Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:21])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].OO.[OH-].[Na+].C(O)(=[O:41])C>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:21])=[O:41])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile (120 mg) in dimethyl sulfoxide (2.5 ml) was added 30% hydrogen peroxide (0.26 ml), and the mixture was stirred at room temperature for 15 minutes. Then, to the reaction mixture was added a 5N sodium hydroxide solution (0.26 ml), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added acetic acid. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 127 mg of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.[N:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[C:37]=[O:38]>CN(C)C=O.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH3:28])=[C:16]([CH:23]4[CH2:24][N:25]([C:37]([NH:36][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])[CH2:26]4)[C:17]([C:18]#[N:19])=[C:20]([Cl:22])[CH:21]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: CC(C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(=O)NC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (20 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) was treated with triethylamine (20 μL, 0.14 mmol) followed by 2-isocyanato-2-methyl-propane (7.2 μL, 0.063 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (16 mg, 64%). The product was isolated as a single enantiomer. LCMS for C24H30ClN8O2 (M+H)+: m/z=497.2; Found: 497.2.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C@:5]1([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:8][C@@H:7]([C:10]([O:12]C)=[O:11])[C:6]1([CH3:15])[CH3:14]>C1COCC1.O.CO.C(OCC)(=O)C>[CH3:19][O:18][C:16]([C@@:5]1([CH3:4])[CH2:9][CH2:8][C@@H:7]([C:10]([OH:12])=[O:11])[C:6]1([CH3:15])[CH3:14])=[O:17]
Reactant: COC(=O)[C@@H]1CC[C@](C)(C(=O)OC)C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@]1(C)CC[C@@H](C(=O)O)C1(C)C
Temperature: 55 °C
Reaction time: 14 h
Yield: 88.6 %

Procedure:
Lithium hydroxide hydrate (407 mg, 9.69 mmol) was added to a solution of (1S,3R)-dimethyl 1,2,2-trimethylcyclopentane-1,3-dicarboxylate (2.213 g, 9.69 mmol) in THF (27.7 ml), water (5.54 ml) and methanol (5.54 ml). The reaction was stirred at 55° C. for 14 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure to yield an oil. The oil was diluted with ethyl acetate and washed with water. The aqueous layer was acidified with 1.0 N HCl, and was extracted with ethyl acetate (3×). The organic extracts were combined, dried with sodium sulfate, filtered and concentrated under reduced pressure, yielding the title compound (1.84 g, 8.59 mmol, 89% yield) as a colorless oil. LC/MS found [M+H]+=215.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.69 (3H, s), 2.84 (1 H, s), 2.52-2.65 (1 H, m), 2.13-2.24 (1 H, m), 1.81-1.90 (1 H, m), 1.53 (1 H, s), 1.27-1.32 (3 H, m), 1.22 (3 H, s), 0.84 (3 H, s).
Reaction SMILES: C(OC(=O)CN(C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](CO)[N:10]=1)(C)(C)C.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:46]=[CH:45][C:33]([CH2:34][NH:35][S:36](C2C=CC=CN=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:31]=[CH:32][C:33]([CH2:34][NH:35][S:36]([C:12]2[CH:11]=[N:10][CH:9]=[CH:14][CH:13]=2)(=[O:38])=[O:37])=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CO)n1
Reactant: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1ccccn1
Product: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate (279 mg, 0.824 mmol) obtained in Reference Example 3-(b), and using N-[4-(thiazol-2-yl)benzyl]pyridin-2-ylsulfonamide (275 mg, 0.830 mmol) obtained in Reference Example 5 in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide to afford the title compound (496 mg) as a white foam. (Yield: 92%)
Reaction SMILES: CCCCCCCCCCCCCCCCCC(OCC(OC(CCCCCCCCCCCCCCCCC)=O)COP(OCCN)(O)=O)=O.P([O-])([O-])([O-])=O.CC([O:60][C:61]1[CH:66]=[CH:65][C:64]2[C:67]3([O:90][C:88](=[O:89])[C:80]4[CH:81]=[CH:82][C:83]([C:85]([OH:87])=[O:86])=[CH:84][C:79]3=4)[C:68]3[CH:74]=[CH:73][C:72]([O:75]C(C)=O)=[CH:71][C:69]=3[O:70][C:63]=2[CH:62]=1)=O.CC(CC(O)=O)=O>[Na+].[Cl-].CS(C)=O>[CH:82]1[C:83]([C:85]([OH:87])=[O:86])=[CH:84][C:79]([C:67]2[C:68]3[CH:74]=[CH:73][C:72]([OH:75])=[CH:71][C:69]=3[O:70][C:63]3[C:64]=2[CH:65]=[CH:66][C:61]([CH:62]=3)=[O:60])=[C:80]([C:88]([OH:90])=[O:89])[CH:81]=1
Reactant: CC(=O)Oc1ccc2c(c1)Oc1cc(OC(C)=O)ccc1C21OC(=O)c2ccc(C(=O)O)cc21
Agent: CC(=O)CC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(=O)OCC(COP(=O)(O)OCCN)OC(=O)CCCCCCCCCCCCCCCCC
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(C(=O)O)c(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c1

Procedure:
To further characterize the liposome uptake, kinetic measurements were made using flow cytometry in which 27 mol % DSPE-ATA liposomes were prepared in 150 mM NaCl, phosphate buffer, pH 7.4 along with dipalmitoylphosphatidylglycerol/DPPC/CHOL (50/1733) liposomes in the same buffer. The liposomes were loaded with 6-carboxyfluorescein diacetate (6-CFDA) by lowering the pH to 5.0 and adding the 6-CFDA dissolved in dimethylsulfoxide (DMSO). This fluorophore is non-fluorescent in the diacetate form. Deacetylation resulting from either base hydrolysis or enzymatic hydrolysis yields the fluorescent compound 6-carboxyfluorescein. The fluorophore was found to be stably entrapped in buffer for at least 7 days and was stably entrapped in the presence of serum for 3 hours at 37° C. Both formulations of 6-CFDA labeled liposomes were incubated with 72 hour phytahemaglutanin stimulated peripheral blood mononuclear cells (PBMCs) and the kinetics of liposome uptake were followed by flow cytometry for 48 hours. The results showed that both monocytes and lymphocytes took up the 27 mol % NEST-PE liposomes better than the 50 mol % DPPG liposomes. The results also showed that the kinetics of uptake for the lymphocytes was slower and saturated later than the monocyte liposome uptake.
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(C)(CF)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)COc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
157 g (0.79 mol) of 1-bromo-3,3-dimethyl-4-fluoro-2-butanone were added dropwise to a stirred mixture of 129 g (0.79 mol) of 2,4-dichlorophenol and 110 g (0.79 mol) of powdered potassium carbonate in 500 ml of acetone at 20° to 30° C., while cooling. The mixture was subsequently stirred at 20° C. for 2 hours, the inorganic salt was filtered off and the filtrate was concentrated. 199.3 g (90% of theory) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were obtained as an oil, which was further reacted directly. ##STR82##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:9]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH3:37].C(OCC)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([CH2:24][CH2:25][C:26]([O:28][CH2:36][CH3:37])=[O:27])[N:9]=1
Reactant: CCI
Reactant: CCc1cc2c(s1)-n1c(C)nnc1C(CCC(=O)O)N=C2c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1N=C(c2ccccc2Cl)c2cc(CC)sc2-n2c(C)nnc21
Reaction time: 4 h

Procedure:
3-(4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-6-yl)propionic acid (13.5 g) was dissolved in dimethylformamide (140 ml). Potassium carbonate (9.1 g) and iodoethane (2.9 ml) were added, and the mixture was stirred for 4 hours. Ethyl acetate and water were added thereto. The organic layer was taken out, washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was crystallized from diisopropyl ether to give 11.2 g of ethyl 3-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-6-yl)propionate.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(Br)cc1F
Solvent: Cc1ccccc1
Product: Fc1cc(Br)ccc1Nc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (1.00 g, 5.26 mmol) in toluene (25 mL) was added 2-chlorobenzoxazole (0.66 mL, 5.79 mmol). The purple solution was heated at reflux for 30 min and then at 100° C. for 17 h. The resulting white suspension/purple solution was cooled to room temperature and the precipitate was filtered. The filter cake was washed with five 2-mL portions of heptane to afford N2-(4-bromo-2-fluorophenyl)-1,3-benzoxazol-2-amine (1.480 g, 92%) as a light purple powder. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=12.87 min, 97%; m/z 307 (MH+).
Reaction SMILES: [Al:1].II.Cl[Si:5]([CH3:8])([CH3:7])[CH3:6].[Li].C(C1CCCCC=1)=O.OCC1CCCCC=1>C(OCC)C.[Hg].[O-2].[O-2].[Mn+4]>[CH3:6][Si:5]([Al:1]([Si:5]([CH3:8])([CH3:7])[CH3:6])[Si:5]([CH3:8])([CH3:7])[CH3:6])([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: [Al]
Agent: [Mn+4]
Agent: II
Agent: O=CC1=CCCCC1
Solvent: CCOCC
Product: C[Si](C)(C)[Al]([Si](C)(C)C)[Si](C)(C)C
Reaction time: 2 h

Procedure:
A mixture of Fluka aluminum powder (20 g, 100-200 micron), Fluka aluminum granules (5 g, 0.15-1.7 mm), dry diethyl ether (200 mL), and iodine (2.0 g) was magnetically stirred under argon in a 3-neck 500 mL r.b. flask until the iodine color had disappeared. Mercury (20 g) was added, followed by chlorotrimethylsilane (120 mL, 945 mmole). The mixture was stirred at room temperature for 3 hr and lithium wire (Aldrich, 3.2 mm diam. - 0.01% Na, 1 mole, 7.0 g, 155 cm) was added in small pieces (0.3-0.5 cm). The stirred mixture was heated in an oil bath at 35°-40° C. for 48 hr. After allowing to cool, the mixture was filtered by suction through dry celite under argon directly in a r.b. flask. Complete transference was ensured by washing the reaction flask and filter funnel with dry diethyl ether and the combined filtrates were evaporated in vacuo. The residue was kept under high vacuum for 2 hr. Pentane (50 mL) was added and the mixture was swirled. After the solid had settled the solution was decanted via syringe and transferred to a new flask under argon. Another portion of pentane (50 mL) was added to the solid material and the procedure was repeated, combining the two pentane solutions. As the pentane solution of tris(trimethylsilyl)aluminum etherate is highly pyrophoric, all operations involving synthesis, storage, and use of the material were carried out under an inert atmosphere. The solution is indefinitely stable stored under argon in a freezer. The solution may be assayed by reaction with 1-formylcyclohexene, freshly prepared from 1-hydroxymethylcyclohexene by manganese dioxide oxidation. The aluminum reagent is added dropwise to 1.0 mmole of the aldehyde in dry diethyl ether (2 mL) under argon at -78° C. The transient red color with each drop no longer appears when the reaction is complete but the reaction is best monitored by thin layer chromatography, the starting material being readily visualized by UV while the product is not, even though the Rf s are similar. On a run following the procedure above, 0.67 mL of the aluminum reagent was required for the assay, indicating a concentration of 1.5N. This figure can be variable, however, depending on the batch of aluminum used and other factors.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2F)[C:19]#[N:20])[CH:10]=[CH:11][CH:12]=1.[H-].[Na+]>CN1C(=O)CCC1.COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[O:25][C:23]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[O:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(F)c(OC[C@@H](O)c2cccc(OCc3ccc(Cl)c(Cl)c3)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: COCCOCCOC
Product: N#Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile (13.0 g) was dissolved in 130 mL of anhydrous NMP:diglyme (1:9) solution under nitrogen and heated to 150° C. A suspension of sodium hydride (1.2 g of 60% NaH in mineral oil) in 26 mL of anhydrous NMP:diglyme (1:9) was added all at once via cannula while stirring. After 15 minutes, the reaction was removed from heating, cooled 5 minutes, and then poured into a mixture of ice, 0.5 L EtOAc, and 0.25 L 1 N HCl. The layers were separated and the organic layer was washed with water and brine, and dried over Na2SO4. The residue was purified by silica gel flash chromatography (DCM to 1:1 DCM/EtOAc) to provide 8.2 g of partially purified solid which was then purified by silica gel column (1:1 DCM:hex to DCM). 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.36 (t, 1H), 7.18-7.28 (m, 3H), 6.95-7.06 (m, 4H) 5.16 (m, 1H), 5.04 (s, 2H), 4.42 (m, 1H), 4.02 (m, 1H).
Reaction SMILES: [CH3:1][NH2:2].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=O)[C:6]=2[CH:5]=[CH:4]1.[BH4-].[Na+]>CO>[NH:3]1[C:11]2[C:6](=[C:7]([CH2:12][NH:2][CH3:1])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CN
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a solution of methanamine (536 mg, 17.24 mmol) in MeOH (10 mL) was added 1H-indole-4-carbaldehyde (500 mg, 3.45 mmol). The reaction mixture was stirred at RT for 14 h. The reaction was cooled in an ice bath and NaBH4 (130 mg, 3.45 mmol) was added in several portions. The reaction was stirred at 0° C. for 5 min then stirred at RT for 4 h. The solvent was removed under reduced pressure to afford 300 mg (54.5%) of (1H-indol-4-yl)-N-methylmethanamine (116) which was used in the next step without further purification: MS (ESI) m/z=161.3 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:7])=[O:6].[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([O:17][CH2:21][CH:20]=[CH2:19])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:6])=[O:7]
Reactant: C=CCBr
Reactant: CN(C)C=NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOc1ccc2nc(S(=O)(=O)N=CN(C)C)sc2c1
Temperature: 60 °C
Yield: 70.7 %

Procedure:
A solution of product from Step A (1.14 gm, 4.0 mmol) and allyl bromide (0.5 mL, 5.5 mmol) in dimethyl sulfoxide (8 mL) containing potassium carbonate (0.75 gm, 5.4 mmol) was warmed at 60° C. for 15-20 hours. The reaction mixture was poured into water and the product was extracted into ethyl acetate, dried (Na2SO4) and evaporated to give a viscous oil (0.92 gm).
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]Br)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C-:15]#[N:16].[Na+].O>CN(C)C=O>[CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:15]#[N:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: O=C(c1ccc(CBr)cc1)C1CCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(C(=O)C2CCC2)cc1

Procedure:
α-Bromo-p-tolyl cyclobutyl ketone (18.5 g) in dimethylformamide (50 ml) was added during 35 minutes to sodium cyanide (4 g) in dimethylformamide (100 ml) which was cooled below 10° and stirred. The solution was allowed to warm to 20° during 2 hours and poured into water (1 l). The mixture was extracted with ether (3× 200 ml) and the combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was extracted with light petroleum (b.p. 60°-80°) (7× 250 ml) and the extracts were evaporated to leave an oil which partly crystallised on standing.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Cl-].[NH4+:16].[OH-].[Na+].[OH-].[NH4+].[O-]Cl.[Na+]>CC(OC)(C)C.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: [NH4+]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2ccccc2n1N
Temperature: 25 °C
Yield: 66.2 %

Procedure:
To a mixture of 1H-indole-2-carboxylic acid ethyl ester (2.07 g, Sigma-Aldridch) in MTBE (25 mL) was added in the order of: ammonium chloride (2.96 g), ALIQUAT 336 (124 mg; Cognis Corp., Monheim, Germany), sodium hydroxide (7.44 g), concentrated ammonium hydroxide solution (4.06 mL); the resulting mixture was rigorously stirred at rt, then a 10% solution of NaOCl (67 mL) was added dropwise over a period of 30 min. The reaction was stirred for 3 h after addition of NaOCl, then diluted with EtOAc, washed with water and sat. NaCl solution respectively, dried over sodium sulfate, filtered, concentrated, then the residue was column-purified to give product (1.48 g) as slightly yellow oil. 1H NMR (CDCl3, δ in ppm): 7.65-7.58 (m, 2H), 7.35 (t, 1H, J=7.0 Hz), 7.18-7.11 (m, 2H), 6-4.5 (very broad, 2H), 4.38 (q, 2H, J=7.0 Hz), 1.42 (t, 3H, J=7.0 Hz).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([CH:15]=[O:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=1.[CH:19]1([NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:19]1([N:24]([C:9]2[C:14]([CH:15]=[O:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)CNC1CCCC1
Reactant: CSc1ncc(C=O)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CN(c1nc(SC)ncc1C=O)C1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
Triethylamine (10.9 mL, 78.2 mmol) was added to a solution of compound 224 (12.3 g, 65.2 mmol) and compound 225 (12.8 g, 81.5 mmol) in THF (200 mL). The reaction was stirred at room temperature. After 6 h, the reaction contents were poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The crude material was crystallized from ethyl acetate and hexanes to afford methyl 2-(cyclopentyl(5-formyl-2-(methylthio)pyrimidin-4-yl)amino)acetate (226) (17.55 g, 87.0% yield).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].CO.[N:28]([Si](C)(C)C)=[N+:29]=[N-:30]>[Cu]I.CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:28]=[N:29][NH:30][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: C#Cc1ccc2c(c1)[C@H](Nc1ccc(C#N)cn1)C[C@H](C)N2C(C)=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 100 °C

Procedure:
A microwaveable vial was charged with 6-(((2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 9) (527 mg, 1.595 mmol), Copper (I) Iodide (30 mg, 0.158 mmol), methanol (0.333 ml), DMF (3 ml). Azidotrimethylsilane (0.423 ml, 3.19 mmol) was added to the solution, the vial sealed and heated at 100° C. for 1 h (microwave). Azidotrimethylsilane (0.211 ml, 1.59 mmol) was added to the vial and the mixture heated for a further 1 h (sealed vial, microwave). Azidotrimethylsilane (0.211 ml, 1.590 mmol), and copper (I) iodide (30 mg, 0.158 mmol) was added. The vial was resealed and heated for a further 1 h. The reaction solution was concentrated in vacuo, diluted with water (15 ml) and extracted with DCM (3×10 ml). The organics were combined and dried (hydrophobic frit). The mixture was concentrated and the sample purified by chromatography on a silica cartridge (50 g) eluting with a methanol/DCM gradient (0-10%). The appropriate fractions were combined and the solvent evaporated in vacuo to give 6-(((2S,4R)-1-acetyl-2-methyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (50 mg). LCMS (formate): Rt 0.71 min, MH+ 374