Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21]C)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8]C.C1(NC2C(C)=NC=C(C)N=2)C2C(=CC=CC=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH3:8]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Agent: Cc1cnc(C)c(NC2CCc3ccccc32)n1
Product: Cc1nc(NC2CCc3ccccc32)c(C)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.86, 2.26, 2.53, 2.70, 2.93, 3.03, 4.50, 5.72, 7.28; 13C NMR (CDCl3) δ 19.23, 23.21, 30.25, 34.56, 56.45, 124.05, 124.81, 124.97, 126.78, 128.03, 136.98, 143.71, 144.09, 148.36, 151.15; MS (ESI+) for C15H16N3Br1 m/z 319.20 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][N:25]([CH3:37])[C:26](=[O:36])[CH2:27][CH2:28][NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][CH2:28][CH2:27][C:26]([N:25]([CH3:24])[CH3:37])=[O:36])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:8][CH2:7]1
Reactant: CN(C)C(=O)CCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (520 mg) and N,N-dimethyl-N3-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-β-alaninamide (330 mg) in 2-propanol (60 mL) was added piperidinium acetate (223 mg). The reaction mixture was stirred at 80° C. for 4 hr and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol). The obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (356 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(O)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(O)c(C)c1
Temperature: 80 °C

Procedure:
A mixture of 2-methylbenzene-1,4-diol (5 g, 40.2 mmol), ethyl 2-bromoacetate (1.1 eq.), and potassium carbonate (2 eq.) in acetonitrile (50 mL) was heated at 80° C. for 18 hours. The reaction was cooled to room temperature, and the acetonitrile was removed in vacuo. Water was added and the crude residue was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to provide ethyl 2-(4-hydroxy-3-methylphenoxy)acetate (682) as a pink solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.[NH2:29][NH2:30].O>CN(C=O)C>[CH2:20]([C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a suspension of 4-hydroxy-3-(1-oxo-2-phenylethyl)-1-phenyl-1,8-naphthyridin-2 (1H)-one (2.33 g, 6.54 mmol, prepared in Synthetic Example 5) in DMF (50 ml) was added hydrazine monohydrate (80%, 970 μl, 24.21 mmol, 3.7 eq.) and the mixture was then stirred at 100 to 110° C. for 4 hours, admixed with water to precipitate crystals, and allowed to stand until it was cooled. Next, the cooled mixture was filtered, washed with water, and dried to give 3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (1.90 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:38])=[C:20]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]3)[CH3:17])=[O:15])=[O:11])=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][N:42]=[CH:41][C:40]=1[C:45](O)=[O:46].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:38][C:19]1[C:18]([N:16]([CH3:17])[C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]2[CH:6]=[N:7][C:2]([NH:1][C:45]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][N:39]=3)=[O:46])=[CH:3][CH:4]=2)=[CH:36][CH:35]=[C:34]([Cl:37])[C:20]=1[CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(N)nc4)c3Cl)c2n1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(=O)c5cnccn5)nc4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 37 h
Yield: 40.7 %

Procedure:
To a mixture of 8-[3-[N-[(E)-3-(6-aminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (90.0 mg), 2-pyrazinecarboxylic acid (24.3 mg) and dimethylformamide (0.9 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (43.9 mg) and 1-hydroxybenzotriazole (35.4 mg). After being stirred for 37 hours at ambient temperature, the mixture was poured into saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform--methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(2-pyrazinecarboxamido)-pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methylquinoline (43.7 mg) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]#N)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.O.[PH2]([O-])=[O:15].[Na+]>C(O)(=O)C.N1C=CC=CC=1.[Ni]>[CH3:1][C:2]1[C:10]([CH:11]=[O:15])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Cc1c(C#N)ccc2[nH]ccc12
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: Cc1c(C=O)ccc2[nH]ccc12

Procedure:
In analogy to the procedure described in preparation 5a), 4-methyl-1H-indole-5-carbonitrile was reacted with sodium hypophosphite monohydrate and Raney-Nickel in acetic acid/pyridine to give 4-methyl-1H-indole-5-carbaldehyde as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15](Cl)[CH3:16])[CH2:11][CH2:10]1.Cl.[CH3:19][NH2:20]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:20][CH3:19])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C(C)Cl)CC1
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CNCCN1CCN(c2ccccc2OC)CC1

Procedure:
8 ml of ethanol were added to a mixture of 8.9 g of 4-(o-methoxyphenyl)-1-chloroethyl-piperazine .HCl in 20 g of an aqueous solution of 34.88% methylamine and the mixture was stirred for 1 hour at room temperature and then for 4 hours at reflux. The ethanol was evaporated and after cooling the mixture, 5 g of sodium hydroxide pellets were added thereto. The mixture was extracted with ethyl ether and the extracts were dried over potassium carbonate and the solvent was evaporated. The oily residue was distilled to obtain 2.6 g of 4-(o-methoxyphenyl)-1-(β-methylaminoethyl)-piperazine in the form of a yellow oil boiling at 153°C under 0.2 mm Hg. The oil was soluble in ethanol and ethyl ether and slightly soluble in water.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CC1C=CC(N2[C:30](=[O:31])[C:29]3[C:28]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([O:32][CH3:33])[CH:26]=5)[N:21](COC)[C:20]=4[C:19]([CH2:37][CH2:38][CH3:39])=[CH:18][C:17]=3[C:15]2=[O:16])=CC=1>>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][N:5]1[C:30](=[O:31])[C:29]2[C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:32][CH3:33])[CH:26]=4)[NH:21][C:20]=3[C:19]([CH2:37][CH2:38][CH3:39])=[CH:18][C:17]=2[C:15]1=[O:16]
Reactant: CCCc1cc2c(c3c4cc(OC)ccc4n(COC)c13)C(=O)N(c1ccc(C)cc1)C2=O
Reactant: CN(C)CCN
Product: CCCc1cc2c(c3c1[nH]c1ccc(OC)cc13)C(=O)N(CCN(C)C)C2=O
Yield: 67 %

Procedure:
1.0 ml of N,N-dimethylethylenediamine was added to 300 mg of N-(4-methylphenyl)-6-methoxy-9-methoxymethyl-1-propylcarbazole-3,4-dicarboximide. The mixture was refluxed for 30 minutes and then concentrated to dryness under reduced pressure. To the residue were added 15 ml of methanol and 1.5 ml of concentrated hydrochloric acid. The mixture was refluxed for 30 minutes. The solvent was removed y distillation under reduced pressure. The residue was mixed with 50 ml of ethyl acetate and 20 ml of an aqueous saturated sodium hydrogencarbonate solution to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 180 mg (yield: 67%) of N-(2-dimethylaminoethyl)-6-methoxy-1-propylcarbazole-3,4-dicarboximide as yellow needles.
Reaction SMILES: CCCCC.[CH2:6]([C:8]1([CH2:16][O:17][CH2:18][C:19]2([CH2:27][CH3:28])[CH2:24][O:23][CH:22]([CH:25]=[CH2:26])[O:21][CH2:20]2)[CH2:13][O:12][CH:11]([CH:14]=[CH2:15])[O:10][CH2:9]1)[CH3:7]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Fe].C(N(CC)CC)C>[CH2:6]([C:8]1([CH2:16][O:17][CH2:18][C:19]2([CH2:27][CH3:28])[CH2:24][O:23][C:22](=[CH:25][CH3:26])[O:21][CH2:20]2)[CH2:13][O:12][C:11](=[CH:14][CH3:15])[O:10][CH2:9]1)[CH3:7]
Reactant: C=CC1OCC(CC)(COCC2(CC)COC(C=C)OC2)CO1
Agent: [Fe]
Agent: [C-]#[O+]
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC=C1OCC(CC)(COCC2(CC)COC(=CC)OC2)CO1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To 220 mL pentane in a 500 mL photochemical reactor was added 14.32 g (43.9 mmol) di[(5-ethyl-2-vinyl-[1,3]dioxan-5-yl)methyl]ether from the previous step. The solution was refluxed vigorously for 20 minutes to degas it, then 115 μL (171 μg, 0.87 μmol, 0.2 mol %) iron pentacarbonyl was added, and the solution refluxed for an additional 20 minutes. The resulting solution was irradiated for one hour, by when NMR showed no vinyl signals. After cooling to room temperature and the addition of 0.5 mL triethylamine, the solution was sparged with dry air for 4 hours. The pentane was removed by evaporation under reduced pressure, and the residual oil was distilled in a Kugelrohr apparatus (pot temperature 220° C., pressure 1-3 mbar) to give 9.04 g (63% yield) of di[(5-ethyl-2-ethylidene-[1,3]dioxan-5-yl)methyl]ether, 3, as a colorless oil. The identity of the product was confirmed by 1H NMR and mass spectra (observed: 363, 345, calculated for C18H35O7 (M+2H2O+H+): 363; calculated for C18H33O6 (M+H2O+H+): 345).
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2=[O:16])([CH3:4])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[OH-].[Na+].OO>O1CCCC1.O>[C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:17])[CH2:8][CH2:9][CH2:10][C@@H:11]2[OH:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)O[C@H]1CCC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
A solution of 2.12 g (8.9 mMol) of (4aS,5S,8aR)-5-tert-Butoxy4a-methyl-octahydro-naphtalen-1-one in 44.5 ml tetrahydrofuran was cooled to -78° C. and 9.8 ml (9.8 mMol) of a one molar solution of L-selectride in tetrahydrofuran was added dropwise under stirring and argon atmosphere. The reaction mixture was kept at this temperature for an additional hour, warmed to room temperature and kept overnight. The temperature was then lowered to -15° C. and 0.17 ml of H2O were added dropwise. This was followed by dropwise addition of 7.60 ml 3N NaOH and 6.36 ml of H2O2. The reaction temperature is kept between -10 to -15° C. The reaction mixture is then poured into water and extracted three times with ethylacetate. The combined organic extracts are washed with brine and evaporated in vacuo to dryness. The residue is chromatographed over 120 g of silicagel with hexane/ethylacetate 4/1 to yield 1.03 g (48%) of pure (1S,4aS,5S,8aR)-5-tert-Butoxy-4a-methyl-decahydronaphtalen-1-ol as an amorphous product.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:42]=[C:41]([C:43]([NH:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([O:53][Si](C(C)(C)C)(C)C)[CH:48]=2)=[O:44])[CH:40]=[C:39]([CH3:61])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:42]=[C:41]([C:43]([NH:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=2)=[O:44])[CH:40]=[C:39]([CH3:61])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:26][NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[O:23]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 M; 1.78 mL, 1.78 mmol) was added in two portions to a solution of N-[2-chloro-4-[[[[3-[[(1,1-dimethylethyl) dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (1.03 g, 1.62 mmol) in dry tetrahydrofuran (20 mL). The solution was stirred at room temperature for 30 min, then diluted with ethyl acetate (100 mL) and washed with water (25 mL) and brine (25 mL). The solution was dried (MgSO4), filtered, evaporated, held under high vacuum for 2.5 h, and then chromatographed (60-70% ethyl acetate/petroleum ether) to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (0.82 g, 97%) as a white foam.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].CO[Si:8](OC)(OC)[CH2:9][CH2:10][CH2:11][Cl:12].Cl>>[ClH:12].[CH2:1]([NH:5][CH2:11][CH2:10][CH2:9][SiH3:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CO[Si](CCCCl)(OC)OC
Agent: Cl
Product: CCCCNCCC[SiH3]

Procedure:
A reaction of n-butylamine with CPTMO with a ratio of 3:1 consumes 1 mol of n-butylamine. 2 moles of n-butylamine can be removed again by distillation without any addition. This is because the reaction forms 1 mol of HCl, and, as a result of the distillation, 1 mol of n-butylaminopropylsilane hydrochloride is present at the end of the reaction.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[S:60][C:61]2[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=2[N:63]=1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[S:60]1[C:61]2[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=2[N:63]=[C:59]1[NH:58][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1nc2ccccc2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1[N+](=O)[O-]
Yield: 43.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (50 mg, 0.15 mmol), triethylamine (0.060 mL, 0.44 mmol), benzotriazol-1yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (98 mg, 0.22 mmol), and 2-aminobenzothiazole (33 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL) was stirred all 25° C. for 3 h. The reaction mixture was then diluted with water (25 ML), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated. The resulting organic layer was washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (31 mg, 45%) as a pale yellow foam: mp 108-113° C. (foam to gel); EI-HRMS m/e calcd for C22H23N3O5S2 (M+) 473.1079, found 473.1077.
Reaction SMILES: CN1CCOCC1.[N+:8]([C:11]1[N:12]([CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:14][N:15]=1)([O-:10])=[O:9].ClC(OCC(C)C)=O.Cl.[F:29][C:30](=[CH2:33])[CH2:31][NH2:32]>C1COCC1>[N+:8]([C:11]1[N:12]([CH2:16][C:17]([NH:32][CH2:31][C:30]([F:29])=[CH2:33])=[O:19])[CH:13]=[CH:14][N:15]=1)([O-:10])=[O:9]
Reactant: C=C(F)CN
Reactant: O=C(O)Cn1ccnc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C(F)CNC(=O)Cn1ccnc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
N-methylmorpholine (1.01 g, 10 mmol) was added to 2-(2-nitro-1H-imidazol-1-yl)-acetic acid (1.71 g, 10 mmol) in 150 mL of dry THF under nitrogen at 0° C. and stirred for 10 minutes. Isobutyl chloroformate (1.43 mL, 11 mmol) was added. After 30 minutes, 2-fluoro allyl amine hydrochloride (1.23 g, 11 mmol) and N-methylmorpholine (1.21 g, 12 mmol) was added to the solution and the mixture was stirred at room temperature overnight. The solution was filtered and the organic solvent evaporated to give a yellow solid. Purified by column afforded a light yellow solid (1.1 g, 50%).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)(=[O:6])=[O:5].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C.O>[N+:13]([C:9]1[CH:8]=[C:7]([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
1-(β-chloroethylsulfonyl)-3-nitrobenzene (2.50 g, 10 mmol) was added to 20 g of toluene, to this solution were added 1.50 g of 49% aqueous potassium carbonate solution (potassium carbonate 5.3 mmol) and 50 mg (0.5 mmol) of triethylamine, and the mixture was stirred for 2 hours at 40° C. Then, 10 g of water was added and the mixture was separated to an organic phase and aqueous phase. This aqueous phase was extracted by chloroform, and the resulted organic phase was combined with the previous organic phase, dried over magnesium sulfate, the solvents were distilled off, to obtain 2.00 g (yield 94.3%) of (3-nitrophenyl)vinylsulfone.
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]1[C:11]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:12][C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:14]([CH:16]=1)N.[ClH:43]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:43][C:14]1[CH:16]=[C:10]([F:9])[C:11]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:12][C:13]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: Cl
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h

Procedure:
A mixture of 11.02 g of isoamyl nitrite and 45 ml of acetonitrile was added dropwise to a mixture of 15.16 g of 5-fluoro-2-{2-(methoxycarbonyl)methoxyphenoxy}-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline (produced in Intermediate Production Example 10), 6.21 g of copper (I) chloride, 12.65 g of copper (II) chloride, and 250 ml of acetonitrile at room temperature, and the mixture was stirred for 2 hour. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 13 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [Compound 3-11 of the present invention].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2)=CC=CC=1CN[C:45]([O:47][CH:48]([CH3:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][C:45]([O:47][C@@H:48]([CH3:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Reactant: CC(OC(=O)NCc1cccc(-c2ccccc2)c1C(=O)NCCc1ccccn1)c1ccccc1
Product: C[C@H](OC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)c1ccccc1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and (S)-α-methylbenzyl N-succinimido-carbonate (precursor 4 h), according to the general working procedure 60 mg of (S)-2′-(α-methylbenzyloxycarbonylaminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained. MS (ES+): m/e=480 (M+l ).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].CCN(CC)CC.O>C1COCC1.CO>[OH:17][C:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[C:2]([NH:1][C:18](=[O:20])[CH3:19])[CH:3]=1
Reactant: Nc1cc(O)ccc1/C=C/c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1cc(O)ccc1/C=C/c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To the solution of 3-amino-4-[(E)-2-(4-hydroxy-phenyl)vinyl]phenol (100 mg) in anhydrous THF was added 225 mg of acetic anhydride and 223 mg of Et3N. The resulting solution was stirred at rt overnight. The reaction mixture was concentrated by vacuum evaporation. The residue, which was identified as mainly desired compound by 1H-NMR, was not further purified and used directly for the next step. The crude mixture from the previous reaction was dissolved in 30 mL of methanol. K2Co3 (197 mg, ˜12 eq.) was added as well as 20 mL of H2O. The resulting solution was vigorously stirred at rt for 1 h. All volatile solvents were evaporated and the residue was loaded on a silica gel column with 5% MeOH/dichloromethane as eluent to give N-{5-hydroxy-2-[(E)-2-(4-hydroxyphenyl)vinyl]phenyl}-acetamide (55 mg, 46.4% in two steps). MS (ES) m/z: 270.14 (M+1); Mp. 227-229° C.