Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:25])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].O>O1CCCC1.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH3:25])=[CH:22][CH:23]=2)[OH:34])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
267 mg of the compound [22-1] was dissolved in a mixed solvent of 10 mL of tetrahydrofuran and 1 mL of methanol, then 22 mg of sodium boronhydride was added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-30/70), to obtain 256 mg of benzyl-4-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]piperidine-1-carboxylate [25-1] (hereinafter, referred to as the compound [25-1]).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:25])=[CH:22]/[CH:23]=O)=[CH:17][CH:16]=1.[C:26]([CH2:28]P(=O)(OCC)OCC)#[N:27]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18](/[C:21](/[CH3:25])=[CH:22]/[CH:23]=[CH:28]/[C:26]#[N:27])=[CH:19][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: C/C(=C\C=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Product: C/C(=C\C=C\C#N)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
According to the method described for Reference Example 35, (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-buten-1-al was allowed to react with diethyl cyanomethylphosphonate gave (E,E)-5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-hexadienenitrile. Recrystallization from ethyl acetate--hexane gave colorless prisms, m.p.134°-136° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CS([Cl:34])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][Cl:34])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CO)cs2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-(4-hydroxymethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (848 mg, 2.83 mmol) and DIPEA (550 mg, 1.5 eq.) in CH2Cl2 (10 mL) was added MsCl (285 L, 1.3 eq.) dropwise. The resulting mixture was stirred overnight. The reaction solution was then concentrated in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:4) to afford the desired product as an oil.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][O:11][S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
To a solution of (R)-Boc-prolinol (500 mg, 2.48 mmol) in pyridine (1.5 mL) was added tosyl chloride (565 mg, 2.96 mmol) in pyridine (1 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 20 min. before allowing it to warm to rt. The mixture was stirred for 8 h at that temperature. The solvent was removed from the resulting suspension, and aq. 1N HCl was added to the crude product and extracted with EtOAc. Organic layer was washed with saturated aq. NaHCO3 followed by water and brine. Organic layer was dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the title product (800 mg, 91%) as a thick oil: MS; m/z 378 (M+Na); 1H NMR (400 MHz, CDCl3); δ 1.38 (m, 9H), 1.79 (m, 2H), 1.93 (m, 2H), 2.44 (s, 3H), 3.26-3.32 (m, 3H), 3.88-3.97 (m, 2H), 4.07-4.14 (m, 2H), 7.34 (br s, 2H), 7.77 (d, 2H, J=8.0 Hz); HPLC (ELSD); 99%.
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[OH2:26]>C(Cl)Cl>[C:1]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O
Reactant: CCCCCCCC/C=C\CCCCCCCCCl
Reactant: C1CNCCN1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N1CCNCC1
Yield: 76 %

Procedure:
A solution of 3.0 g of oleyl chloride in 10 mg of methylene chloride was added portion-wise to a solution of 4.3 g of piperazine in 30 ml of methylene chloride with stirring under ice cooling. After stirring the mixture in situ for additional 2 hours, 10 ml of water was added to the reaction mixture to separate the organic layer. The organic layer was further washed with water and dried over anhydrous sodium sulfate, followed by removal of the solvent by evaporation. The residue obtained was purified by silica gel column chromatography to obtain 2.68 g of the objective compound (yield: 76%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:22]([OH:25])[C:23]#[CH:24]>O1CCCC1.CCOCC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:24]#[C:23][CH2:22][OH:25])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: C#CCO
Reactant: Brc1ccc(C2CC2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: OCC#Cc1ccc(C2CC2)cc1
Temperature: 50 °C

Procedure:
To a degassed solution of 1-bromo-4-cyclopropylbenzene (4.4 g, 22.3 mmol; prepared according to J. Org. Chem. 1976, 41, 2262) in anhydrous tetrahydrofuran (22 mL), copper(I) iodide (134 mg, 0.70 mol) and tetrakis(triphenylphosphine)palladium (773 mg, 0.67 mmol) were added and the mixture was cooled down with ice bath. 1,8-Diazabicyclo[5.4.0]-undec-7-ene (4 mL, 26.8 mmol) was added and the reaction mixture was degassed again. A degassed solution of prop-2-yn-1-ol (1.56 mL, 26.8 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise afterwards and the reaction mixture was stirred at 50° C. over night under nitrogen. After cooling, the mixture was diluted with ether (100 mL) and washed with water (40 mL) and 15% hydrochloric acid (2×40 mL). The aqueous layer was extracted with ether (5×40 mL). Combined organic extracts were finally washed with 10% aqueous solution of sodium hydrogen carbonate (40 mL) and brine (2×40 mL) and dried with anhydrous magnesium sulfate. The crude product was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 10:1-8:1) yielding 3-(4-cyclopropylphenyl)prop-2-yn-1-ol as yellow oil, which solidified in refrigerator.
Reaction SMILES: [Br:1]C1C2SC(C3CC3)=NC=2C=C(C)C=1C=C.ClC1C=C[C:21]([C:24]2C3SC=NC=3C=C(C)C=2C=C)=[CH:20]C=1.[C:36]([O:42][CH2:43][C@@H:44]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:45]1[C:53]([CH3:54])=[CH:52][C:48]2[N:49]=[CH:50][S:51][C:47]=2[C:46]=1C1C=CC(Cl)=CC=1)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>>[C:36]([O:42][CH2:43][C@H:44]([C:45]1[C:53]([CH3:54])=[CH:52][C:48]2[N:49]=[C:50]([CH:24]3[CH2:21][CH2:20]3)[S:51][C:47]=2[C:46]=1[Br:1])[O:62][C:63]([CH3:66])([CH3:64])[CH3:65])(=[O:41])[C:37]([CH3:38])([CH3:40])[CH3:39]
Reactant: C=Cc1c(C)cc2nc(C3CC3)sc2c1Br
Reactant: C=Cc1c(C)cc2ncsc2c1-c1ccc(Cl)cc1
Reactant: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2nc(C3CC3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
Compound 18 was prepared from compound 17 by the method used to convert compound 5G to compound 5J as outlined in Example 1. LCMS-ESI+: calc'd for C22H30BrN2O3S: 468.1 (M+H+). Found: 468.2 (M+H+).
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=O>>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:42]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([N:30]4[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]4)[CH:26]=3)[N:20]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: COc1cccc(C=O)c1
Reactant: CC1CCN(c2ccc(N)c(C(N)=O)c2)CC1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(N4CCC(C)CC4)cc3c(=O)[nH]2)c1
Yield: 59.9 %

Procedure:
According to the preparation of 42, 28 (1.0 g, 4.3 mmol) and 3-methoxybenzaldehyde (34) (0.6 g, 4.3 mmol) were used to afford 58 (0.9 g, 57.6%) as pale yellow prism crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:24][CH:12]([CH3:13])[C:11]([NH:10][C:9]1[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=1)=[O:15]
Reactant: COC(=O)c1cscc1NC(=O)C(C)Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: CC(Oc1ccc(Cl)c(Cl)c1)C(=O)Nc1cscc1C(=O)O

Procedure:
In analogy to Example 2, the title compound was prepared using rac-4-(2-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester and 3,4-dichlorophenol. MS (m/e): 360.0 (M−H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:23]5[CH2:22][NH:21][CH2:20][CH2:19][C:18]=5[N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:26]=[CH:27][N:28]=[CH:29][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30][CH2:31][C:32](O)=[O:33].C(Cl)CCl.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:23]5[CH2:22][N:21]([C:31](=[O:30])[CH2:32][OH:33])[CH2:20][CH2:19][C:18]=5[N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:26]=[CH:27][N:28]=[CH:29][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cc2c3cnc(Nc4ccc5c(n4)CCNC5)nc3n(C3CCCC3)c2cn1
Reactant: O=C(O)CO
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CO)N1CCc2nc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)ccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution of 9-cyclopentyl-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine (21) (145 mg, 0.367 mmol) in DMF (10 mL) were added 2-hydroxyacetic acid (34.3 mg, 0.451 mmol), EDC (191.7 mg, 0.451 mmol), N-hydroxybenzotriazole (61 mg, 0.451 mmol), and N,N-diisopropylethylamine (157 uL, 0.903 mmol). The mixture thus obtained was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluting with 20% to 75% solvent A (DCM:MeOH:NH4OH, 100:10:1) to give the title compound as an off-white solid (117 mg, 70% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.77-1.80 (2H, m), 2.07-2.10 (4H, m), 2.42-2.44 (2H, m), 2.82-2.91 (2H, m), 3.66-3.82 (2H, m), 4.18-4.20 (2H, m), 4.57-4.66 (2H, m), 5.36 (1H, m), 7.68 (1H, d, J=10.0 Hz), 8.06 (1H, d, J=5.0 Hz), 8.19 (1H, d, J=10.0 Hz), 8.48 (1H, d, J=5.0 Hz), 9.03 (1H, s), 9.31 (1H, s) 9.98 (1H, br. s) ppm; LCMS m/z: 444 (M+1).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH2:28])[CH:25]=4)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>C(OCC)(=O)C>[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH:28][C:3]([NH:2][CH3:1])=[O:4])[CH:25]=4)[CH:20]=[CH:19]3)[CH2:16][CH2:17]2)=[CH:8][CH:7]=1
Reactant: NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: CN=C=O
Solvent: CCOC(C)=O
Product: CNC(=O)NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 67.3 %

Procedure:
Under ice cooling, methyl isocyanate (0.02 g) was added dropwise into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.09 g) obtained in Example 132 in ethyl acetate (10 ml) and the resultant mixture was stirred at room temperature for 1 hr. The resulting precipitate was collected by filtration, washed with ether/hexane and dried to give the title compound (0.07 g) as a white powder (yield: 67%).
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH2:2][OH:3].CCC(C[O:12]C(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-].O=O>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:2]([OH:12])(=[O:3])[C:1]([OH:5])=[O:4]
Reactant: O=C([O-])CO
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: O=O
Agent: [Cl-]
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Reaction time: 3.75 h

Procedure:
The reaction in Example 16 was repeated using 15.0 g of Hansenula polymorpha transformant GO1 (109 IU glycolate oxidase and 530,000 IU catalase) which had been permeabilized by treatment with 0.1% Triton X-100/1 freeze-thaw. The mixture was then stirred at 500 rpm and at 5° C. under 120 psig of oxygen, and oxygen was bubbled through the mixture at 50 mL/min using a sparge tube located below the surface of the reaction mixture. After 3.75 h, the yields of glyoxylic acid, oxalic acid, and formic acid were 100%, 0%, and 0%, respectively, with no glycolic acid remaining. The recovered activities of permeabilized-cell glycolate oxidase and catalase were 85% and 166% of their initial values, respectively.
Reaction SMILES: [C:1](#[N:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19].C([O-])(O)=[O:22].[Na+].OOS([O-])=O.[K+].C(Cl)Cl>CC(C)=O.O>[O:22]1[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]#[N:20])[CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19]
Reactant: O=C([O-])O
Reactant: N#CCCCCCCC/C=C/CCCCCCCC#N
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: N#CCCCCCCCC1OC1CCCCCCCC#N
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A mixture of 0.1000 g (E)-octadec-9-enedinitrile and 0.2334 g NaHCO3 in 4.0 mL acetone was cooled in an ice water bath. While stirring, a solution of 0.5365 g Oxone® in 4.0 mL water was added in portions during 30 min. The mixture was allowed to warm to room temperature over 18 h, then 200 mL CH2Cl2 and 10 mL water were added to the reaction mixture to afford a clear 2-phase system. The organic phase was dried over Na2SO4 and evaporated to afford 0.10 g of product as a colorless oil.
Reaction SMILES: [C:1]([C:4]1([O:10][CH2:9]1)[CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[NH2:2].[OH-].[Na+].[C-:13]#[N:14].[Na+].Cl>O>[C:1]([C:4]([OH:10])([CH2:9][C:13]#[N:14])[CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[NH2:2]
Reactant: NC(=O)C1(CC(=O)O)CO1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCC(O)(CC(=O)O)C(N)=O
Reaction time: 27 h
Yield: 101 %

Procedure:
43.5 g (0.3 mol) of the 3-carbamoyl-3,4-epoxybutyric acid was placed in 150 ml of water and 50.2 ml of 5.98 M NaOH solution (0.3 mol) added at 15°C. The pH of the solution was 12.07. 16.2 g of NaCN (0.33 mol) dissolved in 50 ml of water was then added at 15°C. The pH changed to 12.28. The temperature was then raised to 33°-35°C over about 10 min. 6.73 N HCl (approximately 0.3 mol) was then added slowly to maintain the pH at 11. After 27 hrs. the solution was assayed by NMR analysis and showed a 101±2 percent yield of the 3-carbamoyl-3-hydroxy-4-cyanobutyric acid salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][O:8][C:9](=O)[C@@H:10]2[CH2:14][C@@H:13](O)[CH2:12][N:11]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O:55][CH2:56][CH3:57])=O.C(O)(=[S:65])C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[S:65])[C@@H:10]2[CH2:14][C@H:13]([C:56](=[O:55])[CH3:57])[CH2:12][N:11]2[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[O:17])=[CH:30][CH:31]=1
Reactant: COc1ccc(COC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(O)=S
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COC(=S)[C@@H]2C[C@H](C(C)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.5 h

Procedure:
8.6 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline-p-methoxybenzyl ester and 7.86 g of triphenylphosphine were dissolved in 20 ml of dried tetrahydrofuran. To the resulting solution was added dropwise a solution of 5.22 g of diethyl azodicarboxylate in 5 ml of dried tetrahydrofuran under ice-cooling in a nitrogen stream, followed by stirring for 30 minutes at that temperature. Thereafter, 2.28 g of thioacetic acid was added thereto dropwise, and the mixture was stirred for 1 hour under ice-cooling and then at room temperature for 3 hours, followed by concentration. The residue was purified by silica gel column chromatography to obtain cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline p-methoxybenzyl ester.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH2:20]([C:24]1[CH:29]=[CH:28][C:27](O)=CC=1)[CH2:21][CH2:22][CH3:23].C[O:32][C@@H:33](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)[C:34](O)=O>>[CH2:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:15][C:14]=1[O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[C:12]([O:32][CH2:33][CH3:34])[CH:11]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CCCCc1ccccc1Oc1ccc(C[C@H](OC)C(=O)O)c(OCC)c1

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 4-butyl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS(ES) for C22H28O5 [M+Na]+: 395.3.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([O:68][CH2:69][CH2:70][OH:71])=[CH:66][CH:65]=1>>[OH:71][CH2:70][CH2:69][O:68][C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Nc1ccc(OCCO)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(OCCO)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 41.6 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with 2-(4-aminophenoxy)ethanol (0.082 g, 0.53 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide as a yellow solid (Yield 0.11 g, 41%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].O>O1CCCC1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:7]
Reactant: CCNCC
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cccc(CCl)c1
Yield: 89.4 %

Procedure:
A sohtion of 3-(chloromethyl)benzoyl chloride (50 g, 264 mmol) in 200 ml of tetrahydrofuran was poured into a solution of diethylamine (607 mmol, 44.4 g, 63.1 ml) in 450 ml of rapidly stirring water. After 10 m, the mixture was extracted with 100 ml of ether and the extract was dried over MgSO4 and concentrated under recuced pressure affording 53.23 g (236 mmol, 89% yield) of the product as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[OH:28][CH2:29][C:30]1[C:31](C)=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.[C:40]([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:34]3[CH:35]=[C:30]([CH2:29][OH:28])[CH:31]=[CH:32][C:33]=3[CH3:40])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(CO)cccc1B(O)O
Reactant: O=C([O-])[O-]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cc(CO)ccc2C)c1
Yield: 67 %

Procedure:
The procedure used in Example 1: step c was followed using {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 27 (100 mg, 0.2 mmol)), Pd(PPh3)4 (59 mg, 0.05 mmol), 3-hydroxymethyl-2-methyl-phenylboronic acid ((Example 7: step a) 105 mg, 0.63 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Analogous aqueous workup and purification of the crude material by SiO2 flash chromatography (25–50% EtOAc in hexanes) yielded the title compound (72 mg, 67%) as a light-yellow glass. 1H-NMR (CDCl3): δ 8.00 (s, 1H), 7.96 (dt, 1H, J=2.1, 4.4 Hz), 7.93 (m, 1H), 7.54 (m, 2H), 7.27 (m, 2H), 7.18 (d, 1H, J=1.4 Hz), 4.68 (s, 2H), 2.54 (s, 3H), 2.20 (s, 3H), 1.51 (s, 9H).