Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH3:43][NH:44][CH2:45][C:46]([NH2:48])=[O:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:44]([CH2:45][C:46]([NH2:48])=[O:47])[CH3:43])=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CNCC(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(CC(N)=O)C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and methylamino-acetic acid amide with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([CH2:18][CH3:19])[C:8](=[O:20])[NH:7][C:6]1=[O:21])[CH:2]=[CH:3]C.C(N1C(CC2C=CC=CC=2)=C(CC)C(=O)NC1=O)C=CC1C=CC=CC=1>>[CH2:1]([N:5]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([CH2:18][CH3:19])[C:8](=[O:20])[NH:7][C:6]1=[O:21])[CH:2]=[CH2:3]
Reactant: CC=CCn1c(Cc2ccccc2)c(CC)c(=O)[nH]c1=O
Agent: CCc1c(Cc2ccccc2)n(CC=Cc2ccccc2)c(=O)[nH]c1=O
Product: C=CCn1c(Cc2ccccc2)c(CC)c(=O)[nH]c1=O

Procedure:
1-(2-butenyl)-5-ethyl-6-benzyl-2,4-pyrimidinedione; 1-cinnamyl-5-ethyl-6-benzyl-2,4-pyrimidinedione;
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH2:12]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:13][CH3:14].Cl.[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1>>[CH2:12]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:27]2[CH2:28][CH2:29][CH2:30][C:25]2=[O:9])=[CH:18][CH:17]=1)[CH2:13][CH3:14]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: c1ccccc1
Agent: Cl
Product: CCCOc1ccc(C=C2CCCC2=O)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 4-propoxybenzaldehyde and 200 mL of benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C., and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 71.9%.
Reaction SMILES: [C:1]([O-:6])(=O)[C:2]([CH3:4])=O.[OH:7][C:8]1C=C([CH:13]=[CH:14][CH:15]=1)C=O>>[OH:6][C:1]1[CH:2]=[CH:4][CH:13]=[CH:14][C:15]=1[CH:8]=[O:7]
Reactant: CC(=O)C(=O)[O-]
Reactant: O=Cc1cccc(O)c1
Product: O=Cc1ccccc1O

Procedure:
The reaction rate was measured as described in Example 1, using as substrates 5 mM pyruvate and 5 mM 3-hydroxybenzaldehyde. The absorbance values at 346 nm decreased linearly at a rate of 0.15 OD/min, which yielded a decrease of hydroxybenzaldehyde concentration 0.3 μmol/min, when using ε=480 M−1cm−1. The corresponding activity was 0.93 U/mg.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20](Cl)=[O:21])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([NH:31][NH2:32])(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C(Cl)Cl>[C:24]1([C:23]2[O:21][C:20]([C:18]3[CH:17]=[N:16][C:12]4[O:13][CH2:14][CH2:15][N:10]([S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])[C:11]=4[CH:19]=3)=[N:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)N1CCOc2ncc(-c3nnc(-c4ccccc4)o3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.8 %

Procedure:
To a solution of 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (40 mg, 0.118 mmol; Example 1 Step 1) in DCM (1.5 mL) was added benzohydrazide (32.2 mg, 0.236 mmol) and DIPEA (50 μL, 0.286 mmol). The reaction was stirred at room temperature for 16 hours. TLC analysis of the reaction mixture indicated consumption of starting material. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and was extracted with DCM (3×2 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was dissolved in DMF (3 mL) and treated with Burgess reagent (28.1 mg, 0.118 mmol). The reaction mixture was heated to 180° C. by heating under microwave irradiation for 5 minutes. The mixture was concentrated in vacuo. The resulting paste was purified by flash column chromatography using a gradient elution of hexanes with 10-90% EtOAc. The resulting tan solid was triturated with water (2×10 mL) to provide 7-(5-phenyl-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (4.6 mg, 10.39 μmol, 8.80% yield) as a white solid. LCMS (+ESI) m/z=421.0 [M+H]+; 1H-NMR (CDCl3) δ 8.90 (d, 1H), 8.84 (d, 1H), 8.17 (m, 2H), 7.74 (m, 2H), 7.65 (tt, 1H), 7.59-7.51 (m, 5H), 4.02 (m, 2H), 3.95 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.Cl.[OH:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:14]2[CH:15]=[C:11]([CH2:10][O:9][S:28]([CH3:27])(=[O:30])=[O:29])[N:12]=[CH:13]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cnc(COS(C)(=O)=O)c2)cc1
Reaction time: 8 h
Yield: 82 %

Procedure:
Triethylamine (25.9 ml) was added dropwise to a suspension of 4-hydroxymethylimidazole hydrochloride (10.0 g, 74 mmol) in dichloromethane (200 ml) containing 4-methylbenzenesulfonyl chloride (15.6 g) and the mixture stirred overnight before being washed with water and brine, dried (MgSO4), and evaporated to leave a colourless oil. This was chromatographed on silica gel, eluting with ethyl acetate/hexanes to give an oil which solidified on standing (15.0 g). A portion of this solid (1.0 g, 4 mmol) was dissolved in dichloromethane (15 ml), and the solution cooled in an ice bath as triethylamine (0.5 g), followed by methanesulfonyl chloride (0.55 g) in dichloromethane (1 ml) were added dropwise. After tlc indicated reaction to have completed, the mixture was washed with water and brine, then dried (MgSO4), before evaporating to leave the product as a white powder (1.3 g).
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]3[N:23]([C:24]=2[CH:25]=O)[CH:22]=[CH:21][S:20]3)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]3[N:23]([C:24]=2/[CH:25]=[CH:2]/[C:1]([C:4]2[NH:5][CH:6]=[CH:7][CH:8]=2)=[O:3])[CH:22]=[CH:21][S:20]3)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2nc3sccn3c2C=O)cc1
Reactant: CC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccc(-c2nc3sccn3c2/C=C/C(=O)c2ccc[nH]2)cc1
Temperature: 27 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a stirred solution of 2-acetyl pyrrole (109 mg, 1.0 mmol) and a 6-(4-methoxyphenyl) imidazo[2,1-b]thiazol-5-carbaldehyde (258 mg, 1.0 mmol) in ethanol (20 ml) 10% aqueous solution of NaOH was added (5 ml). The reaction mixture was stirred at room temperature 27° C. for 4 h and the reaction was monitored by TLC using ethyl acetate-hexane (3:7) as a solvent system. The solvent was evaporated under vacuum then the residue was dissolved in ethylacetate/water. The organic layer was washed with brine and evaporated. This was further purified by column chromatography using ethyl acetate:hexane (2:8) as a solvent system to obtain the pure product (17a) as yellow solid (286 mg, 82% yield). Mp: 177-179° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[C:14]3[C:9](=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH:8](O)[CH2:7]2)[N:3]=[CH:2]1.[H][H]>C(O)C.Cl.[Pd]>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH2:7][CH:6]2[C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[C:10]([CH3:18])[C:11]=1[CH3:17]
Reactant: [H][H]
Reactant: COc1cc2c(c(C)c1C)C(O)CC2c1c[nH]cn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc2c(c(C)c1C)CCC2c1c[nH]cn1

Procedure:
3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-ol (0.29 g) is dissolved in the mixture of ethanol (30 ml) and concentrated hydrochloric acid (0.2 ml). The solution is hydrogenated at 50-55° C. with 10% palladium on carbon as catalyst until no more hydrogen is consumed. The mixture is filtered and the filtrate is evaporated to dryness. The residue is crystallized from the mixture of ethyl acetate and ethanol. M.p. of the hydrochloride salt is 174-177° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[C:19]=2[C:31]([F:34])([F:33])[F:32])=[O:17])=[CH:11][C:10]=1[CH2:35][NH3+:36].N1C=CC=CC=1>C1COCC1>[C:1]([NH:36][CH2:35][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]([F:29])([F:30])[C:25]([F:28])([F:26])[F:27])[C:19]=2[C:31]([F:32])([F:33])[F:34])=[O:17])[CH:13]=[CH:14][C:9]=1[Cl:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C[NH3+])c1
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCC(=O)NCc1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Reaction time: 20 h
Yield: 73.1 %

Procedure:
Butanoyl chloride (24 mg, 0.23 mmol, 1.1 eq.) in THF (1.5 ml) was added to a solution of [2-chloro-5-({[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)phenyl]methanaminium chloride (100 mg, 0.21 mmol) and pyridine (34 mg, 0.43 mmol, 2.1 eq.) in THF (3 ml). After 20 h at room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (hexane/ethyl acetate) to give N-{3-[(butyrylamino)methyl]-4-chlorophenyl}-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80 mg, 75%).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][C:8]=2[F:24])[CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][C:8]=2[F:24])[CH2:3][CH2:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 3 h

Procedure:
A mixture of (S)-(-)-N-[[3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 47, 1.00g) and 10% palladium-on-carbon (637 mg) in methanol (60 mL) is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for three hours, the catalyst is removed by filtration through Celite and the filtrate is concentrated under reduced pressure to give the title compound, mp 191-192° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[NH2:28][C:27]1[CH:26]=[CH:25][C:24]([CH3:23])=[C:30]([C:2]2[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]3[N:10]([C:15]4[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=4[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=23)[CH:29]=1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(-c2cc(N)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 95 °C

Procedure:
To 5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.342 g, 1 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.256 g, 1.1 mmol) in dioxane (40 mL), was added a solution of K2CO3 (0.417 g, 3 mmol) in water (10 mL). Argon was vigorously bubbled through the mixture for 5 minutes and then tetrakis(triphenyl-phosphine)palladium(0) (0.078 g, 0.05 mmol) was added. The mixture was heated in a 95° C. oil bath for 17 hours. The solvent was pumped off in vacuo, and the residue partitioned between ethyl acetate and water. The phases separated and the organic phase washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was flash chromatographed on silica gel (20 grams) eluted with 0-10% MeOH/CH2Cl2 to give the title product as a white solid. mp 122-125° C. LC-MS m/z 414 (M+H)+, 1.58 min (ret. time).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][O:13][CH2:14][CH2:15][OH:16].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1ccc2ccccc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 78.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 478 mg of 2-(2-quinolylmethyleneaminooxy)ethanol (prepared as described in Preparation 2), 1.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 638 mg of triphenylphosphine and 423 mg of diethyl azodicarboxylate, 1.12 g of the title compound were obtained as a crystalline powder, melting at 127-130° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])(=O)[CH3:2].Cl.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:23]=1[CH2:24][O:25][NH2:26].CC([O-])=O.[Na+]>CCO>[F:20][C:21]([F:35])([F:36])[C:22]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][C:23]=1[CH2:24][O:25][N:26]=[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH3:2]
Reactant: NOCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOCc1ccc(C(F)(F)F)cc1C(F)(F)F)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 88.4 %

Procedure:
A solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (150 mg, 0.50 mmol), O-(2,4-bistrifluoromethylbenzyl)hydroxylamine hydrochloride (154 mg, 0.52 mmol) and anhydrous NaOAc (43 mg, 0.52 mmol) in EtOH (20 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 7:3). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 7.5:92.5 to 1:9) afforded a pale yellow solid which was recrystallized from CH2Cl2/PE to give N-{2-[1-(2,4-bistrifluoromethylbenzyloxyimino)ethyl]-4-chlorophenyl}trifluoromethanesulfonamide 2 (240 mg, 89%), as a colorless oil. 1H n.m.r. (200 MHz, CDCl3) δ 10.96, br s, 1H; 7.96, s, 1H; 7.85, d, J=8.0 Hz, 1H; 7.72, d, J=8.0 Hz, 1H; 7.60, d, J=8.8 Hz, 1H; 7.49, d, J=2.2 Hz, 1H; 7.33, dd, J=2.2 and 8.8 Hz, 1H; 5.46, s, 2H; 2.39, s, 3H. HRMS (M+) 542.0102.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]([CH3:15])([OH:13])[CH2:14][O:23][C:20]2[CH:21]=[CH:22][C:17]([I:16])=[CH:18][CH:19]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC1(CCn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Oc1ccc(I)cc1
Product: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(I)cc1
Yield: 81 %

Procedure:
Reaction of epoxide 140 (see Example 2B) with 4-iodophenol as in Example 2AA at 83° C. for 8 h, followed by chromatography of the product on silica gel, eluting with 0-2% EtOAc/CH2Cl2 (foreruns) and then with 5% EtOAc/CH2Cl2, gave 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-1-(4-iodophenoxy)-2-methyl-2-butanol (143) (81%) as a cream solid: mp (CH2Cl2/pentane) 91-93° C.; 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.59 (dt, J=8.9, 2.6 Hz, 1H), 6.69 (dt, J=8.9, 2.6 Hz, 1H), 4.28 (ddd, J=14.1, 9.6, 6.3 Hz, 1H), 4.23 (ddd, J=14.1, 9.4, 6.5 Hz, 1H), 3.82 (d, J=9.0 Hz, 1H), 3.79 (d, J=9.0 Hz, 1H), 2.22 (ddd, J=13.8, 9.2, 6.5 Hz, 1 H), 2.20 (s, 1H), 2.02 (ddd, J=13.8, 9.6, 6.6 Hz, 1H), 1.39 (s, 3H); HRESIMS calcd for C14H16ClIN3O4 m/z [M+H]+ 453.9840, 451.9869. found 453.9832, 451.9857.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C@H:8]3[CH2:9][CH2:10][C@H:11]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[NH:16][C:15]4=[O:23])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)=[O:39])[CH:34]=1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](NC2CCNCC2)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CCC(N[C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 12 h

Procedure:
To a stirred solution of 0.050 g of 1,3-dihydro-1-{trans-4-[4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one and 0.023 mL of triethylamine in 1.5mL of dichloromethane was added 0.024 g of nicotinoyl chloride hydrochloride. After 12 h, 20 mL of saturated sodium carbonate was added, the organic layer was separated, and the aqueous layer extracted with two additional 20 mL portions of chloroform. The combined organic extracts dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel eluting with 10% methanol/10% conc. NH4OH in chloroform gave 0.024 g of 1,3-dihydro-1-{trans-4-[1-(3-pyridinecarbonyl)-4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.04 (s, 1H), 8.68 (dd, 2H), 7.77 (m, 1H), 7.38 (m, 1H), 7.26 (m, 1H), 7.06 (m, 3H), 4.67 (br s, 1H), 3.75 (br s, 1H), 3.18 (br s, 2H), 2.99 (br s, 1H), 2.87 (br s, 1H), 2.55 (q, 2H), 2.13-1.9 (m, 4 H), 1.72-1.3 (m, 7H). The dihydrochloride salt was precipitated from chloroform/ethyl acetate: Analysis calculated for C24H29 N5O2.2HCl.0.90 CHCl3.0.25 CH3CO2CH2 CH3C: 50.02, H: 5.95, N: 11.26 found C: 51.28, H: 5.49, N: 11.53.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH:17][C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26](=[O:39])[N:27]([CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[N:6][CH:7]=1.C=O.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH:17][C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26](=[O:39])[N:27]([CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][N:36]([CH3:44])[CH2:37][CH2:38]4)[CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[N:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2cccn(CCN3CCNCC3)c2=O)cc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(CCn2cccc(-c3ccc(C(=O)Nc4c(O)cccc4C(=O)Nc4ccc(Cl)cn4)cc3)c2=O)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 9 h
Yield: 282.3 %

Procedure:
N-(5-chloropyridin-2-yl)-3-hydroxy-2-({4-[2-oxo-1-(2-piperazin-1-ylethyl)-1,2-dihydropyridin-3-yl]benzoyl}amino)benzamide (393 mg) was dissolved in tetrahydrofuran (10 mL), and an aqueous 37% formalin solution (134 μL) and sodium triacetoxyborohydride (436 mg) were added, followed by stirring at room temperature for 9 hours. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (methanol/chloroform=0% to 5%). The resulting compound was dissolved in ethyl acetate, and 4 N hydrochloric acid/ethyl acetate was added, followed by stirring at room temperature for 30 minutes. The precipitate formed was collected by filtration and dried under reduced pressure to obtain N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[2-(4-methylpiperazin-1-yl)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzoyl)amino]benzamide dihydrochloride (426 mg) as a yellow white solid.
Reaction SMILES: Cl.[NH:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1.CNC1C=CC=CC=1.[F:27][C:28]([F:32])=[C:29](F)F.C(=O)([O-])[OH:34].[Na+]>CN(C)C=O.C(N(CC)CC)C>[F:27][CH:28]([F:32])[C:29]([N:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1)=[O:34]
Reactant: O=C([O-])O
Reactant: FC(F)=C(F)F
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Agent: Cl
Agent: [Na+]
Solvent: CNc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 80 °C
Reaction time: 30 h
Yield: 27 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline hydrochloride (1.47 g, 5.0 mmol), triethylamine (2 ml) and N-methylaniline (1.29 g, 12.0 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow into the flask (ca. 0.7 liter/hr), with vigorous stirring at 80° C. for 30 hours. After cooling to an ambient temperature, the reaction mixture was poured intoa saturated aqueous sodium hydrogencarbonate solution (100 ml), and extracted twice with toluene (100 ml×2). The combined toluene layer was washed twice with 10% hydrochloric acid (50 ml×2) and water (70 ml) and then brine (70 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.45 g, 1.34 mmol, yield 27%).