Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])(C)C.[NH2:22][C:23]1[C:28]([C:29]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])=[O:30])=[CH:27][N:26]=[C:25](S(CC)(=O)=O)[N:24]=1>>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:25]3[N:24]=[C:23]([NH2:22])[C:28]([C:29](=[O:30])[C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[O:38][CH3:39])=[CH:27][N:26]=3)=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])[CH3:4]
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccc(N)cc2)C1
Product: CCOC(=O)N1CCCC(Oc2ccc(Nc3ncc(C(=O)c4cc(F)ccc4OC)c(N)n3)cc2)C1

Procedure:
3-(4-Amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester ((prepared as described above in Example 139) and the compound of Example 48 were treated as in Example 113, the resulting product was then treated as in Example 114, and then as in Example 115 to give 3-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-phenoxy]-piperidine-1-carboxylic acid ethyl ester. MS(ES) (M+H)+=510.
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.C(NC(C)[CH2:19][C:20]1[C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=3)[C:26]=12)(C)C.O>CCCCCC.O1CCCC1>[CH3:19][C:20]1[C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=3)[C:26]=12
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(C)=C21

Procedure:
The starting material is prepared as follows: 19.2 ml of tetramethyl-ethylenediamine are added under nitrogen to 53.3 ml of 2.4 M n-butyl lithium in hexane at room temperature and the mixture is allowed to react for 15 minutes. Thereupon the solution of 10.9 g of 1-(2-isopropylaminopropyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one in 160 ml of anhydrous tetrahydrofuran is added dropwise. The mixture is refluxed for 30 minutes and subsequently cooled in an ice bath. 120 ml of water are added dropwise and the mixture is stirred with cooling for 30 minutes. The precipitate is collected, washed with water and diethyl ether and dried, to yield the 1-methyl-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one melting at 215°-218°.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].IC.[C:16](OCC)(=O)C>CN(C)C=O>[F:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCF
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CCF)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Under nitrogen atmosphere, tert-butyl (2-fluoroethyl)carbamate (I-286) (2 g, 20.1 mmol) was dissolved in N,N-dimethylformamide (50 ml), then sodium hydride (55%, w/w) (803 mg, 18.4 mmol) was added to the solution at 0° C., followed by stirring at 0° C. for 30 minutes. After 30 minutes, iodomethane (1.2 ml, 19.7 mmol) was added, followed by stirring at room temperature for 19 hours. Ethyl acetate was added to the reaction liquid, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1, v/V) to obtain the entitled compound (970 mg, 45%) as a white crystal.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].[C:29]1(B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[C:3]([CH3:28])[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)c(C2=CCCCC2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.67 g) and 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.48 g) in tetrahydrofuran (40 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.06 g), and the mixture was stirred at 70° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.58 g, 86%) as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.[I:18]I.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.CN(C=O)C>[I:18][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[OH:7])=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: II
Reactant: Oc1ccnc2ccccc12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1c(I)cnc2ccccc12
Yield: 96.4 %

Procedure:
Potassium carbonate(5.2 g) was added to a DMF solution(50 ml) of 4-hydroxy quinoline(5.0 g) and the mixture was stirred. Iodine (9.6 g) was added to the mixture, followed by stirring at room temperature for 3 hours. A saturated sodium hydrogencarbonate aqueous solution (73 ml) of 25% sodium sulfite, and water(50 ml) were added to the reaction mixture. The mixture was stirred and the precipitated insoluble matter was separated. The filtrate was washed with water and dried to give the title compound (9.0 g) as a white powder.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 54, 100 mg, 0.231 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (48.65 mg, 0.254 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 46% (65 g, 0.107 mmol) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([OH:19])[C:11]=23)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([O:19][C@@H:34]4[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]4[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])[C:11]=23)=[CH:4][CH:3]=1
Reactant: Oc1ccc(CCc2ccnc3[nH]nc(O)c23)cc1
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: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
4-[2-(4-Hydroxyphenyl)ethyl]-1H-pyrazolo[3,4-b]-pyridin-3-ol (3.48 g) was stirred at 100° C. to be dissolved in N,N-dimethylformamide (55 mL). The solution was cooled to room temperature. To the solution were added potassium carbonate (3.77 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (9.48 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2-1/1-2/3) to give the title compound (2.26 g).
Reaction SMILES: [CH2:1]([C:8]1([C:13]2[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=2)[O:16][CH2:17][CH2:18][NH:19][S:20]([C:23]2[N:24]=[CH:25][N:26]([CH3:28])[CH:27]=2)(=[O:22])=[O:21])[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][C:33]([CH3:35])=O.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[CH2:1]([C:8]1([C:13]2[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=2)[O:16][CH2:17][CH2:18][NH:19][S:20]([C:23]2[N:24]=[CH:25][N:26]([CH3:28])[CH:27]=2)(=[O:22])=[O:21])[CH2:12][CH2:11][N:10]([CH:33]([CH3:35])[CH3:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2cccc(C3(Cc4ccccc4)CCNC3)c2)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCC(Cc2ccccc2)(c2cccc(OCCNS(=O)(=O)c3cn(C)cn3)c2)C1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a solution of 1-methyl-1H-imidazole-4-sulfonic acid {2-[3-(3-benzyl-pyrrolidin-3-yl)phenoxy]-ethyl}-amide (example 61, 59 mg, 0.13 mmol) in dichloromethane under nitrogen was added acetone (8 mg, 0.14 mmol), two drops acetic acid, 2 mg Na2SO4, sodium triacetoxyborohydride. The mixture was stirred over night at room temperature. Saturated NaHCO3-solution was added and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over Na2SO4 and the solvent evaporated affording 54 mg of colorless oil. Purification on 4 g Si % with dichloromethane+5% MeOH to 10% MeOH afforded 4 mg of product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:13]([NH2:16])([CH3:15])[CH3:14]>CN(C=O)C>[CH:13]([NH:16][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])([CH3:15])[CH3:14]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CNC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A mixture of 2.00 g of methyl 3-(bromomethyl)benzoate, 1.55 g of isopropylamine, and 10 mL of DMF was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 1.20 g of methyl 3-[(isopropylamino)methyl]benzoate as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[N:8][N:7]2[CH:4]2[CH2:3][CH2:2][N:1]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:6][CH2:5]2)=[CH:11][CH:12]=1
Reactant: Nc1ccc2cnn(C3CCNCC3)c2c1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2cnn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Yield: 42.2 %

Procedure:
1-(Piperidin-4-yl)-1H-indazol-6-amine (3.33 mmol, 0.721 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.33 mmol, 1.124 g) and potassium carbonate (6.67 mmol, 0.921 g) were combined and stirred overnight at room temperature in acetonitrile (15 mL). The reaction mixture was concentrated at reduced pressure and the resulting residue taken up in dichloromethane. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed and the resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 8% methanol/dichloromethane) to afford the title compound (664 mg). MS (ESI) m/z 473.5 [M+H]+
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:3].CN(C=O)C.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CS(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CN(C)C=O
Product: CS(=O)c1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1
Temperature: 50 °C
Yield: 62.7 %

Procedure:
To a solution of 4-methanesulfinyl-phenol (1.52 g, 9.7 mmol) in DMF (30 ml) cesium carbonate (4.2 g, 12.9 mmol) was added, followed by addition of 5-bromo-2-nitro pyridine (1.75 g, 8.6 mmol) and the mixture was stirred at 50° C. over night. The suspension was filtered and evaporated+co-evaporated with toluene. The compound was purified by chromatography (0→10% EtOH in Methylene chloride) to give 1.5 g (56%) of 5-(4-Methanesulfinyl-phenoxy)-2-nitro-pyridine.
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.[O:10]=[C:11]1[NH:15][C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][S:12]1>O>[O:10]=[C:11]1[NH:15][C:14]([C:16](=[O:4])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][S:12]1
Reactant: CCOC(=O)Cc1csc(=O)[nH]1
Reactant: C1COCCO1
Agent: CCOC(=O)Cc1csc(O)n1
Agent: O=[Se]=O
Solvent: O
Product: CCOC(=O)C(=O)c1csc(=O)[nH]1

Procedure:
To a solution prepared by heating a mixture of selenium dioxide (0.33 g.), dioxane (15 ml.) and water (0.3 ml.) at 110° C. with stirring was added ethyl 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-hydroxy-1,3-thiazol-4-yl)acetate, (0.56 g.) without heating, and then the mixture was stirred for 30 minutes at 110° C. After the reaction, the reaction liquid was separated and the residue was washed with a small amount of dioxane. The reaction liquid and the washings were combined together, and the solvents were distilled off. To the residue was added ethyl acetate, and the mixture was washed with water and dried over magnesium sulfate. The solvent was distilled off from the mixture to give a solid of ethyl 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylate, (0.55 g.)
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:20]([O:22]CC)=O)[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.Cl.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]1.C(N(CC)CC)C.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[OH:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([N:26]2[CH2:2][CH2:3][C@:4]3([CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:11])[CH2:5]3)[C:20]2=[O:22])[CH2:28][CH2:29]1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OCc2ccccc2)C1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC[C@]2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-benzyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (1.0 g, 0.0030 mol, prepared by using procedures analogous to those described for the synthesis of example 1, steps 1 and 2), trans-4-aminocyclohexanol hydrochloride (0.50 g, 0.0033 mol), and triethylamine (0.48 g, 0.0048 mol) in 1,2-dichloroethane (8 mL, 0.1 mol) was stirred at rt for 30 min. To the mixture was added sodium triacetoxyborohydride (1.6 g, 0.0075 mol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture then was warmed to 80° C. with stirring for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with dichloromethane and the solution was washed with 1N HCl, water, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in-vacuo and the resulting residue was purified by flash column chromatography to afford 1.04 g of the desired product. Further purification by chiral HPLC was carried out (Chiralcel OD-H column (3.0×25 cm, 5 micron particle size, Chiral Technologies; Item number 14475) eluting with 15% ethanol/hexanes (isocratic, 26 mL/min.); Detection: 220 nm; retention time: 10.0 minute for peak 1, 12.5 minute for peak 2). The first peak to elute was found to be the R configuration and the second peak was found to be the S configuration and used for analog synthesis. LC-MS: 387.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:23]Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[Cl:23])=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Reactant: ClCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(-n2ncc(Cl)c2-c2ccc(Cl)cc2)cc1
Yield: 78 %

Procedure:
4-[5-(4-Chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide from Step 2 (3.0 g, 9 mmol) was dissolved in 50 mL of acetic acid, and 9 mL of 1M chlorine in acetic acid was added dropwise. The mixture was stirred for 16 hours when sat. aq. sodium bicarbonate solution was slowly added until the mixture was neutral to pH paper. The mixture was extracted with ethyl acetate (3×50 mL), combined and washed with sat. aq. sodium bicarbonate and with brine, dried over magnesium sulfate, filtered, and concentrated. The resultant product was recrystallized from isopropanol to yield 2.6 g (78%) of a white solid: mp 168-171° C. (dec); 1H NMR (DMSO-D6/300 MHz) 8.08 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.46 (brs, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.7 Hz, 2H). Anal. Calc'd for C15H11N3SO2Cl2: C, 48.93; H, 3.01; N, 11.41. Found: C, 49.01; H. 2.97; N, 11.41.
Reaction SMILES: Cl.[NH2:2]O.C([O:6][C:7](=O)[CH2:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)C>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:18][N:2]=[C:7]([OH:6])[CH:8]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Product: COc1ccc(-c2cc(O)no2)cc1

Procedure:
The above-identified compound was synthesized according to the process of (Example 2) using hydroxylamine hydrochloride and 4-methoxybenzoylacetic acid ethylester.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>CCO>[CH3:11][C:10]1[NH:9][N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cn[nH]c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]ncc1C(=O)O
Temperature: 80 °C
Yield: 74.9 %

Procedure:
A portion of the 5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.7 g, 18 mmol) is dissolved in EtOH (15 mL) and treated with aqueous sodium hydroxide solution (2.0 N solution, 20 mL, 40 mmol). The reaction is heated at 80° C. for 4 hours. The resultant mixture is then cooled and concentrated in vacuo to remove most of the EtOH. The crude is then acidified with 6N HCl until a precipitate is formed and filtered to afford 5-methyl-1H-pyrazole-4-carboxylic acid as a colorless solid (1.7 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:19].C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.BrBr>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:19][C:3]1[CH:4]=[C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Agent: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2noc(-c3sccc3Cl)n2)cc1CBr
Temperature: 25 °C
Reaction time: 17 h
Yield: 44.4 %

Procedure:
A solution of 3-(4-chloro-3-methyl-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole (1.45 g, 4.66 mmol), NBS (0.923 g, 5.19 mmol), AIBN (0.844 g, 5.14 mmol) and CCl4 (300 mL) was refluxed at 80° C. for 2 h. The solution was cooled to room temperature and additional NBS (0.913 g, 5.13 mmol) and AIBN (0.218 g, 1.33 mmol) was added and the solution was refluxed for 1 h. The solution was cooled to room temperature and stirred for 17 h. TLC indicated that the reaction had not occurred so bromine (0.240 mL, 4.67 mmol) was added and the solution was then brought to reflux. While refluxing, the solution was irradiated with a UV lamp (254 nm, 18.4 watts) for 2 h. The solution was cooled to room temperature, filtered and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, hexanes:dichloromethane, 8:3), to give 0.808 g (44%) of the title compound as a white solid. 1H NMR (CDCl3): 8.24 (d, 1H, J=2.2 Hz), 8.06 (dd, 1H, J=8.5 and 2.2 Hz), 7.63 (d, 1H, J=5.2 Hz), 7.54 (d, 1H, J=8.3 Hz), 7.14 (d, 1H, J=5.2 Hz), 4.66 (s, 2H).