Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1>CN(C)C=O>[C:16]([C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:10][CH2:9][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:13][CH:14]=1)(=[O:17])[NH2:18]
Reactant: NC(=O)c1ccc(OCCCl)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCCn2ccnc2)cc1
Temperature: 100 °C
Yield: 50.8 %

Procedure:
Sodium hydride (14.4 g, 50% suspension in mineral oil) was added cautiously to a stirred and cooled solution of imidazole (20.4 g) in dry N,N-dimethylformamide (100 ml). After the initial vigorous reaction had subsided the mixture was heated to 100° C. for 10 minutes and then stirred at room temperature for a further 1 hour. A solution of 4-(2-chloroethoxy)benzamide (60.0 g) in the minimum volume of N,N-dimethylformamide was added and the mixture was heated at 100° C. for 5.5 hours. The solvent was evaporated and the residue was poured into water. The mixture was extracted several times with chloroform and the combined chloroform extracts were dried (MgSO4) and evaporated to give a mixture of oil and solid. The mixture was triturated with ether and the solid was collected and crystallised from a mixture of methanol and ethyl acetate to give 1-[2-(4-carbamoyl phenoxy)ethyl]imidazole (35.2 g), m.p. 148°-149° C. Found: C, 62.25; H, 5.61; N, 18.54. C12H13N3O2 requires: C, 62.32; H, 5.67; N, 18.17%.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[CH:4]=[C:5]([C:10]2[O:11][C:12]([CH3:33])=[C:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C@H:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:22][CH2:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].[Li+].[OH-].O>C(O)C.C1COCC1>[CH3:34][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([C:10]2[O:11][C:12]([CH3:33])=[C:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C@H:23]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C)c(N(C)C)c4)oc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)O)c(C)o2)cc1N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a solution of ethyl [(1S)-5-(2-{2-[3-(dimethylamino)-4-methylphenyl]-5-methyl-1,3-oxazol-4-yl}ethoxy)-2,3-dihydro-1H-inden-1-yl]acetate (175.0 mg, 0.38 mmol) in ethanol (1 mL) and THF (1 mL) was added LiOH (159 mg) followed by addition of 1 mL water. The reaction mixture was then stirred at rt for 4 h. The reaction mixture was then acidified to pH 5-6 and the solvent was removed by reduced pressure. The residue was redissolved in methanol, filtered through a plug of C8-Silica plug before preparative HPLC purification using 10 to 70% acetonitrile in water to afford desired product 156 mg (95% yield). 1H NMR (300 MHz/CD2Cl2) δ 7.96 (s, 1H), 7.80 (d, 1H), 7.35 (d, 1H), 7.06 (d, 1H), 6.77 (s, 1H), 6.67 (d, 1H), 4.21 (t, 2H), 3.47 (qr, 1H), 3.11 (s, 6 H), 2.97 (t, 2H), 2.75-2.90 (m, 2H), 2.70 (dd, 1H), 2.54 (s, 3H), 2.29-2.46 (m, 5H), 1.65-1.78 (m, 1H). EI-LCMS(rel abundance), m/z 435.4 (MH+, 100%). HPLC RT: 3.52 min.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:29])[C:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH3:29])[C:7]([C:10](=[S:39])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(=O)c2ccc(OC)cc2OCC(=O)OC(C)(C)C)n1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCc1ncc(C(=S)c2ccc(OC)cc2OCC(=O)OC(C)(C)C)n1C

Procedure:
2-n-Butyl-1-methyl-5-(2-t-butoxycarbonylmethoxy-4-methoxybenzoyl)-1H-imidazole (465 mg, 1.16 mmol) dissolved in toluene (5 ml) was mixed with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (258 mg, 0.638 mmol) and the solution heated to 95° for 1 h under argon. The reaction was cooled and the toluene solution applied directly to a silica gel column. Elution with 50% EtOAc/hexanes afforded the title compound as a deep purple-green solid. (206 mg, 53%).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3cc(F)ccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2cc(F)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(6-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (403 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (355 mg, 93%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3]/[C:4](/[CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:5]/[C:6]([OH:8])=[O:7].C1OCCOCCOCCOCCOC1.FC(F)(F)S(O[C@H:34]1[CH2:39][C@@H:38]([CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])[O:37][C@@:36]([O:60][CH3:61])([C@@H:45]2[CH2:49][S:48][C:47](=[O:50])[N:46]2[CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)[CH2:35]1)(=O)=O>C1COCC1>[CH3:3]/[C:4](/[CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:5]/[C:6]([O:8][C@@H:34]1[CH2:39][C@@H:38]([CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])[O:37][C@@:36]([O:60][CH3:61])([C@@H:45]2[CH2:49][S:48][C:47](=[O:50])[N:46]2[CH2:51][C:52]2[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)[CH2:35]1)=[O:7]
Reactant: C=CCCC[C@@H]1C[C@H](OS(=O)(=O)C(F)(F)F)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: C=CCC/C(C)=C\C(=O)O
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCC=C)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 100 mL dry flask under a nitrogen atmosphere was charged with NaH (60% in mineral oil, 186 mg, 4.65 mmol). The NaH was washed with pentane (5 mL), THF (2 mL) was added, and the reaction was cooled to 0° C. The title compound from Example 21 (651 mg, 4.65 mmol) in THF (3 mL) was added dropwise, after which 15-crown-5 (1.41 mL, 7.12 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 10 minutes, and then was cooled to 0° C. again. A solution of the title compound from Example 22 (1.19 mmol, used directly from the previous reaction) in THF (2 mL) was added, and the reaction was stirred at room temperature overnight.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH:17]=1.C(N1CCC(OC2C=CC=CN=2)CC1)(OC(C)(C)C)=O>>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1cc(Cl)ccn1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C#N)c2)CC1

Procedure:
Prepared from 1-Boc-4-hydroxypiperidine and 4-chloro-2-cyanopyridine using methods substantially equivalent to those described for the synthesis of 1-Boc-4-(pyridin-2-yloxy)piperidine. The product was purified by chromatography over silica gel, eluting with 25% ethyl acetate in hexanes.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[NH:19][C:18]2[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24]/[C:25](=[N:28]/[H])/[NH:26]O)[C:15](=[O:30])[N:14]([CH2:31][CH2:32][CH3:33])[C:13]=2[N:12]=1>CS(C)=O>[Cl:10][C:11]1[NH:19][C:18]2[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[N:26]=[C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:9][N:28]=3)[C:15](=[O:30])[N:14]([CH2:31][CH2:32][CH3:33])[C:13]=2[N:12]=1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCC)c1=O)NO
Reactant: O=C(O)c1ccccc1
Solvent: CS(C)=O
Product: CCCn1c(=O)n(CCCCc2noc(-c3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 1.9 %

Procedure:
Benzoic acid (9 mg, 0.074 mmol) and CDl (13 mg, 0.081 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(8-Chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (28 mg, 0.081 mmol) was added and the mixture was stirred at 80° C. for 4 h. The mixture was purified by MDAP to give the title compound as a white solid (0.6 mg, 2%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].O=[C:11]([CH2:15][CH2:16][C:17]([O-:19])=[O:18])[C:12]([O-:14])=[O:13]>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH3:3].[NH2:1][C@H:11]([C:12]([OH:14])=[O:13])[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C([O-])CCC(=O)C(=O)[O-]
Agent: N[C@@H](CC(=O)O)C(=O)O
Product: C[C@H](N)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
The enzymatic reaction was carried out exactly as in Example 1 except that the concentration of L-aspartic acid was 420 mM and the concentration of 2-ketoglutarate was 17 mM. Assay of the product by amino acid analysis again showed complete conversion of the L-aspartic acid to produce L-alanine and L-glutamic acid. The reaction progress of this example repeated under similar conditions but with a reaction time of 24 hrs. is illustrated graphically in FIG. 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:27]#[C:26][CH2:25][CH2:24][OH:28])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (17.0 g, 60.7 mmol; Intermediate 1), Pd(PPh3)2Cl2 (5.80 g, 6.07 mmol), CuI (1.20 g, 6.07 mmol), and triethylamine (170 mL) was added but-3-yn-1-ol (6.80 g, 97.2 mmol) under N2 atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and washed with water (3×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30˜50% EtOAc in petroleum ether) affording the title compound (8.0 g). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.83 (s, 1H), 7.70 (d, 1H), 7.40 (d, 1H), 5.84 (dd, 1H), 4.90 (br, 1H), 3.91-3.87 (m, 1H), 3.77-3.70 (m, 1H), 3.60 (t, 2H), 2.56 (t, 2H), 2.48-2.33 (m, 1H), 2.04-1.94 (m, 2H), 1.76-1.69 (m, 1H), 1.60-1.55 (m, 2H); LCMS: 271 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][S:11][C:10]=2[CH:13]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc2c(-c3ccc(F)cc3)csc2c1
Product: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1

Procedure:
In analogy to example 27.1, 3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene, MS: 378 (M, 1Br).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH:8]1[C:18]2[C:19]3[C:11](=[C:12]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:13]([CH2:20][C:21](OC)=[O:22])[C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9]1.O>O1CCCC1>[NH2:7][CH:8]1[C:18]2[C:19]3[C:11](=[C:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:13]([CH2:20][CH2:21][OH:22])[C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9]1
Reactant: COC(=O)Cn1c(-c2ccccc2)c2c3c(cccc31)C(N)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC1CCc2c(-c3ccccc3)n(CCO)c3cccc1c23
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
Lithium aluminum hydride (35 mg) was suspended in anhydrous tetrahydrofuran (THF; 1 ml) and to the suspension was added a solution of the compound (197 mg) obtained in Example 115 in anhydrous THF (7 ml) at room temperature. The mixture was stirred for 5 minutes. To the reaction mixture were slowly added water, then 1N aqueous solution of sodium hydroxide, followed by extraction with two portions of ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from ether to yield 149 mg (83%) of the titled compound as pale yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:27][C:26]4[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc(-c2ccn(Cc3ccc(Cl)cc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 90 °C
Yield: 25 %

Procedure:
To a solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide (0.2 g, 0.67 mmol) in dimethyl sulfoxide (5 mL) was added with 4-chlorobenzyl bromide (0.14 g, 0.67 mmol) and potassium carbonate (0.30 g, 2.0 mmol). The reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 2-[1-(4-chloro-benzyl)-1H-pyrazol-3-yl]-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)amide as a white solid (0.071 g, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.54-8.56 (m, 1H), 7.71 (d, J=8 Hz, 1H), 7.39 (s, 1H) 7.26-7.33 (m, 3H), 7.18 (d, J=4 Hz, 2H), 6.84 (d, J=4 Hz, 1H), 6.18-6.21 (m, 1H), 5.31 (s, 2H), 4.62 (d, J=4 Hz, 2H), 2.74 (s, 3H). MS (M+H)+=423.9; Rt=1.29 min; HRMS (M+H)+=424.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:18]([O-])([O-])=O.[K+].[K+].[CH3:24][C:25]#N>>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:25][CH3:24])[CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)cc(N2CCNCC2)c1
Reactant: CC#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCCN1CCN(c2cc(Cl)cc(C(F)(F)F)c2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine (100 mg) and ground K2CO3 (200 mg) was stirred in CH3CN (30 mL) at room temperature. A solution of 1-bromo-propyl (52 mg) in CH3CN (5 mL) was added dropwise. The mixture was stirred at 50° C. overnight. The reaction mixture was filtered and the volatiles were evaporated in vacuum. The oily residue was chromatographed on a silica column with MeOH: CH2Cl2 (1:9 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the title compound (85 mg). MS m/z (relative intensity, 70 eV) 306 (M+, 25), 277 (bp), 234 (23), 206 (23), 179 (23).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:8](CC)CC)C.[Br:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>ClCCl>[N:1]1([NH:8][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Br:13])[CH:15]=2)(=[O:22])=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CCN(CC)CC
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=S(=O)(NN1CCCC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pyrrolidine (0.33 ml) and triethylamine (0.6 ml) in dichloromethane (10 ml) was added dropwise to a stirred solution of 3-bromobenzenesulfonyl chloride (1 g) in dichloromethane (20 ml), and the mixture stirred at room temperature for 18 hours. The reaction was poured onto water, and the aqueous mixture was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give an oil. This was purified by column chromatography over silica gel, eluting with ethyl acetate isohexane (1:4) to give the sub-title compound as a solid (1.10 g)
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:1][CH:2]1[O:6][C@H:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1ccc([C@@H]2CCC(=O)O2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc([C@@H]2CCC(O)O2)cc1
Temperature: -30 °C
Yield: 64 %

Procedure:
N-[4-[(2S)-Tetrahydro-5-oxo-2-furanyl]-phenyl]methanesulfonamide (IIb) from Preparation 3 (9.823 g, 38.5 mmol) was dissolved in a CH2Cl2/toluene (100 ml/41 ml) at 23° C., then cooled to −30° C. The mixture was a slurry. DIBAL-H (59 ml, 1.5 M in toluene) was added slowly to the mixture (1 ml/min). After addition was complete, the solution was stirred until less than 1% of lactone remained by HPLC assay. When the reaction was complete, excess DIBAL-H was pre-quenched with EtOAc (15 ml). This mixture was then added to a pre-cooled (0° C.) aqueous solution of disodium citrate (1.0 M, 200 ml). The reaction mixture was not allowed to warm during this addition period. Ethyl acetate (200 ml) was added, and the resulting two-phase mixture was stirred for at least 5 hours. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 ml). The combined organic layers were washed with brine (2×150 ml). The solvent was removed under reduced pressure. The crude solids were crystallized from ethyl acetate (6 mL/g). A white solid was obtained (8.04 g), having 3% diol by area. Recrystallization from ethyl acetate provided 6.4 g of the title product as a white, powdery solid (64% yield, 93 area %, GT 99% ee). Melting point=129-130° C. 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.21 (d, J=8.1 Hz, 2H), 5.65 (m, 0.5H), 5.53 (m, 0.5H), 5.14 (t, J=6.9 Hz, 0.5H), 4.93 (t, J=7.6 Hz, 0.5H), 2.92 (s, 3H), 2.49 (m, 1H), 2.25 (m, 1H), 1.98 (m, 1H), 1.92 (m, 1H); 13C NMR (100 MHz, CD3OD) δ C 142.9, 141.2, 140.6, 138.6, 138.5; CH 128.4, 127.9, 121.7, 121.6, 99.9, 99.5, 83.2, 80.3, 74.4, 74.3; CH2 35.5, 35.1, 34.4, 34.2, 33.9; CH3 39.1, 39.0. MS (EI) m/z calcd for C11H15NO4S 257.07 (M+).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.NC1C=C(O)C=CC=1.C(#N)CC#N.[OH2:28].[NH2:29][NH2:30]>>[NH2:12][C:11]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[C:6]([OH:28])[CH:7]=[CH:2][CH:3]=2)[C:13]([NH2:14])=[N:30][N:29]=1
Reactant: O
Reactant: NN
Reactant: N#CC(C#N)=NNc1cccc(O)c1
Agent: Nc1cccc(O)c1
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1cccc(O)c1
Yield: 33 %

Procedure:
3-[N′-(3,5-Diaminopyrazol-4-ylidene)hydrazino]phenol was prepared using 93 mg (0.5 mmol) of 2-[(3-hydroxyphenyl)hydrazono]malononitrile, which was derived from 3-aminophenol (109 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. After heating for 4 hrs, a small amount of solid had formed. The solid was filtered off and the filtrate was concentrated to a gummy black solid. This material was dissolved in ethyl acetate and a small amount of gummy solid was precipitated from the solution by the addition of hexanes. The solid was removed by filtration and the filtrate was again concentrated. The resulting solid was purified by flash chromatography eluting with methylene chloride/ methanol (7:1) to yield 45 mg (33%) of the title compound as a black solid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:56])[CH2:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40](OS(C(F)(F)F)(=O)=O)[CH:39]=1>>[CH3:34][O:35][C:36](=[O:56])[CH2:37][C:38]1[CH:39]=[C:40]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([CH2:31][CH3:32])[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH:41]=[C:42]([C:44]([F:46])([F:45])[F:47])[CH:43]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 3-benzyl-1-ethyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][N:47]=1>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:50]([C:49]3[CH:53]=[CH:54][C:46](=[O:45])[NH:47][CH:48]=3)=[O:51])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1ccc(=O)[nH]c1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.1 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.174 g, 0.50 mmol), HOBt (0.068 g, 0.50 mmol), EDCI (0.115 g, 0.60 mmol) and 6-hydroxynicotinoic acid (0.078 g, 0.55 mmol) were dissolved in 5 ml of dry DMF. The mixture allowed to stir at room temperature for 10 hours. The reaction mixture was concentrated and dried under reduced pressure. Then residue was dissolved in EtOAc (30 ml) and the mixture was washed with saturated NaHCO3 (15 ml) and brine (15 ml). The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 5% to 10% MeOH in CHCl3 to afford the title compound 6 (colorless solid, 195 mg, 83%). LC: 100%. MS: m/z=469.