Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:9])[C:6]([OH:8])=O)(=[O:3])[CH3:2].[F:10][C:11]([F:33])([F:32])[O:12][C:13]1[CH:14]=[C:15]([C:19]2[C:23]3[CH:24]=[C:25]([C:28]([NH:30][NH2:31])=[O:29])[CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1>>[C:1]([O:4][CH:5]([CH3:9])[C:6](=[O:8])[NH:31][NH:30][C:28]([C:25]1[CH:26]=[CH:27][C:22]2[O:21][CH:20]=[C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:11]([F:10])([F:32])[F:33])[CH:14]=3)[C:23]=2[CH:24]=1)=[O:29])(=[O:3])[CH3:2]
Reactant: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Reactant: CC(=O)OC(C)C(=O)O
Product: CC(=O)OC(C)C(=O)NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Yield: 48 %

Procedure:
In the same manner as in Reference Example 1 and using (±)-2-acetoxypropionic acid instead of benzothiazole-6-carboxylic acid and 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide instead of tert-butyl carbazate, the title compound (yield 48%) was obtained as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH:12]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:13]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
1-(4-Nitro-phenyl)-azetidin-3-ol (which was obtained in Example 396) (5.0 g, 25.8 mmol) was added to a solution of methanesulfonyl chloride (2.2 mL, 28.3 mmol) in dry pyridine (35 mL) and stirred at room temperature overnight. Water was added and the resultant precipitate was captured on a filter, washed with water, methanol, and hexanes to give 3.72 g of the desired product as an orange solid; 1H NMR (DMSO-d6) δ3.35 (s, 3H), 4.15(m, 3H), 4.45(m, 2H), 5.48(m, 1H), 6.53(d, 2H, J=9.12 Hz), 8.09(d, 2H, J=9.12 Hz); MS (ES) m/z: 273.5 (MH+); Anal. Calcd. for C10H12N2O5S: C, 44.11; H, 4.44; N, 10.29. Found: C, 44.50; H, 4.48; N, 10.64.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[CH2:12]([N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[C:16]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[N:15]1)[CH3:13]>>[Cl:8][C:6]1[N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]2=[C:2]([C:17]2[C:16]([C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[N:15][N:14]([CH2:12][CH3:13])[CH:18]=2)[CH:7]=1
Reactant: Clc1cc(Br)c2cc[nH]c2n1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CCn1cc(-c2cc(Cl)nc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 6 with 4-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine and 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole afforded the title compound. ESMS [M+H]+: 368.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[C:26]([NH:34][NH2:35])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:35][NH:34][C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:33])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O)c1ccccc1

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and benzohydrazide employing methods similar to those described in Example 9 and was obtained as a light yellow solid: 1H NMR (d6-DMSO) δ 12.08 (1H, br s), 11.83 (1H, br s), 11.05 (1H, br s), 8.55 (1H, br s), 7.91-7.89 (2H, m), 7.60-7.49 (4H, m), 7.34-7.30 (2H, m), 7.16-7.13 (2H, m), 4.14 (2H, m); HRMS calcd for C23H17FN4O4+H+: 433.1312. Found 433.1311.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH2:32][C@H:33]([CH:36]([CH3:38])[CH3:37])[CH2:34][OH:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:32][C@@H:33]([CH2:34][OH:35])[CH:36]([CH3:38])[CH3:37])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(C)[C@@H](N)CO
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN[C@@H](CO)C(C)C)c4)cc23)CC1
Yield: 32.5 %

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), (2R)-2-amino-3-methyl-1-butanol (10.2 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (14.9 mg, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].[H-].[Na+].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)#[N:22].O>CN(C=O)C>[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[CH:31][C:32]([CH2:33][N:12]([C:4]2[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:35][CH:36]=1)#[N:22]
Reactant: CCCCC(=O)Nc1c(OC)cccc1[N+](=O)[O-]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)c1c(OC)cccc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
To a solution of N-(2-methoxy-6-nitrophenyl)valeramide (3.2 g) in DMF (15 ml) was added, under ice-cooling, sodium hydride (60% oil, 0.61 g). The mixture was stirred for 20 minutes and then there was added 4-(2-cyanophenyl)benzyl bromide (3.5 g), followed by stirring for one hour at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to give a yellow oil (5.8 g, quantitatively).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3](=O)[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClC1C=CC=CC=1.CCOC(C)=O>[CH:2]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1)([CH3:13])[CH3:1]
Reactant: CC(C)C(=O)CSc1ccccc1
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: CC(C)c1csc2ccccc12
Temperature: 136 °C
Reaction time: 18 h

Procedure:
To a hot solution (136° C.) of PPA (8.2 g) in chlorobenzene (50 mL) is added a solution of compound 563-C (4.34 g; 22.4 mmol) in chlorobenzene (35 mL). The reaction was stirred at 136° C. for 18 h, cooled to ambient temperature, diluted with EtOAc, quenched with H2O, and the EtOAc layer was washed with H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford compound 563-D as an oil. 1H-NMR (DMSO-d6): δ 1.31-1.33 (d, 6H), 3.26-3.31 (m, 1H), 7.33-7.43 (m, 2H), 7.83-7.85 (m, 1H), 7.95-7.97 (m, 1H); MS: m/z 328.0 (MH+).
Reaction SMILES: FC1C=N[C:5]([N:8]2[CH2:12][CH:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=NC=1.[F:22][C:23](F)([F:27])C(O)=O.C1(C)C=CC=CC=1>ClCCl>[F:22][CH:23]([F:27])[CH2:20][N:10]1[CH:11]([C:13]([OH:15])=[O:14])[CH2:12][N:8]([CH3:5])[C:9]1=[O:21]
Reactant: O=C(O)C(F)(F)F
Reactant: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1CC(C(=O)O)N(CC(F)F)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml) at −35° C. under argon was added sodium hydride (39.9 mg, 0.999 mmol). The mixture was stirred for 15 minutes, 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) was added and the reaction mixture was stirred at −35° C. for 30 minutes then slowly warmed to −15° C. After 1 hour the reaction mixture was quenched with water (10 ml), warmed to room temperature and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with sodium hydrogen carbonate saturated solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was then dried (magnesium sulfate), filtered and evaporated. The crude residue was purified by silica gel chromatography eluting with 10-100% of ethyl acetate in isohexane to give 1,1-dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg). LC/MS [M+H]+=265. (ii) 1,1-Dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg, 0.674 mmol) was dissolved in dichloromethane (3.00 ml) and trifluoroacetic acid (1 ml) was added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with dichloromethane and toluene to give a crude 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylic acid (assume 0.674 mmol) which was used for the next reaction. LC/MS [M+H]+=209.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[C:27]([CH3:38])[C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[N:29][C:28]([O:31][CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[C:27]([CH3:38])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Br)cnc1OC1CCOCC1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: Cc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)cnc1OC1CCOCC1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 5-bromo-3-methyl-2-(tetrahydro-pyran-4-yloxy)-pyridine (Intermediate 24) in analogy to Example 1a): MS (ISN): 493.1 and 495.2 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:21]2[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=1.[CH3:40][Zn]C.C1(C)C=CC=CC=1>>[O:19]=[S:16]1(=[O:20])[CH2:17][CH2:18][N:13]([C:11]2[S:12][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:40])[N:7]=3)=[C:9]([C:21]3[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=3)[N:10]=2)[CH2:14][CH2:15]1
Reactant: O=S1(=O)CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(N3CCS(=O)(=O)CC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.325 mmol) and 2N dimethylzinc in toluene (0.325 mL, 0.649 mmol), the title compound was obtained as a solid (110 mg, 59% yield). MS (ESI): 596 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[C:15]2[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[S:9][C:8]=1[CH3:28]>>[N:1]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:15]3[CH:7]=[C:8]([CH3:28])[S:9][C:10]=3[N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2ncnc(NCCc3ccc4c(c3)OCO4)c2c1Cl
Reactant: c1cn[nH]c1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 5-chloro-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3- d]-pyrimidine.
Reaction SMILES: Br[C:2]1[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([CH2:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:20])[C:7]=1[CH3:8].[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([CH2:9][C:10]3[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=3[F:20])[C:7]=2[CH3:8])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC#N
Product: Cc1c(N2CCN(Cc3ccccc3)CC2)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 120 °C
Yield: 78.8 %

Procedure:
5-bromo-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione (1.50 g, 3.94 mmol), 1-benzyl-piperazine (5.5 mL, 31.5 mmol), and acetonitrile (1 mL) were placed in a microwave vessel and heated at 120° C. for 1.5 hr by microwave irradiation with stirring. Following concentration, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/2/1) and dried in a vacuum to afford the 1.48 g of the compound as a white solid (yield 79%). 1H NMR (300 MHz, CDCl3) δ 2.15 (2H, m), 2.31 (3H, s), 2.50 (2H, m), 2.78 (2H, m), 3.52 (3H, s), 3.58 (2H, m), 5.36 (2H, s), 7.19-7.41 (7H, m), 7.53 (1H, d)
Reaction SMILES: [C:1]([C:4]([CH3:6])=[O:5])([CH3:3])=[O:2].[OH-].[Na+].[O:9]1CCO[CH2:11][CH2:10]1>>[O:2]1[CH2:11][CH2:10][O:9][CH2:3][CH:1]1[C:4](=[O:5])[CH3:6]
Reactant: CC(=O)C(C)=O
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C1COCCO1
Temperature: 0 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of benzoic peroxide (20 g, 141 mmol) in 200 mL 1,4-dioxane at room temperature under nitrogen atmosphere was added biacetyl (24.3 g, 282 mmol). After the addition, the mixture was heated to reflux and stirred for 24 hours. The reaction mixture was cooled to 0° C. The pH was adjusted to around 9 by progressively adding 2N sodium hydroxide below 0° C., extracted with 2-methoxy-2-methylpropane (10 mL×3), and concentrated to give 1-(1,4-dioxan-2-yl)ethanone (13 g, 36%) as a yellow oil which was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O1CCCC1.C(Cl)Cl>[N:16]1([CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=2[F:1])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: Fc1ccc(Br)cc1COCCCCBr
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1COCCCCN1CCOCC1
Reaction time: 72 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (550 mg, 1.62 mmol) in tetrahydrofuran (8 ml) was treated with morpholine (1.4 ml, 16.2 mmol). The resulting reaction mixture was stirred for about 72 hours. The reaction mixture was then diluted with methylene chloride and washed with saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(SCCc2ccc(Cl)cc2)cc1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc(SCCc3ccc(Cl)cc3)cc2)S1

Procedure:
4-[2-(4-Chlorophenyl)ethylthio]benzaldehyde and thiazolidine-2,4-dione were coupled according to the method of Example 5 to form present title product in similar yield; m.p. 215°-225° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.O1[CH2:14][CH2:13][NH:12]C1=O>C(OCC)C.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:14][CH2:13][NH2:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NCCO1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of 3-bromoaniline (0.50 g, 2.9 mmol) in diethyl ether (Et2O, 5 mL) was added 4 M HCl in dioxane (1 mL), and the mixture was stirred at 25° C. for 1 h. Solvent was removed under reduced pressure, and the resulting HCl salt was dissolved in 2-(2-methoxyethoxy)ethanol (2 mL). 2-Oxazolidinone (0.429 g, 4.93 mmol) was added, and the reaction mixture was heated to 180° C. for 24 h. The collected crude solid was purified by column chromatography (0-10% (1% NH4OH in MeOH)/CH2Cl2) to provide N1-(3-bromo-phenyl)-ethane-1,2-diamine (0.10 g, 16%). 3-(Piperidine-1-carbonyl)-benzaldehyde (Example 1, step D; 0.091 g, 0.42 mmol) was added to a solution of the phenyl-diamine in 1,2-dichloroethane (10 mL), and the reaction mixture was stirred at 25° C. for 15 min. The mixture was treated with NaBH(OAc)3 (0.128 g, 0.604 mmol), and the resulting suspension was stirred at 25° C. for 18 h. The suspension was partitioned with satd NH4Cl (20 mL) and CH2Cl2 (20 mL), and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (2-10% CH3OH/CH2Cl2), and then by preparative TLC (10% CH3OH/CH2Cl2) to provide the desired product (0.060 g, 34%). MS (ESI): mass calculated for C21H26BrN3O, 415.13; m/z found, 416.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.28-7.26 (m, 3H), 7.21-7.16 (m, 1H), 6.93 (t, J=8.0 Hz, 1H), 6.74-6.71 (m, 1H), 6.67 (t, J=2.0 Hz, 1H), 6.47-6.44 (m, 1H), 4.23 (br s, 1H), 3.75 (s, 2H), 3.64 (br s, 2H), 3.25 (br s, 2H), 3.10 (t, J=5.6 Hz, 2H), 2.83-2.80 (m, 2H), 1.60-1.43 (m, 6H).
Reaction SMILES: C(O[C:4](=[O:13])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][CH3:12])C.O.[NH2:15][NH2:16]>C(O)CCC>[CH2:11]([C:7]1[N:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:13])[CH:10]=[CH:9][N:8]=1)[CH3:12]
Reactant: NN
Reactant: CCOC(=O)Cn1ccnc1CC
Solvent: O
Solvent: CCCCO
Product: CCc1nccn1CC(=O)NN
Yield: 94 %

Procedure:
As described for example 112a, (2-ethyl-imidazol-1-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at 100° C. for 6 h. Evaporation of all volatiles and crystallization from methanol/diisopropylether afforded the title compound as a white solid (yield: 94%). MS: m/e=169.3 [M+H]+.
Reaction SMILES: C(OCC)C.C([Li])CCC.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:21]([C:20]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:19]=2[Cl:18])[OH:22])[CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1ccc(Cl)cc1Cl
Temperature: -120 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml 3-neck round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet was added 150 ml of anhydrous diethyl ether and 94 ml of 1.6 molar butyllithium solution (in hexane). The system was cooled to -120° C. and 14.5 ml of 3-bromopyridine in 75 ml of tetrahydrofuran was added over 1 hour. After addition of the 3-bromopyridine, the system was stirred for an additional 45 minutes. At this time, 26.25 gm of 2,4-dichlorobenzaldehyde in 75 ml of tetrahydrofuran was added to the system while still maintaining at temperatures of -120° C. The system was kept at -120° C. for an additional 6 hours after addition of the 2,4-dichlorobenzaldehyde and afterwards allowed to come to room temperature. After 10 hours at room temperature, the system was quenched with saturated ammonium chloride (in water). The system was then adjusted to a pH 2 with concentrated HCl solution. The solution was extracted with diethyl ether. The aqueous solution was made basic with a 50% NaOH solution. The product was extracted with methylene chloride and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 25.75 gm of the 3-pyridyl-2,4-dichlorophenyl-carbinol as tan solid, m.p. 108°-111° C., and listed as compound number 2 in Table I.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][O:31][CH2:32]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:30][O:31][CH3:32])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cc(Cl)cnc1Br)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.22 mmol) and K2CO3 (91 mg, 0.66 mmol) in THF (5 mL) was added chloromethyl methyl ether (0.054 mL, 0.66 mmol) at room temperature. The resulting mixture was stirred for 3 h at room temperature then filtered. The filter cake was washed with THF and the combined filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to provide desired product. Mass spectrum m/z: 494.9 (M+H).