Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([F:34])=[C:10]([C:35](=[N:37][OH:38])[NH2:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.ClC1C2N=C(N3CC[O:63][C@@H:62]4CCC[C@@H]34)N(C[C@H]3CC[C@H](C)CC3)C=2C(C2C=NC=C(Cl)C=2)=NC=1C(=NO)N.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([F:34])=[C:10]([C:35]3[NH:36][C:62](=[O:63])[O:38][N:37]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(F)c(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(F)c(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3:1 mixture of 4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide and 7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (33 mg, 0.06 mmol) in acetonitrile (2 mL) was added 1,1′-carbonyldiimidazole (19.7 mg, 0.122 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.037 mL, 0.244 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated. The residue was purified by mass triggered reverse phase HPLC (C-18) eluting with acetonitrile/water+0.1% TFA to afford pure 3-{4-(5-chloropyridin-3-yl)-7-fluoro-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (TFA salt). MS ESI calc'd for C28H31ClFN7O3 [M+H]+=568. found=568. 1H NMR (600 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.91 (d, J=1.8 Hz, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.43 (m, 1H), 3.94 (d, J=9.6 Hz, 1H), 3.78-3.87 (m, 2H), 3.63 (dd, J=14.4, 3.6 Hz, 1H), 3.56 (d, J=12.6 Hz, 1H), 3.39 (m, 1H), 3.04 (m, 1H), 2.84 (m, 1H), 2.27 (m, 1H), 1.86 (m, 1H), 1.69 (m, 1H), 1.51-1.64 (m, 2H), 1.32-1.41 (m, 2H), 1.12 (m, 1H), 1.04 (m, 1H), 0.80 (m, 1H), 0.63-0.74 (m, 6H), 0.47 (m, 1H), 0.29-0.42 (m, 2H).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[N:29]([CH2:31][CH2:32][N:33]=[N+]=[N-])[CH3:30])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:37]([C:40]1[CH:50]=[CH:49][C:43]([CH2:44][O:45][C:46](Cl)=[O:47])=[CH:42][CH:41]=1)([O-:39])=[O:38].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[N:29]([CH3:30])[CH2:31][CH2:32][NH:33][C:46]([O:45][CH2:44][C:43]3[CH:42]=[CH:41][C:40]([N+:37]([O-:39])=[O:38])=[CH:50][CH:49]=3)=[O:47])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN(CCN=[N+]=[N-])C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
A solution of 3-t-butyldiphenylsilyloxy-1-{4-[N-(2-azidoethyl)-N-methyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (1.05 g, 2.02 mmol) (obtained as described in Reference Example 58(2)) in methanol (60 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (1.05 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst, and the filtrate concentrated under reduced pressure. To a solution of the obtained crude product in methylene chloride (52.3 ml) were added chloroformic acid p-nitrobenzyl ester (650.7 mg, 3.02 mmol) and triethylamine (0.42 ml, 3.01 mmol) in an ice bath. The mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (2:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (699.5 mg, yield 52%) as a pale yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)=[O:18].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C.CN(C=O)C>[C:17]([C:19]1[CH:20]=[C:21]([NH:25][C:13]([C:11]2[S:12][C:8]([Cl:7])=[CH:9][CH:10]=2)=[O:15])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[CH3:16]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(=O)c1cccc(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)c2ccc(Cl)s2)c1
Reaction time: 8 h
Yield: 81 %

Procedure:
Oxalyl chloride (4.9 mL, 56.00 mmol) was added to solution of 5-chloro-thiophene-2-carboxylic acid (4.78 g, 29.40 mmol), DMF (0.25 mL), and CH2Cl2 (50 ml) at room temperature. After stirring overnight, the reaction was stripped of solvent and unreacted oxalyl choride in vacuo, giving a colorless oil. The oil was dissolved in CH2Cl2 (50 mL), and treated with 3-aminoacetophenone (3.78 g, 28.00 mmol) and triethylamine (4.68 mL, 33.60 mmol). After stirring for 1 h, the mixture was diluted with 800 mL of ethyl acetate, extracted with 1N HCl, 1N NaHCO3, brine, and dried over MgSO4. The resulting solution was concentrated in vacuo to a volume of 100 mL, giving 5-chloro-thiophene-2-carboxylic acid (3-acetyl-phenyl)-amide as a white powder, which was collected by filtration and dried under high vacuum (8.12 g, 81% yield).
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[OH:13][C:12]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2
Reactant: C=CCc1c(O)ccc2c1ccn2-c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2c1ccn2-c1ccc(Cl)cc1

Procedure:
4-allyl-5-hydroxy-N-(4-chlorophenyl)indole (Step C; 1.0 g, 3.54 mmol) was taken up in 25 mL ethyl acetate and hydrogenated (1 atm) at ambient temperature using 5% palladium on charcoal (40 mg) for 2 hours. The reaction was filtered through celite and concentrated in vacuo to provide the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C)C=O.[Cl:19]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[Cl:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1cc(Br)cc2cc[nH]c12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)cc2c(Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
To a solution of 12.00 g (49.8 mmol) of 5-bromo-7-nitro-1H-indole in 140 ml of tetrahydrofuran were added 1.4 ml of dimethylformamide and 6.98 g (52.3 mmol) of N-chlorosuccinimide followed by stirring at room temperature overnight. A 10% aqueous solution of sodium thiosulfate was added thereto followed by extracting with ethyl acetate. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated to dryness to give 14.84 g of the title compound.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.Cl[CH2:12][P:13]1(=[O:19])[O:18][CH2:17][CH2:16][CH2:15][O:14]1>>[O:19]=[P:13]1([CH2:12][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[O:18][CH2:17][CH:16]=[CH:15][O:14]1
Reactant: CCOP(OCC)OCC
Reactant: O=P1(CCl)OCCCO1
Product: CCOP(=O)(CP1(=O)OC=CCO1)OCC

Procedure:
Diethyl (2-oxo-1,3,2-dioxaphosphorin-2-yl)methylphosphonate was prepared by the Arbuzov reaction of triethyl phosphite and 2-chloromethyl-2-oxo-1,3,2-dioxaphosphorinan. (IR: 1260 and 1030 cm-1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:22]3[C:13](=[N:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:12][CH2:11][C:10]=2[CH2:23][N:24]([CH3:26])[CH3:25])[CH:6]=[CH:7][CH:8]=1.N[C@H](C(O)=O)CCSC>CS(O)(=O)=O>[CH3:26][N:24]([CH2:23][C:10]1[CH2:11][CH2:12][C:13]2[C:22](=[CH:21][C:20]3[C:15]([N:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]=1[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)[CH3:25]
Reactant: COc1cccc(C2=C(CN(C)C)CCc3nc4ccccc4cc32)c1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: CN(C)CC1=C(c2cccc(O)c2)c2cc3ccccc3nc2CC1
Temperature: 20 °C
Yield: 46.3 %

Procedure:
5.4 g [1-(3-methoxy-phenyl)-3,4-dihydro-acridin-2-yl-methyl]-dimethylamine base were treated at room temperature with 40 ml methanesulfonic acid and 5.4 g methionine. The reaction mixture was stirred for ten days at 20° C. and was evaporated to dryness under vacuum. The solid was dissolved in water, the solution was covered with ethyl acetate, and the mixture was made alkaline with saturated sodium carbonate solution. The aqueous phase was extracted three times with 200 ml portions of ethyl acetate each time, and the combined organic phases were dried over magnesium sulfate and evaporated to dryness under vacuum. 2.4 g [3-(2-dimethylaminomethyl-3,4-dihydro-acridin-1-yl)]-phenol base were obtained. Dissolution of the yellow, amorphous solid in acetone with heating, followed by treating the solution with trimethylchlorosilane and water in equimolar amounts, gave 2.3 g [3-(2-dimethylaminomethyl-3,4-dihydro-acridin-1-yl)]-phenol hydrochloride (48% theoretical) in the form of light yellow crystals. (m.p.: >250° C.).
Reaction SMILES: [Br-:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:36])[CH2:10][N+:11]23[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]2)[C@@H:13]([O:19][C:20](=[O:35])[C@@H:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]3)=[CH:5][CH:4]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].CC#N.O>C(Cl)Cl>[Br-:1].[CH3:37][S:38]([O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:36])[CH2:10][N+:11]23[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]2)[C@@H:13]([O:19][C:20](=[O:35])[C@@H:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:12]3)=[CH:5][CH:4]=1)(=[O:40])=[O:39]
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Oc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.2 %

Procedure:
To a solution of (R)-1-(2-(4-hydroxyphenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (diastereomer 1 of I71) (70 mg, 0.13 mmol) in DCM, were sequentially added methanesulfonyl chloride (9.9 μl, 0.13 mmol) and then TEA (17.7 μl, 0.13 mmol). The reaction mixture was stirred at room temperature for two days. The solvent was evaporated, and the crude product was purified first by trituration with Et2O and then by preparative HPLC (eluents: CH3CN/H2O) to obtain (R)-1-(2-(4-(methylsulfonyloxy)phenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (25.5 mg, 31.9% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:13]([O:12][C:11]([N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][CH:34]=2)=[CH:3][CH:4]=1)[CH2:18][C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[OH:20])=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of tert-butyl N-[2-(4-bromophenyl)ethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (435 mg) in 1,2-dimethoxyethane (6 ml) were added 4-methoxycarbonyl-phenyl boronic acid (224 mg), tetrakis(triphenylphosphine)-palladium (55 mg) and aqueous solution of sodium carbonate (2M, 1.0 ml), and the mixture was stirred at 80° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate (400 mg).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:29]1[O:39][C:38]2[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][C:31]=2[O:30]1>>[O:39]1[C:38]2[CH:37]=[CH:36][C:33]([CH2:34][N:19]3[C:14]4[C:15](=[O:18])[N:16]([CH3:17])[C:11]([CH:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:7]([OH:9])=[O:8])=[C:12]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)[C:13]=4[CH:21]=[CH:20]3)=[CH:32][C:31]=2[O:30][CH2:29]1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Reactant: ClCc1ccc2c(c1)OCO2
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc3c(c2)OCO3)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 27 step D from methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 3,4-methylenedioxybenzyl chloride (50% in dcm), and was isolated as beige solid after reverse phase chromatography (41%): 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.99 (s, 9H), 2.42 (s, 3H), 3.67 (s, 3H), 5.46 (s, 1H), 5.63-5.81 (m, 2H), 5.92 (s, 2H), 6.01 (d, J=2.9 Hz, 1H), 6.70-6.84 (m, 3H), 7.00 (d, J=2.8 Hz, 1H), 7.27-7.30 (m, 2H), 7.30-7.38 (m, 1H), 7.46-7.58 (m, 1H). LCMS (m/z) ES+=503 (M+1).
Reaction SMILES: [Cs].[P:2]([O-:20])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].P([O-])([O-])([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:33][N:34]1[C:38](=[O:39])[CH:37]([CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[N:36]([CH3:45])[S:35]1(=[O:47])=[O:46]>CO>[CH2:13]([O:12][P:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O:20][CH2:33][N:34]1[C:38](=[O:39])[CH:37]([CH2:40][CH2:41][CH:42]([CH3:43])[CH3:44])[N:36]([CH3:45])[S:35]1(=[O:46])=[O:47])=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)CCC1C(=O)N(CCl)S(=O)(=O)N1C
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CC(C)CCC1C(=O)N(COP(=O)(OCc2ccccc2)OCc2ccccc2)S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 15 %

Procedure:
To the cesium salt of dibenzyl phosphate (Formula III: A=B=CH2Ph) (prepared from 2.07 g of the phosphate and 1.21 g of cesium carbonate in methanol followed by removal of the methanol) in 30 ml of DMF was added 2-chloromethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 3.72 mmol) and the mixture was allowed to stir at room temperature for 48 hours. The mixture was poured into ice/water, extracted with ethyl acetate, and the organic layer was washed with water, brine and dried. The solvent was concentrated in vacuo and the residue purified by silica gel flash chromatography (60% ethyl acetate/hexane) to afford 0.29 g (15%) of 2-(dibenzyloxyphosphinyloxymethyl)-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3 ; A=B=CH2Ph) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].Cl>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(OCCCC(F)(F)F)ccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(OCCCC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.5 %

Procedure:
To a solution of methyl 2-chloro-5-(4,4,4-trifluorobutoxy)benzoate (74 mg) in MeOH (1 mL) was added 1M aqueous lithium hydroxide solution (0.99 mL) and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was stirred under ice-cooling, and 2M hydrochloric acid was added slowly to acidify to pH 2-3. The precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain the titled compound (49 mg) as a colorless powder.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:26])[NH:8][CH:9]([C:11]2[S:15][C:14]([C:16]([NH:18][O:19]C3CCCCO3)=[O:17])=[CH:13][CH:12]=2)[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C1COCC1.O1CCOCC1>[CH:1]1([NH:6][C:7](=[O:26])[NH:8][CH:9]([C:11]2[S:15][C:14]([C:16]([NH:18][OH:19])=[O:17])=[CH:13][CH:12]=2)[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(NC(=O)NC1CCCC1)c1ccc(C(=O)NOC2CCCCO2)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(NC(=O)NC1CCCC1)c1ccc(C(=O)NO)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16 %

Procedure:
To a solution of 5-(1-(3-cyclopentylureido)ethyl)-N-(tetrahydro-2H-pyran-2-yloxy)thiophene-2-carboxamide obtained in step 3 was dissolved in THF (1 mL) was added 4.0 M HCl in dioxane (0.25 mL). The reaction was stirred for 4 hours at room temperature, evaporated to dryness, redissolved in DMSO (1 mL) and purified on Agilent 1100 LC/MSD instrument to afford the title compounds as a white solid (2.7 mg, 16%) LC-MS: (FA) ES+ 298.
Reaction SMILES: C([O:8][C:9](=[O:26])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:11]C(OC(C)(C)C)=O)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])O.[Na+]>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:11][C@H:10]([C:9]([OH:26])=[O:8])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: COc1ccccc1
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of N-t-butoxycarbonyl-L-phenylalanine benzyl ester (1 g) in methylene chloride (10 ml) is added aluminum chloride (1 g) in anisole (12 ml), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into an aqueous sodium hydrogen carbonate solution and filtered to remove insoluble material. The filtrate is washed with methylene chloride, acidified to pH 2.5 with hydrochloric acid, and adsorbed on high porous polymer HP-20 (manufactured by Mitsubishi Chemical Co., Ltd.). After washing with water, the resin is washed with methanol. Concentration of the methanol eluent gives crystals of L-phenylalanine (0.3 g) melting at 270° C. Yield: 54%.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1)[C:4](=[O:6])[CH3:5])[CH3:2].[CH3:27][O:28][C:29](=[O:49])[CH2:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33](OS(C(F)(F)F)(=O)=O)[CH:32]=1>>[CH3:27][O:28][C:29](=[O:49])[CH2:30][C:31]1[CH:32]=[C:33]([C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:16])[F:17])=[CH:13][C:8]=2[CH2:7][N:3]([C:4](=[O:6])[CH3:5])[CH2:1][CH3:2])[CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(C)=O
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: N-ethyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-acetamide and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].[CH:19](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:20].CN(C)CCN>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([CH:19]=[O:20])[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=COc1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: CN(C)CCN
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (38.22 g, prepared according to the procedure described in WO 96/31478 Step B page 94) in dry dichloromethane (400 mL) was treated with pentafluorophenyl formate (43.32 g, prepared according to the procedure of Kisfaludy and Otvos, Synthesis, 1987, 510). After stirring at room temperature overnight the reaction mixture was treated with N,N-dimethylethylenediamine (32.5 mL) and stirring continued for a further 1.5 hours. The reaction mixture was then washed with 1 M hydrochloric acid (400 mL), then a saturated solution of sodium hydrogen carbonate (400 mL), then water (400 mL), dried over sodium sulfate and then evaporated. The residue was triturated with a mixture of diethyl ether and pentane to give the title compound (27.21 g) as an off white solid, MS: 309 [MNa]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=3)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1.[OH-].[Na+].CO>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=3)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1
Reactant: COC(=O)c1cccc(Cn2c(C)nc3cc(-c4nc5ccccc5o4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1Cc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-1-(3-methoxycarbonylphenylmethyl)-2-methylbenzimidazole (see Working Example 117-2) (125 mg, 0.315 mmol) in chloroform (3 mL) was added aqueous sodium hydroxide solution (1 M, 1 mL, 1 mmol). This two-layer solution was homogenized by the addition of methanol, and this was stirred at room temperature for 20 hours. After the reaction was complete, the solution was concentrated, aqueous acetic acid solution was added, and this was stirred at room temperature. The precipitated crystals were filtered, and after washing with water were dried to yield the title compound (120 mg, 99% yield) as white crystals.