Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:26])([F:25])[C:22](O)=O.FC(F)(F)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH2:36][CH2:37][NH:38]C[CH:40]=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>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:38]2[CH2:37][CH:36]=[C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=3)[CH2:40][CH:22]2[C:21]([F:26])([F:25])[F:20])=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)C(F)(F)F
Reactant: FC(F)(F)c1ccccc1C1=CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2C(F)(F)F)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (115 mg, 0.424 mmol) and 4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine trifluoroacetate (152 mg, 0.445 mmol) in methylene chloride (2 mL) was added triethylamine (0.21 g, 2.1 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (210 mg, 0.47 mmol). After being stirred overnight at room temperature, the reaction was quenched with saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. Purification by flash chromatography on silica gel (0-50% B over 15 min. Bottle A=hexanes, Bottle B=EtOAc) provided 174 mg of desired product as a white solid. MS calculated for C26H35F3N2O3:(M+H) 481; found 481.1.
Reaction SMILES: [C:1]1([C:7]2([C:11]([Cl:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]1>CS(C)=O.C(O)(C(F)(F)F)=O>[ClH:13].[C:1]1([C:7]2([C:11]([O:20][CH:17]3[CH2:18][CH2:19][N:15]([CH3:14])[CH2:16]3)=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C1(c2ccccc2)CCC1
Reactant: CN1CCC(O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CN1CCC(OC(=O)C2(c3ccccc3)CCC2)C1
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to that in Example 36 by reacting 1-phenylcyclobutanecarbonyl chloride with 1-methyl-3-hydroxypyrrolidine at 80° C. for 17 h. The yield was 1.1 g (67%); mp 153-155° C.; 1H NMR (DMSO-d6, 1% TFA) δ 1.83 (m, 1.5H), 1.96 (m, 1.5H), 2.17 (m, 0.5H), 2.38-2.51 (m, 2.5H), 2.64 (t, 1.5H), 2.73-2.92 (m, 4H), 2.97 (m, 0.5H), 3.06 (m, 0.5H), 3.32 (m, 0.5H), 3.54 (m, 1.5H), 3.76 (m, 0.5H), 5.26 (m, 1H), 7.23-7.39 (m, 5H). Anal. (C16H21NO2.HCl) C, H, N. The compound exists in two forms in DMSO-TFA solution.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][CH2:5]2.C1C[O:17][CH2:16]C1.[Li]CCCC.CN(C=O)C>CCOC(C)=O>[CH3:12][C:7]1([CH3:13])[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:16]=[O:17])[CH:3]=2)[O:8]1
Reactant: C1CCOC1
Reactant: CC1(C)CCc2cc(Br)ccc2O1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CCc2cc(C=O)ccc2O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen flushed 100 mL round bottom flask were added 6-bromo-2,2-dimethyl-3,4-dihydro-2H-chromene (0.41 g, 1.7 mmol) and THF (6 mL). A solution of n-BuLi in hexanes (0.69 mL, 2.6 M, 1.79 mmol) was added at −78° C. The resulting reaction mixture was stirred at −78° C. for 10 minutes when DMF (0.20 mL, 2.55 mmol) was added. The reaction mixture was allowed to warm to room temperature and was diluted with EtOAc (25 mL). It was stirred over wet silica gel (10 g silica gel/0.5 mL water) for 10 minutes and was filtered. The solid was rinsed with EtOAc and the filtrate was concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 20% EtOAc/hexanes to give the title intermediate (0.25 g) as a light yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10](O)[CH:11]([CH3:13])[CH3:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]([CH3:13])[CH3:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CS
Reactant: CC(C)C(O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)C(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 77.5 %

Procedure:
A mixture comprising 2 g of 1-(1,3-benzodioxol-5-yl)-2-methyl-1-propanol, 1.3 g of mercaptoacetic acid, a catalytic amount of p-toluenesulfonic acid and 50 ml of benzene was heated under reflux for 5.5 hours, followed by the addition of ethyl acetate. The mixture was washed with water and extracted with a 2N aqueous solution of sodium hydroxide. The aqueous layer was washed with chloroform, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in a vacuum to obtain a residue. This residue was purified by silica gel column chromatography (chloroform/methanol=20:1) to obtain 2.14 g of the title compound as a colorless oil.
Reaction SMILES: CC([O-])(C)C.[K+].CC(O)(C)C.[CH2:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)[C:13]#[CH:14]>O>[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=[C:13]=[CH2:14]
Reactant: C#CCOc1ccc(C(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: C=C=COc1ccc(C(=O)O)cc1
Yield: 43 %

Procedure:
Into a similar reaction vessel, as used in the abovementioned reaction, were placed 7.920 parts of t-BuOK and 44.882 parts of t-BuOH and to this, a mixture of 10,000 parts of 1-propargyloxybenzene-4-carboxylic acid and 23.333 parts of t-BuOH was added dropwise. The content was reacted at 50° C. for 60 minutes and then a deionized water was added to stop the reaction. t-BuOH layer and water layer were removed by using an evaporator, and the residue was added with 1N-HCl and then extracted with an ether. The ether solvent was removed and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 1-allenyloxy benzene-4-carboxylic acid as a colorless clear oily product. This compound was identified by FT-NMR(H) and IR spectrum. The reaction yield was 43.0%.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]/[C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]/[C:60]([CH3:70])([O:62][Si:63]([CH2:66][CH3:67])([CH2:68][CH3:69])[CH2:64][CH3:65])[CH3:61])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C/CBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C/CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 88.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10μl) and (E)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (116 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (73.4mg, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)N(C)[C:10]1[C:9]3[CH:16]=C[CH:18]=[CH:19][C:8]=3[S:7][CH2:6][C:5]2=1.[C:20]([Cu])#[N:21].[CH3:23][N:24]([CH:26]=O)C>>[CH3:16][CH:9]1[C:10]2[C:23]3[N:24]=[CH:26][CH:18]=[CH:19][C:8]=3[S:7][CH2:6][C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([C:20]#[N:21])[CH:3]=2
Reactant: N#C[Cu]
Reactant: CN(C)C=O
Reactant: Cn1c2c(c3cc(Br)ccc31)CSc1ccccc1-2
Product: CC1C2=C(CSc3cccnc32)c2cc(C#N)ccc21
Temperature: 170 °C

Procedure:
A mixture of 8-bromo-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (270 mg), as prepared in Example 57, and CuCN (270 mg) in DMF (25 ml) was reflux overnight at 170° C. The reaction mixture was filtered through a pad of Celite and then partitioned between saturated NaHCO3 aqueous solution and EtOAc. The aqueous layer was extracted with EtOAc, the organic layers were dried and concentrated to yield crude product. The crude product was purified by chromatography (Hexane:ethyl acetate=5:1) to yield the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]([C@H:16]([CH3:32])[C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:15])([CH3:14])[C@@H:4]([OH:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CN=C1.[CH2:38]([Si:40](Cl)([CH2:43][CH3:44])[CH2:41][CH3:42])[CH3:39].O>CN(C)C=O>[O:1]=[C:2]([C@H:16]([CH3:32])[C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:29])([Cl:30])[Cl:31])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:14])([CH3:15])[C@@H:4]([O:13][Si:40]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:38][CH3:39])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC

Procedure:
A solution of tert-butyl (3S,6R,7S,8S)-5-oxo-3-hydroxy-4,4,6,8-tetramethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoate (1.8 g), imidazole (0.48 g), and triethylsilyl chloride (0.68 g) in 5 mL of dimethylformamide is stirred for 2 hours at ambient temperature, then poured into water and extracted with ether. The extract is washed with sat. aq. NaCl, dried over MgSO4, filtered, and evaporated. The product is purified by chromatography on SiO2 (20:1 toluene/ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH3:19])[C:7]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH:22]1[CH:27]=[C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([CH:32]=O)[C:25]2=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>ClCCl.O.C(O)(=O)C>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:7]2[N:6]([CH3:19])[C:5]3[CH:20]=[CH:21][C:2]([NH:1][CH2:32][C:31]4[C:25]5[C:26](=[CH:27][CH:22]=[CH:23][CH:24]=5)[CH:28]=[CH:29][CH:30]=4)=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1)#[N:18]
Reactant: O=Cc1cccc2ccccc12
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(NCc3cccc4ccccc34)ccc21

Procedure:
1.0 g (3.6 mmol) of 5-amino-2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazole and 1-naphthylaldehyde (0.33 mL, 3.6 mmol) are combined with 0.22 mL acetic acid in 25 mL of dichloromethane at ambient temperature and Na[HB(Oac)3] is added thereto with stirring. The mixture is stirred for 1 h at ambient temperature, covered with water, carefully acidified with concentrated aqueous hydrochloric acid and then made alkaline with 4N NaOH solution. The organic phase is separated off, dried and evaporated down. The product is chromatographed over silica gel and optionally crystallised from diethyl ether.
Reaction SMILES: [C:1]1([CH:7](Cl)[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:34])[CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:17][CH2:16]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH:21]([CH3:34])[CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:19][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(O)CC1
Reactant: ClC(c1ccccc1)c1cccs1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(OC(c2ccccc2)c2cccs2)CC1

Procedure:
The procedure of Example 36 (a) was repeated except for using phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-(phenyl-2-thienylmethoxy)-1-[3-(2-nitrophenoxy)-1-methylpropyl]piperidine.
Reaction SMILES: Cl[C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].[CH:9]1([CH2:12][O:13][C:14]([C:16]2[CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[N:18]=[C:19]([CH3:23])[NH:20][C:21]=2[CH3:22])=[O:15])[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH2:40]([N:47]([CH2:49]CO)[CH3:48])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.[Cl-].[Na+]>[CH2:40]([N:47]([CH2:49][CH2:5][O:4][C:2]([N:18]1[CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[C:16]([C:14]([O:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)=[O:15])=[C:21]([CH3:22])[N:20]=[C:19]1[CH3:23])=[O:3])[CH3:48])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CN(CCO)Cc1ccccc1
Reactant: CC1=NC(c2ccccc2[N+](=O)[O-])C(C(=O)OCC2CC2)=C(C)N1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=NC(C)=C(C(=O)OCC2CC2)C(c2ccccc2[N+](=O)[O-])N1C(=O)OCCN(C)Cc1ccccc1
Temperature: -23 °C
Yield: 68 %

Procedure:
Trichloromethyl chloroformate (144 μl) was dissolved in 10 ml of tetrahydrofuran (THF). To the resulting solution, a mixture of 5-cyclo-propylmethoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyrimidine (329 mg) and triethylamine (607 ml) in THF (20 ml) was added under stirring at -23° C., followed by stirring for an additional one hour. To the resulting mixture, 2-(N-benzyl-N-methylamino)ethan-1-ol (991 mg) in THF (10 ml) was added at 0° C., followed by stirring for one hour. The stirring was continued for one more hour at room temperature and, thereafter, the reaction mixture was diluted with a saturated aqueous solution of sodium chloride and subjected to extraction with chloroform. After drying the extract, the solvent was evaporated and the residue (1.32 g) was subjected to silica gel chromatography. By elution with 1% methanol-chloroform, the desired compound was obtained in an amount of 354 mg (yield: 68%). The physicochemical data of the compound are shown in Table 1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][C@@H:17]([C:19]([N:21]1[C@H:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[NH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:37]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:38]([OH:40])=[O:39]>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][C@@H:17]([C:19]([N:21]1[C@H:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[NH:18][CH:37]([C:38]([OH:40])=[O:39])[CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2CN1C(=O)[C@@H](N)CCSCCNC(=O)OCc1ccccc1
Reactant: O=C(O)C(=O)CCc1ccccc1
Solvent: CO
Product: CCOC(=O)[C@@H]1Cc2ccccc2CN1C(=O)[C@H](CCSCCNC(=O)OCc1ccccc1)NC(CCc1ccccc1)C(=O)O
Yield: 25 %

Procedure:
S-(2-Benzyloxycarbonylaminoethyl)-N-tert-butoxy-carbonyl-L-homocysteine (2.14 g., 0.00518 mole) and ethyl 1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (1.12 g., 0.00545 mole) were coupled via the procedure described in Example 5 to give 2.24 g. (72%) of ethyl N-[S-(2-benzyloxycarbonylaminoethyl)-N-tert-butoxycarbonyl-L-homocysteinyl]-1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (1); an oil. Compound 1 (1.10 g., 0.00183 mole) was stirred for 50 minutes at room temperature with 25 ml of trifluoroacetate acid. Concentration in vacuo gave ethyl N-[S-(2-benzyloxycarbonylaminoethyl)-L-homocysteinyl]1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (2) as a crude orange oil. This intermediate (2) was reductively alkylated with 2-oxo-4-phenylbutyric acid (3.00 g., 0.0068 mole) according to the procedure described in Example 5. After chromatography on an LH-20 column with methanol, 0.30 g. (25%) of ethyl N-[S-(2-benzyloxycarbonylaminoethyl)-N-(1-carboxy-3-phenylpropyl)-L-homocysteinyl]-1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (3) was obtained; a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15](#[N:18])[CH:16]=[CH2:17].N12CCCN=C1CCCCC2>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:17][CH2:16][C:15]#[N:18])[CH:10]=2)[O:3]1
Reactant: C=CC#N
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Reaction time: 2 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.00 g, 25.8 mmol) in acetonitrile (50 mL) was added acrylonitrile (3.4 mL, 52 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.94 mL, 12.9 mmol). After about 2 hours, the reaction mixture was concentrated under reduced pressure. The crude material was then dissolved in a minimal amount of dichloromethane and purified via silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in heptane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (s, 1H), 7.64 (s, 1H), 4.40 (t, J=6.4 Hz, 2H), 3.06 (t, J=6.4 Hz, 2H), 1.26 (s, 12H). MS (ESI+) m/z 247.3 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@H:27]1[O:31][C:30](=[O:32])[C@H:29]([CH3:33])[CH2:28]1)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.Cl.[CH2:35]([C@H:42]([CH2:46][C:47]([N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)=[O:48])[C:43]([OH:45])=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[CH2:35]([C@H:42]([CH2:46][C:47]([N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)=[O:48])[C:43]([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@H:27]1[O:31][C:30](=[O:32])[C@H:29]([CH3:33])[CH2:28]1)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:45])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)OC(C)(C)C)OC1=O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)[C@@H](CC(=O)N2CCOCC2)Cc2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of 1.7 g (3.64 mmole) of (3R, 5S)-5-{(1S)-1-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl ]amino-2-cyclohexylethyl}-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 25) and 20 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 60 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue, and the resulting mixture was concentrated by evaporation under reduced pressure. This operation was repeated three times, in total. After the final residue had been dried under reduced pressure for 8 hours, the dried materials were suspended in 30 ml of anhydrous tetrahydrofuran. 1.11 g (4.0 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were then added to the suspension, after which 0.71 ml (4.37 mmole) of 95% diethyl cyanophosphonate and 2.0 ml (14.56 mmole) of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred at room temperature for 15 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by medium pressure column chromatography through silica gel (using ethyl acetate as the eluent), to afford 1.43 g of the title compound as a colourless amorphous product.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:12][C:13]2[C:14]([F:22])=[C:15]([CH2:20][NH2:21])[CH:16]=[CH:17][C:18]=2[Cl:19])[CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:23][C:24]1[N:25]=[CH:26][N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:28]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[C:7]([O:12][C:13]2[C:14]([F:22])=[C:15]([CH2:20][NH:21][C:29]([C:28]3[N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[CH:26]=[N:25][C:24]=3[Cl:23])=[O:30])[CH:16]=[CH:17][C:18]=2[Cl:19])[CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
To a solution of ({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (105 mg, 0.307 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (85 mg, 0.307 mmol) and HATU (117 mg, 0.307 mmol) in DMF (3 ml) was added diisopropylethyl amine (0.107 ml, 0.614 mmol) and the reaction mixture was stirred at rt for 45 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give N-({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (151 mg, 0.251 mmol, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (t, 1H), 7.95 (s, 1H), 7.39-7.46 (m, 1H), 7.34 (t, 1H), 6.99 (s, 1H), 6.70 (s, 1H), 6.66 (s, 1H), 5.47 (s, 2H), 4.45 (d, 2H), 3.36 (t, 2H), 2.50 (t, 2H), 1.46 (t, 2H), 1.16-1.28 (m, 2H), 0.82 (t, 3 H), 0.73 (t, 2H), −0.12 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([OH:24])[CH:18]=1.I[CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][CH2:16][C:17]1[CH:18]=[C:19]([O:24][CH2:26][CH2:27][CH3:28])[CH:20]=[C:21]([OH:23])[CH:22]=1
Reactant: CCCI
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(O)cc(CNC=C2C(=O)NC(=O)c3ccc(Br)cc32)c1
Temperature: 100 °C
Yield: 34.4 %

Procedure:
(4Z)-6-bromo-4-{[(3,5-dihydroxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (50 mg, 0.128 mmol) is dissolved in 1 mL N,N-dimethylformamide (DMF) (1 mL). To the resulting solution is added 1-iodo-propane (25 μL, 0.256 mmol) and K2CO3 (53 mg, 0.384 mmol). The reaction mixture is heated at 100° C. for 2 hours. The solid is filtered and purified by HPLC eluting with 20% CH3CN/H2O to 100% CH3CN over 30 minutes to give 19 mg (34%) of the title compound as a tan powder. MS (ESI) m/z 431.1(M+H)+