@H:18]1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=1[F:44])=[O:16].ClC1C=C(C=CC=1)C(OO)=[O:50].[OH2:56]>ClCCl>[CH3:13][S:12]([CH2:11][CH2:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([NH:14][C:15]([C@@H:17]2[NH:21][C@@H:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[C@H:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])=[C:3]([O:2][CH3:1])[CH:8]=1)(=[O:50])=[O:56]
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(OCCSC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Solvent: ClCCl
Product: COc1cc(OCCS(C)(=O)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [2-methoxy-4-(2-methylsulfanyl-ethoxy)-phenyl]-amide (0.17 g, 0.26 mmol) prepared in Example 169 in dichloromethane (5 mL) was added 3-chloroperoxybenzoic acid (MCPBA, Aldrich, 77%) (0.11 g mL, 0.52 mmol). The reaction mixture was stirred at room temperature for 2 h. The crude mixture was diluted with water, and extracted with dichloremethane three times. The combined organic extract was washed with aqueous saturated Na2S2O3 solution, brine, dried over MgSO4, and concentrated. TLC analysis indicated the complete consumption of starting material and the formation of two major products. The residue was purified by chromatography (0-50% EtOAc in dichlormethane) to give the first product chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-methanesulfonyl-ethoxy)-2-methoxy-phenyl]-amide as a light red solid (Yield, 98 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:19])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Cc1cc(N)ccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)C=Cc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To 4-chloro-3-methylaniline (3.33 g, 19.98 mmole) in dichloromethane (100 mL) and pyridine (20 mL) was added cinnamoyl chloride (2.83 g, 19.98 mmole) at 0° C. The mixture was stirred at room temperature for 2 h. Solvent and pyridine were removed by rotary evaporator under reduced pressure. The residue was diluted with ethyl acetate and washed 1N HCl (2×100 mL), water (2×100 mL), sodium bicarbonate solution (2×100 mL) and dried over sodium sulfate. After removing solvent a white solid was recovered (5.38 g, 99% yield). The product was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.76-7.24 (m, 10H), 6.58 (d, 1H), 2.55 (s, 3H); MS (ESI) m/z: Calculated for C16H14ClNO: 271.1. found: 272 (M+H)+.
Reaction SMILES: C1(C(C=C[C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=O)CC1.[C:16](OC(C)C)(=[O:18])[CH3:17].S(Cl)(Cl)=[O:24]>O>[OH:24][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:18][CH2:16][CH2:17][N:15]=2)=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(C=CC(=O)C2CC2)cc1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OC(C)C
Solvent: O
Product: Oc1ccc(C2=NCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A 22 liter, three-necked flask was charged with 634 g (3.5 moles) of the β-hydroxyamide of part (a) and 5.2 liters of isopropyl acetate. The flask was cooled externally in a bath with tap water (10°-15° C.) and 390 ml (5.25 moles) of thionyl chloride was added to the stirred suspension over 45 minutes. A mild exotherm was apparent, but the temperature was maintained between 25° and 30° C. After stirring 2 hr at ambient temperature, the suspension was filtered and the cake washed with isopropyl acetate. After air drying for two hours, the solid was transferred to a 22 liter flask and dissolved in 1.4 liters of water. The solution was treated with saturated sodium bicarbonate solution until slightly basic. A heavy white precipitate formed during the addition. The suspension was filtered and the resulting white solid was washed with cold water and dried overnight in vacuo at 65° C. A total of 522 g (91.5%) of the 4,5-dihydro-2-(4-hydroxyphenyl)oxazole, m.p. 209°-211° C., was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1.[CH:17]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18]1.[NH4+].[Cl-]>CCCCO>[CH:17]1([N:20]2[CH2:25][CH2:24][N:23]([C:2]3[N:3]=[N:4][C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=4)=[CH:6][CH:7]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18]1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=[N+]([O-])c1cccc(-c2ccc(Cl)nn2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCO
Product: O=[N+]([O-])c1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 5.2 %

Procedure:
To a solution of 3-chloro-6-(3-nitro-phenyl)-pyridazine (10.0 g, 424 mmol) in n-BuOH (150 mL) was added 1-cyclopropyl-piperazine (8.55 g, 678 mmol) and NH4Cl (2.27 g, 424 mmol) and the mixture was stirred for 48 h at 80° C. The solvent was removed under reduced pressure, and the residue was diluted with water. After alkalization with ammonia, the mixture was extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated to give 7.2 g of crude 3-(4-cyclopropyl-piperazin-1-yl)-6-(3-nitro-phenyl)-pyridazine.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[CH:8]=1.C([Li])CCC.[F:21][C:22]([F:27])([F:26])[C:23]([CH3:25])=[O:24]>O.CCCCCC>[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[C:8]=1[C:23]([OH:24])([CH3:25])[C:22]([F:27])([F:26])[F:21]
Reactant: CC(=O)C(F)(F)F
Reactant: COc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(F)c(C(C)(O)C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a tetrahydrofuran (100 ml) solution of 1,3-difluoro-5-methoxybenzene (7 g, 48.6 mmol) was added 1.6 M hexane solution of n-butyllithium (30 ml, 48.6 mmol) dropwise at −78° C. over 30 minutes and the mixture was stirred for 2 hours at −78° C. 1,1,1-Trifluoroacetone (6.5 g, 58.3 mmol) was added at −78° C. and the mixture was stirred for 2 hours at −78° C. followed by additional stirring for 1 hour at room temperature. Then, the reaction was diluted with water and the product was extracted with ethyl acetate. Then, the organic layer was filtrated, evaporated and concentrated. The residue was purified by silica gel column chromatography, eluting with hexane/ethyl acetate (10:1), to furnish 9.7 g (78% yield) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[Cl:19][C:20]1[NH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(C#N)(C)=O>[Cl:19][C:20]1[N:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=1
Reactant: NC(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: Clc1nc2ccccc2[nH]1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)Cc1cccc(Nc2ncnc(-n3c(Cl)nc4ccccc43)n2)c1
Temperature: 70 °C

Procedure:
2-[3-(4-Chloro-[1,3,5]triazin-2-ylamino)-phenyl]-acetamide (136.5 mg, 0.5177 mmol) is combined with 2-chlorobenzimidazole (86.9 mg, 0.5177 mmol) and potassium carbonate (93 mg, 0.673 mmol) in AcCN (5 ml) and heated at 65-75° C. for 2 to 20 hours. The reaction mix is cooled to RT and the inorganic salts were filtered off. The AcCN solution is concentrated down under reduced pressure. The crude is purified on a silica gel column with an EtOAc/hexane to MeOH/CH2Cl2 elution gradient, giving 2-{3-[4-(2-chloro-benzoimidazol-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}acetamide.
Reaction SMILES: [Cl:1][C:2]([Cl:18])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:9]([O:10][CH2:11][CH2:12]O)=[C:8]([Cl:17])[CH:7]=1.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C(Cl)Cl.CS(C)=O.O>[Cl:1][C:2]([Cl:18])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:9]([O:10][CH2:11][CH2:12][N:24]=[N+:25]=[N-:26])=[C:8]([Cl:17])[CH:7]=1
Reactant: OCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A mixture of 1.0 gram (0.003 mole) of 2-(4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy)ethan-1-ol, 0.33 gram (0.0033 mole) of TEA and 0.37 gram (0.0032 mole) of methanesulfonyl chloride in 10 mL of methylene chloride was stirred at ambient temperature for two hours. The reaction mixture was diluted with 25 mL of methylene chloride and was washed first with 25 mL of water followed by 10 mL of a saturated aqueous sodium chloride solution. The organic phase was dried with magnesium sulfate, filtered and the filtrate concentrated under reduced pressure leaving an oil, which solidified upon standing. The solid was dissolved in 10 mL of DMSO to which 0.32 gram (0.005 mole) of sodium azide was added. The reaction mixture stirred at ambient temperature for about 18 hours at which time the reaction mixture was heated at 60° C. for one hour. The mixture was allowed to cool to ambient temperature, diluted with 25 mL of water and extracted with two 25 mL portions of ethyl acetate. The combined extracts were washed with 20 mL of an aqueous saturated sodium chloride solution, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure providing 0.86 gram of the subject compound as a foam. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:10]=1.C(O)(=O)C>O>[O:1]=[CH:2][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:10]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCCC3OCCO3)cc2)S1
Solvent: O
Solvent: CC(=O)O
Product: O=CCCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 40.4 %

Procedure:
A solution of 6.30 g of 5-{4-[2-(1,3-dioxolan-2-yl)ethoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Preparation 106) in 50 ml of a 4:1 mixture of acetic acid and water was stirred at 60° C. for 6 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.20 g of the title compound, melting at 48°-51° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[N:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[CH:16][CH:15]=3)=[O:14])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[N:24]=1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)n1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)c(C)n1
Yield: 64.2 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (422 mg) described in Preparation Example 37 and 1-(3,5-dimethylpyrazin-2-yl)piperazine hydrochloride (457 mg) described in Preparation Example 59, the title compound (484 mg) was obtained.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[CH3:26][O:27][C:28]1[CH:51]=[CH:50][C:31]([CH2:32][N:33]2[C:37]([NH:38][CH:39]=[C:40]3[C:45](=[O:46])OC(C)(C)OC3=O)=[CH:36][CH:35]=[N:34]2)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[C:37]3[N:38]=[CH:39][CH:40]=[C:45]([OH:46])[C:36]=3[CH:35]=[N:34]2)=[CH:50][CH:51]=1
Reactant: COc1ccc(Cn2nccc2NC=C2C(=O)OC(C)(C)OC2=O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Temperature: 240 °C

Procedure:
2,2-dimethyl-1,3-dioxane-4,6-dione 1 (meldrum's acid) (20 g, 139 mmol), 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (2) (28.2 g, 139 mmol, 1 eq) (prepared according to the procedure described by Misra, R. N., et al. Bioorg. Med. Chem. Lett. (2003), 13, 1133-1136) in presence of triethoxymethane (30.8 g, 208 mmol, 1 eq) was heated to 85° C. for 1 hr, subsequently worked up and treated with diethyl ether, and provided the pure 5-(((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3) as yellow solid (39.3 g). To a stirred solution of DOWTHERM™ (80 mL) was added compound 3 (39.3 g at 200° C. under N2 in portions over a 30 min). After completion of additions, the RM was heated at 240° C. for 1 hr. After completion of the reaction from TLC, the mixture was diluted with hexanes (300 mL) to separate the DOWTHERM™ from the crude RM. The resulting crude mixture on treatment with DCM and diethyl ether provided the off-white solid of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (4) (24.56 g). Chlorination of compound 4 (24 g, 94 mmol) on treatment with phosphoryl trichloride (43 g, 282 mmol) in dichloroethane (10 mL) at 40° C. for 4 hr yielded 19 g of 4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine 5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([CH3:22])[N:3]=1.P(Cl)(Cl)([Cl:25])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:25])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([CH3:22])[N:3]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2O)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OC)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
The product from step (ii) (8.6 g) was added to phosphorous oxychloride (50 ml) and the resulting suspension stirred at 100° C. for 15 h. The reaction mixture was allowed to cool and the phosphorous oxychloride evaporated under reduced pressure. The residue was diluted with water (100 mL) and the suspension adjusted to pH 7 with NaHCO3. The mixture was heated at 50° C. for 1 h and allowed to cool. The solid was collected by filtration, washed with water, EtOAc and dried under vacuum to give the subtitle compound 9.05 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[N:11][OH:12])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC1(C)CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(=NO)CC1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 4,4-dimethylcyclohexanone (3.0 g, 0.024 mole) and hydroxylamine hydrochloride (2.2 g, 0.031 mole) in a mixture of ethanol (15 mL) and water (20 mL) at room temperature was added dropwise a solution of sodium carbonate (3.3 g, 0.031 mole) in water (10 mL). The mixture was heated at reflux for 3 hours, cooled to room temperature and concentrated in vacuo to remove the ethanol. The aqueous residue was extracted several times with ethyl acetate. The organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give 3.0 g (88%) of the desired 4,4-dimethylcyclohexanone oxime as a white solid. This was used without further purification.