Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=3[Cl:31])[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:33]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[C:22]=3[Cl:31])[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1Oc1ccc2nc(N)sc2n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(F)(F)F)c4Cl)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 28 h
Yield: 74.6 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-2-chloro-3-(trifluoromethyl)benzamide (200 mg, 0.417 mmol) produced in Example C78(iv) in pyridine (5 mL) were added acetyl chloride (118 μL, 1.67 mmol) and N,N-dimethylpyridine-4-amine (6.2 mg, 0.0507 mmol), and the mixture was stirred at room temperature for 28 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and filtered through a pad filled with basic silica gel. The solvent was concentrated under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate to give the title compound (162 mg, 74%) as white crystals.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[C:4]=1[C:22]#[C:23][Si](C)(C)C)[CH3:2]>[OH-].[K+]>[C:22]([C:4]1[C:5]([NH:9][C@H:10]2[CH2:11][CH2:12][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)=[N:6][CH:7]=[N:8][C:3]=1[CH2:1][CH3:2])#[CH:23]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1C#C[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Product: C#Cc1c(CC)ncnc1N[C@H]1CC[C@@H](c2ccccc2)CC1

Procedure:
Prepared as in Example 6 from 6-ethyl-4-(cis-4-phenylcyclohexylamino)-5-trimethylsilylethynylpyrimidine (Example 9) by eliminating the silyl group in methanolic potassium hydroxide solution.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[O:13][C:12](=[O:14])[NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH2:18][CH3:19].CN(C)C=O.[H-].[Na+]>O>[CH2:18]([N:11]1[N:10]=[C:9]([CH2:8][C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:13][C:12]1=[O:14])[CH3:19]
Reactant: CCI
Reactant: O=c1[nH]nc(Cc2ccc([N+](=O)[O-])cc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Cc2ccc([N+](=O)[O-])cc2)oc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a mixture of 5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one (1.50 g), iodoethane (1.59 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.30 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hrs. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-ethyl-5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one as colorless crystals (0.99 g, yield 59%) from a fraction eluted with hexane-ethyl acetate (3:1-2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 108-109° C.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:8][C:7]=2[CH:31]=1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1.C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]=[CH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[CH:8][C:7]=2[CH:31]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Brc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: COc1ccc(C=Cc2cc3cc(Br)ccc3o2)cc1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
91.5 g of (5-bromo-2-benzofuranyl)methyltriphenylphosphonium chloride and 25 g of p-anisaldehyde were dissolved in a mixture solvent of 180 ml of tetrahydrofuran and 180 ml of ethanol. With stirring at room temperature, 27.58 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added to the above solution, and the mixture was stirred for 18 hours. Thereafter, the reaction solution was concentrated to collect precipitated crystals by filtration, thereby obtaining 32.8 g of 5-bromo-2-[2-(4-methoxyphenyl)vinyl]benzofuran as one of the stereoisomers.
Reaction SMILES: [SH:1][C@H:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)(=[O:9])=[O:8])[C@H:4]([C:20]([N:22]([CH2:31][C:32]([OH:34])=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH2:3]1.[NH:35]([C:52]([CH3:54])=[O:53])[C@H:36]([C:49]([OH:51])=[O:50])[CH2:37][S:38]SC1N=CC=CC=1[N+]([O-])=O>>[C:52]([NH:35][CH:36]([CH2:37][S:38][S:1][CH:2]1[CH2:3][CH:4]([C:20](=[O:21])[N:22]([CH2:31][C:32]([OH:34])=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:5]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)(=[O:9])=[O:8])[CH2:6]1)[C:49]([OH:51])=[O:50])(=[O:53])[CH3:54]
Reactant: O=C(O)CN(CCc1ccccc1)C(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: CC(=O)N[C@@H](CSSc1ncccc1[N+](=O)[O-])C(=O)O
Product: CC(=O)NC(CSSC1CC(C(=O)N(CCc2ccccc2)CC(=O)O)N(S(=O)(=O)c2ccc3ccccc3c2)C1)C(=O)O
Reaction time: 2 h

Procedure:
(2S,4R)-{[4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid (32.6 mg, 0.07 mmol) and Ac-Cys(Npys)—OH (20.6 mg, 0.07 mmol) were dissolved in argon-degassed DMF (abs. 2 ml) and degassed 0.1 M phosphate buffer (pH 6.2, 2 ml) was added. The reaction mixture was magnetically stirred for 2 h under argon. Ethyl acetate (30 ml), water (20 ml) were added and the organic phase was washed with water (3×20 ml) and concentrated under reduced pressure to give a yellow oil: 37 mg. Prep. RP-HPLC purification followed by pooling and freeze-drying of desired fractions yielded 2-acetylamino-3-[5-(carboxymethyl-phenethyl-carbamoyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yldisulfanyl]-propionic acid as a white lyophilisate (20 mg) MS: 657.9 (M-H)−.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:30])[N:15]([CH3:29])[C:16](=[O:28])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH3:27])[CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H].C1(C)C=CC=CC=1>CO.C(OC(=O)C)C.[Pd]>[C:1]1([C@H:13]2[C@@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[C:16](=[O:28])[N:15]([CH3:29])[C:14]2=[O:30])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cn3c4c(cccc24)CCC3)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN1C(=O)[C@H](c2cn(C)c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1=O
Yield: 56.7 %

Procedure:
To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl) pyrrole-2,5-dione (100 mg, see Example 1) in anhydrous dimethylformamide (5 ml) was added potassium carbonate (0.5 g) and methyl iodide (0.1 ml). The mixture was stirred at room temperature for 48 hours then poured into ethyl acetate. (100 ml), washed with water (100 ml), dried over anhydrous sodium sulfate and evaporated to give 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1-methylindol-3-yl)-1-methylpyrrole-2,5-dione as a red solid (93 mg). Step 2: To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1-methylindol-3-yl)-1-methylpyrrole-2,5-dione (93 mg) in methanol (5 ml) and ethylacetate (5 ml) was added 10% Pd—C (50 mg) and the mixture stirred at room temperature under 1 atmosphere of hydrogen for 48 hours. Toluene (50 ml) was added and the mixture again stirred at room temperature under 1 atmosphere of hydrogen for 2 hours. The mixture was then filtered through a pad of celite and evaporated to dryness to yield a residue. The residue was purified using silica gel chromatography eluting with 35-40% ethylacetate in hexanes to give (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1-methylindol-3-yl)-1-methylpyrrolidine-2,5-dione as a pale yellow solid (53 mg). 1H NMR (CDCl3) 400 MHz δ: 7.23 (s, 1H), 7.05-7.07 (m, 2H), 7.01 (d, 1H, J=7.2 Hz), 6.92-6.97 (m, 1H), 6.85 (t, 1H, J=7.2 Hz), 6.74 (d, 1H, J=6.8 Hz), 6.64 (d, 2H, J=6.4 Hz), 4.78 (m, 2H), 3.75-3.84 (m, 2H), 3.45 (s, 3H), 3.27 (s, 3H), 2.79 (t, 2H, J=5.6 Hz), 1.98 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:14]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([CH3:25])=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4C(OC(C)(C)C)=O)([O:12][CH3:13])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(OC)C)N(COCC[Si](C)(C)C)C=2C=1)#N.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN.[Cl-].[NH4+].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(OCC)(=O)C>[CH3:13][O:12][C:10]([C:8]1[NH:7][C:6]2[CH:41]=[CH:42][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([C:14]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([CH3:25])=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2)[CH3:11]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(OC)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(OC)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: NCCN
Product: COc1cc(C)c2[nH]ccc2c1C(C)(OC)c1nc2cc(C#N)ccc2[nH]1
Temperature: 65 °C

Procedure:
To a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxy ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.494 g, 0.836 mmol) in tetrahydrofuran (8.36 mL) was added TBAF (1M in THF, 8.36 mL, 8.36 mmol) and ethylenediamine (0.28 mL, 4.18 mmol). The reaction was heated at 65° C. for 26 hours. The reaction was cooled to room temperature and treated with 10 mL of a saturated solution of aq. ammonium chloride and then diluted with ethyl acetate. The layers were separated and the organic layer was washed with water (3×100 mL), dried over magnesium sulfate and concentrated. The resulting residue was dissolved in MeOH and cesium carbonate (1.38 g, 4.25 mmol) was added and the reaction was heated at 60° C. for 1.5 hours. The reaction was cooled to room temperature, diluted with EtOAc and then washed with a saturated solution of aq. ammonium chloride. The organic extract was dried over magnesium sulfate, filtered and concentrated. The resulting residues was purified by flash chromatography (0-10% MeOH in DCM) to provide the title compound. 1H NMR (400 MHz, DMSO-d6 with about 5 μL TFA) δ ppm 11.14 (br. s., 1H) 8.23 (s, 1H) 7.66-8.01 (m, 2H) 7.39 (t, J=2.91 Hz, 1H) 6.48-6.88 (m, 2H) 3.28 (s, 3H) 3.17 (s, 3H) 2.48 (s, 3H) 2.13 (s, 3H). HRMS calcd. for C21H20N4O2 (M+H)+ 361.1659. found 361.1675.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[CH:12]1([C:17]([OH:30])([C:28]#[CH:29])[CH2:18][C:19]2[O:24][C:23]([CH3:26])([CH3:25])[O:22][C:21](=[O:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(NC(C)C)(C)C>CN(C=O)C.CCOC(C)=O.[Cu]I.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>[CH:12]1([C:17]([OH:30])([C:28]#[C:29][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[C:4]([F:11])[CH:3]=2)[CH2:18][C:19]2[O:24][C:23]([CH3:26])([CH3:25])[O:22][C:21](=[O:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Reactant: CC(C)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Temperature: 90 °C
Yield: 89.2 %

Procedure:
4-Bromo-2-fluoro-1-isopropylbenzene (5.0 g, 23.2 mmol), 6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (5.56 g, 21.0 mmol) were dissolved in anhydrous DMF (30 mL). To this solution, CuI (120 mg, 0.63 mmol), Pd(PPh3)2Cl2 (0.59 g, 0.84 mmol), and diisopropylamine (60 mL), were added sequentially. The mixture was then heated at 90° C. for 20 min before it was cooled down to 25° C. The reaction was diluted with EtOAc (150 mL) and washed with aqueous NH4Cl, brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (040% EtOAc in hexanes) to give the desired product (7.5 g, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[C:41]([CH2:45][NH2:46])[CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:46][CH2:45][C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([C:36]4[CH:37]=[CH:38][C:33]([O:32][C:31]([F:30])([F:47])[F:48])=[CH:34][CH:35]=4)[CH:40]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cccc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
A solution of acid 18 (0.20 g, 0.65 mmol) in THF (15 mL) was added with DEPC (0.13 mL, 1.3 mol eq) and the mixture was stirred at room temperature for 10 minutes. Then [3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine 23B (0.19 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (45 mL) and washed with water (40 mL) and brine. The separated organic phase was dried over an. Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography (1/1 EtOAc/Petroleum ether) to afford a white solid (0.2 g). Yield=59%, 1HNMR (DMSO, 200 MHz) δ 1.23 (m, 5H), 1.41 (m, 2H), 3.36 (m, 2H), 4.39 (d, 2H, J=6.1), 7.25 (m, 2H), 7.45 (m, 4H), 7.57 (m, 2H), 7.79 (d, 2H, J=7.9), 8.09 (t, 1H). [M+1] 559.31 (C24H22ClF3N2O4S2 requires 559.02).
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:6]([OH:7])[C:5]=1O>>[CH3:3][C:4]1[CH:5]=[C:6]([OH:7])[CH:8]=[C:9]([CH3:11])[C:10]=1[OH:1]
Reactant: Cc1cc(C)c(O)c(O)c1
Reactant: OO
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 53, except that 60 percent hydrogen peroxide was increased from 2.88 g. (50.8 m. moles) to 4.50 g. (79.4 m. moles), 4.69 g. (34.0 m. moles) of 3,5-dimethylcatechol and 2.75 g. (19.9 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 67.9 percent.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][C:11]3=[O:16])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCn1ccnc1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(-c4ccccc4)cc32)c(C)c1C(=O)NCCCn1ccnc1
Yield: 58.9 %

Procedure:
5-Phenyl-1,3-dihydroindol-2-one (8 mg, 0.04 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide (10 mg) to give 10 mg (59%) of the title compound as an orange solid.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([N:28]1[CH2:34][CH:33]2[CH:30]([CH2:31][NH:32]2)[CH2:29]1)=[O:27].ClC1N=C(C)C=C(C)N=1>>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([N:28]1[CH2:34][CH:33]2[CH:30]([CH2:31][N:32]2[C:9]2[N:8]=[C:15]([CH3:14])[CH:16]=[C:11]([CH3:12])[N:10]=2)[CH2:29]1)=[O:27]
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: O=C(c1ccccc1Br)N1CC2CNC2C1
Agent: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4Br)CC32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 23 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C18H19BrN4O, 387.28; m/z found, 389.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:9]([C:23]([OH:25])=O)[CH2:10][CH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][C:35]([CH3:38])([OH:37])[CH3:36].C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CCO.C(Cl)Cl>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:12]1[CH2:13][N:14]([CH2:34][C:35]([OH:37])([CH3:38])[CH3:36])[C:23](=[O:25])[C@H:9]([N:8]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Reactant: CC(C)(O)CCl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CN1C[C@H](c2cccc(F)c2F)CC[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1=O
Reaction time: 8 h
Yield: 33 %

Procedure:
A solution of (5S)-N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.569 g, 1.24 mmol), 1-chloro-2-methyl-2-propanol (0.202 g, 1.86 mmol) and diisopropylethylamine (0.529 g, 4.10 mmol) in EtOH (5 mL) was heated at 75° C. overnight. The reaction was concentrated to dryness, diluted with DCM (20 mL) and EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol) were added followed by diisopropylethylamine (0.650 mL, 3.73 mmol). After stirring overnight, NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and the residue purified by silica gel chromatography (10%→35% EtOAc/hexanes) to give the title compound (0.21 g). MS 513.1 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.1 (m, 3H), 5.24 (d, J=10.7 Hz, 1H), 4.02 (m, 1H), 3.69 (d, J=13.9 Hz, 1H), 3.60 (d, J=15.1 Hz, 1H), 3.39 (m, 1H), 3.24 (d, J=14.2 Hz, 1H), 2.4 (m, 1H), 2.1 (m, 3H), 1.5 (s, 18H), 1.20 (s, 3H), 1.16 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[O:27].CCN(CC)CC.Cl>C1COCC1>[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccccc1I
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1I
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methoxyphenylacetate (1.94 g, 8.16 mmol) in THF (20 ml) was added 2-iodophenylisocyanate (2.0 g, 8.16 mmol) and Et3N (114 ul, 0.816 mmol). After stirring overnight, the mixture was poured into 1 N HCl (200 ml). The resulting precipitate was collected by filtration and dissolved in CHCl3 (200 ml). The solution was dried over MgSO4 and evaporated to give tert-butyl 4-[N′-(2-iodophenyl)ureido]-3-methoxyphenylacetate (3.93 g, quant) as a pale yellow amorphous solid 1H-NMR (CDCl3) δ1.44 (s, 9 H), 3.49 (s, 2 H), 3.85 (s, 3 H), 6.78-6.88 (m, 4 H), 7.07 (s, 1 H), 7.31-7.35 (m, 1 H), 7.76 (dd, J=7.8, 1.5 Hz, 1 H), 7.95 (d, J=8.3 Hz, 1 H), 7.99 (dd, J=8.3, 1.5 Hz, 1 H). MS (ESI), m/z 483 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].IC.[CH2:23](C(C)=O)[CH3:24]>O>[CH2:23]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:24]
Reactant: CCC(C)=O
Reactant: CCn1cc(C#N)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCOc1ccc2c(C#N)cn(CC)c2c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution 6-hydoxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone was added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodomethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture was cooled, diluted with H2O and extracted with EtOAc (3×). The combined organic phases were dried and concentrated. Flash chromatography (CH2Cl2) gave 94 mg (100%) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[Cl:30][CH2:31][CH2:32]O.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:32][CH2:31][Cl:30])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: OCCCl
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCCCl

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A of Example 31 after reaction with 2-chloroethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-chloroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+39°±4° (c=0.25% in benzene).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (257) (0.7 g, 1.13 mmol) in tetrahydrofuran (10.0 mL) was added HCl (0.062 g, 1.70 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. After completion of the reaction, the mixture was extracted with ethyl acetate. The combined organic layer was washed with water, separated and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by normal silica gel column chromatography (using 60% ethyl acetate in hexane followed by 5% methanol in ethyl acetate) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (258) (0.43 g, 75.0%) as a white solid.