Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C@H:3]1[C:9](=[O:10])[N:8]2[C@@H:4]1[CH2:5][C:6](=O)[C@@H:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12].C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:48]([NH:51][CH2:52][CH2:53][SH:54])(=[O:50])[CH3:49]>CN(C)C=O.C(OCC)(=O)C>[C:48]([NH:51][CH2:52][CH2:53][S:54][C:6]1[CH2:5][C@H:4]2[N:8]([C:9](=[O:10])[C@@H:3]2[N:2]([CH3:1])[CH3:25])[C:7]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)=[O:12])(=[O:50])[CH3:49]
Reactant: CC(=O)NCCS
Reactant: CN(C)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](N(C)C)[C@H]2C1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
69 mg (0.21 mmol) of p-nitrobenzyl (2R,5R,6R)-6-dimethylamino-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate [34] was dissolved in 1.5 ml of dimethylformamide. The solution was cooled to -35° C., and 45 microliters (0.32 mmol) of triethylamine and 58 microliters (0.28 mmol) of diphenylphosphoryl chloride was added, and the mixture was reacted at the above temperature for 30 minutes. The progress of the reaction was determined by the formation of a spot showing a UV absorption at an Rf of 0.46 in silica gel TLC developed with ethyl acetate, and the subsequent reaction was carried out. Specifically, 0.5 ml of a dimethylformamide solution of 54 microliters (0.38 mmol) of triethylamine and 46 mg (0.38 mmol) of N-acetylcysteamine was gradually added dropwise to the reaction mixture at -35° C. The reaction was carried out at the same temperature for 30 minutes. The reaction mixture was poured into 50 ml of ethyl acetate, and washed with 30 ml of 0.1M phosphate buffer (pH 8.9) and 20 ml of a saturated aqueous solution of sodium chloride. The washings were again extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The extracts were combined, and dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure to remove the solvent and 26 mg of crystals of the captioned compound were collected by filtration. The mother liquor was dried under reduced pressure, and dissolved in methylene chloride. The solution was adsorbed on a column of silica gel (7 g). The column was eluted with ethyl acetate, acetone and ethyl acetate/methanol (2/1). Those fractions in the eluates which had a UV absorption at an Rf of 0.15 in silca gel TLC developed with acetone were collected and dried under reduce pressure to give 49 mg (yield 83%) of the captioned compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C=[C:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11]1)C.Cl[CH2:30][Cl:31]>>[Cl:31][C:30]1[CH:10]=[CH:11][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:13][C:14]=1[CH:15]=[O:16]
Reactant: ClCCl
Reactant: CN(C)C=C1CC(c2ccccc2)(c2ccccc2)C=CC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1=C(Cl)C=CC(c2ccccc2)(c2ccccc2)C1
Temperature: 20 °C

Procedure:
0.193 cm3 of phosphorus oxychloride is added to a solution of 0.607 g of 6-dimethylaminomethylene-4,4-diphenylcyclohex-2-enone in 15 cm3 of dichloromethane. The mixture is heated to the reflux temperature and refluxing is maintained for about 3 hours. After cooling to a temperature in the region of 20° C., the solution is concentrated to dryness under reduced pressure (13 kPa). The residue is dissolved in 20 cm3 of tetrahydrofuran and 20 cm3 of water are added in a single portion. The mixture is refluxed for about 24 hours. After cooling to a temperature in the region of 20° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 10 cm3 of ethyl acetate. The solution is washed three times with 30 cm3 of water and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). 0.6 g of 2-chloro-5,5-diphenylcyclohexa-1,3-dienecarbaldehyde is thus obtained in the form of an orange-coloured resin, which is used without further modification in subsequent syntheses and the characteristics of which are as follows:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=3)[C:10]2=[S:29])=[CH:5][C:4]=1[F:30].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1>[F:30][C:4]1[CH:5]=[C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:27])([F:26])[F:28])[CH:18]=3)[C:10]2=[S:29])[CH:7]=[CH:8][C:3]=1[CH2:2][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CCl)c(F)c1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CN2CCCCC2)c(F)c1
Yield: 12.3 %

Procedure:
Compound 7 was prepared according to General Method 2. A solution of 4-(3-(4-(chloromethyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.21 mmol) and piperidine (93 mg, 1.05 mmol) in toluene (10 mL) was refluxed for 12 h. The solvent was removed and residue was purified by silica gel chromatography (eluant: 60% ethyl acetate in hexane) to obtain 13 mg of 4-(3-(3-fluoro-4-((piperidin-1-yl)methyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile, HPLC, Column: SUNFIRE C18, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 7.635 min, M+1, 505.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:22][C:23]1[C:24]([O:8][C:6]2[C:5]([C:9]3[CH:14]=[CH:13][N:12]=[N:11][CH:10]=3)=[CH:4][C:3]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:2]([Cl:1])[CH:7]=2)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:30])=[O:31])[CH:28]=1
Reactant: Oc1cc(Cl)c(-c2ccc(F)cc2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4ccc(F)cc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
2-Chloro-4′-fluoro-5-(pyridazin-4-yl)biphenyl-4-ol (Preparation 71, 148 mg, 0.49 mmol) was dissolved in dimethylsulfoxide (3 mL) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 273 mg, 0.59 mmol) and potassium carbonate (204 mg, 1.48 mmol) were added. The reaction was stirred at 20° C. for 18 hours and then partitioned between water and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% heptane in ethyl acetate) to give the title compound (224 mg, 62%) as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1>>[OH:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:2]2[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:14])[N:3]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(C)c1C#N
Product: Cc1nc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c(C)c1C#N

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 6-chloro-2,4-dimethyl-5-nitronicotinonitrile (step 3) and 4-aminophenylethyl alcohol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:36].[N:37]12[CH2:44][CH2:43][CH:40]([CH2:41][CH2:42]1)[C@@H:39]([NH:45][C:46]([C:48]1[S:49][C:50]3[C:56](Br)=[CH:55][CH:54]=[CH:53][C:51]=3[CH:52]=1)=[O:47])[CH2:38]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:36].[N:37]12[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44]1)[C@@H:39]([NH:45][C:46]([C:48]1[S:49][C:50]3[C:56]([C:2]4[CH:7]=[CH:6][CH:5]=[C:4]([N:8]5[CH2:12][CH2:11][CH2:10][CH2:9]5)[CH:3]=4)=[CH:55][CH:54]=[CH:53][C:51]=3[CH:52]=1)=[O:47])[CH2:38]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: Brc1cccc(N2CCCC2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(N4CCCC4)c3)c2s1

Procedure:
109.8 mg (0.49 mmol) of 1-(3-bromophenyl)pyrrolidine, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 150.0 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 ml of DMF are reacted by general method D. Drying under high vacuum results in 88.4 mg (51% of theory) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][CH2:10][CH2:11][CH3:12])[C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH2:22][O:23][CH3:24]>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][CH2:10][CH2:11][CH3:12])[C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH2:22][O:23][CH3:24])=[O:1]
Reactant: CCCOc1ncnc(CO)c1-c1ccc(OC)cc1OCOC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCOc1ncnc(C=O)c1-c1ccc(OC)cc1OCOC
Reaction time: 24 h
Yield: 62 %

Procedure:
A solution of 6-hydroxymethyl-5-(2-methoxymethoxy-4-methoxyphenyl)-4-propoxy-pyrimidine in CH2Cl2 was treated with MnO2 and stirred vigorously for 24 h. The mixture was filtered through celite and concentrated to afford the title compound (1.48 g, 62%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18](=[O:26])[NH:17]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:15][C:4]1[N:3]=[C:2]([N:17]2[C:18](=[O:26])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=1
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Reactant: O=C1Cc2ccccc2CN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N3Cc4ccccc4CC3=O)nc(N)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (20 mg, 0.09 mmol, Example 1) and 1,4-dihydroisoquinolin-3(2H)-one (16 mg, 0.10 mmol, Tyger, Cat. No. D30080) in 1,4-dioxane (1 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20 mg, 0.04 mmol, Aldrich, Cat. No. 526460), palladium acetate (4 mg, 0.02 mmol, Aldrich, Cat. No. 205869) and cesium carbonate (60 mg, 0.2 mmol, Aldrich, Cat. No. 202126). The mixture was degassed with nitrogen and heated at 100° C. 20 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH, and purified by RP-HPLC (pH=10 system) to afford the desired compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]>CN(C=O)C>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH3:21])=[CH:8][N:9]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a 500 mL flask equipped with addition funnel at 0° C. was added NaH (8.26 g, 95%, 327 mmol), followed by slow addition of DMF (100 mL). The mixture was stirred for 10 minutes. The addition funnel was then charged with 6-methyl-pyridin-3-ol (30.2 g, 277 mmol) and DMF (100 mL), and the solution in addition funnel was added to the flask dropwise over 45 minutes. The reaction mixture was stirred at 0oC. for another 30 minutes once the addition was finished. To the addition funnel was then added 4-fluoro-3-methyl-nitrobenzene (39.1 g, 252 mmol) and DMF (100 mL) and the resulting solution was added to the flask dropwise over 45 minutes. The cold bath was removed at the end of the addition and the reaction mixture was allowed to stir at room temperature for 15 hours. The red dark solution was cooled to 0° C. and water (100 mL) was added cautiously to the reaction mixture. The resulting solution was stirred for 30 minutes and solid product was purified by filtration and washed with cold water (500 mL). The wet solid was dried in vacuo to give product (49.8 g, 81%).
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[H-].[Na+].[CH3:9][C:10]1([CH3:17])[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.C([O-])(O)=O.[Na+]>C1COCC1>[OH:16][C:13]1[CH2:14][CH2:15][C:10]([CH3:17])([CH3:9])[CH2:11][C:12]=1[C:1]([O:4][CH3:5])=[O:6]
Reactant: COC(=O)OC
Reactant: CC1(C)CCC(=O)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)CCC(C)(C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl carbonate (31.5 g, 350 mmol) in dry THF (600 mL) was added sodium hydride (14.4 g, 360 mmol) by portion at 0° C. The resulting mixture was stirred at 0° C. for 30 min and then was added a solution of 4,4-dimethylcyclohexanone (15 g, 119 mmol) in THF (150 mL) dropwise over 30 min. The resultant mixture was heated at 60° C.-80° C. for 3 h before cooled to room temperature. The reaction mixture was poured into saturated NaHCO3 solution and extracted with a mixture of 33% ethyl acetate in petroleum ether. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give 26.5 g crude of methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate, which was used in next step without further purification. 1H NMR (DMSO-d6) δ 12.09 (s, 1H), 3.71 (s, 3H), 2.25-2.26 (m, 2H), 1.99 (s, 2H), 1.40-1.41 (m, 2H), 0.92 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=2)[CH:6]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@H:49]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1.Cl.N[C@H](C1C=CC(F)=CC=1)C1C=CC(P(C)(=O)OCC)=CC=1>CC#N>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([NH:48][C@H:49]([C:62]3[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=3)[C:50]3[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=3)=[O:16])=[CH:9][N:8]=2)[CH:6]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](N)c2ccc(F)cc2)cc1
Reactant: O=C(O)c1cnc(-n2cc(F)cn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cc(F)cn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.7 %

Procedure:
To a stirred solution of 28-g (2.8 g, 12 mmol) and Et3N (3.5 g, 34 mmol) in MeCN (30 ml) was added HATU (4.8 g, 12 mmol). The mixture was stirred for 5 min at room temperature and then ethyl 4-((R)-amino(4-fluoro phenyl)methyl)phenyl(methyl)phosphinate, 18-e, (3.5 g, 11 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=1/1) to provide the product, 29-a, (1 g, 15.7%).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:2]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].[H-].[Na+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>CN(C=O)C>[C:12]([O:11][C:9]([N:1]([CH2:19][C:20]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])[C:2]([O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:3])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1cc(F)ccc1CBr
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)ccc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
In a dry flask under nitrogen, di-tert-butyl iminodicarboxylate (Aldrich, 3.86 g, 17.8 mmol) was dissolved in dry DMF (5 mL) and treated with NaH (60% dispersion in oil, 0.71 g, 17.8 mmol). After the evolution of gas had ceased, Methyl 2-(bromomethyl)-5-fluorobenzoate (4 g, 16.2 mmole) dissolved in DMF (5 mL) was added. An additional 5 mL of DMF was added to aid stirring. The reaction was stirred for 2 hrs, then partitioned between water and EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated and the residue was purified on silica eluting first with toluene, then with a gradient of 0-5% MeOH/CHCl3. The impure product thus obtained was re-chromatographed on silica eluting with a gradient of 0-30% EtOAc/Hexanes. The product was obtained as a clear oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH:33][CH2:34][CH:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCC1CCOCC1
Product: O=C(NCC1CCOCC1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 68 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-aminomethyltetrahydropyran (available from Aldrich Chemical Company, Inc.; 71 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-[(tetrahydro-pyran-4-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid (81 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.22 (br s, 1H), 8.58 (t, J=5.8 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 3.86 (dd, J=11.2, 2.6 Hz, 2H), 3.27 (t, J=10.9 Hz, 2H), 3.19 (t, J=6.4 Hz, 2H), 1.77-1.87 (m, 1H), 1.61 (d, J=11.3 Hz, 2H), 1.15-1.27 (m, 2H).
Reaction SMILES: C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H](CC1CCCCC1)[C@@H](O)C(C1CC1)=O)=[O:15])=O)(=O)=O)(C)(C)C.Cl.NO.C(N(CC)CC)C>CO>[NH:36]1[CH:37]=[C:33]([CH2:32][CH2:13][C:14]([NH2:16])=[O:15])[N:34]=[CH:35]1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)C1CC1
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=O)CCc1c[nH]cn1

Procedure:
A mixture of 62.8 mg (0.1 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R)-1-(cyclohexylmethyl)-3-cyclopropyl-2-hydroxy-3-oxopropyl]imidazole-4-propionamide, 12 mg (0.2 mmol) of hydroxylamine hydrochloride and 0.027 ml (0.2 mmol) of triethylamine in 2.5 ml of methanol is heated to reflux for 20 hours. After the usual working-up the crude product obtained is purified by chromatography on 10 g of silica gel using a 8:1 mixture of methylene chloride and methanol as the eluting agent. There are obtained 28 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,E/Z=2:1)-1-(cyclohexylmethyl)-3-cyclopropyl-2-hydroxy-3-(hydroxyimino)propyl]imidazole-4-propionamide as an amorphous solid; MS: 644 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([OH:10])=O)[C:4]=1[CH3:11])=[O:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([CH3:19])[NH:14]1>>[CH3:12][C@H:13]1[NH:14][C@@H:15]([CH3:19])[CH2:16][N:17]([C:8]([C:5]2[C:4]([CH3:11])=[C:3]([CH:1]=[O:2])[NH:7][CH:6]=2)=[O:10])[CH2:18]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1c(C(=O)O)c[nH]c1C=O
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Yield: 87.7 %

Procedure:
5-Formyl-4-methyl-1H-pyrrole-3-carboxylic acid (1.00 g, 6.54 mmol) reacted with cis-2,6-dimethylpiperazine (822 mg, 7.19 mmol) to give 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (1.43 g, 88%).
Reaction SMILES: [Na][Na].[C:3]([C:5]1[C:9](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[NH:8][C:7](=[O:15])[C:6]=1O)#[N:4].[CH2:17]([CH:19]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:20][N:21]([CH2:28][CH2:29][CH3:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:18].P(Cl)(Cl)(Cl)=O>CC(C)=O.O.CN(C)C=O>[CH2:17]([CH:19]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:20][N:21]([C:22]1[CH:23]=[CH:24][C:25]([C:6]2[C:7](=[O:15])[NH:8][C:9](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:5]=2[C:3]#[N:4])=[CH:26][CH:27]=1)[CH2:28][CH2:29][CH3:30])[CH3:18]
Reactant: N#CC(C#N)=C1NC(=O)C(O)=C1C#N
Reactant: CCCCC(CC)CN(CCC)c1ccccc1
Agent: [Na][Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCC(CC)CN(CCC)c1ccc(C2=C(C#N)C(=C(C#N)C#N)NC2=O)cc1
Temperature: -10 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
A stirred mixture of disodium salt of 4-cyano-5-dicyanomethylidene-3-hydroxy-2-oxo-2,5-dihydropyrrole (29.9 parts) and dry N,N-dimethylformamide (150 parts) was cooled to -10° C. and N-(2-ethylhexyl)-N-propylaniline containing 30% acetic anhydride (63 parts) was added followed by the dropwise addition of phosphorous oxychloride (34 parts) maintaining the temperature at less than -5° C. The mixture was allowed to warm up to room temperature and stirred for 20 hours. The reaction mixture was poured into a stirred mixture of ice and water (200 parts) and acetone (200 parts) and then stirred for 0.5 hours. The solid was filtered off, washed with hot water and dried under vacuum to give 3-(4-(N-(2-ethylhexyl)-N-propylamino)phenyl)-4-cyano-5-dicyanomethylidene-2-oxo-2,5-dihydropyrrole (48.5 parts, 90%).