Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([NH:19][CH2:20][CH2:21][CH:22]3[CH2:24][CH2:23]3)[S:10]2)[C@H:6]1[O:25]C(=O)C)(=O)C.N>CO>[CH:22]1([CH2:21][CH2:20][NH:19][C:9]2[S:10][C@H:11]3[O:12][C@H:13]([CH2:14][OH:15])[C@@H:5]([OH:4])[C@H:6]([OH:25])[C@H:7]3[N:8]=2)[CH2:24][CH2:23]1
Reactant: CC(=O)OC[C@H]1O[C@@H]2SC(NCCC3CC3)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H]2SC(NCCC3CC3)=N[C@@H]2[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-5-(acetoxymethyl)-2-(2-cyclopropylethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (15 g, 36 mmol) in MeOH (400 mL) was bubbled with NH3(g) for 2 h. After stirred overnight at room temperature, the reaction mixture was condensed to give a residue, which was washed with hot ethyl acetate to provide the title compound as a white solid (9 g, 86%). (ES, m/z): [M+H]+289.0; 1H NMR (300 MHz, CDCl3) δ 6.18-6.20 (d, J=6.3 Hz, 1H), 4.10-4.12 (m, 1H), 3.93-3.97 (m, 1H), 3.70-3.75 (m, 1H), 3.47-3.62 (m, 3H), 3.20-3.25 (m, 2H), 1.32-1.38 (m, 2H), 0.61-0.65 (m, 1H), 0.36-0.37 (m, 2H), 0.08-0.12 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[C@@H:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Yield: 93.4 %

Procedure:
A solution of 1-{2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine hydrochloride (nafoxidene hydrochloride) (1.0 g, 2.16 mmol) in 20 mL of absolute ethanol containing 1.0 g of palladium hydroxide on carbon was hydrogenated at 60 psi at 20° C. for 19 hr. Filtration and evaporation provided 863 mg (93%) of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine: 1H-NMR (CDCl3): δ 3.50-3.80 (m, 3H), 3.85 (s, 3H), 4.20-4.40 (m, 3H), 6.80-7.00 (m, 3H); MS 428 (P++1).
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19].[OH-].[Na+]>O.O1CCCC1>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:23][OH:24])[CH2:18][OH:19]
Reactant: CCOC(=O)C(CCCCCl)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCC(CO)CCCCCl
Yield: 102.6 %

Procedure:
To 214 ml of dry ether was added 8 g of lithium aluminium hydride, and a solution of 26.7 g of diethyl (4-chlorobutyl)malonate/53 ml of dry ether was added dropwise with stirring under ice-cooling. After 1-hour-stirring at room temperature, the mixture was cooled with ice-cold water, and 173 ml of tetrahydrofuran/14.7 ml of water was added gradually. Then, 14.7 ml of 1N sodium hydroxide solution and 35 ml of water were added, stirred for 15 minutes, filtrated to remove insolubles. The filtrate was concentrated to provide 18.2 g of the objective compound as colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH:12](Br)[CH:13]1[O:30][C@H:16]2[CH2:17][C@@H:18]([OH:29])[C@H:19](/[CH:20]=[CH:21]/[C@@H:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@H:15]2[CH2:14]1.C1CCN2C(=NCCC2)CC1.Cl.P([O-])([O-])([O-])=O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:32])[CH2:9][CH2:10][CH2:11]/[CH:12]=[C:13]1/[CH2:14][C@@H:15]2[C@@H:19](/[CH:20]=[CH:21]/[C@@H:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@H:18]([OH:29])[CH2:17][C@@H:16]2[O:30]/1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OCCCCCO)O[C@H]2C[C@H]1O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCC(=O)OCCCCCO)O[C@H]2C[C@H]1O
Yield: 64.9 %

Procedure:
197 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-bromo-6,9-epoxy-11,15-dihydroxyprost-13-enoic acid 5-hydroxypentyl ester (prepared as described in Example 3) and 0.66 ml of DBU were stirred for 3 hours at 50°-60° C. under a nitrogen atmosphere. The solution obtained was cooled to 0°-5° C., 3.3 ml of 1 N hydrochloric acid and 3.3 ml of a phosphate buffer with a pH of 6.86, cooled to 0°-5° C., were added and the mixture was extracted with diethyl ether. The extract was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on "Florisil" (an activated magnesium silicate: "Florisil" is a registered Trade Mark of Florin Co.) using as eluent ethyl acetate containing 0.1% v/v of triethylamine to give 108 mg of the title compound having the following physical characteristics.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].Cl.[Cl:24][C:25]1[CH:41]=[CH:40][C:28]2[CH2:29][O:30][C:31](=[O:39])[N:32]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:27]=2[CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:24][C:25]1[CH:41]=[CH:40][C:28]2[CH2:29][O:30][C:31](=[O:39])[N:32]([CH:33]3[CH2:34][CH2:35][N:36]([C:2]4[CH:7]=[CH:6][C:5]([C:8]([C:10]5[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=5[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=4[N+:20]([O-:22])=[O:21])[CH2:37][CH2:38]3)[C:27]=2[CH:26]=1
Reactant: O=C1OCc2ccc(Cl)cc2N1C1CCNCC1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccc(Cl)cc43)CC2)c([N+](=O)[O-])c1

Procedure:
Methyl 2-[(4-chloro-3-nitrophenyl)carbonyl]benzoate (0.5 g), the product from step (ii) (0.47 g) and triethylamine (0.5 ml) in N,N-dimethylformamide (2.5 ml) were heated at 60° C. overnight. The mixture was evaporated under reduced pressure and the residue purified by chromatography eluting with 25% ethyl acetate/toluene. Yield 0.7 g of a solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.Cl>CN(C)C=O>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CCc2ccccc2)[nH]n1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a mixture of 3-tert-butyl-5-(2-phenylethyl)-1H-pyrazole (1.57 g, 6.87 mmol), sodium hydride (60% in oil, 280 mg, 7 mmol), and N,N-dimethylformamide (15 mL) was added methyl 4-(bromomethyl)benzoate (2.29 g, 10.0 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (1.75 g, yield 68%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.[NH:11]1[C:16](=[O:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18].BrC1C=CC=CC=1CCN1C(=O)CN(C)C1=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][N:11]1[C:16](=[O:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18]
Reactant: O=C1COCC(=O)N1
Reactant: OCCc1ccccc1Br
Agent: CN1CC(=O)N(CCc2ccccc2Br)C1=O
Product: O=C1COCC(=O)N1CCc1ccccc1Br

Procedure:
2-Bromophenethyl alcohol (402 mg, 2 mmol) and morpholine-3,5-dione (322 mg, 2.8 mmol) were treated as described in the preparation of compound 436. Purification was done by flash chromatography (petroleum ether/ethyl acetate 4:1) to provide the title compound as a colorless solid.
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]([CH2:25][CH3:26])[C@@H:22]([OH:24])[CH3:23])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([OH:32])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:36]>C1COCC1>[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]([CH2:25][CH3:26])[C@@H:22]([OH:24])[CH3:23])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([O:32][CH3:36])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H]([C@H](C)O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H]([C@H](C)O)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 260 mg (0.543 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 152) in 5 mL of THF was added 60% sodium hydride (217 mg, 5.43 mmol) at 0° C. After being stirred at 0° C. for 20 min, iodomethane (271 uL, 4.35 mmol) was added. The reaction was allowed to warm to ambient temperature, and stirred for an additional 3 h until completion. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered and the filtrate was concentrated to provide the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C[Si](I)(C)C.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3ccnc(C#N)c3)n2)CC1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#Cc1cc(-c2nc(COC3CCNCC3)no2)ccn1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-[5-(2-cyanopyridin-4-yl)[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 42, 2.0 g, 5.2 mmol) in chloroform (100 ml) under argon, was added trimethylsilyl iodide (2.95 ml, 20.8 mmol) and the reaction mixture stirred for 1 h MeOH was added until a solution formed then sodium thiosulphate (6.6 g, 41.5 mmol) was added and the reaction mixture stirred vigorously for 10 min. The solids were removed by filtration and the filtrate adsorbed onto silica gel. Purification via column chromatography (DCM-MeOH, 9:1) afforded the title compound: RT=1.92 min; m/z (ES+)=286.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16](Br)=[CH:17][N:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22]/[CH:23]=[CH:24]/B1OC(C)(C)C(C)(C)O1)[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.CCOC(C)=O.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16](/[CH:21]=[CH:20]/[O:22][CH2:23][CH3:24])=[CH:17][N:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ncc1Br
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCO/C=C/c1cnc(OCc2ccccc2)cc1C(=O)OC
Temperature: 70 °C
Yield: 82.2 %

Procedure:
To a suspension of methyl 2-(benzyloxy)-5-bromoisonicotinate (Preparation 84, 1.5 g, 4.66 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 29, 1.844 g, 9.31 mmol) and Na2CO3 (0.99 g, 9.31 mmol) in toluene (5 mL), EtOH (5 mL) and water (5 mL) was added Pd(PPh3)4 (377 mg, 0.326 mmol). The reaction mixture was heated to 70° C. for 18 hours, under nitrogen. The reaction mixture was diluted with EtOAc (75 mL) and water (75 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% EtOAc in cyclohexane to give the title compound (1.2 g, 82%). 1H NMR (500 MHz, CDCl3): δ 8.23 (s, 1H), 7.47 (d, J=7.5, 1.5 Hz, 2H), 7.39 (td, J=8.5, 2.5 Hz, 2H), 7.33 (m, 1H), 7.24 (s, 1H), 6.80 (d, J=13.0 Hz, 1H), 6.39 (d, J=13.0 Hz, 1H), 5.40 (s, 2H), 3.95 (q, J=7.5 Hz, 2H), 3.92 (s, 3H), 1.37 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:11])([CH2:9]O)[C:5]([O:7][CH3:8])=[O:6].S(Cl)([Cl:14])=O.N1C=CC=CC=1>>[CH3:1][O:2][CH2:3][C:4]([CH3:11])([CH2:9][Cl:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COCC(C)(CO)C(=O)OC
Solvent: c1ccncc1
Product: COCC(C)(CCl)C(=O)OC
Temperature: 60 °C
Yield: 91 %

Procedure:
The methyl 2-methoxymethyl-2-methyl-3-hydroxypropionate was added at from 15° to 20° C. to 438 g (3.68 mol) of thionyl chloride, the temperature was then raised to 60° C. and the mixture was stirred until the evolution of gas had ended. Excess thionyl chloride was distilled off, 0.2 g (0.0025 mol) of pyridine was added to the residue, and the temperature was raised to 135° C. After the evolution of SO2 had ended, distillation gave 317.0 g (1.76 mol) of methyl 2-methoxymethyl-2-methyl-3chloropropionate of boiling point 94° C. 35 mbar, corresponding to a 91% yield, based on methyl 2-methoxymethyl-2-methyl-3-hydroxypropionate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([SH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:5](=[O:7])[C:4]=2[CH:8]=[CH:9][CH:10]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1cccc(C(=O)O)c1S
Solvent: c1ccncc1
Product: Cc1cccc2c(=O)nc(-c3ccccn3)sc12
Yield: 52.9 %

Procedure:
A mixture of 3-methyl-2-mercaptobenzoic acid (2.40 g, 14.3 mmol), 2-cyanopyridine (1.20 g, 11.9 mmol) and pyridine (50.0 ml) was refluxed for 9 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.60 g, 52%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=O)[CH2:2]1.[CH3:19][C:20]#[N:21]>>[O:14]=[C:12]([C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][O:1][CH2:2]2)[CH:10]=1)[CH2:19][C:20]#[N:21]
Reactant: COC(=O)c1cccc(OCC2CCCOC2)c1
Reactant: CC#N
Product: N#CCC(=O)c1cccc(OCC2CCCOC2)c1

Procedure:
Reaction between methyl 3-((tetrahydro-2H-pyran-3-yl)methoxy)benzoate and CH3CN following the method used in Example 1 gave 3-oxo-3-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propanenitrile as a white solid. Yield (84%); 1H NMR (400 MHz, DMSO-d6) 87.52-7.45 (m, 2H), 7.43 (s, 1H), 7.29-7.26 (m, 1H), 4.75 (s, 2H), 3.93-3.87 (m, 3H), 3.75-3.71 (m, 1H), 3.39-3.36 (m, 1H), 3.28-3.25 (m, 1H), 2.01-1.98 (m, 1H), 1.86-1.83 (m, 1H), 1.60-1.58 (m, 1H), 1.53-1.49 (m, 1H), 1.42-1.39 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[NH4+].[Cl-]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])[CH:3]=1
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(C)ccc1CO
Temperature: 0 °C
Reaction time: 5 h
Yield: 103.9 %

Procedure:
(S)-Methyl 4-methyl-2-(pent-4-en-2-yloxy)benzoate (1 g, 4.27 mmol) was dissolved in THF and cooled to 0° C. To this was added lithium aluminum hydride (0.162 g, 4.27 mmol) and the reaction stirred 5 h at room temp. The mixture was cooled to 0° C. and ethyl acetate added, after which it was stirred for 15 min. Sat'd NH4Cl was added and the ice bath removed. Stirring was continued for 0.5 h then the mixture was transferred to a separatory funnel. The solution was extracted with ethyl acetate then dried over Na2SO4. After filtration the solvent was removed under vacuum. The crude product was purified by silica gel chromatography using a Biotage apparatus to provided 915 mg of the title compound as an oil. 1H NMR (400 MHz, DMSO) δ 1.22 (3H, d), 2.28 (3H, s), 2.37 (2H, m), 4.44 (2H, d), 4.50 (1H, m), 5.09 (2H, m), 5.86 (1H, m), 6.72 (1H, d0, 6.77 (1H, s), 7.24 (1H, d).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])[CH3:11].C(=O)([O-])[O-].[Ca+2]>CS(C)=O>[CH2:10]([O:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:19][CH2:20]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(c2ccccc2C=O)CC1
Yield: 68 %

Procedure:
2-Fluorobenzaldehyde (3.0 g, 24.2 mmol), 1-(ethoxycarbonyl)piperazine (4.2 ml, 28.7 ml), and calcium carbonate (2.46 g, 24.6 mmol) were reacted at 120° C. for 7.5 hours in dimethylsulfoxide (12 ml). After the reaction was completed, the insolubles were filtered off and the resulting filtrate was extracted by adding water and ethyl acetate thereto. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give oily substances. The resulting oily substances were purified by silica gel column chromatography (eluent: from hexane/ethyl acetate=4/1 to hexane/ethyl acetate=1/1) to give the title compound (4.29 g, 68%).
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:9](=[O:29])[C:8]([C:30]([O:32]CC)=[O:31])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CO.Cl>O>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:9](=[O:29])[C:8]([C:30]([OH:32])=[O:31])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(=O)OCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1ncc(C(=O)O)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The title compound is prepared by treating 2-n-butyl-3-(2'-(tetrazol-5-yl)-biphen-4-yl)methyl-5-ethoxycarbonylpyrimidin-4(3H)-one (from Example 8) with an ester hydrolyzing agent such as sodium hydroxide in an appropriate solvent such as methanol, possibly with heating. Addition of water, acidification with concentrated HCl, saturation with NaCl, extraction with ether, washing of the combined organic extracts with brine, drying of the organic material over an appropriate drying agent such as MgSO4, and stripping of solvent in vacuo should give the crude organic acid which may then be purified by appropriate means such as silica gel chromatography. Alternatively, the ester from Example 8 is hydrolyzed using an appropriate esterase such as pig liver esterase followed by standard purification procedures.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[N:29]=[C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[S:31][CH:32]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[S:31][CH:32]=[C:28]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=4[F:20])[N:29]=3)[CH2:34][CH2:35]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1F
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4cccc(F)c4F)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 36.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (255 mg, 0.782 mmol), 1-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over magnesium sulfate anhydrous, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 119 mg (36.6%) of the desired product as a solid.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].Cl.C(N=C=NCCCN(C)C)C.S([O-])([O-])(=O)=O.[Mg+2]>ClCCl.O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28])=[O:19]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.87 g of stearic acid was dissolved in 50 ml of dichloromethane, to which 0.76 g of N-hydroxysuccinimide and 1.25 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added and stirred at room temperature for 24 hours. After the reaction, the solution was combined with 100 ml of water and subjected to liquid-liquid separation using a separatory funnel. The organic phase obtained was dehydrated with magnesium sulfate, and enriched using an evaporator. The enriched solution was added dropwise to 20 volumes of ethanol to form a white precipitate, which was collected by filtration and dried under reduced pressure to obtain N-succinimidyl stearate.