Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[NH:7][N:6]=1)=[O:4].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:13][O:12][C:10]([C:8]1[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]([CH3:14])[N:7]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)OC)[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(C(=O)OC)n(C)n1
Reaction time: 0.67 h

Procedure:
1H-Pyrazole-3,5-dicarboxylic acid dimethyl ester (639, 9.1 g, 49.0 mmol) was combined with acetone (400 mL) and potassium carbonate (10.2 g, 74.1 mmol). The mixture was stirred for 40 minutes under an atmosphere of nitrogen. To the stirring suspension, methyl iodide (3.4 mL, 54.0 mmol) was added dropwise. The reaction was stirred at room temperature overnight and then the solvent was evaporated under reduced pressure. The resulting solid was washed with water and filtered. After toluene was added, the solvent was removed under reduced pressure. The resulting compound 640 was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)#[N:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCNCCc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a solution of methyl 3-[(4-methoxy-phenethyl)amino]-propionate (3.0 g, 12.6 mmol) in anhydrous methylene chloride (35 mL) was added 4-cyanobenzenesulfonyl chloride (2.6 g, 12.6 mmol), followed by triethylamine (2.6 g, 25.3 mmol). After stirring for 18 h at room temperature, the mixture was quenched with 1 N HCl solution (150 mL) and extracted with methylene chloride (2×100 mL). Combined organic layers was washed successively with 1 N HCl solution (100 mL) and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (2/1: hexanes/EtOAc) to provide methyl 3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (3.14 g, 7.8 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:24](=[O:26])[CH3:25])=[N:13][CH:14]=2)[O:5]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52.5 %

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.3 g, 1.36 mmol) was dissolved in dichloromethane (5 mL) and 4-dimethylaminopyridine 17 mg, 0.136 mmol) was added, followed by triethylamine (0.38 mL, 2.73 mmol) then acetic anhydride (0.153, 1.5 mmol). The mixture was stirred at room temperature for 3.5 h then diluted with dichloromethane and washed with NH4Cl (sat aq) then brine. The organic layer was dried (MgSO4), filtered and concentrated. Chromatography eluting with ethyl acetate gave the desired product (187 mg, 52% yield). 1H-NMR (300 MHz, CDCl3) δ 9.3 (s, 1H), 8.6 (s, 1H), 8.2 (d, 1H), 8.05 (d, 1H), 2.2 (s, 3H), 1.2 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:37][CH2:38][OH:39])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: OCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 453) (50 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (54 mg) and 2-bromoethanol (0.03 ml) were added to the suspension, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (34 mg, yield 61%).
Reaction SMILES: Cl[Si:2]([Cl:5])([CH3:4])[CH3:3].[C:6]1([Li])[C:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1>CCCCCC>[Cl:5][Si:2]([CH3:3])([CH3:4])[CH:17]1[C:18]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Solvent: CCCCCC
Product: C[Si](C)(Cl)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Into a 3000 ml flask, under nitrogen, was placed a solution of dichlorodimethyl silane (80.2 ml, 0.64 mol.) in 1000 ml of dry hexane, and the solution was Dre-cooled to −78° C. A suspension of fluorenyllithium (53.13 g, 0.32 mol.) in 2000 ml of hexane was slowly added via a cannula and the reaction mixture was stirred for an additional one hour at this temperature. The resulting mixture was gradually allowed to warm to room temperature and stirred for another 16 hours. The reaction mixture was then filtered under nitrogen, through a Celite plug (250 ml). The filtrate was concentrated and kept at −20° C. overnight. The resulting light-green crystals were recrystallised from hexane at −20° C. to afford 75.09 g (90.68 % yield) of chlorodimethyl-(9-fluorenyl)silane.
Reaction SMILES: Br[CH:2]([CH2:5][CH2:6][CH3:7])[CH2:3][CH3:4].[CH2:8]([O:15][NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][N:16]([CH:2]([CH2:3][CH3:4])[CH2:5][CH2:6][CH3:7])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NOCc1ccccc1)Nc1ccccc1
Reactant: CCCC(Br)CC
Product: CCCC(CC)N(OCc1ccccc1)C(=O)Nc1ccccc1
Yield: 34.5 %

Procedure:
Using the general method of Compound 42 Part B, 3-bromohexane (4.59 mL, 32.6 mmole) was reacted with 1-benzyloxy-3-phenylurea (7.3 g, 30.2 mmole) to provide 3.4 g of 1-benzyloxy-1-(1-ethylbutyl)-3-phenylurea.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:23])[CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:23][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NC1CCC1
Product: O=C(NC1CCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(cyclobutyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.34 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.42 mmol of cyclobutylamine. LC/MS [9.86 min; 412 (M+1)]
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)[CH2:3]1.[CH:35](O)=[O:36].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:30]1([N:27]2[CH2:28][CH2:29][CH:24]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:10]4[C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=[C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][CH:35]=[O:36])[CH2:3]5)[N:9]=4)=[CH:23][CH:22]=3)[CH2:25][CH2:26]2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=CO
Reactant: NC(=O)c1ncc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ncc(N2CCC[C@@H](NC=O)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (436) (50 mg, 0.1 mmol) was dissolved in 4 mL DMF. To it were added formic acid (20 μL, 0.5 mmol), DIEA (180 μL, 1.0 mmol) and then PyBOP (105 mg, 0.2 mmol). The mixture was stirred at RT for 2 hours, quenched with 0.3 mL TFA, and directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and nest MeCN to isolate the title compound, (R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-formamidopiperidin-1-yl)pyrazine-2-carboxamide (437), as HCl salt (24 mg). LC-MS (ESI): m/z (M+1) 492.7. UV: λ=267, 276, 305, 335, 372 nm. Proton NMR (CD3OD): δ 8.06 (1H, s), 7.65 (1H, s), 7.58 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.19 (1H, m), 4.01 (1H, m), 3.93 (1H, m), 3.71 (2H, d, J=12.0 Hz), 3.54 (1H, m), 3.46 (1H, m), 3.38 (1H, m), 3.12 (2H, m), 2.86 (1H, m), 2.22-1.66 (16H, m) ppm.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[S:10][C:9]2[C:11](=[O:15])[CH:12]([CH3:14])[CH2:13][C:8]=2[CH:7]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][C:7]1[C:8]2[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[C:9]=2[S:10][C:6]=1[CH3:5]
Reactant: BrBr
Reactant: Cc1cc2c(s1)C(=O)C(C)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(c1Br)CC(C)C2=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To a suspension of 92.4 g (693 mmol) of AlCl3 (anhydrous powder) in 120 ml of CHCl3, 51.2 g (308 mmol) of 2,5-dimethyl-4,5-dihydro-cyclopenta[b]thiophen-6-one in 50 ml of CHCl3 was added at 0° C. over 0.5 hour. The reaction mixture was stirred for 10 minutes at this temperature; then a solution of 16.6 ml of Br2 (323 mmol) in 30 ml of CHCl3 was added dropwise over 1 hour. The resulting mixture was stirred for 1 hour at room temperature, and then poured over 1000 cm3 of ice. The organic layer was separated. The aqueous layer was extracted with 4×200 ml of CH2Cl2. The combined organic fractions were washed with 1000 ml of saturated aqueous Na2CO3, dried over K2CO3, passed through a short Silica Gel 60 column (40-63 μm, d 40 mm, 1 50 mm), and evaporated to dryness. Fractional distillation gave white crystalline product, b.p. 130° C./0.4 mm Hg. Yield 69.2 g (92%) of the title product contaminated with ca. 12% of 3-bromo-2,5-dimethyl-5,6-dihydro-cyclopenta[b]thiophen-4-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[N:18][OH:19])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(-c2ccc(O)cc2)ccc1C=O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cc(-c2ccc(O)cc2)ccc1C=NO
Yield: 53.3 %

Procedure:
A mixture of 4′-hydroxy-3-methyl[1,1′-biphenyl]-4-carbaldehyde (310 mg, 1.46 mmol), hydroxylamine hydrochloride (203 mg, 2.92 mmol) and pyridine (236 ul, 2.92 mmol) in 15 mL absolute methanol was refluxed for 2.5 h. The solvent was removed under reduced pressure and the mixture was dissolved in ethyl acetate and water, extracted with ethyl acetate (×3), washed with brine, dried over sodium sulfate, and filtered. Evaporation of the solvent and purification by recrystallization (ethyl acetate, acetone and hexane) gave 177 mg (53%) of the title compound as a yellowish solid: mp 195-197° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[S:7][C:8]([C:10]3[N:14]4[N:15]=[C:16]([NH:19][C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=5)[CH:17]=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:5]=2[CH:4]=1.[H-].[Na+].I[CH3:37]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[S:7][C:8]([C:10]3[N:14]4[N:15]=[C:16]([N:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=5)[CH3:37])[CH:17]=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:5]=2[CH:4]=1
Reactant: CI
Reactant: COc1ccc(Nc2ccc3ncc(-c4cc5cc(OC)c(OC)cc5s4)n3n2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2ccc3ncc(-c4cc5cc(OC)c(OC)cc5s4)n3n2)cc1OC
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 3-(5,6-dimethoxybenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine (50 mg, 0.108 mmol, 1.0 equiv) in DMF (5.0 mL) was added NaH (13 mg, 0.324 mmol, 3.0 equiv) followed by iodomethane (0.07 mL, 0.541 mmol, 5.0 equiv). After 1 h, the reaction was quenched with saturated aqueous solution of ammonium chloride then extracted with ethyl acetate. Purification by column chromatography using 2% methanol in dichloromethane elution gave 30 mg of the brown solid, 58%.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[C:4]([F:15])[CH:3]=1.[Li]C(C)(C)C.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24]>C1COCC1.CCCCC>[CH3:9][C:8]([CH3:11])([CH3:10])[C:7]([NH:6][C:5]1[C:4]([F:15])=[CH:3][C:2]([Cl:1])=[CH:14][C:13]=1[C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])=[O:12]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1F
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1c(F)cc(Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.8 %

Procedure:
To a stirred, cooled (-50° C.) solution of 0.92 g (4.0 mmol) of 4'-chloro-2'-fluoro-2,2-dimethylpropionanilide in 10 mL of THF was added 2.5 mL (4.2 mmol) of 1.7M t-BuLi in pentane over 5 min. The solution was stirred for 5 min. and treated with 1.0 mL (8.4 mmol) of ethyl trifluoroacetate over 2 min. The reaction was warmed to ambient temperature, stirred 15 min., and quenched with 1N aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed sequentially with water then brine. The solution was dried(MgSO4) and concentrated under reduced pressure to give an oil. The crude amide was chromatographed on silica gel (elution with 3:1 hexanes-ether followed by 1:1 hexanes-ether) to give 570 mg (43%) of 2'-(trimethylacetamido)-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone as an off-white solid. 1H NMR(300 MHz, CDCl3) δ8.68(s, 1H); 7.45-7.47(m, 1H); 7.08(dd, 1H, J=9.5, 2.6 Hz); 1.3(s, 9H). High resolution mass spec: calculated for C13H13NO2ClF4 (M+H)+ : 326.0571, found: 326.0579.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:14]([F:15])=[CH:13][C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:11][C:10]=1[F:29])C1C=CC=CC=1>[Pd].CO>[NH2:8][C:9]1[C:10]([F:29])=[CH:11][C:12]([N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]2)=[CH:13][C:14]=1[F:15]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(N(Cc3ccccc3)Cc3ccccc3)c(F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(N)c(F)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of the product of Example 16C (560 mg, 1.1 mmol) and 10% palladium on carbon in methanol (30 mL) was stirred at ambient temperature under hydrogen until TLC indicated no starting material remained. The mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 4/1 petroleum ether/ethyl acetate to give the title compound. MS: 314 (M+H+),
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][C:10]([CH:12]1[CH2:14][CH:13]1[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26]#[N:27])=[O:16])=[O:11])[CH3:8]>O1CCCC1>[CH2:7]([O:9][C:10]([CH:12]1[CH2:14][CH:13]1[CH:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26]#[N:27])[OH:16])=[O:11])[CH3:8]
Reactant: CCOC(=O)C1CC1C(=O)c1ccc2[nH]cc(C#N)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1C(O)c1ccc2[nH]cc(C#N)c2c1
Temperature: -45 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A suspension of lithium aluminum hydride (0.3 g, 7.94 mmol) in anhydrous tetrahydrofuran (50 ml) was cooled to −45° C. and treated with a solution of the 2-(3-Cyano-1H-indole-5-carbonyl)-cyclopropanecarboxylic acid ethyl ester (1.12 g dissolved in 10 ml THF). The mixture was stirred for 1 h and quenched with water followed by sodium hydroxide solution. The aluminum salts were removed by filtration. The filtrate was concentrated in vacuo to afford 2-[(3-cyano-1H-indol-5-yl)-hydroxy-methyl]-cyclopropanecarboxylic acid ethyl ester (1.0 g) as an amber oil. LC-MS: 1.49 min; 291.1 (MNa)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C@H:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][C@@H:23]2[CH3:35])[CH3:21])=[CH:16][CH:15]=1.[B:36](OC(C)C)([O:41]C(C)C)[O:37]C(C)C.[OH-].[Na+]>C1COCC1>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C@@H:20]([C:17]2[CH:16]=[C:15]([B:36]([OH:41])[OH:37])[C:14]([F:13])=[N:19][CH:18]=2)[CH3:21])[C@@H:23]([CH3:35])[CH2:24]1)=[O:29])([CH3:33])([CH3:32])[CH3:34]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C[C@H](c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
n-Butyllithium (2.5 M in hexanes; 7.23 mL, 18.07 mmol) was added dropwise to a solution of diisopropylamine (2.55 mL, 18.07 mmol) in 8 mL of THF at −40° C. The mixture was stirred for 1 h at −40° C. This solution was cannulated into a 3-necked 250-mL round-bottomed flask that contained a solution of tert-butyl(3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (4.87 g, 15.06 mmol) in 60 mL of THF at −78° C. After 15 min at −78° C., triisopropyl borate (Aldrich; 6.92 mL, 30.1 mmol) was added, and the resulting mixture was stirred at −78° C. for 15 min and then allowed to warm to ambient temperature. The reaction mixture was subsequently treated with 1 M NaOH (80 mL) and allowed to stir for 20 min. The aqueous layer was separated and the organic layer was discarded. The aqueous layer was treated with 10% HCl (aq) until a pH of about 5 to 6 was achieved. The resulting mixture was diluted with EtOAc (20 mL) and the mixture was extracted with 8:2 EtOAc/MeOH (200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (5.01 g, 13.64 mmol, 91% yield) as an off-white solid. m/z (ESI, +ve) 368.1 (M+H)−.
Reaction SMILES: [CH:1]1[C:6](NN)=[CH:5][CH:4]=[C:3]([N:9]2[CH:13]=NN=C2)[CH:2]=1.[C:14]([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[NH:9]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:1][CH:2]=2)[CH:14]=[CH:13]1
Reactant: O=C([O-])[O-]
Reactant: NNc1ccc(-n2cnnc2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Yield: 17 %

Procedure:
A mixture of intermediates 1 (1.0 g, 5.71 mmol) and 2 (2.07 g, 6.86 mmol) in 4% sulphuric acid (30 ml) was heated at reflux for 48 h. The solution was cooled in an ice-bath, basified with solid K2CO3 and extracted with butan-1-ol (×3). The solvent was removed under vacuum and azeotroped with hexane (×2). The crude product was chromatographed through silica gel eluting with CH2Cl2 /MeOH/NH3 (30:8:1) to give the title-indole (282 mg, 17%). The succinate hemihydrate salt was prepared: mp 227°-228° C. (Found: C, 59.11; H, 6.58; N, 22.54.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[CH2:25]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:25]=[CH:24]/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cccnc1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(/C=C/c3cccnc3)cc2OCc2ccccc2)S(=O)(=O)N1

Procedure:
The title compound is prepared using 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 3-vinylpyridine analogous to Example 2, step C.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.P(Br)(Br)([Br:21])=O.C([O-])(O)=O.[Na+]>>[Br:21][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-n2ccc(Br)cc2=O)cc1
Temperature: 100 °C
Yield: 46 %

Procedure:
A mixture of 4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (106.1 mg, 0.4 mmol) and phosphorous oxybromide (573.4 mg, 2 0 mmol, Alfa Aesar) was heated at 100° C. for 45 min and then cooed to room temperature. To the above residue was added saturated NaHCO3 aqueous solution at 0° C. followed by extraction with CH2Cl2 (3×). The combined extracts were washed with saturated NaHCO3 aqueous solution and brine, dried (Na2SO4) and evaporated. The residual was purified by flash chromatography (0 to 100% EtOAc/hexanes) to yield 60.7 mg (46%) of the product as a yellow solid. MS (ESI) 328 (M+H).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH:28]=O)[C@H:6]([CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([N:21]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[CH3:27])[N:15]=1)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:1]([O:4][C@@H:5]([CH2:28][NH:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:6]([CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([N:21]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[CH3:27])[N:15]=1)[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H](C=O)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: C=CCO[C@@H](CNCc1ccccc1)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 16 (240 mg, 0.6 mmol) in THF (5 mL) was added benzylamine (100 μL, 0.9 mmol) followed by NaHB(OAc)3 (153 mg, 0.72 mmol). The reaction was allowed to stir for an additional 3 h then partitioned between EtOAc (100 mL) and brine (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (EtOAc:hexanes, 1:2-1:1) to give 19 (270 mg, 0.55 mmol, 92%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 0.99-1.01 (d, J=6.5 Hz, 3H), 1.09-1.11 (d, J=6.5 Hz, 3H), 2.13 (s, 6H), 2.37 (s, 3H), 2.76-2.85 (ddd, J=4.5, 5.0, 12.5, Hz, 1H), 2.98-3.08 (ddd, J=5.5, 14.0, 15.5, Hz, 1H), 3.49-3.52 (m, 1H), 3.81 (s, 2H), 3.82-3.89 (m, 1H), 4.04-4.08 (dd, J=6.0, 12.5, Hz, 1H), 4.09-4.12 ((dd, J=5.5, 13.0, Hz, 1H), 4.86-4.89 (m, 1H), 5.13-5.15 (dd, J=1.0, 10.0, Hz, 1H), 5.23-5.28 (dd, J=1.5, 17.0, Hz, 1H), 5.86-5.91 (m, 3H), 6.85 (s, 1H), 7.00 (s, 1H), 7.20-7.27 (m, 2H), 7.27-7.35 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 13.6, 21.2, 21.8, 21.9, 35.1, 47.6, 49.9, 54.0, 68.0, 71.4, 79.4, 106.8, 117.2, 120.3, 123.4, 127.2, 128.4, 128.6, 128.8, 134.9, 140.4, 149.5, 151.7, 159.4, 173.0; LCQ-MS (M+H+) calcd for C30H40N3O3 490. found 490; LC-TOF-MS (M+H+) calcd for C30H40N3O3 490.30697. found 490.30644.