Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:3][N:2]=1.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:3][N:2]=1
Reactant: O=C(Nc1cncc2ccccc12)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cncc2ccccc12)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 28.5 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl isoquinolin-4-ylcarbamate (236 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 87.7 mg (28.5%) of the desired product as a solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=4[Cl:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:26]([OH:30])[CH2:27][CH2:28][CH3:29])=[CH:6][CH:5]=1.[CH3:31]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=4[Cl:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:26]([O:30][CH3:31])[CH2:27][CH2:28][CH3:29])=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
Sodium hydride (60% in oil, 7.6 mg, 0.190 mmol) was added to a stirred solution of 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butan-1-ol (69.5 mg, 0.158 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature. After stirring 5 min, methyl iodide (33.6 mg, 0.237 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (43.4 mg, 0.0958 mmol, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][C:13]1[O:17][N:16]=[CH:15][CH:14]=1>CO.O>[O:17]1[C:13]([CH2:12][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=[N:16]1
Reactant: Nc1ccc(S)cc1
Reactant: BrCc1ccno1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(SCc2ccno2)cc1
Yield: 99.9 %

Procedure:
To a mixed solution of 4-aminothiophenol (600 mg) and sodium hydroxide (276 mg) in methanol (10 ml) and water (6 ml), a solution of 5-bromomethyl isoxazole (932 mg) in methanol (5 ml) was added at 0° C. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, to give 4-[(isoxazol-5-ylmethyl)sulfanyl]aniline (988 mg) as oil.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=12.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([N:2]2[CH:3]=[C:4]3[C:5]([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]3)=[N:1]2)=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]nc2CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C#N)cc3)nc2CC1

Procedure:
1,1-Dimethylethyl 4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 9) (1.80 g, 7.58 mmol), 4-cyanophenyl boronic acid (2.23 g, 15.16 mmol; commercially available from e.g. Aldrich), copper(II) acetate (4.15 g, 22.76 mmol), pyridine (1.21 ml, 15.16 mmol) and powdered 4 Å molecular sieves (5.33 g) were stirred in dichloromethane (80 ml) at room temperature in air for 40 hours. The mixture was filtered through a pad of Kieselguhr and the filtrate evaporated. The residue was dissolved in ethyl acetate and the solution washed with 5% sodium bicarbonate solution (×3), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography eluting with 10-40% ethyl acetate in n-pentane to give the title compound (D10). MS (ES+) m/e 339 [M+H]+
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[O:6]1[C:10]2(CCC(=O)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:5]=[C:4]1[CH2:12][CH2:11][C:10]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:2][CH2:3]1
Reactant: [Li]CCCC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 30 ml, 75 mmol) was slowly added to a suspension of methyltriphenylphosphonium bromide (28.07 g, 79 mmol) in THF (150 ml) at −10° C. After stirring for 1 h, 1,4-dioxaspiro[4.5]decan-8-one (8.01 g, 51.3 mmol) was added. The reaction was warmed to room temperature and stirred for 4 h. The reaction was quenched with sat. aq. NH4Cl and extracted by diethyl ether. The combined organic extracts were dried (Na2SO4), concentrated at 200 mbar and 30° C. The residue was diluted with DCM and hexanes (1:1), and the solid was filtered. The organic extracts were concentrated at 200 mbar and 30° C., followed by silica gel chromatography (EtOAc/hexanes: 0-10%-20% gradient) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:19][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:20]
Reactant: COC(=O)CCCCCCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCO
Product: COC(=O)/C=C/c1c(C#CCCCCO)cccc1OCCCCCCCC(=O)OC
Yield: 67 %

Procedure:
Using the procedure of example 122, (E)-3-[(2-hydroxy-6-(6-hydroxy-1-hexynyl)phenyl]-2-propenoic acid methyl ester (example 176) was alkylated with methyl 8-bromo-octanoate giving the title compound, in 67% yield, as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[OH:13][C:14]1[CH:22]=[CH:21][C:17]2[CH:18]=[CH:19][O:20][C:16]=2[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[O:20]1[C:16]2[CH:15]=[C:14]([O:13][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:22]=[CH:21][C:17]=2[CH:18]=[CH:19]1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc2ccoc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc2ccoc2c1
Temperature: 120 °C
Yield: 24.9 %

Procedure:
##STR16## (±)-α-(Chloromethyl)-3-pyridinepropanol (0.339 g, Example 2a)) was dissolved in anhydrous N,N-dimethylformamide (5 ml) and added to a suspension of 6-hydroxybenzofuran (0.245 g, Bull. Soc. Chim. Fr., 1973, 2355) and cesium carbonate (0.596 g) in anhydrous N,N-dimethylformamide (5 ml) which had been heated previously for one hour at 120° C. The mixture was then heated at 120° C. for 7 hours before being cooled to room temperature. The mixture was then poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethanol (19:1) and recrystallised from ethyl acetate:hexane to give the title compound (0.129 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(Cl)(Cl)Cl.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.[Pd]>[CH3:5][N:4]1[C@H:3]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:8][C:7]([C:2]4[CH:3]=[N:4][C:5]5[C:10]([CH:11]=4)=[CH:9][CH:8]=[CH:7][CH:6]=5)=[CH:6][C:19]=3[CH2:20][CH2:2]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: Brc1cnc2ccccc2c1
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cnc5ccccc5c4)cc3CC[C@@H]12
Yield: 56 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. An additional 23 mg of the palladium reagent was added, and the mixture was heated an additional 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 130 mg (56%) of the title compound as an amorphous solid. mp 180°-185°. FDMS: m/e=356. α[D]589 =+80.22 (c=0.37, chloroform).
Reaction SMILES: Cl.[C:2]1([CH3:18])[CH:7]=[CH:6][C:5]([C:8]([N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)N)=[O:9])=[CH:4][CH:3]=1.[CH3:19][CH2:20][O:21][C:22]([CH:24]1[CH2:30][CH2:29][C:27](=O)[CH2:26][CH2:25]1)=[O:23].C(O)(=O)C.Cl>O>[C:2]1([CH3:18])[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:27]3[CH2:29][CH2:30][CH:24]([C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:25][C:26]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Cc1ccc(C(=O)N(N)c2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CCc2c(c3ccccc3n2C(=O)c2ccc(C)cc2)C1

Procedure:
1-(4-Toluoyl)-1-phenylhydrazine hydrochloride (13 g.) and 8.7 g. of ethyl cyclohexanone-4-carboxylate (prepared in situ from the corresponding ethylene ketal) in 40 ml. glacial acetic acid, and 5 ml. glacial acetic acid saturated with hydrogen chloride was warmed on a steam bath for thirty minutes, diluted with water and extracted with ether. The ether extracts were washed with potassium bicarbonate solution and water, dried, and evaporated to dryness. The residue was chromatographed on silica gel using 10% ether-pentane as eluant to give 12.7 g. of the title compound; m.p. 70°-72°C. (hexane-ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9]C(=O)C(C)(C)C)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.O.N1C=CC=CC=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Nc1nc(Cl)ccc1Cl
Temperature: 115 °C

Procedure:
A slurry of N-(3,6-dichloropyridin-2-yl)pivalamide (1.83 g, 7.41 mmol) in 75 mL 5N aq HCl with water cooled reflux pyridine was heated in a 115° C. bath overnight, to give a clear yellow solution. The reaction mixture was cooled and poured onto ice, and was basified with 10 N NaOH. The resulting white precipitate was extracted with DCM, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vauco to give 3,6-dichloropyridin-2-amine as an off-white solid. MS (ESI) m/z: calculated: 162.0; Observed: 163.0 (M++1).
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[Br:14][C:15]1[CH:33]=[CH:32][C:18]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:2]3[N:12]4[C:13]5[C:8]([CH2:9][CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[CH2:22][CH:21]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:32][CH:33]=1
Reactant: Brc1ccc(OC2CCNCC2c2ccccc2)cc1
Reactant: Clc1nc2cccc3c2n1CCC3
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1ccc(OC2CCN(c3nc4cccc5c4n3CCC5)CC2c2ccccc2)cc1
Yield: 55.9 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.00 g), 4-(4-bromophenoxy)-3-phenylpiperidine (5.20 g), triethylamine (1.62 g) and dimethylformamide (50 ml) was stirred at 115° C., under nitrogen, overnight. The solution was poured onto ice water (600 ml) and the precipitate was collected. The precipitate was dissolved in dichloromethane and the solution was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was triturated with ethyl acetate and then recrystallized from chloroform-ether to give 4.25 g (56%) of product, mp 188°-189° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][N:15]3[C:21]4[CH:22]=[CH:23][S:24][C:20]=4[C:19](=[O:25])[N:18]([CH3:26])[CH2:17][C:16]=23)[N:8]=1.[CH3:27]N(C)C=O>>[CH2:1]([NH:4][CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][N:15]3[C:21]4[CH:22]=[CH:23][S:24][C:20]=4[C:19](=[O:25])[N:18]4[CH2:26][CH2:27][C@H:17]4[C:16]=23)[N:8]=1)[CH2:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CCCN
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccsc2C1=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
0.73 ml (9 mmol) of propylamine was added to a suspension of 1 g (3 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one in 30 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 12 hours. The solution was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution was extracted with methylene chloride and the organic phases were dried, filtered and evaporated. The residue was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1). There was obtained 0.86 g (80%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.38 (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@:10]([CH2:33][CH:34]=[O:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)=[O:38]>O.OS(O)(=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@:10]([CH2:33][C:34]([OH:38])=[O:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde (Example 91, Step E) (125 mg, 0.242 mmol) in acetone (2 mL) was added 3 mL of a mixture of CrO3 in water (2 mL) and concentrated H2SO4 (1 ml). The reaction mixture was stirred at room temperature for 2 hours and then diluted with water (10 mL) and ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA) to provide the title compound.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:36])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:35])[CH2:33][OH:34])[CH:30]=3)[C:25]([OH:27])=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.N12CCCN=C1CCCCC2>C(#N)C>[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:36])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:35])[CH2:33][O:34][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:30]=3)[C:25]([OH:27])=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
tert-Butyldimethylsilyl chloride (2.78 g, 18.4 mmol) was added to a mixture of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoic acid (3.74 g, 9.19 mmol) and 1,8-diazabicyclo(5,4,0)undec-7-ene (2.75 mL, 7.36 mmol) in acetonitrile (40 mL) and stirred at RT for 24 hours. The solvent was removed in vacuo and water (80 mL) added to the resultant oil. The mixture was adjusted to pH 10 with 1M sodium bicarbonate solution and washed with ether to remove any impurities. The aqueous layer was adjusted to pH 3 with 1M citric acid and extracted into ethyl acetate (2×100 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a white foam (2.9 g).
Reaction SMILES: [P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].C(O)C.[C:22]([NH:30][NH2:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CO>C(Cl)Cl>[P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[N:31][NH:30][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCSP(=O)(OCC)Oc1cccc(C=O)c1
Reactant: NNC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CCCSP(=O)(OCC)Oc1cccc(C=NNC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl O-(3-formylphenyl) thiophosphate (6.0 grams; 0.016 mole), ethanol (100 ml) and benzoylhydrazine (2.18 grams; 0.016 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture was stirred at room temperature overnight. After this time the reaction mixture was stripped of methanol leaving an orange oil. This oil was dissolved in methylene chloride and the resulting solution was washed twice with water (100 ml), twice with aqueous sodium hydroxide (50 ml; 0.1 N) and again twice with water (100 ml). The washed solution was then dried over anhydrous magnesium sulfate and was stripped of solvent under vacuum to yield the desired product O-ethyl S-propyl O-[3-(benzoylhydrazonomethyl)phenyl]thiophosphate as a viscous orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 116.8 %

Procedure:
A solution of nickel (II) chloride hexahydrate (180 mg, 0.8 mmol) and (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylic acid methyl ester (695 mg, 2.0 mmol) in methanol (15 mL) was cooled to 0° C. and then treated with sodium borohydride (454 mg, 12 mmol) in five portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 d. The reaction mixture was concentrated in vacuo, and the residue was diluted with a 3N aqueous hydrochloric acid solution (50 mL) and ethyl acetate (75 mL). The two layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionic acid methyl ester (815 mg, 99%) as a viscous oil: EI-HRMS m/e calcd for C17H21ClN4O2 (M+) 348.1353, found 348.1359.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[C:19]1([CH3:32])[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][CH:27]=[CH:28][C:29](=[O:31])[CH3:30])[CH:20]=1>>[C:29]([C:28]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:26]([CH2:25][C:21]2[CH:20]=[C:19]([CH3:32])[CH:24]=[CH:23][CH:22]=2)[CH:27]=1)(=[O:31])[CH3:30]
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Reactant: CC(=O)C=CNCc1cccc(C)c1
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3cccc(C)c3)C=C1C(C)=O)C2=O

Procedure:
The title compound 61 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 62 (80 mg, 0.42 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 61 as a yellow solid. (Yield 115 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:11][C:2]=1[NH:1][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCOCC2)cc1NC(C)=O
Reaction time: 22 h

Procedure:
To a stirred solution of methyl 2-amino-4-morpholin-4-ylbenzoate (55 mg; 0.23 mmol) in dry CH2Cl2 (2 mL) was added acetic anhydride (0.05 mL; 0.53 mmol) and pyridine (0.02 mL; 0.25 mmol) via syringe at room temperature under a nitrogen atmosphere. The resulting solution was allowed to stir for 22 hours, then diluted with EtOAc (15 mL) and washed with 0.5 N aqueous hydrochloric acid, water, and brine, then dried (MgSO4), filtered and concentrated in vacuo to provide the amide as a white solid (56 mg; 88%).