Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:20](N1C=CN=C1)(N1C=CN=C1)=O.CO.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:12][CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1CCC(Oc2cc(F)c(C(=O)O)cc2Cl)CC1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)c(OC2CCC(=O)CC2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
To a solution of 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoic acid (1.14 g, 3.98 mmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1′-carbonyldiimidazole (1.71 g, 10.50 mmol). The solution was heated to reflux under a nitrogen atmosphere for 1 hours and cooled to ambient temperature. To the solution was added anhydrous methanol (0.49 mL, 12.00 mmol) and 1,8-diazabicycloundec-7-ene (1.8 mL, 12.00 mmol). The solution was stirred at ambient temperature for 4 h, then diluted with ethyl acetate (150 mL) and washed with 1 M hydrochloric acid (2×150 mL), brine (150 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford the title compound as an off-white solid (1.05 g, 87%): 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J=7.6 Hz, 1H), 6.74 (d, J=12.0 Hz, 1H), 4.79 (br s, 1H), 3.89 (s, 3H), 2.79-2.68 (m, 2H), 2.39-2.31 (m, 4H), 2.13-2.02 (m, 2H); MS (ES+) m/z 300.9 (M+1).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:21](=[O:24])([O-])[O-].[K+].[K+].C[C:28]([CH3:30])=[O:29]>>[CH2:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:2][CH2:1][O:13][CH2:14][CH2:15][O:29][CH2:28][CH2:30][O:24][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)=O
Reactant: CCCCCCCCCCCCOc1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCCCOc1ccccc1OCCOCCOCCOC
Yield: 74 %

Procedure:
A mixture of 2-dodecyloxyphenol (4.75 g, 17.1 mmole), 3,6,9-trioxadecyl-p-toluene sulphonate24 (6 g, 18.9 mmole), dry acetone (50 ml) and anhydrous potassium carbonate (2.6 g, 18.9 mmole) was stirred and heated to reflux under a nitrogen atmosphere for 48 h. Upon cooling the reaction mixture was filtered and the acetone removed under reduced pressure. Distillation of the resultant oil, under reduced pressure, gave 1-dodecyloxy-2-(1,4,7,10-tetraoxaundecyl)benzene as a clear oil (5.4 g, 74%), b.p. 245° C./0.4 mmHg; MS (CI) m/e 442 (M+ +NH4+), δH (200 MHz, CDCl3) 0.88(t, 3H), 1.26(br s, 18H), 1.80(q, 2H), 3.38 (s, 3H), 3.50-3.80 (m, 8H), 3.87 (t, 2H), 3.98 (t, 2H), 4.17(t, 2H) and 6.90(s, 4H) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([C:31]#[N:32])=[C:12]([CH2:20]C3C4C(=CC=CC=4)C=CC=3)[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:8]2[S:7][CH2:6]1)=[O:4].COC([C@H]1N2C(=O)C(Br)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3C=CC=CC=3)=C2SC1)=O.COC([C@H]1N2C(=O)C(Br)=C(C)C(C3C=CC=CC=3)=C2SC1)=O>>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([C:31]#[N:32])=[C:12]([CH3:20])[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(C)c(Br)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(Br)c(=O)n21
Product: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(C)c(C#N)c(=O)n21
Yield: 86 %

Procedure:
By following the procedure described for the preparation of 6a from 5a, 5c (150 mg, 0.39 mmol) gave 6c as a pale yellow foam (110 mg, 86%): [α]D-161 (c 1.0, CHCl3); IR λ 3012, 2956, 2215, 1749, 1648, 1440, 1365, 1257,1216 cm−1. 1H NMR (400 MHz, CDCl3) δ7.50-7.39 (m, 3H), 7.25-7.18 (m, 2H), 5.72 (dd, J=8.8, 2.3, 1H), 3.85 (s, 3H), 3.72 (dd, J=11.9, 8.8, 1H), 3.51 (dd, J=11.9, 2.3, 1H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ167.6, 158.8, 158.4, 154.3, 135.0, 129.7, 129.5, 129.1 (splitted), 128.9, 116.5, 115.4, 99.5, 64.1, 53.5, 31.7, 20.0; HRMS (FAB+) calcd for C17H15N2O3S 327.0803, obsd 327.0805.
Reaction SMILES: [Sn].[CH2:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C]=O.[H][H].C(C1C=CC=CC=1)C.C1(C(C)[CH2:29][OH:30])C=CC=CC=1>C1(=O)OC(C)CO1.C1C=CC=CC=1>[C:4]1([CH2:3][CH2:2][CH2:29][OH:30])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(CO)c1ccccc1
Reactant: [H][H]
Reactant: C=Cc1ccccc1
Agent: [C]=O
Agent: [Sn]
Solvent: c1ccccc1
Solvent: CC1COC(=O)O1
Solvent: CCc1ccccc1
Product: OCCCc1ccccc1
Temperature: 90 °C

Procedure:
Tin methylate Sn(OCH3)2 is produced according to the method disclosed by J. Morrison and H. Haendler, 29 J. Inorg. Nucl. Chem., 393-400 (1967). A catalytic system comprising 66.4 mg of LPtCl2 (L being the same ligand as in example 12) and 15.7 mg tin methylate in a solvent consisting of a mixture of 15 cm3 benzene and 10 cm3 propylene carbonate is introduced under nitrogen into a 100 cm3 stainless steel autoclave reactor equipped with a bar magnet stirring system. Then, 1.23 g styrene is added. The reactor is heated to a temperature of 90° C. and then filled with an equimolar mixture of carbon monoxide and hydrogen (synthesis gas). The resulting mixture is stirred and the reaction continued at 90° C. under a pressure of 100 bars for a time (T) expressed in hours. A mixture of ethylbenzene, 2-phenylpropanol and 3-phenylpropanol is obtained with a degree of conversion (DC). The proportion by weight of ethylbenzene (EB) and the molar ratio (n/b) are determined as above. The results are reported in Table V below.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:21][C:22]1[CH:50]=[CH:49][C:25]2[NH:26][C:27]([C:32]3[C:33](=[O:48])[N:34]([CH2:43][CH2:44][CH:45]([CH3:47])[CH3:46])[C:35]4[C:40]([C:41]=3[OH:42])=[CH:39][CH:38]=[CH:37][N:36]=4)=[N:28][S:29](=[O:31])(=[O:30])[C:24]=2[CH:23]=1.[N+:51]([O-])([O-:53])=[O:52].[K+]>>[F:1][C:2]([F:7])([F:6])[C:3]([NH:21][C:22]1[CH:50]=[CH:49][C:25]2[NH:26][C:27]([C:32]3[C:33](=[O:48])[N:34]([CH2:43][CH2:44][CH:45]([CH3:47])[CH3:46])[C:35]4[C:40]([C:41]=3[OH:42])=[CH:39][CH:38]=[CH:37][N:36]=4)=[N:28][S:29](=[O:31])(=[O:30])[C:24]=2[C:23]=1[N+:51]([O-:53])=[O:52])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(NC(=O)C(F)(F)F)c3[N+](=O)[O-])N2)c(O)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of trifluoroacetic acid (2.5 mL) and trifluoroacetic anhydride (2.5 mL) at 0° C. was added portion wise the product of Example 205 (0.5 g, 1.17 mmol). The resulting red solution was stirred at 0° C. for 30 minutes, cooled to −20° C. and treated portion wise with potassium nitrate (0.13 g, 1.3 mmol). The mixture was stirred at −20° C. for 1 hour, poured onto ice and the resulting tan solid was collected by filtration, washed with water and dried to constant mass to give the title compound (0.628 g, 94% yield). MS (ESI−) m/z 567 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (d, J=6.62 Hz, 6 H) 1.49 (m, 2 H) 1.64 (m, 1 H) 4.30 (m, 2 H) 7.16 (dd, J=7.72, 4.78 Hz, 1 H) 7.67 (m, 2 H) 8.38 (dd, J=7.54, 2.02 Hz, 1 H) 8.57 (dd, J=4.41, 1.84 Hz, 1 H) 11.61 (s, 1 H) 16.67 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([Br:7])[N:6]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.O>[Br:1][C:2]1[S:3][C:4]([CH2:8][O:9][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20])=[C:5]([Br:7])[N:6]=1
Reactant: OCc1sc(Br)nc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of (2,4-dibromo-1,3-thiazol-5-yl)methanol (2.64 g, 9.6 mmol) and imidazole (1.6 g, 24 mmol) in DMF (15 mL) was added a solution of tert-butyl(chloro)dimethylsilane (1.7 g, 11.5 mmol) in DMF (15 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured in water (400 mL), and the resultant mixture was extracted with EtOAc (3×50 mL). The organic extracts were combined, extracted with brine (2×150 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 2,4-dibromo-5-{[(tert-butyldimethylsilyl)oxy]methyl}-1,3-thiazole (3.44 g, 93%). The product was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[C:9]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CC[C@@H](CO)O1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C1CC[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
105.5 g of (5S)-5-(hydroxymethyl)tetrahydro-2-furanone was dissolved in 1.2 L pyridine, and 380 g of trityl chloride was added thereto at room temperature, and the mixture was stirred at 80° C. overnight. After the reaction was completed, the mixture was cooled, water was added thereto, extracted with ethyl acetate, and then washed with brine. The solvent was removed, and the resulting residue was dissolved in 300 ml chloroform, and after 600 ml silica gel was added thereto, the solvent was removed. The resulting residue was purified by silica gel column chromatography to give 149.3 g of (5S)-5-[(trityloxy)methyl]tetrahydro-2-furanone.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([NH:32][C:33](=[O:35])[CH3:34])[CH:31]=1)[NH:28][C:27](=[O:36])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([NH:32][C:33](=[O:35])[CH3:34])[CH:31]=1)[NH:28][C:27](=[O:36])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: CC(=O)Nc1cc(F)cc2c1NC(=O)C2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: CC(=O)Nc1cc(F)cc2c1NC(=O)C2=Cc1[nH]c2c(c1C)C(=O)N(CCN1CCOCC1)CC2
Yield: 37 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-7-yl}-acetamide (33 mg, 37%) as an orange solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I.O>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:14][CH3:17])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: OC1(c2ccc(I)cc2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccc(I)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under an argon atmosphere, a solution of tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (2.99 g) in anhydrous DMF (10 ml) was added dropwise to a suspension of sodium hydride (60 wt %) (432 mg) in anhydrous DMF (20 ml) at room temperature, and the resulting mixture was stirred at room temperature for 75 minutes. Methyl iodide (0.92 ml) was added dropwise to the reaction solution and the resulting mixture was stirred at room temperature for 8.5 hours. Water was added thereto and the resulting mixture was extracted twice with ethyl acetate. Organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane/ethyl acetate=10/1) to obtain tetrahydro-4-(4-iodophenyl)-4-methoxy-2H-pyran (2.87 g). NMR (H1, CDCl3): δ 1.90-2.02 (4H, m), 2.97 (3H, s), 3.80-3.88 (4H, m), 7.14 (1H, d, J=8.5 Hz), 7.70 (1H, d, J=8.5 Hz)
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C@@H:3]1[CH2:12][C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[CH3:19]I>CN(C=O)C.O>[CH3:19][N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C@H:3]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:2]1=[O:1]
Reactant: CI
Reactant: COC(=O)C[C@H]1Nc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1Nc2ccccc2N(C)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl [(2R)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate (Example 1, Step 2, 650 mg, 2.95 mmol) in DMF (5 mL) at 0° C. was added NaH (142 mg, 3.54 mmol). After stirring at 0° C. for 20 minutes, MeI (220 uL, 3.54 mmol) was added and the reaction mixture was stirred for an additional 15 minutes at 0° C. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (2×50 mL). Combined organics were washed with water (1×50 mL), dried over sodium sulfate, filtered, and concentrated to give methyl [(2R)-4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate, which was used without further purification. LCMS (ES) 235.1 m/z (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]2[CH:16]=[CH:15][C:14]([O:17]CC3C=CC(OC)=CC=3)=[CH:13][C:12]2=[O:27])[CH2:10][CH2:9]1>>[CH:8]1([N:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]2=[O:27])[CH2:10][CH2:9]1
Reactant: COc1ccc(COc2ccn(C3CC3)c(=O)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(O)ccn1C1CC1
Temperature: 25 °C

Procedure:
Trifluoroacetic acid (1 mL) was added to a flask charged with a stir bar and 1-cyclopropyl-4-(4-methoxy-benzyloxy)-1H-pyridin-2-one (0.17 g) and chilled in an ice/EtOH bath. The resulting mixture was stirred with cooling for 1.5 h and at ambient temperature for another 4.5 h. Then, the solution was concentrated under reduced pressure and the residue was triturated with tert-butyl methyl ether and dried to give the title compound as a solid. Yield: 0.10 g (quantitative). Mass spectrum (ESI+): m/z=152 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:47][OH:48].CN([CH:52]=[O:53])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:47][O:48][C:52]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:9]=1)=[O:53]
Reactant: CO
Reactant: CN(C)C=O
Reactant: N#Cc1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2cc(C#N)ccc2c1
Temperature: 60 °C
Yield: 50 %

Procedure:
To a solution of trifluoromethanesulfonic acid 6-cyano-naphthalen-2-yl ester from Example 95 (1.50 g, 4.98 mmol) in 20 mL of anhydrous DMF was added palladium(II) acetate (33.53 mg, 0.15 mmol), triphenylphosphine (78.36 mg, 0.30 mmol), triethylamine (1.39 mL, 9.96 mmol) and 5 mL of methanol. This mixture was purged with carbon monoxide for ten minutes. The reaction mixture was then placed under balloon pressure of carbon monoxide and heated to 60° C. for 16 hours. The mixture was then diluted with brine, extracted with EtOAc (3×100 mL), extracts washed with 1N HCl (2×100 mL), dried over MgSO4, and concentrated under reduced pressure. Flash chromatography (hexane to 20% EtOAc/hexane) afforded the desired product as a white solid (525 mg, 50%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][CH:14]1[CH2:19][CH2:18][O:17][C:15]1=[O:16].[CH3:20][S:21]SC>O1CCCC1>[CH3:13][C:14]1([S:21][CH3:20])[CH2:19][CH2:18][O:17][C:15]1=[O:16]
Reactant: CSSC
Reactant: CC1CCOC1=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSC1(C)CCOC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
Under an argon atmosphere, n-butyllithium (1.7 M in hexane, 1800 ml, 3.06 mole) was added slowly to a stirred solution of diisopropylamine (309.4 g, 3.06 mole) in tetrahydrofuran (1800 ml) at -78° C. Upon completion of addition, the reaction mixture was allowed to stir for 30 minutes at which time alpha-methyl-gamma-butyrolactone (278.0 g, 2.78 mole) was added dropwise, also at -78° C. The reaction mixture was stirred 30 minutes then dimethyl disulfide (392.8 g, 4.17 mole) was added dropwise. After stirring for 30 minutes at -78° C., the reaction mixture was warmed to ambient temperature during a one hour period. The reaction mixture was quenched with 5% aqueous hydrochloric acid (1500 ml) and then diluted with ethyl acetate (2000 ml). The layers were separated, and the organic layer was washed with aqueous 10% hydrochloric acid (1×200 ml) and then saturated aqueous sodium bicarbonate (1×100 ml). The organic layer was dried and concentrated under reduced pressure. The residue was distilled to yield 234.6 g of alpha-methyl-alpha-methylthio-gamma-butyrolactone as a colorless oil, b.p. 104°-105° C./8 mm Hg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f29) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ccccc3C2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ccccc3C2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[3,4-dihydro-2(1H)-isoquinolinylcarbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 19) (343 mg, 0.71 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (281 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][CH2:6][CH2:7][O:8][CH3:9].BrC1C(C)=C(N([CH2:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=2)CCCC)C=CC=1>>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N:5]([CH2:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=2)[CH2:6][CH2:7][O:8][CH3:9])[CH:10]=[CH:11][CH:12]=1
Reactant: COCCNc1cccc(Br)c1C
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Product: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(Br)c2C)cc1C

Procedure:
Prepared from 3-bromo-N-(2-methoxyethyl)-2-methylaniline using the procedure described for Intermediate 59.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:30]=[CH:29][C:20]([CH2:21][N:22]([CH2:26]CO)[CH2:23][CH2:24]O)=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:8][C:7]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C)C=O.Cl[CH2:43][Cl:44]>>[Cl:3][CH2:24][CH2:23][N:22]([CH2:26][CH2:43][Cl:44])[CH2:21][C:20]1[CH:29]=[CH:30][C:17]([C:14]2[N:13]=[C:12]([C:10]3[CH:9]=[CH:8][C:7]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:6]([F:5])[CH:11]=3)[O:16][N:15]=2)=[CH:18][CH:19]=1
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Reactant: OCCN(CCO)Cc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(F)c3)n2)cc1
Solvent: CN(C)C=O
Product: Fc1cc(-c2nc(-c3ccc(CN(CCCl)CCCl)cc3)no2)ccc1-c1ccccc1
Temperature: 80 °C

Procedure:
Thionyl chloride (52 mL, 0.716 mol) is added drop wise to a stirred solution of 2-[{4-[5-(2-fluoro-biphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}(2-hydroxyethyl)-amino]ethanol (31 g, 0.0715 mol) in dichloromethane (150 mL) at 0° C. N,N-Dimethylformamide (2 mL) is added and the reaction mixture is heated at 80° C. for 1 h. Excess thionyl chloride is removed under reduced pressure and the residue is made alkaline (pH ˜9) by the addition of an aqueous sodium hydroxide solution (4N, 150 mL) at room temperature. The aqueous layer is extracted with ethyl acetate (2×100 mL) and combined organic layers are dried over sodium sulphate. Removal of solvent under reduced pressure gives a viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate 7:3) to give bis-(2-chloroethyl){4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}amine.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])[O:8][N:7]=1)=O)C.C1COCC1>C(Cl)Cl.CO>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:8][N:7]=[C:6]([CH2:4][OH:3])[N:10]=1
Reactant: CCOC(=O)c1noc(-c2ccncc2Nc2ccc(I)cc2F)n1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: OCc1noc(-c2ccncc2Nc2ccc(I)cc2F)n1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of 5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester (768 mg, 1.69 mmL, 1 eq) in THF (6 mL) LiBH4 (55 mg, 2.54 mmol, 1.5 eq) was added. The reaction mixture was stirred overnight and the solvent was evaporated. The residue was dissolved in EtOAc, washed with brine, and dried with anhydrous MgSO4. Filtration and removal of the solvent afforded the crude product which was subjected to silica gel column chromatography (eluent:CH2Cl2:MeOH 70:1) to give rise to pure product (497 mg). [5.01 min; 413 (M+1)]