Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]([CH3:29])([O:6][C:7]([NH:9][C@H:10]([C:26]([OH:28])=[O:27])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:8])[CH3:5].[N+:30](=C)=[N-:31].[C:33](O)(=O)[CH3:34].N#N.CC(C)(OC(N[C@H](C(OC)=O)CCCCNC(OCC1C=CC=CC=1)=O)=O)C>C(OCC)(=O)C.CC(C)=O.CCCCCC>[N:30]#[N:31].[CH3:5][C:4]([CH3:29])([O:6][C:7]([NH:9][C@H:10]([C:26]([O:28][CH2:33][CH3:34])=[O:27])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:8])[CH3:3]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)O
Agent: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: N#N
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
N2 -[(1,1-Dimethylethoxy)carbonyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysine (5.48 g., 14.4 mmole) is dissolved in ethyl acetate (130 ml.). Diazomethane is added until a yellow color persists. Acetic acid is added to quench the excess diazomethane, and the volatiles are evaporated. The residue is partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer is dried over sodium sulfate, filtered, and then the volatiles are evaporated. Purification of the residue by column chromatography on LPS-1 silica eluting with 30% ethyl acetate/hexane yields 4.0 g. of N2 -[(1,1-dimethylethoxy)carbonyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysine, methyl ester. TLC (silica gel; hexane:acetone, 1:1) Rf =0.69.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[CH3:8][S:9][C:10](SC)=[CH:11][C:12]#[N:13].[H-].[Na+]>CN(C=O)C>[CH3:8][S:9][C:10]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:11][C:12]#[N:13]
Reactant: Nc1ccncc1
Reactant: CSC(=CC#N)SC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(=CC#N)Nc1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of pyridin-4-ylamine (1.0 g, 11.0 mmol) and 3,3-Bis-methylsulfanyl-acrylonitrile (2.05 g, 12.6 mmol) in DMF at room temperature, was added powdered 4 A molecular sieves. The mixture was stirred for 1 hr. Subsequently the mixture was cooled to 0° C., 60% NaH dispersion in oil (0.92 g, 23.0 mmol) was added portionwise over 1 hr. and it was stirred at 0° C. for an additional 2 hrs. The cold bath was removed and the mixture was stirred at room temperature for 20 hrs. DMF was removed in vacuo and the crude was purified by column chromatography (gradient of EtOAc to 25% MeOH/EtOAc) to afford the desired product as an off-white solid (1.9 g, 89%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH2:11])[CH2:9][O:8][CH2:7]2)[CH2:3][CH2:2]1.Br[C:13]1[C:14](=[O:25])[N:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:17][N:18]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH:11][C:13]3[C:14](=[O:25])[N:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:17][N:18]=3)[CH2:9][O:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cn1ccnc(Br)c1=O
Reactant: N[C@@H]1COC[C@H]1OCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1ccnc(N[C@@H]2COC[C@H]2OCC2CC2)c1=O
Temperature: 25 °C

Procedure:
A stirred solution of trans-3-cyclopropylmethoxy-4-aminotetrahydrofuran from step 4 above (1.1 g, 7.0 mmol), 3-bromo-1-ethoxycarbonylmethylpyrazinone (1.8 g, 7.0 mmol), and DIEA (1.4 mL, 8.0 mmol) in toluene (20 mL) was heated to reflux for 24 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed with aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient elution of 50-67% tOAc:hexanes to give the title compound as an amorphous solid (1.4 g; TLC Rf=0.4, 3:2 EtOAc:hexanes; HPLC RT=5.05 min, method A).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:47][C:48]([CH3:50])=[CH2:49]>C1COCC1>[CH3:1][O:2][C:3](=[O:35])[CH:4]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:21]2[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH:6]=1)[CH2:49][C:48]([CH3:50])=[CH2:47]
Reactant: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: C=C(C)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a solution of [2-(3,5-bis-trifluoromethyl-phenyl)-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-acetic acid methyl ester (150 mg, 0.3 mmol) in THF (5 mL) at −78° C. under argon was added potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 600 μL, 0.3 mmol). After stirring for 30 minutes, 3-bromo-2-methylpropene (40 mg, 0.3 mmol) was added and stirred for an additional 30 minutes. The reaction mixture was allowed to warm up slowly and stirred for another 30 minutes at 0° C. The mixture was then concentrated and purified by column chromatography on silica gel (20-60% methylene chloride in heptane) to give the product as a white solid (85 mg, 51%). 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 2H), 8.23 (d, J=8.29 Hz, 2H), 7.96 (s, 1H), 7.69-7.86 (m, 4H), 4.80 (d, J=19.59 Hz, 2H), 4.01 (dd, J=6.78, 9.04 Hz, 1H), 3.74 (s, 3H), 2.97 (dd, J=9.04, 14.69 Hz, 1H), 2.58 (dd, J=6.78, 14.69 Hz, 1H), 1.79 (s, 3H). MS m/e 562.2 (M+H).
Reaction SMILES: CC(C(C)(C)C)=O.[C:8]([C:12]([CH:14]=[O:15])=O)([CH3:11])([CH3:10])[CH3:9].CC(=[N:19][OH:20])C>>[C:8]([C:12](=[N:19][OH:20])[CH:14]=[O:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)=NO
Reactant: CC(C)(C)C(=O)C=O
Solvent: CC(=O)C(C)(C)C
Product: CC(C)(C)C(C=O)=NO

Procedure:
Yet another oxime intermediate is prepared from t-butyl methyl ketone, which is first transformed into t-butylglyoxal using the procedure of Fuson et al., J. Am. Chem. Soc. 61, 1938 (1939). The t-butylglyoxal, in aqueous solution at pH 4-5, is allowed to react with acetone oxime (commercially available) at about room temperature for about two days. The reaction product mixture is worked up by extracting it with ether, and the t-butylglyoxal oxime is isolated from the ether extract as colorless needles having a melting point of about 50°-52° C.
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[OH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[Cl:4][CH2:3][CH2:2][O:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1ccc(F)cc1OCCCl

Procedure:
40.5 ml of 1-bromo-2-chloroethane (490 mmol) are added at room temperature to a solution of 25 g of 1-[2-hydroxy-4-fluorophenyl]ethanone (162 mmol) in 2-butanone (400 ml), followed by addition of 45 g of potassium carbonate (320 mmol) and 1.26 g of potassium iodide (7.59 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([CH2:15][O:16]C(=O)C)[CH:8]=3.C[O-].[Na+].P([O-])([O-])([O-])=O>CO.C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([CH2:15][OH:16])[CH:8]=3
Reactant: CC(=O)OCc1ccc2c(c1)C(=O)c1ccc(Br)cc1-2
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1c2cc(CO)ccc2-c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 97.1 %

Procedure:
3-bromo-7-acetoxymethyl-9-fluorenone (1.18 g) was suspended in methanol (102 ml) and THF (23 ml). To this suspension was added 0.045M NaOMe (6.6 ml). The reaction mixture was stirred at room temperature for 1.25 hours. It was then neutralized with 0.2M pH 7 phosphate buffer. The tetrahydrofuran and methanol were removed under reduced pressure. Reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried and evaporated gave the product (1.0 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C@:4]2([N:8]=[C:7]([C:9]3[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:28].C(N)(C)(C)C.B.Cl.CC(C)=O.C(=O)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:4]2([NH:8][CH:7]([C:9]3[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=4)[N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:28]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C2=N[C@@]3(CC2)CCN(C)C3=O)n1
Agent: B
Agent: Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CC(C)(C)N
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C2CCC3(CCN(C)C3=O)N2)n1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
(5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 9) (78.34 g, 201.7 mmol) was added to a 5 L three necked round bottomed flask containing an overhead stirrer, 500 ml pressure-equalising dropping funnel with a nitrogen inlet and thermometer. To this was added DCM (1000 mL) and the stirred mixture cooled to approx. −70° C. The dropping funnel was charged with a pre-sonicated solution of borane tert-butylamine (19.3 g, 221.87 mmol) in DCM (200 mL). The borane complex was added slowly maintaining the temperature below −70° C. over approx. 30 minutes. After addition the reaction was stirred at below −70° C. for 90 minutes. The dropping funnel was charged with 6M HCl (400 ml) and this was added dropwise over approx. 15 minutes. The reaction temperature warmed to −50° C. during the addition. After addition was complete the acetone/dry-ice bath was removed and the reaction mixture warmed to room temperature then stirred for a further 30 minutes. In a separate 10 L flask was added sodium carbonate (200 g) and water (1 L). To this flask was added an overhead stirrer. The reaction mixture was carefully added (note: gas evolution) to the sodium carbonate solution and stirring was maintained until gas evolution ceased. The mixture was transferred to a 6 L separating funnel and the phases were separated. The aqueous layer was washed with DCM (2×200 ml) and the combined organics were dried (MgSO4). The solvent was evaporated to afford 7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one as an amber oil (77.8 g), a 96:4 ratio of (2R,5S) and (2S,5S) isomers.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:8]=[CH:7]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:9]2[N:8]=[CH:7][NH:6][C:10]=2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Cn2cnc(-c3ccc(F)cc3)c2-c2ccnc(NC(N)=O)c2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: NC(=O)Nc1cc(-c2[nH]cnc2-c2ccc(F)cc2)ccn1
Yield: 96 %

Procedure:
To the solution of {4-[3-(2,4-Dimethoxy-benzyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridin-2-yl}-urea (Example 51, 15 mg, 0.034 mmol) in DCM (1.0 mL) is added trifluoroacetic acid (0.1 mL). The reaction mixture is stirred for 6.5 days at room temperature before saturated NaHCO3 aqueous solution (2 mL) is added along with water (10 ml). The mixture is extracted with EtOAc (3×20 mL) and the organic layers are combined, dried and concentrated to give the crude product. Purification by silica flash column chromatography using 10% MeOH in DCM affords 9.7 mg of the titled product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.[C:30]([CH2:34][C:35](Cl)=[O:36])([CH3:33])([CH3:32])[CH3:31].O>C(Cl)Cl>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:34][C:35]([O:20][C:17]1[CH:16]=[CH:15][C:14]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)=[CH:19][CH:18]=1)=[O:36]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCCn1nc(-c2ccc(O)cc2)c2cccc(Cl)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCn1nc(-c2ccc(OC(=O)CC(C)(C)C)cc2)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 4-(7-chloro-1-propyl-1H-indazol-3-yl)phenol (0.100 g, 0.35 mmol) and N,N-diisopropylethyl amine (0.5 g, 0.38 mmol) in CH2Cl2 (5 mL) was added dropwise tert-butylacetyl chloride (0.051 g, 0.38 mmol). The solution was allowed to stir overnight at room temperature. Water was added and the solution was extracted with CH2Cl2. The organic layer was washed with brine and dried (MgSO4). The product was purified by flash chromatography (5/1 hexane/ethyl acetate) to yield a white solid (0.098 g, 72%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C1C(N=C=S)=CC=C([O:16][CH:17]2[O:22][CH:21]([CH2:23][OH:24])[CH:20]([OH:25])[CH:19]([OH:26])[CH:18]2[OH:27])C=1>CN(C)C=O>[O:16]=[CH:17][C@H:18]([C@H:19]([C@@H:20]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:25])[OH:26])[OH:27]
Reactant: OCC1OC(Oc2ccc(N=C=S)cc2)C(O)C(O)C1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 16 h

Procedure:
Synthetic glycoprotein carriers were constructed in which poly (L-lysine), average chain length 100 (Mr 20,000 Da), was glycosylated using a-D-mannopyranosyl phenylisothiocyanate dissolved in N,N-dimethylformamide. The solution was adjusted to pH 9.5 by the addition of 1 M Sodium carbonate, pH 9.5. Shielded from light and incubated for 16 hours at 22° C., the solution was dialyzed against 5 mM Sodium chloride for two days. Approximately 0.8 to 1.0% of the amine side chains in the polylysine are glycosylated, as determined by absorbance spectroscopy at 250 nm. As a control, an alternative glycoprotein carrier was synthesized by substituting a-D-mannopyranosyl phenylisothiocyanate with a-D-galactopyranosyl phenylisothiocyanate.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][N:11]=[C:12]([Cl:22])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[OH2:10].[OH2:31].[O-:31][N+:1]1([CH2:7][CH2:8][CH2:9][O:10][N:11]=[C:12]([Cl:22])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(C(Cl)=NOCCCN2CCCCC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O
Product: O=[N+]([O-])c1cccc(C(Cl)=NOCCC[N+]2([O-])CCCCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1.0 g (3.0 mmol) of N-[3-(1-piperidinyl)propoxy]-3-nitro-benzimidoyl-chloride in 5 ml of chloroform a solution of 0.725 g (4.2 mmol) of m-chloroperbenzoic acid in 6 ml of chloroform is added. The reaction mixture is stirred for 6 hours at 25° C., then evaporated. To the residue 12 ml of 2 M potassium carbonate solution is added, and extracted 5 times with 20 ml of chloroform. The combined extracts are dried over magnesium sulfate, filtered and evaporated. The product is dissolved in ethanol; the solution is treated with charcoal then evaporated. The obtained material is triturated with ethylacetate, filtered and dried.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[C:9]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[C:9]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=[C:15]([C:5](=[O:7])[CH3:6])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cccc2c1OCCC2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a suspension of AlCl3 (0.54 g, 4.05 mmol, 1.1 equiv) in CH2Cl2 (20 mL) is added acetyl chloride (0.28 mL, 4.05 mmol, 1.1 equiv). The resulting suspension is allowed to stir at -78° C. for 30 min, and a solution of 8-tert-butyl-2,3-dihydrobenzopyran (0.70 g, 3.68 mmol) in CH2Cl2 (5 mL) is added dropwise using an addition funnel. After the addition is complete, the reaction mixture (pale yellow precipitate) is allowed to warm to room temperature over 4 h. The resulting suspension is cooled to 0° C and quenched with water, washed with water and brine. The aqueous layers are extracted with CH2Cl2, the combined organic layer is dried (MgSO4), filtered and concentrated. The resulting off-white solid is recrystallized using hexanes to give the title compound (0.67 g, 79%) as white crystals.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([C:23]1[N:27]3[CH:28]=[C:29]([C@@H:32]([N:37]4[CH2:41][CH2:40][C@H:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38]4)[C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:31][C:26]3=[N:25][N:24]=1)[CH:19]=[CH:18]2)[CH3:11])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.[Cl:57]CCl>>[ClH:57].[ClH:57].[NH2:42][C@H:39]1[CH2:40][CH2:41][N:37]([C@H:32]([C:29]2[CH:30]=[CH:31][C:26]3[N:27]([C:23]([C:20]4[CH:19]=[CH:18][C:17]5[C:22](=[C:13]([O:12][C@H:10]([CH3:11])[CH2:9][OH:8])[CH:14]=[CH:15][CH:16]=5)[N:21]=4)=[N:24][N:25]=3)[CH:28]=2)[C:33]([F:35])([F:36])[F:34])[CH2:38]1
Reactant: ClCCl
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CO)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-1-(3-(8-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (0.29 g, 0.41 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (2 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-80% acetonitrile/water). The material isolated after purification was dissolved in methanol (0.5 mL) and added dropwise to hydrochloric acid (2M in diethyl ether; 5 mL). The resulting salt was collected by vacuum filtration to provide the title compound (0.17 g, 73%). LCMS APCI (+) m/z 487 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([Cl:28])=[CH:25][C:26]=2[CH3:27])[NH2:23])=[C:13]([CH2:31][CH2:32][CH3:33])[C:12]=1[OH:34])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C:4]([NH:23][C:22]1[C:24]([Cl:28])=[CH:25][C:26]([CH3:27])=[C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[CH:29]=[CH:30][C:11]([C:8](=[O:10])[CH3:9])=[C:12]([OH:34])[C:13]=2[CH2:31][CH2:32][CH3:33])[CH:21]=1)=[O:5]
Reactant: COC(=O)C(=O)Cl
Reactant: CCCc1c(OCCCOc2cc(N)c(Cl)cc2C)ccc(C(C)=O)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCCCOc2cc(NC(=O)C(=O)OC)c(Cl)cc2C)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In the course of approximately 5 minutes a solution of 1.9 ml (21 mmol) of chloro-oxalic acid methyl ester in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 7.0 g (17.8 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chloroaniline and 22.2 g (21.4 mmol) of triethylamine in 100 ml of methylene chloride. The reaction mixture is stirred for a further 90 minutes at room temperature, poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether yields N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chlorophenyl}-oxamic acid methyl ester having a melting point of 101°-102°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[NH:19][C:18](=O)[N:17]=[CH:16][CH:15]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:21].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:18]1[N:19]=[C:14]([C:13]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:21])[CH:4]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=[CH:16][N:17]=1
Reactant: Cc1cc(-c2ncccc2-c2ccnc(=O)[nH]2)ccc1F
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ncccc2-c2ccnc(Cl)n2)ccc1F
Temperature: 25 °C

Procedure:
6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2(1H)-one (0.83 g) and POCl3 (3 mL) were heated at 130° C. under nitrogen. The reaction mixture was cooled to room temperature upon completion of the reaction (2 h). The volatiles were removed and quenched the concentrate with ice. The semi-heterogeneous slurry was neutralized with aq. NaHCO3 solution while stirring, warmed to room temperature and diluted with EtOAc (200 mL). The organic layer was separated, stirred over MgSO4, filtered, concentrated and purified by flash chromatography (Combiflash® companion System® with RediSep® silica gel column 12 g and 10-50% EtOAc/Hexanes as eluting solvent) to obtain 2-chloro-4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidine as a clear viscous liquid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:32]C)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([O-:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1)([O-:22])=[O:21].[CH3:23][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Yield: 187 %

Procedure:
A mixture of 5.83 g (22.2 mmol) of triphenylphosphine and 5.00 g (23.0 mmol) methyl 4-nitrobenzenesulfonate was allowed to react for 2 hrs at 145° C. A total of 10.3 g (21.5 mmol, 96.8%) of the product was obtained, which was further purified by recrystallization from 90:10 toluene-acetonitrile. Analyses: mp 127.0°-128.6° C.
Reaction SMILES: ClCCCl.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[CH:17]=2)=[CH:9][CH:8]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[C:17]=2[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccccc2)cc1

Procedure:
To 300 ml. of 1,2-dichloroethane maintained at 0° C. were added 6.0 g. (0.022 mole) of 2-(4-methoxyphenyl)-6-methoxybenzothiophene and 3.10 g. (0.022 mole) of benzoyl chloride. The mixture was stirred vigorously, and 3.2 g. (0.024 mole) of aluminum chloride were added in small portions. The resulting red solution was stirred for one hour, and water then was added. The yellow organic layer was separated, washed with 200 ml. of 1N sodium hydroxide and then with 200 ml. of saturated sodium chloride solution. The mixture then was dried over potassium carbonate, and the solvent was evaporated to give a pale yellow solid which was purified by chromatography over silica gel using benzene and 5% ethyl acetate in benzene as eluant. The appropriate fractions gave product as yellow crystals. The product was recrystallized from methanol to obtain 3.5 g. (42 percent) of 2-(4-methoxyphenyl)-3-benozyl-6-methoxybenzothiophene, melting point 110.5°-111° C.