Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.Cl.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31]Cl.C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])=[O:19])(=[O:16])=[O:15]
Reactant: CN(C)CCCCl
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCCOC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 31, piretanide can be reacted with 3-(dimethylamino)propyl chloride hydrochloride, triethylamine and sodium iodide in dimethylformamide (DMF) to yield 3-(N,N-dimethylaminopropyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:18][C:19](=[CH2:21])[CH3:20].[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:7]
Reactant: C=C(C)C
Reactant: COc1cc(C(=O)O)ccc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(C(=O)OC(C)(C)C)ccc1C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of 3-methoxy-4-methylbenzoic acid (10.0 g), concentrated sulfuric acid (1 ml), and condensed isobutylene (200 ml) in methylene chloride (200 ml) was placed in a pressure vessel and stirred for 16 hours. The vessel was then opened to vent unreacted isobutylene. The remaining liquid was poured into 10% (w/v) sodium hydroxide solution (150 ml) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), and evaporated. The residue was purified by flash chromatography, eluting with 1:9 ethyl acetate:hexane, to give t-butyl 3-methoxy-4-methylbenzoate (9.1 g, 70%) as a colorless oil; NMR (80 MHz, CDCl3): 1.6[s, 9H, C(CH3)3 ], 2.27(s, 3H, CH3), 3.86(s, 3H, OCH3), 7.11(d, 1H), 7.49(m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[NH:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:33])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: C=CCOCC1(c2cccc(C#N)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOCC1(c2cccc(C#N)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C

Procedure:
To a solution of 358 mg of 4-[4-(3-cyanophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in DMF (1.5 mL) 135 mg of potassium carbonate and 101 μL of methyl iodide are added. The mixture is stirred during the night at room temperature, evaporated, washed with brine, extracted with ethyl acetate, dried over magnesium sulfate and concentrated to give the desired compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]#[N:11].[OH-:14].[Na+].OO>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]([NH2:11])=[O:14]
Reactant: [OH-]
Reactant: CC(C)(C#N)c1cccc(F)c1F
Agent: OO
Agent: [Na+]
Product: CC(C)(C(N)=O)c1cccc(F)c1F

Procedure:
Hydrolysis of 2-(2,3-difluorophenyl)-2-methylpropionitrile was performed according to the procedure of Example 10 using sodium hydroxide in the presence of hydrogen peroxide to provide 2-(2,3-difluorophenyl)isobutyramide [1H-NMR (CDCl3): δ 7.17-7.08 (m, 3H), 5.98 (br s, 1H), 5.45 (br s, 1H), 1.60 (s, 6H)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[S:16][C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc(-c2ccc(NC(=O)OC(C)(C)C)nc2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(-c2ccc(NC(=O)OC(C)(C)C)nc2)sc1C(=O)O
Temperature: 70 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A mixture of ethyl 2-(2-tert-butoxycarbonylamino-5-pyridyl)-4-methyl-5-thiazolecarboxylate (180 mg), 1N NaOH (2 ml) and EtOH-THF (2:1, 6 ml) was stirred at 70° C. for 1 hour, to which was added 1 N HCl (2 ml) to give the title compound (151 mg).
Reaction SMILES: Br.Br[CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1.[OH2:22]>>[OH:22][CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1
Reactant: O
Reactant: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Agent: Br
Product: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1

Procedure:
treating the reaction mixture containing the compound (VI) directly with water and reacting by stirring at 50°-100° C., preferably at 60°-80° C., to give 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII), and
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:21])([CH3:20])[C:12]1=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:23][NH2:24]>>[CH3:20][C:13]1([CH3:21])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2][NH:24][CH3:23])[C:12]1=[O:22]
Reactant: CC1(C)C(=O)N([C@H](CCCl)c2ccccc2)c2ccccc21
Reactant: CN
Product: CNCC[C@H](c1ccccc1)N1C(=O)C(C)(C)c2ccccc21
Temperature: 125 °C
Yield: 93 %

Procedure:
A mixture of 1-[(1R)-3-chloro-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (220 mg, 0.700 mmol) and ethanolic solution of methylamine (33% in ethanol, 5 mL) was heated at 125° C. for 2 h with stirring in a sealed reaction vessel. Upon cooling, all volatiles were removed under reduced pressure. The resulting residue was dissolved in dichloromethane (20 mL), washed with aqueous potassium carbonate (5 mL), dried (anhydrous sodium sulfate), and concentrated. Purification by Isco CombiFlash Companion chromatography (RediSep 4-g silica column, 0-15% methanol/dichloromethane/0.5% triethylamine) gave 200 mg (93%) of 3,3-dimethyl-1-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one as a viscous colorless liquid, which was dissolved dichloromethane (5 mL) and treated with an ethereal solution of hydrochloric acid (1 M, 0.7 mL, 0.7 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield 3,3-dimethyl-1-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one hydrochloride as a white powder. MS (ES) m/z 308.9 ([M+H]+); HRMS: calculated for C20H24N2O+H+, 309.1961; found (ESI, [M+H]+), 309.1953.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][C:7]1([CH3:13])[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.[O:19]=[C:20]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][N:21]1[CH2:37][C:38](O)=[O:39].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][C:7]1([CH3:13])[NH:8][CH2:9][CH2:10][N:11]([C:38](=[O:39])[CH2:37][N:21]2[CH2:22][CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:20]2=[O:19])[CH2:12]1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: COc1ccc(CC2(C)CNCCN2)cc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC2(C)CN(C(=O)CN3CCC(c4ccccc4)(c4ccccc4)C3=O)CCN2)cc1OC
Reaction time: 8 h

Procedure:
To 2-(3,4-dimethoxybenzyl)-2-methylpiperazine (0.052 g, 0.208 mmol; German Patent No. DE2438725), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.061 g, 0.208 mmol; Example 1C) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.079 g, 0.208 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.054 mL, 0.312 mmol) and the reaction stirred overnight. The reaction was loaded onto silica gel and the product eluted using a gradient of 0.5% methanol/dichloromethane to 5% methanol/dichloromethane containing 7 N NH3 over 30 minutes to provide the title compound. MS (ESI+) m/z 528.2 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5](Cl)[CH:4]=[C:3]([C:8]([O:10]O)=O)[CH:2]=1.[CH2:12]([N:16]1CCCCC1)[CH2:13]C#C>C(Cl)Cl>[CH2:3]1[CH:2]2[N:16]([CH2:4][CH2:5][CH2:6][CH2:1]2)[CH2:12][CH2:13][C:8]1=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCCN1CCCCC1
Solvent: ClCCl
Product: O=C1CCN2CCCCC2C1

Procedure:
m-CPBA (600 mg, 3.65 mmol) was added into a solution of 1-(but-3-ynyl)piperidine (500 mg, 3.65 mmol and 4 Å MS (5× weight of m-CPBA) in DCM under N2 at 0° C. The N-oxide formation was monitored by TLC. After completion, Ph3PAuNTf2 (134 mg, 0.18 mmol) was added to the reaction at 0° C. Upon completion, the mixture was diluted with DCM and the molecular sieves were filtered off. The filtrate was washed with 5% aqueous Na2CO3, dried over Na2SO4 and concentrated under vacuum. The residue was used for the next reaction without further purification. MS (ESI): 154 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:9]=1[CH3:20])[CH3:6])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]([N:7]([C:30](=[O:31])[CH2:29][O:28][CH3:27])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:9]=1[CH3:20])[CH3:6])=[O:4]
Reactant: COCC(=O)Cl
Reactant: COC(=O)C(C)Nc1c(C)ccc(COC(C)=O)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCC(=O)N(c1c(C)ccc(COC(C)=O)c1C)C(C)C(=O)OC
Reaction time: 7 h

Procedure:
35.0 g of N-(1'-methoxycarbonyl-ethyl)-2,6-dimethyl-3-acetoxymethylaniline and 13.3 g of sodium carbonate were placed into 250 ml of toluene, and 20.0 g of methoxyacetic acid chloride, dissolved in 50 ml of toluene, were slowly added. After the exothermic reaction had subsided, the temperature was held at 45° C. for 7 hours by means of a water-bath. The cooled reaction mixture was filtered, and the filtrate was concentrated in a rotary evaporator. The oily residue was distilled: b.p. 167°-171° C. at 0.07 bar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[C:25]2[CH:41]=[CH:42][CH:43]=[CH:44][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[C:25]2[CH:41]=[CH:42][CH:43]=[CH:44][C:24]1=2)=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CCCCCCC1C(=O)N(NC(=O)[C@@H](N)C(C)C)c2ccccc2-c2ccccc21
Agent: Cl
Product: CCCCCCC1C(=O)N(NC(=O)[C@@H](NC(=O)[C@@H](O)c2cc(F)cc(F)c2)C(C)C)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-V), the title compound was prepared. The product was purified by chromatography (silica, 5% MeOH/CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[S:21][C:20]([C:22](O)=O)=[CH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl-].[Cl-].[NH2:39][C:40]1[C:48]([NH2:49])=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43]>N1C=CC=CC=1.CN(C=O)C>[C:42]([C:41]1[C:40]2[N:39]=[C:22]([C:20]3[S:21][C:17]([CH:12]4[CH2:13][CH2:14][CH2:15][CH2:16][N:11]4[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:18][CH:19]=3)[NH:49][C:48]=2[CH:47]=[CH:46][CH:45]=1)(=[O:43])[NH2:44]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccc(C2CCCCN2C(=O)OCc2ccccc2)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCCN4C(=O)OCc4ccccc4)s3)nc12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 28D (0.35 g) in pyridine (10 mL) and DMF (10 mL) was added CDI (0.23 g), and the mixture was heated at 40° C. for 1 hour. 2,3-Diaminobenzamide dichloride (0.22 g) was added, and the mixture stirred at ambient temperature overnight and concentrated. The concentrate was stirred in acetic acid (20 mL) at 80° C. for 4 hours and concentrated. The concentrate was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The extract was washed with water and concentrated, and the concentrate was flash chromatographed on silica gel with 40-80% ethyl acetate in hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:29]([O-:31])=[O:30])=[C:11]([F:28])[CH:12]=[C:13]([CH:15](C(OCC)=O)[C:16]([O:18][C:19](C)(C)[CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([N+:29]([O-:31])=[O:30])=[C:11]([F:28])[CH:12]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(F)c([N+](=O)[O-])c(OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(F)c([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.6 %

Procedure:
In methylene chloride (30 ml) was dissolved tert-butyl ethyl 5-benzyloxy-3-fluoro-4-nitrophenylmalonate (2.89 g, 6.67 mmol) . To the resulting solution was added trifluoroacetic acid (30 ml). The resulting mixture was stirred at room temperature for 3.5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was neutralized with an aqueous saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate/hexane (1/5) eluate fractions, ethyl 5-benzyloxy-3-fluoro-4-nitrophenylacetate (1.57 g, 70%) was obtained as a yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:17]([O:21][C:22]([N:24]1[C@@H:29]([C@@H:30]([OH:41])[C@@H:31]([NH2:40])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=2)[CH2:28][O:27][C@@H:26]([O:42][CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C@@H:25]1[CH3:48])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH:29]([C@@H:30]([OH:41])[C@@H:31]([NH:40][C:1](=[O:3])[CH3:2])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=2)[CH2:28][O:27][C@@H:26]([O:42][CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C@@H:25]1[CH3:48])=[O:23])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](O)[C@@H](N)Cc2cccc(O)c2)N1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)C1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 34.7 %

Procedure:
Add acetic anhydride (320 μL, 3.4 mmol) and N,N-diisopropylethylamine (590 μL, 3.4 mmol) to a solution of 5-(R)-[2-(S)-amino-1-(S)-hydroxy-3-(3-hydroxyphenyl)-propyl]-2-(R)-(2,2-dimethylpropoxy)-3-(S)-methylmorpholine-4-carboxylic acid tert-butyl ester (770 mg, 1.70 mmol). Stir for 2.5 hours. Dilute with ethyl acetate, wash with 1 N hydrochloric acid (twice), saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 20:80 to 25:75 ethyl acetate:hexanes) to give the desired compound (292 mg).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8]C(C2C=CC(C)=CC=2)=O)[O:5][C@@H:4]([N:18]2[CH:25]=[C:24]([C:26]#[C:27][Si](C)(C)C)[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1.[Na]>C[O-].[Na+].CO>[C:26]([C:24]1[C:22](=[O:23])[NH:21][C:19](=[O:20])[N:18]([CH:25]=1)[C@@H:4]1[O:5][C@H:6]([CH2:7][OH:8])[C@@H:2]([F:1])[CH2:3]1)#[CH:27]
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(C#C[Si](C)(C)C)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: C#Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product of Stage c), in 0.2M sodium methoxide in methanol (freshly prepared from sodium and methanol) is stirred at room temperature for 3.0 hr. then neutralized by portionwise addition of Dowex 50 (H+) ion exchange resin. The resin is filtered off and washed well with methanol. The filtrate is evaporated to dryness and the residue partitioned between water and ether. The aqueous layer is washed with ether then evaporated to dryness, the residue triturated with ethanol and the solid filtered and washed with ether to give the title compound.
Reaction SMILES: [CH2:1]([Si:3]([CH2:35][CH3:36])([CH2:33][CH3:34])[O:4][CH:5]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)[CH2:6][C:7](N1[C@@H]2CC3C(C)(C)C2(CC3)CS1(=O)=O)=[O:8])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.CCCCCC>[CH2:35]([Si:3]([CH2:1][CH3:2])([CH2:33][CH3:34])[O:4][C@H:5]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)[CH2:6][CH:7]=[O:8])[CH3:36]
Reactant: CC[Si](CC)(CC)OC(CC(=O)N1[C@@H]2CC3CCC2(CS1(=O)=O)C3(C)C)c1ccc2ncccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC[Si](CC)(CC)O[C@@H](CC=O)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
A solution of (2R)-N-[3-(triethylsilyloxy)-3-(6-quinolyl)-propionyl]bomane-10,2-sultam (52.8 gm) in 1000 mL of CH2Cl2 is cooled to −78° C., and a 1.0 M solution of diisobutylaluminum hydride in hexane is added dropwise so as to keep the reaction temperature below −65° C. The mixture is stirred for an additional 6 hours at −78° C., then is quenched by addition of sat. aq. NH4Cl and allowed to warm to ambient temperature. The mixture is washed with brine, and the organic phase is dried over MgSO4, filtered, and evaporated. The product is purified by silica gel chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:28]1[O:32][CH:31]=[C:30]([C:33]([OH:35])=O)[CH:29]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[NH2:36][CH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>C(Cl)Cl>[CH:37]1([NH:36][C:33]([C:30]2[CH:29]=[C:28]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)[O:32][CH:31]=2)=[O:35])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38]1
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)O)co1)C(=O)N1CCC[C@@H]21
Reactant: NC1CCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)NC3CCc4ccccc43)co1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-{(9aS)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}-3-furoic acid (0.100 g, 0.209 mmol) was dissolved in CH2Cl2. 1-aminoindane (0.037 mL, 0.313 mmol) was added followed by EDCI (0. 048 g, 0.251 mmol) and HOBt (0.034 g, 0.251 mmol). After 14 h of stirring at ambient temperature the reaction mixture was poured onto 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a brown residue. Chromatography on silica gel using 4:1 EtOAc:Hexanes eluted the product to provide the title compound upon concentration as a white solid (0.062 g, 0.105 mmol, 50% yield): 1H NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 8.11 (d, J=9.5 Hz, 1H), 7.32 (m, 1H), 7.25–7.15 (m, 5H), 6.96 (t, J=8.6 Hz, 2H), 6.32 (m, 1H), 5.69 (dd, J=15.5, 7.7 Hz, 1H), 4.65 (dd, J=10.4, 6.2 Hz, 1H), 4.37 (dd, J=14.2, 7.0), 3.73–3.63 (m, 1H), 3.44–3.38 (m, 1H), 3.17–3.01 (m, 5H), 2.92–2.83 (m, 1H), 2.68–2.60 (m, 1H), 2.48–2.40 (m,1H), 2.37–2.25 (m, 2H), 1.96–1.86 (m, 1H), 1.38–1.30 (m, 1H), 1.27 (t, J=7.1 Hz, 3H); ESMS m/z 594 (M+H)+, 592 (M−H)+; Anal. Calcd. For C35H32FN3O5.½H2O: C, 69.75; H, 5.52; N, 6.97; found: C, 69.58; H, 5.43; N, 7.05.
Reaction SMILES: C[Si](C)(C)Cl.[CH2:6]([O:8][P:9](C(OCC)OCC)([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[CH3:7].C(O)C>ClCCl>[CH2:6]([O:8][PH:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[CH3:7]
Reactant: CCOC(OCC)P(=O)(CC1CCCCC1)OCC
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCO[PH](=O)CC1CCCCC1
Reaction time: 72 h

Procedure:
107 g of trimethylchlorosilane are added to a solution of 151 g of diethoxymethyl(cyclohexylmethyl)phosphinic acid ethyl ester in 430 ml of dichloromethane that contains 10% by volume ethanol and the mixture is left to stand for 3 days at room temperature, then concentrated to dryness by evaporation and distilled under reduced pressure, yielding cyclohexylmethylphosphinic acid ethyl ester having a boiling point of 50° (3×10-4 bar).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:26]([C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH:26]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CCCN2)cc1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCC[C@H]2C(c2ccccc2)c2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, (2S)-2-benzhydrylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 5.18 minutes; C34H30Cl2N4O2 (597.54); mass spectrum: (M−H)−=597/599/601 (chlorine isotope).