Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:26][C@H:25]([CH2:27][O:28]C(C3C=CC(C)=CC=3)=O)[C@@H:14]([O:15]C(C3C=CC(C)=CC=3)=O)[CH2:13]1)[C:6]([Br:38])=[C:5]2[C:39](=[O:41])[CH3:40].C[O-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[CH2:13]1)[C:6]([Br:38])=[C:5]2[C:39](=[O:41])[CH3:40]
Reactant: CC(=O)c1c(Br)n([C@H]2C[C@H](OC(=O)c3ccc(C)cc3)[C@@H](COC(=O)c3ccc(C)cc3)O2)c2cc(Cl)c(Cl)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)c1c(Br)n([C@H]2C[C@H](O)[C@@H](CO)O2)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
5,6-Dichloro-2-bromo-3-acetyl-1-[3,5-di-O-(p-toluoyl)-2-deoxy-β-D-ribofuranosyl]indole (4.142, 1.24 g, 1.7 mmol) was suspended in absolute MeOH (75 mL) to which was added sodium methoxide (250 mg, 4.6 mmol). The suspension was stirred at room temperature for 2 h, after which time the solution first clarified and then a precipitate formed. Water (100 mL) was added, and the suspension was evaporated until no more MeOH remained. The remaining solids were filtered and recrystallized twice from MeOH/H2O to yield 475 mg (68%) of 4.143 as a white crystalline solid: mp slow dec. >235° C.; Rf 0.5 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.37 (s, 1H), 6.56 (dd, 1H), 5.46 (s, 1H, D2O exch.), 5.31 (s, 1H, D2O exch.), 4.48 (d, 1H), 3.92 (d, 1H), 3.76 (s, 2H), 2.65 (s, 3H), 2.48 (m, 1H), 2.13 (ddd, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 192.59, 133.20, 126.74, 125.89, 125.77, 121.91, 121.80, 115.94, 115.32, 87.59, 87.30, 69.84, 60.66, 39.23 (under DMSO), 30.95. HRMS (EI) m/z calcd. for C15H14BrCl2NO4 420.9483. found 420.9493. Anal calcd for C15H14BrCl2NO4: C, 42.58; H, 3.34; N, 3.31. Found: C, 42.77; H, 3.25; N, 3.22.
Reaction SMILES: O[C@H](C)CC(OC1(C)CCC(C(C)C)CC1)=O.[CH3:18][C@H:19]1[CH2:24][C@@H:23]([OH:25])[C@H:22]([CH:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]1>>[CH:19]1([CH3:18])[CH2:20][CH2:21][CH:22]([CH:26]([CH3:27])[CH3:28])[CH:23]([OH:25])[CH2:24]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: CC(C)C1CCC(C)(OC(=O)C[C@@H](C)O)CC1
Product: CC1CCC(C(C)C)C(O)C1

Procedure:
A sensate composition was prepared by mixing the (3R)-1-menthyl 3-hydroxybutyrate obtained in Example 1 with 1-menthol at a ratio of 1:9 (weight ratio). Oral sensory evaluation was carried out by preparing 1,000 ml of a 20 ppm aqueous solution of the thus obtained sensate composition, and the oral sensory evaluation was carried out also on a 20 ppm aqueous solution of 1-menthol alone as a comparison.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:34][OH:35])[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:35][N:34]=[C:22]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=3)[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Product: CCc1ccccc1-c1ccc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)cc1COC
Temperature: 25 °C

Procedure:
The title compound was prepared following procedure described for example 35, step 1, but starting from Intermediate 36 (1 135.37 mg; 4.20 mmol) and Intermediate 1 (891.15 mg; 4.20 mmol). The reaction mixture was cooled to RT and concentrated affording yellow oil. It was precipitating in ACN. Solvent were removed and the solid was washed with MeOH, filtered off and dried under vacuum to afford the title compound as a white powder. 1H NMR (CDCl3) δ 8.43 (s, 1H), 8.18-7.99 (m, 4H), 7.41-7.35 (m, 3H), 7.29-7.24 (m, 1H), 7.11 (d, J=7.2 Hz, 1H), 4.27-4.17 (m, 2H), 3.98 (s, 3H), 3.34 (s, 3H), 2.50-2.28 (m, 2H), 1.05 (t, J=7.5 Hz, 3H). LC/MS (Method B): 447.2 (M+H)+. HPLC (Method A) Rt 6.14 min (Purity: 99.5%).
Reaction SMILES: [N:1]1([C:5]2[CH:6]=[CH:7][C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[C:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:13]=3)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:26]=1.C(N(CC)CC)C>CS(C)=O.O>[N:1]1([C:5]2[CH:6]=[CH:7][C:8]([O:11][C:12]3[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=3)[CH:18]=[C:19]3[CH2:20][CH2:21][N:22]([C:32]([NH:31][C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[O:33])[CH2:23][CH2:24]3)=[N:9][CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: C(=C1CCNCC1)c1cccc(Oc2ccc(N3CCC3)cn2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(N4CCC4)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a solution of 5-(azetidin-1-yl)-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.098 g, 0.304 mmol) in DMSO (2 mL) was added phenyl pyridin-3-ylcarbamate (0.065 g, 0.304 mmol) followed by triethylamine (0.049 mL, 0.354 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (32% acetone/hexane) to give the title compound (0.099 g, 73.8% yield). 1H NMR (500 MHz, CDCl3): δ 8.62 (s, 1H), 8.23 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 7.45 (s, 1H), 7.28 (m, 2H), 7.09 (s, 1H), 6.93 (d, J=7.55 Hz, 1H), 6.88 (m, 3H), 6.80 (m, 1H), 6.37 (s, 1H), 3.87 (t, J=7.05 Hz, 4H), 3.62 (m, 2H), 3.51 (m, 2H), 2.57 (m, 2H), 2.39 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 156.02, 155.42, 154.56, 145.26, 143.28, 140.75, 138.71, 137.58, 136.56, 130.88, 129.34, 127.80, 124.88, 124.01, 123.70, 123.09, 119.85, 117.62, 112.61, 53.85, 53.09, 45.71, 44.75, 35.75, 31.74, 29.71, 29.29, 29.16, 17.52; m/z (442.2, MH+); HPLC: 97.8%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)([OH:31])=[O:30].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21](=[O:27])[C:18]1[CH:19]=[CH:20][C:15]([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([C:29]([OH:31])=[O:30])[CH:37]=2)=[CH:16][CH:17]=1)[CH3:24]
Reactant: CCN(CC)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc(C(=O)O)c2)cc1
Temperature: 90 °C
Yield: 70 %

Procedure:
A mixture of 4-[bromo-(4-diethylcarbamoyl-phenyl)-methylene]-piperidine-1-carboxylic acid tert-butyl ester (1a, 451 mg, 1.0 mmol), 3-carboxyphenyl boronic acid (330 mg, 2.0 mmol), 2M Na2CO3 (3 mL), and tetrakis(triphenyl phosphine) palladium(0) (25 mg) in toluene (degassed, 10 mL) and ethanol (degassed, 10 mL) was refluxed at 90° C. for 4 hrs under N2. The reaction mixture was then quenched with aqueous NH4Cl after cooling down to 0° C., and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over MgSO4, and evaporated to give a crude product, which was purified by flash silica gel column to provide the desired compound 2a (345 mg, 70%): 1H NMR (CDCl3) δ 1.15 (3 H, br m, CH3CH2—), 1.23 (3 H, br m, CH3CH2—), 1.47 (9 H, s, C(CH3)3), 2.31 (2 H, m, piperidine CH—), 2.35 (2 H, m, piperidine CH—), 3.30 (2 H, br m, CH3CH2N—), 3.48 (4 H, m, piperidine CH—), 3.54 (2 H, br m, CH3CH2N—), 7.14 (2 H, d, J=8.0 Hz, ArH), 7.24 (1 H, m, ArH), 7.33 (2 H, d, J=8.0 Hz, ArH), 7.42 (1 H, t, J=7.6 Hz, ArH), 7.86(1 H, s, ArH), 7.97 (1 H, d, J=7.6 Hz, ArH). IR (NaCl)2976, 1718, 1691, 1598, 1430, 1233, 1166 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)=[O:12].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH3:10])=[CH:14][CH:15]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Nc2cc(Cl)nc(Cl)c2)cc1

Procedure:
To 2,6-dichloro-4-iodopyridine (0.8177 g, 3 mmol) and 4-aminoacetophenone (0.4891 g, 3.6 mmol) dissolved in dry toluene (10 mL) and THF (2 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.0571 g, 0.06 mmol), 1,3-bis(diphenyl-phospino)propane (0.0499 g, 0.12 mmol), and sodium-tert-butoxide (0.4042 g, 4.2 mmol). The reaction mixture was stirred and refluxed for 12 to 14 hours under N2. The reaction mixture was diluted with CH2Cl2 and filtered through Celite™, then rinsed with CH2Cl2. The filtrate was washed two times with water and one time with brine. The organic phase was collected and dried over potassium carbonate. The filtered sample was concentrated, and the resulting solid was dried for 12-18 hours under vacuum.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)=[O:13].Cl.N1C=CC=CC=1>O>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:13][C:3]3[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=3[CH:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cc2cc(OC)ccc2OC)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A mixture of 74 (1.5 g, 5.2 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1.5 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc and the organic layer was dried, concentrated to give a solid which was triturated with CH2Cl2 to give a solid (0.6 g, 51%): Mp=275–278° C.; 1H NMR (DMSO-d6) δ 9.81 (br s, 1 H), 9.12 (br s, 1 H), 7.66 (d, 2 H, J=2.5 Hz), 7.32 (d, 1 H, J=8.5 Hz), 7.00 (s, 1 H), 6.90–6.83 (m, 3 H), 6.65 (dd, 1 H, J=8.6 Hz, 2.6 Hz); MS 225 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:19])[CH:3]=1.CCN(CC)CC.[C:27](Cl)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:5][C:4](=[O:19])[C:3]=1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=CC(=O)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(Cc2ccccc2)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17 mL, 1.2 mmol), benzoyl chloride (0.13 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.51 g, 8.1 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 1% MeOH in CH2 Cl2) to provide a solid (0.215 g, 46°-48° C.). 1H NMR (400 MHz, DMSO-d6) δ10.864 (bs, 1H), 7.375-7.248 (m, 7H), 7.026-7.000 (m, 2H), 6.737-6.713 (m, 1H), 3.393-3.332 (2H, obscured by solvent), 3.110 (AB, 2H, JAB =17 Hz), 1.933-1.870 (m, 2H), 1.402-1.353 (m, 1H), 1.132-1.084 (m, 1H), 0.891-0.710 (m, 7H).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([C:20]3[S:21][C:22]([CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:23][CH:24]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[NH:10][CH:11]=[C:12]2[C:20]1[S:21][C:22]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:23][CH:24]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccc(CN3CCCC3)s2)c2cccc(F)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Fc1cccc2c(-c3ccc(CN4CCCC4)s3)c[nH]c12
Yield: 76.1 %

Procedure:
1-benzenesulfonyl-7-fluoro-3-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-indole (0.20 g, 0.46 mmol) and potassium carbonate (0.25 g, 1.82 mmol) were treated with a mixture of methanol and water (3:1 v/v; 4 ml) and subjected to microwave irradiation at 100° C. for 600 s. The resulting suspension was then concentrated under reduced pressure and partitioned between dichloromethane (10 ml) and water (10 ml). The organic phase was separated and the aqueous phase washed with dichloromethane (10 ml). The combined organic layers were dried with sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 0-10% (v/v) methanol in dichloromethane to afford 7-fluoro-3-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-indole as a colourless solid (0.10 g, 0.35 mmol).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)Cl>[NH2:26][C:22]1[C:21]2[N:20]([C:19]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:43](=[O:45])[CH3:44])[CH2:30][CH2:29]3)=[N:18][C:17]=2[C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8]3)=[CH:13][CH:12]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 0.25 h

Procedure:
1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine (100.00 mg, 0.23 mmol) in a dried 10 mL round-bottom flask was dissolved in 1.7 mL of methylene chloride and was charged with PS-DIEA (117.95 mg, 0.46 mmol). Acetic anhydride (Ac2O) (11 μL, 0.51 equiv) was added in one portion. After 15 min., another 5.5 μL of Ac2O (0.25 equiv) was added. After another 15 min., another 2.64 μL of Ac2O (0.12 equiv) was added. After another 15 min., another 11 μL of Ac2O (0.51 equiv) was added. The reaction was filtered through a fritted funnel, and the resins were rinsed multiple times with methylene chloride. The crude product was purified by silica gel flash chromatography (wetted with 100% EtOAc, eluted with 5% (7N NH3) in MeOH/EtOAc) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=1.68), 8.28 (1H, d, J=8.20), 8.19 (2H, dd, J=1.51 Hz, J=1.18), 7.93 (3H, m), 7.53 (3H, m), 7.23 (1H, d, J=5.10), 7.12 (1H, d, J=5.76), 5.55 (2H, m), 4.67 (1H, d, J=13.28), 3.83 (1H, d, J=12.26), 3.06 (1H, m), 2.96 (2H, m), 2.56 (1H, m), 2.27 (1H, m), 2.10 (3H, s), 1.85 (2H, t), 1.31 (2 H, m); MS (ES+): m/z 477.11/478.08 (40/20) [MH+]; HPLC: tR=2.11 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:21])[C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)=[N:13][CH:14]=3)=[CH:4][C:3]=1[C:22](O)=[O:23].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[CH2:35][CH2:34][NH:33][C:30]2=[CH:31][N:32]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O.CN(C)C=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[CH2:35][CH2:34][N:33]([C:22]([C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[CH3:1])[N:9]3[C:12]([CH:15]5[CH2:20][CH2:19][CH2:18][O:17][CH2:16]5)=[N:13][CH:14]=[C:8]3[C:7](=[O:21])[NH:6]4)=[O:23])[C:30]2=[CH:31][N:32]=1
Reactant: Cc1cc2c(cc1C(=O)O)[nH]c(=O)c1cnc(C3CCCOC3)n12
Reactant: COc1cc2c(cn1)NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cn1)N(C(=O)c1cc3[nH]c(=O)c4cnc(C5CCCOC5)n4c3cc1C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 200 mg of 8-methyl-4-oxo-1-(tetrahydro-2H-pyran-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid, 100 mg of 5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 0.42 mL of N,N-diisopropylethylamine, and 5 mL of N,N-dimethyl formamide was added 235 mg of TBTU, followed by stirring at room temperature overnight. To the reaction mixture were added water and a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0-95/5). The obtained solid was washed with methanol to obtain 148 mg of 7-[(5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)carbonyl]-8-methyl-1-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]quinoxalin-4(5H)-one.
Reaction SMILES: Br[C:2]1[C:11]([N:12]([CH3:14])[CH3:13])=[CH:10][C:9]2[C:8]([CH3:16])([CH3:15])[CH2:7][CH2:6][C:5]([CH3:18])([CH3:17])[C:4]=2[CH:3]=1.C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>C1COCC1>[CH3:13][N:12]([CH3:14])[C:11]1[C:2]([B:24]([OH:29])[OH:25])=[CH:3][C:4]2[C:5]([CH3:18])([CH3:17])[CH2:6][CH2:7][C:8]([CH3:16])([CH3:15])[C:9]=2[CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C)c1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)c1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a solution of 2-Bromo-3-dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (67.08 g, 0.216 mol) in 300 mL of anhydrous THF at −78° C. was added dropwise at −78° C. a 1.6 molar solution of n-butyl lithium (1.6 M, 203 mL, 1.5 eq.) over a period of 30 minutes. The reaction was stirred for 10 min. at −78° C. and 150 ml of tri(iso-propyl) borate (3 eq.) was added dropwise over 0.5 hr. The mixture was allowed to warm to room temperature overnight. The resulting thick mixture was diluted with THF, cooled to 0° C. and 1N hydrochloric acid was added. The reaction was stirred for 0.5 hr at room temperature. The resulting layers were separated and the aqueous phase was washed with EtOAc. The aqueous layer was neutralized to pH 7 to give a precipitate that was extracted with dichloromethane. The aqueous phase was saturated with sodium chloride and extraction was continued. The combined organic layers were dried over sodium sulfate, filtered and evaporated to yield an oil which slowly crystallized on standing. The solid was collected by filtration, washed with hexane and dried to afford 23.00 g of (3-dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (39%). 1H-NMR (300 MHz, DMSO-d6): 1.20 (s, 6 H), 1.23 (s, 6 H), 1.60 (s, 4 H), 2.62 (s, 6 H), 7.25 (s, 1 H), 7.64 (s, 1 H), 9.14 (s, 2 H).
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([F:14])[CH:13]=1)[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2)(=O)C.ClC1C=CC=[C:19]([C:23]([O:25]O)=[O:24])C=1>C(Cl)(Cl)Cl>[C:23]([O:25][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([F:14])[CH:13]=1)[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2)(=[O:24])[CH3:19]
Reactant: CC(=O)c1cc(F)c2c(c1)CCC(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(F)c2c(c1)CCC(=O)N2
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a stirring solution of 6-acetyl-8-fluoro-3,4-dihydroquinolin-2(1H)-one (1.6 g, 7.72 mmol) in CHCl3 (100 mL) at room temperature was added in portions m-chloroperbenzoic acid (2.077 g, 9.27 mmol). The reaction mixture was stirred at reflux for 18 h, then cooled to room temperature and quenched with saturated sodium bicarbonate solution. The reaction was extracted with DCM (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to a yellow oil. This was purified by column chromatography on silica gel using 1% MeOH in DCM to give 8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl acetate as a white foam (1.3 g, 75%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28 (s, 1H), 6.84-6.72 (m, 1H), 2.77-2.54 (m, 2H), 2.45-2.21 (m, 2H), 1.62 (s, 3H). LCMS: R.T.=1.382 min; [M+H]+=224.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].C([O:14][C:15]([CH:17]1[C:21](=O)[CH2:20][CH2:19][O:18]1)=O)C>CCO>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:4]2[N:6]=[C:15]([OH:14])[C:17]3[O:18][CH2:19][CH2:20][C:21]=3[N:5]=2)[CH:7]=1
Reactant: N=C(N)c1cc(Cl)ccc1F
Reactant: CCOC(=O)C1OCCC1=O
Solvent: CCO
Product: Oc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Temperature: 80 °C
Yield: 48.2 %

Procedure:
To a solution of 2-fluoro-5-chlorobenzamidine (1.05 g, 6.08 mmol, 1.2 eq) in EtOH (20 ml) was added 3-oxo-tetrahydrofuran-2-carboxylic acid ethyl ester (prepared according to Moyer, M. P; Feldman, P. L.; Rapoport, H. J. Org. Chem, 1985, 50, 5223-5230; 800 mg, 5.06 mmol, 1 eq) in ethanol (5 ml). The reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to r.t. and the crude residue was purified by flash column chromatography (5% MeOH in CHCl3) to afford a white solid 2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ol (650 mg, 53%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:11])=[O:10])=[C:4]([N+:23]([O-])=O)[CH:3]=1.Cl[Sn]Cl>Cl.CCO>[NH2:23][C:4]1[CH:3]=[C:2]([F:1])[C:7]([CH3:8])=[CH:6][C:5]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:10])=[O:11]
Reactant: Cc1cc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])cc1F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1cc(S(=O)(=O)Nc2cccc3cccnc23)c(N)cc1F

Procedure:
In a similar fashion using route 1 general procedure 4, 4-fluoro-5-methyl-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 269) (520 mg, 1.44 mmol), SnCl2 (1.08 g, 5.76 mmol), 6N HCl (2 drops) and EtOH (5 ml) gave the title compound after purification by column chromatography with DCM/MeOH (98:2) (340 mg, 71%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:26]([CH3:25])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:16]
Reactant: CNc1ccccc1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1cnc2c(n1)c(C(=O)C(C)(C)C)cn2COCC[Si](C)(C)C
Temperature: 120 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
A mixture of 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.053 g, 0.129 mmol), N-methylaniline (0.021 mL, 0.19 mmol), Pd2(dba)3 (0.012 g, 0.013 mmol), BINAP (0.012 g, 0.019 mmol) and cesium carbonate (0.084 g, 0.258 mmol) in 2 mL of toluene was stirred at 120° C. in a microwave for 1 h, then at 150° C. in a microwave for 1 h, then at 180° C. in a microwave for 1 h, then concentrated to a residue. Column chromatography (0→30% EtOAc/hexanes) afforded 0.021 g (37%) of 2,2-dimethyl-1-[2-(methyl-phenyl-amino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a yellow oil.