Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].[C:19](=[S:21])=[S:20].Br[CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1>CS(C)=O>[C:28]([C:27]1[CH:31]=[CH:32][C:24]([CH2:23][S:20][C:19]([N:2]2[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:21])=[CH:25][CH:26]=1)([OH:30])=[O:29]
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(CSC(=S)N2Cc3[nH]c4ccccc4c3CC2C(=O)O)cc1
Yield: 57.7 %

Procedure:
In the same manner as described in Example 16, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.08 g), 10N NaOH (1.5 ml), carbon disulfide (456 mg), dimethylsulfoxide and 4-bromomethylbenzoic acid (1.29 g) are reacted and treated. The product is crystallized from chloroform to give the title compound (1.23 g, 53%), m.p. 152°-153° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C:12]#[N:13].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[C:12]([C:3]1[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=1[N:1]=[CH:16][N:17]([CH3:19])[CH3:18])#[N:13]
Reactant: COC(OC)N(C)C
Reactant: Cn1c(N)c(C#N)c(=O)n(C)c1=O
Solvent: CN(C)C=O
Product: CN(C)C=Nc1c(C#N)c(=O)n(C)c(=O)n1C
Yield: 99.5 %

Procedure:
3.6 g (20 mmol) of 6-amino-5-cyano-1,3-dimethyluracil and 9.36 g (80 mmol) of dimethylformamide dimethyl acetal were added to 36 ml of dimethylformamide, and the reaction mixture was refluxed for 30 minutes. The solvent was removed by distillation under reduced pressure. The crude product was crystallized from ether, filtered off, and recrystallized from ethyl acetate to give 4.68 g of 5-cyano-6-dimethylaminomethyleneamino-1,3-dimethyluracil (compound 15) in a 99% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CN=C1.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](O[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis/trans-4-hydroxycyclohexane carboxylic acid ethyl ester (2:1) (5.0 g, 29 mmol) and imidazole (4.4 g, 64 mmol) in N,N-dimethylformamide (90 ml) was added trimethylsilyl chloride (4.0 ml, 32 mmol) at 0-5° C. Stirring for 1 h at room temperature was followed by partitioning between tert-butyl methyl ether (300 ml) and water (150 ml). The layers were separated. The organic layer was washed with two 150-ml portions of water and one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (6.7 g, 94%) as colorless oil. MS m/e: 245 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[O:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[C:23]2[C:30]([CH3:31])=[C:29]([C:32](=[O:34])[NH2:33])[S:28][C:24]=2[N:25]=[CH:26][N:27]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[O:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[C:23]2[C:30]([CH3:31])=[C:29]([C:32]([NH2:33])=[O:34])[S:28][C:24]=2[N:25]=[CH:26][N:27]=1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCCC3NC(=O)OC(C)(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@@H]3N)c12

Procedure:
A reaction mixture of 2.1 g 1S,2S) {2-(2-(6-carbamoyl-5-methyl-thieno[2,3-d]pyrimidin-4-ylamino)-5-fluoro-phenoxy]-cyclopentyl}-carbamic acid tert-butyl ester, and 1.24 ml trifluoroacetic acid in 50 ml DCM was stirred for 3 days at 46° C. The mixture was concentrated, diluted with toluenel and concentrated. The residue was extracted with DCM and water, whereby the water layer had the pH range of 10. The organic layer was dried and concentrated in vacuo. The residue was purified by chromatography.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:35])=[C:7]([C:24]([NH:26][CH2:27][CH:28]([CH2:30][CH:31]([OH:34])[CH2:32][OH:33])[OH:29])=[O:25])[C:8]([I:23])=[C:9]([C:21]=1[I:22])[C:10]([NH:12][CH2:13][CH:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[OH:15])=[O:11])(=[O:3])[CH3:2].Cl[CH2:37][CH2:38][OH:39].OS(O)(=O)=O>[OH-].[Na+]>[OH:34][CH:31]([CH2:32][OH:33])[CH2:30][CH:28]([OH:29])[CH2:27][NH:26][C:24](=[O:25])[C:7]1[C:6]([I:35])=[C:5]([N:4]([CH2:37][CH2:38][OH:39])[C:1](=[O:3])[CH3:2])[C:21]([I:22])=[C:9]([C:10]([NH:12][CH2:13][CH:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[OH:15])=[O:11])[C:8]=1[I:23]
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Reactant: OCCCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(CCO)c1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Acetamido-N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide, prepared as in Example 2, Step B, (83.5 g, 0.1 g-mole) is dissolved in 1N NaOH (140 ml, 0.14 g-mole) and the solution is stirred at room temperature for 1 hour and 2-chloroethanol (13.7 g, 0.17 g-mole) is added. The solution is stirred at 50° C. for 5 hours to complete the reaction. The solution is acidified with H2SO4 and evaporated to dryness under reduced pressure. The residue is triturated with MeOH and the precipitated solid is filtered. The mother liquor is concentrated under vacuum and the crude product is purified by reverse-phase (C18) HPLC to give the purified final product. The yield of this reaction and purification is 80%.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:40][O:41][CH3:42])[C:14]([NH:16][CH:17]2[C:38](=[O:39])[N:19]3[C:20]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[O:26])=[C:21](O)[CH2:22][S:23][C@H:18]23)=[O:15])[N:12]=1)=[O:6].C(OCC)(=O)C.O>CN(C)C=O>[CH:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:40][O:41][CH3:42])[C:14]([NH:16][CH:17]2[C:38](=[O:39])[N:19]3[C:20]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[O:26])=[C:21]([Cl:3])[CH2:22][S:23][C@H:18]23)=[O:15])[N:12]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 1.1 h
Yield: 19.4 %

Procedure:
Thionyl chloride (0.423 g.) was dropwise added to a stirred solution of 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 1 g.) in N,N-dimethylformamide (10 ml.) under ice cooling over 2 minutes, and the solution was stirred at room temperature for 1.1 hours. Ethyl acetate (40 ml.) and water (30 ml.) were added to the resultant solution and shaken sufficiently. The aqueous layer was extracted with ethyl acetate, and the extract was combined with the ethyl acetate layer separated above. The ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (30 g.) and eluted with chloroform and then a mixture of chloroform and ethyl acetate (7:3). The latter eluate was concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 0.2 g.), mp 216° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][N:12]([C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(C2(CCCOC3CCCCO3)CCNC2)cc1Cl
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidine (2 mmol) and 3,4,5-trimethoxy-benzoyl chloride (2 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([CH3:28])[C:22]([CH3:30])([CH3:29])[CH2:21]1.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:19][CH:20]1[CH2:21][C:22]([CH3:29])([CH3:30])[N:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:16]
Reactant: CO/C(=C\C=C\c1cc2ccccc2s1)C(=O)O
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: CO/C(=C\C=C\c1cc2ccccc2s1)C(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Yield: 26.6 %

Procedure:
A solution of (2Z,4E)-5-(benzothiophen-2-yl)-2-methoxy-2,4-pentadienoic acid (53 mg, 0.20 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (34 mg, 0.20 mmol), 1-hydroxy-7-azabenzotriazole hydrate (27 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmol) in DMF (1 ml) was stirred at RT for 6 hours. After the same work up as seen in example 3 pure title compound was obtained (22 mg, 0.054 mmol, yield 26.6%) as white crystals, m.p.=240°.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH:22]([Mg]Br)=[CH2:23].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH:22]=[CH2:23]
Reactant: C=C[Mg]Br
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C)(O)CCC=C(C)CCC=C(C)COC1CCCCO1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
A solution of 6,10-dimethyl-11-(2-tetrahydropyranyl) oxy-5,9-undecadien-2-one (80 mg, 0.27 mmol) in tetrahydrofuran (3 ml) was stirred on an ice bath under argon atmosphere. To the solution was added vinylmagnesium bromide in tetrahydrofuran (0.3 ml, 0.3 mmol, 1.0 M), and the mixture was warmed to room temperature and stirred for 10 hours. After addition of saturated aqueous ammonium chloride (2 ml), the reaction mixture was extracted with ether. The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a crude product, which was purified with silica gel column chromatography to obtain 3,7,11-trimethyl-12-(2-tetrahydropyranyl)oxy-1,6,10-dodecatrien-3-ol (61 mg, 70%). IR(film)cm-1 ; 3460, 2950, 2880, 1200, 1118, 1075, 1022, 905, 865, 810.
Reaction SMILES: [IH:1].[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:9][C:10](=[NH:13])SC)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23]N>ClC1C=CC=CC=1Cl>[IH:1].[C:2]1([CH:8]([NH:9][C:10]2[NH:20][CH2:21][CH2:22][CH2:23][N:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCN
Reactant: CSC(=N)NC(c1ccccc1)c1ccccc1
Agent: I
Solvent: Clc1ccccc1Cl
Product: c1ccc(C(NC2=NCCCN2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To 38.43 grams (0.10 mole) of 1-diphenylmethyl-2-methyl-2-thiopseudourea hydroiodide in 25 milliliters of o-dichlorobenzene was added 7.41 grams (0.10 mole) of 1,3-diaminopropane, and the mixture heated (below reflux temperature) for four hours with stirring; then the temperature was increased to reflux temperature and maintained under reflux for 12 hours. The mixture was allowed to cool to room temperature, the solvent decanted off and the residue dissolved in methanol. The methanol solution was concentrated while simultaneously adding isopropanol to obtain 24.6 grams (62.6 percent yield) of 2-diphenylmethylamino-1,4,5,6-tetrahydropyrimidine hydroiodide product, m.p. (185° C.) 197°-200° C. After two recrystallizations from methanol-isopropanol, a purified product of melting point 207°-209° C. was obtained.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([OH:18])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[Na+]>C(Cl)Cl>[C:10]([F:7])(=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(F)c1ccccc1
Yield: 80 %

Procedure:
Diethylaminosulfur trifluoride, 2.5 ml (0.02 mole) was slowly added to a stirred solution of 2.44 g (0.02 mole) of benzoic acid in 20 ml methylene chloride cooled to 0°. Powdered sodium fluoride, 1 g, was added to remove the HF, and the reaction mixture was filtered. The filtrate was distilled to give 1.98 g (80%) of benzoyl fluoride as a colorless liquid, bp 50° (10 mm) (identified by its infrared spectrum).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:28]=[CH:29][C:30]([Cl:42])=[C:31]3[C:35]=2[N:34]([CH3:36])[N:33]=[C:32]3[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:5]([C@@H:9]([NH:19][C:20](=[O:26])OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:6][C:7]=1[Cl:8].[F:43][C:44]1([F:61])[C:48]2[N:49]([CH2:56]C(O)=O)[N:50]=[C:51]([C:52]([F:55])([F:54])[F:53])[C:47]=2[C@H:46]2[CH2:60][C@@H:45]12.FC(F)C1C2[C@H]3C[C@H]3C(F)(F)C=2N(CC(O)=O)N=1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:28]=[CH:29][C:30]([Cl:42])=[C:31]3[C:35]=2[N:34]([CH3:36])[N:33]=[C:32]3[NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:5]([C@@H:9]([NH:19][C:20](=[O:26])[CH2:56][N:49]2[C:48]3[C:44]([F:43])([F:61])[C@@H:45]4[CH2:60][C@@H:46]4[C:47]=3[C:51]([C:52]([F:53])([F:54])[F:55])=[N:50]2)[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)c(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Agent: O=C(O)Cn1nc(C(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)c(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21

Procedure:
Compound 54 was prepared from compound 53A according to the method presented for the synthesis of Example 49 substituting 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid for 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid to provide 13 mg of title compound: 1H NMR (400 MHz, Methanol-d4) δ 7.12-6.94 (m, 2H), 6.81-6.60 (m, 1H), 6.55-6.35 (m, 2H), 6.25 (d, 1H), 5.01-4.90 (m, 1H), 4.76 (t, 2H), 3.41 (s, 2H), 3.24 (d, 3H), 3.15-2.88 (m, 3H), 2.48 (q, 2H), 1.47-1.38 (m, 1H), 1.16-1.04 (m, 1H). MS (m/z) 805 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:44]([NH:47][NH2:48])(=[O:46])[CH3:45]>O.CN(C)C=O>[C:44]([NH:47][NH:48][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])(=[O:46])[CH3:45]
Reactant: CC(=O)NN
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.70 g), 1H-1,2,3-benzotriazol-1-ol (0.36 g) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.51 g) at room temperature. The mixture was stirred for 10 min and acetohydrazide (0.33 g) was added. The reaction mixture was stirred at room temperature for 2 hr, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.65 g, yield 77%) as colorless crystals. melting point 254-256° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C@H:38]([OH:41])[CH2:39][OH:40])[N:33]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:22])[F:23])[C:12]2=[O:24])[C:8]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][C@H:38]([OH:41])[CH2:39][OH:40])[N:33]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccn(C[C@H](O)CO)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(C[C@H](O)CO)n1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride (5 mL) and N,N-dimethylformamide (5 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 200 μL, 0.40 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (5 mL) and then added dropwise to a separate reaction flask containing a mixture of (S)-3-(3-amino-pyrazol-1-yl)-propane-1,2-diol (prepared as in US 20080021032, Example 34, 70 mg, 0.45 mmol) and 2,6-lutidine (250 μL) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride. The organic layer was then washed with a 1 N aqueous hydrochloric acid solution. The organic layer was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 100% ethyl acetate to 5% methanol/ethyl acetate) to afford (S)-3-cyclopentyl-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (99 mg, 69%) as a white foam: [α]28D=−12.0°, (c=0.15, methanol); HR-ES(+) m/e calcd for C23H27N4O4F3 [M+H]+ 481.2057, observed 481.2057; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 7.94-8.05 (m, 2H), 7.73-7.80 (m, 1H), 7.53 (d, J=2.13 Hz, 1H), 6.40 (d, J=2.13 Hz, 1H), 4.98-5.11 (m, 2H), 4.93 (d, J=5.33 Hz, 1H), 4.67-4.75 (m, 2H), 4.09 (dd, J=4.05, 13.64 Hz, 1H), 3.81-3.91 (m, 1H), 3.77 (br. s., 1H), 3.24-3.30 (m, 2H), 1.99-2.09 (m, 1H), 1.06-1.95 (m, 10H).
Reaction SMILES: C[O-].[Na+].[N+:4]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([O-:6])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[CH:17]=[O:18].C(O)(=O)C>CO.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]([C:7]2([N+:4]([O-:6])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[OH:18])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: O=[N+]([O-])C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C1(C(O)c2cc(Cl)cc(Cl)c2)CCCCC1
Reaction time: 0.5 h

Procedure:
25% sodium methoxide solution (24.9 mmol, 5.7 mL) was diluted with methanol (40 mL), cooled in an ice bath, and nitrocyclohexane was added dropwise over 10 min. The mixture was stirred for 30 min, cooled in an ice bath, and solid 3,5-dichlorobenzaldehyde was added. The mixture was stirred over the weekend, recooled in an ice bath, and treated with 2 mL of glacial acetic acid. The mixture was poured into water (125 mL) and extracted with ether (2×75 mL). The combined ether extracts were washed with water (100 mL) and dried over MgSO4. Removal of the solvent left crude (3,5-dichloro-phenyl)-(1-nitro-cyclohexyl)-methanol (8.93 g) as a yellow oil. Flash chromatography on silica gel, eluting with a 0-100% ether in hexanes gradient provided product of increased purity (ca. 70%). 1H NMR (500 MHz, CDCl3) δ(ppm): 7.35 (s, 1H), 7.19 (s, 2H), 4.90 (s, 1H), 0.9-1.8 (m, 10H).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([I:18])[C:7]([F:19])=[C:6]([Cl:20])[CH:5]=1)(=[O:3])[CH3:2].[CH2:21](O)[CH2:22][OH:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:20][C:6]1[CH:5]=[C:4]([C:1]2([CH3:2])[O:23][CH2:22][CH2:21][O:3]2)[C:9]([O:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([I:18])[C:7]=1[F:19]
Reactant: CCOC(=O)C(C)Oc1c(C(C)=O)cc(Cl)c(F)c1I
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)Oc1c(C2(C)OCCO2)cc(Cl)c(F)c1I
Yield: 56.8 %

Procedure:
A solution of ethyl 2-(6-acetyl-4-chloro-3-fluoro-2-iodophenoxy)propanoate (3.58 g, 8.63 mmol) and 1,2-ethanediol (1.20 mL, 21.6 mmol) in toluene (16.3 mL) was treated with p-toluenesulfonic acid monohydrate (246 mg, 1.30 mmol) and heated at reflux in a flask fitted with a Dean-Stark trap filled with sieves. The reaction mixture was cooled and poured into saturated sodium bicarbonate (150 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 10% EtOAc/hexanes) gave the desired product (2.25 g, 57%) as a mixture of enantiomers. LCMS calculated for C15H18ClFIO5 (M+H)+: m/z=459.0; found: 459.0.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([S:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:31]1([O:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>C1COCC1>[C:31]1([O:37][C:38](=[O:39])[NH:1][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([S:13](=[O:14])(=[O:15])[NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH:8]=3)[N:5]=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COCCNS(=O)(=O)c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCNS(=O)(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
To a mixture of 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-N-(2-methoxyethyl)benzene sulfonamide (940 mg, 2.67 mmol) and solid sodium carbonate (493 mg, 5.87 mmol, 2.2 eq) in anhydrous THF was slowly added phenylchloroformate (0.40 mL, 3.20 mmol, 1.2 eq), and the reaction mixture was stirred at room temperature under nitrogen for 6 h. The reaction mixture was poured into ethyl acetate, and then the organic phase was separated and washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. Purification by MPLC (35% EtOAc/hexane) afforded the title compound (887 mg, 70%) as a white solid. 1H-NMR (CD3OD) δ 10.17 (broad s, 1H), 7.94 (t, J=1.5 Hz, 1H), 7.89 (t, J=6.0 Hz, 1H), 7.81 to 7.69 (m, 3H), 7.34 to 7.29 (m, 2H), 7.19 (t, J=7.2 Hz, 1H), 7.09 (broad s, 2H), 6.38 (s, 1H), 3.25 (t, J=6.0 Hz, 2H), 3.09 (s, 3H), 2.90 (broad s, 2H), 1.26 (s, 9H).