Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:13](=[O:23])[NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[OH:22])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH3:30][C:31]1[N:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:33][CH:32]=1.CO>ClCCl.Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:13](=[O:23])[NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([S:37]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:30])[N:36]=2)(=[O:39])=[O:38])[CH2:17][CH:16]1[OH:22])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cccc(S(=O)(=O)Cl)n1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCNCC1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)N2CCCC(NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(O)C2)n1

Procedure:
To a solution of [(S)-1-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester of Example 2 (1.0 g) in dichloromethane (20 mL) was added saturated sodium bicarbonate (50 mL). To this solution was added 6-methyl-pyridine-2-sulphonyl chloride (6.44 mL of a 0.13 g/mL solution in 9M HCl). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dichloromethane) provided the title compound (1.2 g).
Reaction SMILES: Br[C:2]1[C:3]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17]>CN(C)C=O.O.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>[CH2:17]([C:2]1[C:3]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1)[CH:16]=[CH2:15]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)c1c(Br)cnc2c1CCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(c1[Si](C)(C)C)CCO2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
A mixture of 5-bromo-4-(trimethylsilyl)-2,3-dihydrofuro[2,3-b]pyridine (37.5 g, 138 mmol), allyltributyltin (65.8 mL, 212 mmol) and trans-dichlorobis(triphenylphosphine)palladium(II) (9.9 g, 14.1 mmol) in N,N-dimethylformamide (500 mL) was stirred at 100° C. for 1.5 hr. The reaction solution was diluted with water, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=25/75→33/67) to give the title compound (30.9 g, yield 96%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]([NH:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:16]([CH3:32])([CH3:31])[CH2:15]1)=[O:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:39](Br)[CH3:40]>>[CH2:39]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]([NH:13][CH:14]1[CH2:15][C:16]([CH3:31])([CH3:32])[N:17]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:18]([CH3:20])([CH3:21])[CH2:19]1)=[O:12])=[O:10])[CH3:40]
Reactant: CCCCCCCCON1C(C)(C)CC(NC(=O)C(=O)Nc2ccccc2O)CC1(C)C
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCON1C(C)(C)CC(NC(=O)C(=O)Nc2ccccc2OCC)CC1(C)C

Procedure:
The above-named compound is prepared by reacting the compound prepared in Example 13A with potassium carbonate and ethyl bromide.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([C:25]1[N:26]=[CH:27][N:28]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]=1[CH3:30])[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3>N1C=CC=CC=1>[C:1]([O:8][CH:9]([C:25]1[N:26]=[CH:27][N:28]([C:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:29]=1[CH3:30])[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2]
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)C1CCc2c(C)c3ccccc3n2C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Acetic anhydride (5 ml) was added to a solution of 8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (4 g, a mixture of the isomers A and B) in pyridine (50 ml). After being stirred at room temperature for 20 hours, the solution was evaporated in vacuo. Silica gel column chromatography (1% methanol-methylene chloride) of the oil obtained gave 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (4.30 g) as an amorphous powder.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[CH2:6]2.[C:12]([C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)([CH3:15])([CH3:14])[CH3:13]>CCOCC>[C:12]([C:16]1[CH:17]=[C:18]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH3:11])[CH2:6]3)[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc([Mg]Br)cc(C(C)(C)C)c1
Reactant: CC1=Cc2c(Cl)cccc2C1
Solvent: CCOCC
Product: CC1=Cc2c(cccc2-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-methylindene (6.1 g, 37 mmol) and NiCl]2(PPh3)2 (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-Di-t-butylphenylmagnesium bromide (10 g, 37 mmol) as a Et2O solution was added to the solution and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 4.6 g (40%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:11][C@@H:10]([C:27](=[O:47])[N:28]([CH:44]2[CH2:46][CH2:45]2)[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:49][CH2:50][N:51]1[C:59](=[O:60])[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]1=[O:61].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([CH2:49][CH2:50][N:51]2[C:52](=[O:61])[C:53]3[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:59]2=[O:60])[S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:11][C@@H:10]([C:27](=[O:47])[N:28]([CH:44]2[CH2:46][CH2:45]2)[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NS(=O)(=O)c3ccccc3[N+](=O)[O-])CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N(CCN3C(=O)c4ccccc4C3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 60 °C
Reaction time: 13 h

Procedure:
To a solution of (3R*,5S*)3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-(2-nitro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.60 mmol), 2-(2-hydroxyethyl) isoindole-1,3-dione (171 mg, 0.9 mmol), and PPh3 (315 mg, 1.2 mmol) in THF is added DEAD (208 mg, 1.2 mmol) at room temperature, then the mixture is stirred at 60° C. After 13 h, the reaction mixture is quenched by H2O (20 mL) and extracted with EtOAc (50 mL). The organic phase is successively washed with 5% aqueous KHSO4, H2O, and brine, then dried over Na2SO4 and concentrated in reduced pressure. The residue is purified by silica gel column chromatography to afford the title compound as yellow amorphous material. MS: 843 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 4.41 min.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=1)[CH:3]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)[C:4]([OH:6])=[O:5]>[OH-].[Na+].CO>[OH:1][CH:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)[CH:3]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(O)C(C(=O)O)c2ccc3c(c2)OCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(O)C(C(=O)O)c2ccc3c(c2)OCO3)cc1
Yield: 78.2 %

Procedure:
A solution of (2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxy-phenyl)-3-(4-methoxycarbonylphenyl)propionic acid (80 mg) in 1N aqueous sodium hydroxide solution (1.2 ml) and methanol (5 ml) was stirred at ambient temperature for 18 hours. The reaction was quenched with iN-hydrochloric acid and then the resulting mixture was diluted with ethyl acetate. The layers were separated and the organic layer was washed with brine. The organic layer was dried and evaporated to afford (2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-carboxyphenyl)propionic acid (60 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH4+].[Cl-]>[Zn].C1C=CC=CC=1>[CH3:14][S:13][C:4]1[N:3]=[CH:2][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)c1cnc(SC)nc1
Temperature: 80 °C

Procedure:
Ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (12.5 g, 53.88 mmol) and Zn powder (14.1 g, 215.52 mmol) were combined and benzene (60 ml) and 3M NH4Cl (140 ml) were added. The suspension was stirred vigorously and heated to 80° C. for 30 h. The reaction mixture was filtered through celite and washed with EtOAc (200 ml). The filtrate was concentrated in vacuo to about 50 ml and then partitioned between H2O (400 ml) and EtOAc (400 ml). The aqueous layer was further extracted with EtOAc (250 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to a dark oil. This was purified by column chromatography eluting with neat heptane followed by 1:1:1 heptane/CH2Cl2/Et2O and finally 2:2:0.5 heptane/CH2Cl2/Et2O. The title compound was obtained as a colourless oil (13 g, 61%). m/z 199 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.30 (3H, t), 2.60 (3H, s), 4.35 (2H, q), 9.0 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[CH:15]=[CH:14]4)[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[N:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc4c(ccn4Cc4ccccc4Cl)c3)c3c(N)ncnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc3c(ccn3Cc3ccccc3Cl)c1)nn2C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of EXAMPLE 201B (1.28 g, 2.3 mmol) in anhydrous CH2Cl2 (30 ml) was cooled in an ice bath and TFA (7.5 ml) was added dropwise under inert atmosphere. After stirring 15 min the ice bath was removed and the reaction allowed to warm to ambient temperature while stirring 1 hr. The reaction was concentrated and the residue dissolved in 1M-HCl. The solution washed with EtOAc, basified with 1M-Na2CO3 (pH 9-10) and extracted with 5% MeOH/CH2Cl2 (3×100 ml). The combined extracts were dried over Na2SO4, filtered, concentrated and dried to give the title compound as a tan foam (70%). MS (ESI+) m/e 458 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 8.22 (s, 1H), 7.88 (s, 1H), 7.55 (m, 3H), 7.42 (d, 1H), 7.33 (m, 1H), 7.25 (m, 1H), 6.74 (dd, 1H), 6.67 (d, 1H), 6.24 (vbr s, 3H), 5.59 (s, 2H), 4.73 (m, 1H), 3.07 (m, 2H), 2.63 (m, 2H), 2.04 (m, 2H), 1.82 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH:13]1[CH:14]=[CH:15][C:16]([C@H:19]2O[C@@H:20]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:18]=1.B(F)(F)F.CCOCC>O1CCOCC1>[C:16]1([C:19]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=c1oc2ccccc2c(O)c1C(=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flame-dried flask containing a mixture of 650 mg of 4-hydroxycoumarin and 1.0 g of commercially available trans-stilbene oxide in 20 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is flash column chromatographed with 50% to 66% ethyl acetate in hexane to yield 880 mg of the title product as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][O:4][CH2:5][CH2:6][CH:7]=[O:8].[C:16]1(CCCCOCCC(O)CCC=C)[CH:21]=CC=[CH:18][CH:17]=1>>[F:1][C:2]([F:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][O:4][CH2:5][CH2:6][CH:7]([OH:8])[CH2:18][CH2:17][CH:16]=[CH2:21]
Reactant: O=CCCOCC(F)(F)c1ccccc1
Reactant: C=CCCC(O)CCOCCCCc1ccccc1
Product: C=CCCC(O)CCOCC(F)(F)c1ccccc1
Yield: 53 %

Procedure:
Obtained from Intermediate 82 (1.86 g, 8.7 mmol) by the procedure described in Intermediate 14. Purification by column chromatography with silica gel eluting with ethyl acetate/n-hexane (1:6) gave the title compound (1.24 g, 53%) as oil.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:45])[CH2:5][CH:6]([CH2:26][O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[I-:46].[Na+]>C(#N)C>[I:46][CH2:2][O:3][C:4](=[O:45])[CH2:5][CH:6]([CH2:26][O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCI

Procedure:
3,3-bis(N-CBz-L-valyloxymethyl)-propionic acid chloromethyl ester (900 mg, 1.38 mmole) was dissolved in acetonitrile (5 ml). Sodium iodide (289 mg, 1.93 mmole) was added to the solution. After reaction at 70° C. for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (5 ml) and refiltered. The solution was dried and gave the titled product. 800 mg.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]1[CH2:8][C@@H:7]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Cl:21][C:18]1[CH:17]=[N:16][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C@H:7]3[CH2:8][C@H:6]3[CH2:5][CH2:4][NH2:1])[CH2:10][CH2:11]2)=[N:20][CH:19]=1
Reactant: [N-]=[N+]=NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-{4-[(1S,2S)-2-(2-azidoethyl)cyclopropyl]piperidin-1-yl}-5-chloropyrimidine (34 mg, 0.11 mmol) from step 2 of this example was dissolved in THF (1 mL), triphenylphosphine (58.1 mg, 0.22 mmol) was added, then water (0.085 mL). The reaction was run at room temperature for 1 hour, then 40° C. 1 hour. The reaction was cooled down to room temperature, concentrated to dryness and purified by column chromatography through a 12 gram RediSep Rf™ silica gel cartridge eluting with 10% methanol/dichloromethane to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Cl:11].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:6][C:5]=1[Cl:11]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCOCC2)cc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A mixture of 2-chloro-4-fluoro-benzoic acid methyl ester (3.51 g, 18.6 mmol), morpholine (1.95 mL, 22.3 mmol) and potassium carbonate (5.12 g, 37.1 mmol) in N-methylpyrrolidinone (20 mL) was stirred at 120° C. for 5 h. The reaction was cooled, diluted with ethyl acetate and filtered through Celite. The filtrate was washed four times with water, once with brine, was dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 2:8 ethyl acetate:hexanes to provide 2-chloro-4-morpholin-4-yl-benzoic acid methyl ester (3.08 g, 65% yield) as a white solid. 1H-NMR (CDCl3, 500 MHz) 7.79 (d, 1H), 6.81 (d, 1H), 6.67 (dd, 1H), 3.81 (s, 3H), 3.78 (m, 4H), 3.20 (m, 4H) ppm; MS (FIA) 256.1 (M+H); HPLC (Method A) 3.275 min.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[CH:15][C:14]=1[N+:27]([O-:29])=[O:28]>CS(C)=O>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:14]([N+:27]([O-:29])=[O:28])[CH:15]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(-c2ccccc2OC)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Dimethyl malonate (14 mL) was added dropwise to 2.9 g of sodium hydride suspended in 50 mL of dimethylsulfoxide. The mixture was stirred at 100° C. for 15 minutes and cooled to room temperature. Crude 4-fluoro-2′-methoxy-3-nitrobiphenyl in 60 mL of dimethylsulfoxide was added and the mixture stirred at 100° C. for 2 hours. The reaction mixture was cooled, quenched with 300 mL of saturated ammonium chloride solution and extracted twice with ethyl acetate. The extracts were combined, washed with saturated ammonium chloride, water, and brine, dried over anhydrous sodium sulfate and concentrated to give crude dimethyl 2′-methoxy-3-nitrobiphenyl-4-malonate as a yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27]C)=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:24][O:23][C:21]([CH:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:30][CH:29]=1)[C:25]([OH:27])=[O:26])=[O:22]
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of dimethyl 4-[2-(2-naphthoxy)ethoxy]benzylmalonate (0.44 g, 1.07 mmol) in a mixture of methanol (4.3 ml) and tetrahydrofuran (2.1 ml) at 0° C. is added a 2 mol/L aqueous solution of sodium hydroxide (0.59 ml, 1.18 mmol). The mixture is stirred for 2 h at room temperature, and then the solvent is removed under a vacuum. The residue was dissolved in saturated aqueous sodium bicarbonate (10 ml) and washed with ethyl acetate (10 ml). The aqueous solution is acidified to pH 2–3 with dilute hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined extracts are washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate to give the title compound (0.35 g, 83%). HRMS calcd for C23H22O6: 394.4208. Found: 394.4206. MA calcd for C23H22O6: C, 70.04%; H, 5.62%. Found: C, 70.18%; H, 5.66%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:36]([O:38][CH3:39])=[O:37]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)[C:36]([O:38][CH3:39])=[O:37])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3C2)c1
Reactant: COC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(=O)OC)C2Cc3ccccc3C2)c1

Procedure:
Prepared according to the procedure described in Example 23, Step 1, using the following starting materials: [2′-(indan-2-ylaminomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][N:4]=[C:5]([NH2:27])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])=S)[N:11]=1.C(N(CC)CC)C>CN(C)C=O.[N+]([O-])([O-])=O.[Ag+]>[F:1][C:2]([F:29])([F:28])[CH2:3][N:4]=[C:5]([NH2:27])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[NH:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)[N:11]=1
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCCCNC(=S)Nc2ccccc2N)cs1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNc2nc3ccccc3[nH]2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)-guanidino]-4-[4-(3-[2-aminophenyl]thioureido)butyl]thiazole (0.45 g.), silver nitrate (0.34 g.) and triethylamine (0.28 ml.) in dimethylformamide (3 ml.) was stirred vigorously at ambient temperature overnight. Hydrogen sulphide gas was then bubbled through the reaction mixture until no more solid precipitated. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate evaporated to dryness in vacuo. The residue was purified by low pressure liquid chromatography using chloroform/methanol/ammonia, 9:1:0.1 v/v/v as eluant to give 2-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]benzimidazole which was converted to the hydrogen maleate salt (0.25 g.), mp. 183°-186°.