Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[Cl:31]C1C=CC(C=O)=CC=1>>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:4]1[CH:5]=[CH:6][C:7]([Cl:31])=[CH:2][CH:3]=1)[CH2:17][C:16]2=[O:18]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2ccc(Cl)cc2)Oc2ccc(O)cc21

Procedure:
6-Hydroxy-2-(4-chlorophenyl)chroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 2.8 g of 4-chlorobenzaldehyde. The product was triturated from ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.46 (s, 1H), 7.56 (d, 2H, J 8.5 Hz), 7.45 (d, 2H, J 8.5 Hz), 7.11 (d, 1H, J 2.8 Hz), 7.04 (dd, 1H, J 8.9, 2.8 Hz), 6.96 (d, 1H, J 8.9 Hz), 5.58 (dd, 1H, J 13.1, 2.9 Hz), 3.15 (dd, 1H, J −16.8, 13.1 Hz), 2.79 (dd, 1H, J −16.8, 2.9 Hz).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:7][C@H:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH2:5]1.C(N(C(C)C)C(C)C)C.CS([C:33]1[S:34][C:35]2[C:40]([N:41]=1)=[CH:39][CH:38]=[CH:37][N:36]=2)(=O)=O>CS(C)=O.CCOC(C)=O.O>[CH3:18][C:10]1([CH3:17])[C:11]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[N:8]([C@H:6]2[CH2:7][C@H:4]([NH:3][C:33]3[S:34][C:35]4[C:40]([N:41]=3)=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:5]2)[C:9]1=[O:19]
Reactant: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2nccnc21
Reactant: CS(=O)(=O)c1nc2cccnc2s1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4cccnc4s3)C2)c2nccnc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(trans-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one dihydrochloride (Intermediate 83, 51 mg, 0.167 mmol), N-ethyl-N-isopropylpropan-2-amine (102 μl, 0.585 mmol), and 2-(methylsulfonyl)thiazolo[5,4-b]pyridine (Intermediate 76) (43.0 mg, 0.201 mmol) in DMSO (0.3 ml) was stirred at 100° C. for 3 h. The mixture was diluted with EtOAc and water in a separatory funnel. The aqueous layer was extracted with EtOAc twice. The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The crude solution was purified by silica gel chromatography (ISCO 12 g, 0-70% EtOAc-hexane) to give 7,7-dimethyl-5-(trans-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclobutyl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (37 mg, 0.101 mmol, 60.4% yield) as off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 6 H) 2.50 (ddd, J=14.03, 9.35, 3.51 Hz, 2 H) 3.37-3.55 (m, 2 H) 5.30 (t, J=8.48 Hz, 1 H) 5.73 (br. s., 1 H) 7.17-7.25 (m, 1 H) 7.74 (dd, J=8.04, 1.46 Hz, 1 H) 8.05-8.16 (m, 2 H) 8.22 (dd, J=4.75, 1.53 Hz, 1 H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:34](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOCC>[CH3:34][O:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cccc(CCCCCC(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COC(=O)CCCCCc1cccc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)c1
Reaction time: 6 h
Yield: 70.8 %

Procedure:
To a solution of 6-[3-(tert-butyl-diphenyl-silanyloxymethyl)-phenyl]-hexanoic acid (3.3 g, 7.2 mmol) in DMF (15 mL) is added potassium carbonate (1.09 g, 7.9 mmol) and iodomethane (500 μL, 7.9 mmol). The mixture is stirred for 6 hrs then diluted with ether. The organic layer is washed with water, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ether/hexanes) to give 2.42 g of title compound. 1H NMR (300 MHz, CDCl3) δ 7.70 (m, 4H), 7.38 (m, 6H), 7.20 (m, 2H), 7.12 (s, 1H), 7.06 (d, 1H), 4.76 (s, 2H), 3.65 (s, 3H), 2.59 (t, 2H), 2.30 (t, 2H), 1.64 (m, 4H), 1.37 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].C[O:8][CH2:9][CH2:10][O:11]C.Cl[C:14]1[N:19]=[C:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:17]=[C:16]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[C:15]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40]>C(O)CO>[OH:8][CH2:9][CH2:10][O:11][C:14]1[N:19]=[C:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:17]=[C:16]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[C:15]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40]
Reactant: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(Cl)c1Oc1ccccc1OC
Reactant: COCCOC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: OCCO
Product: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Temperature: 85 °C

Procedure:
To a solution of potassium tert.-butoxide (366.5 mg) in ethylene glycol (5 ml) was added 1,2-dimethoxy ethane (5 ml) and ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (420 mg). The reaction mixture was heated to 85° C. for 7 days, concentrated in vacuo, poured onto water, acidified by 2N HCl, and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The precipitated product was washed with diethyl ether, filtered and dried at HV to give ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (400 mg). LC-MS: tR: 3.45, [M+H]+: 448.24.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([Br:19])[C:16]([NH2:20])=[C:15]([CH3:21])[C:14]=1[CH2:22][O:23]C(=O)C)[CH2:6][C:7]([O:9][CH2:10]C)=[O:8])C.COC(=O)[C@@H](CC1C(CO)=C2C(=CC=1)N[N:42]=C2)CC(OC)=O>>[Br:19][C:17]1[CH:18]=[C:13]([CH2:12][C@@H:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:4]([O:3][CH3:1])=[O:27])[C:14]([CH2:22][OH:23])=[C:15]2[C:16]=1[NH:20][N:42]=[CH:21]2
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c(N)c(C)c1COC(C)=O)C(=O)OCC
Reactant: COC(=O)C[C@H](Cc1ccc2[nH]ncc2c1CO)C(=O)OC
Product: COC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CO)C(=O)OC
Yield: 96 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic acid diethyl ester (2.78 g, 6.1 mmol) was converted to the title compound in a manner analogous to the preparation of 2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethyl ester. Material was obtained as amber solid in 96% yield. MS m/e (M−H)−=383.0, 385.0.
Reaction SMILES: [I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)C=CC=CC=1.[CH2:28]([O:30][C:31](=[O:45])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([S:40][CH:41]2[CH2:43][CH2:42]2)=[C:36]([Br:44])[CH:35]=1)=O)[CH3:29].Cl>C1COCC1>[Br:44][C:36]1[CH:35]=[C:34]([C:32](=[CH:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:31]([O:30][CH2:28][CH3:29])=[O:45])[CH:39]=[CH:38][C:37]=1[S:40][CH:41]1[CH2:43][CH2:42]1
Reactant: CCOC(=O)C(=O)c1ccc(SC2CC2)c(Br)c1
Reactant: c1ccc([P+](CC2CCOCC2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC1CCOCC1)c1ccc(SC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a suspension of triphenyl(tetrahydro-2H-pyran-4-yl-methyl)phosphonium iodide (9.27 g) in THF (70 mL) was added dropwise lithium-1,1,1,3,3,3-hexamethyldisilazide (1 M THF solution, 19.0 mL) at 0° C. or lower, followed by stirring at around 0° C. for 1 hour. To the reaction mixture was added dropwise a solution of ethyl[3-bromo-4-(cyclopropylsulfanyl)phenyl](oxo)acetate (5.0 g) in THF (10 mL) at 2° C. or lower. The reaction mixture was stirred for 30 minutes under ice-cooling and then stirred at room temperature for 15 hours. 4 M Hydrochloric acid was added dropwise thereto at 10° C. or lower, adjusted to pH 7, and then concentrated under reduced pressure. To the residue was added diethyl ether and the resulting solid was separated by filtration. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 2-[3-bromo-4-(cyclopropylsulfanyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylate (4.57 g) as an (E)/(Z)-mixture of olefin.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][C:20]([CH3:25])([CH2:23]O)[CH2:21][OH:22].CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.CC1C=CC=CC=1>[CH3:19][C:20]1([CH3:25])[CH2:21][O:22][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:9][CH2:23]1
Reactant: CC(C)(CO)CO
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)COC(c2ccccc2)(c2ccc(N)c([N+](=O)[O-])c2)OC1
Yield: 55 %

Procedure:
A mixture of 31.5 parts of (4-amino-3-nitrophenyl)phenylmethanone, 21 parts of 2,2-dimethyl-1,3-propanediol, 2 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 450 parts of methylbenzene is stirred and refluxed for 16 hours with water-separator. The reaction mixture is cooled and washed with ammonium hydroxide. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 27.5 parts (55%) of 4-(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl)-2-nitrobenzenamine; mp. 139.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[N+:11]([C:14]1[O:18][C:17]([CH:19]=[CH:20][C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:25]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:20]=[CH:19][C:17]1[O:18][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ncc[nH]2)o1
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(Cn2ccnc2C=Cc2ccc([N+](=O)[O-])o2)c1

Procedure:
Using the same general procedure of Example 1, the captioned compound was prepared using 3-methoxybenzyl chloride and 2-[2-(5-nitro-2-furyl)vinyl]imidazole. After recrystallization from ethanol water the product melted at 143°-145°.
Reaction SMILES: [CH:1]1([CH:6]([O:26][CH3:27])[C:7]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:8]=2[CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:1]1([CH:6]([O:26][CH3:27])[C:7]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:8]=2[CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C)C1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(c1ccc(C(F)(F)F)cc1CO)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of (2-(cyclopentyl(methoxy)methyl)-5-(trifluoromethyl)benzyloxy)(tert-butyl)-dimethylsilane (120 mg, 0.298 mmol) in THF at room temperature was added TBAF in THF (1.0M, 0.45 mL, 0.45 mmol). The mixture was stirred at room temperature overnight. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20% ethyl acetate in hexane) to afford the title compound as a colorless oil (70 mg, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.16 (m, 1H) 1.23-1.35 (m, 1H) 1.38-1.69 (m, 5H) 1.81-1.91 (m, 1H) 2.19-2.33 (m, 1H) 2.92-2.99 (m, 1H) 3.17 (s, 3H) 4.21 (d, J=8.71 Hz, 1H) 4.80 (s, 2H) 7.47 (d, J=7.88 Hz, 1H) 7.54 (d, J=7.88 Hz, 1H) 7.69 (s, 1H). The racemic mixture was separated by chiral chromatography using preparative HPLC (Column: ChiralPak AD; Dimension: 5 cm×50 cm; Mobile phase: 98/2 heptane/ethanol, Flow rate: 120 mL/minutes). The expected preparative retention times for the two enantiomers were 15 minutes (Enantiomer 1) and 20 minutes (Enantiomer 2). Enantiomer 1: 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.17 (m, 1H) 1.26-1.37 (m, 1H) 1.42-1.72 (m, 5H) 1.83-1.92 (m, 1H) 2.23-2.33 (m, 1H) 2.38-2.47 (m, 1H) 3.18 (s, 3H) 4.20 (d, J=8.30 Hz, 1H) 4.82 (d, J=3.73 Hz, 2H) 7.47 (d, J=8.30 Hz, 1H) 7.55 (d, J=7.88 Hz, 1H) 7.69 (s, 1H). Enantiomer 2: 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.17 (m, 1H) 1.28-1.36 (m, 1H) 1.42-1.71 (m, 5H) 1.81-1.93 (m, 1H) 2.22-2.35 (m, 1H) 2.36-2.48 (m, 1H) 3.18 (s, 3H) 4.20 (d, J=8.71 Hz, 1H) 4.82 (d, J=3.73 Hz, 2H) 7.47 (d, J=8.30 Hz, 1H) 7.55 (d, J=8.30 Hz, 1H) 7.69 (s, 1H).
Reaction SMILES: [CH3:1][C:2](=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16].C([N-]C(C)C)(C)C.[Li+]>>[CH3:17][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:25])[CH3:26])[C:19]=1[NH:27][C:28](=[O:29])[CH2:1][C:2](=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:16]
Reactant: CCCCCCCCCCCC(C)=O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 64 %

Procedure:
The title compound was prepared from 2-tridecanone (10.0 g, 0.050 mol), 2,6-diisopropylphenyl isocyanate (10.16 g, 0.050 mol) and lithium diisopropylamide (0.050 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 15% EtOAc/hexane) yielded 13.14 g (0.032 mol, 65%) of the desired product.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:16]=[C:17]2[N:26]([CH3:27])[CH:25]=[CH:24][C:18]2=[N:19][C:20]=1[C@@H:21]([NH2:23])[CH3:22].CC([O-])(C)C.[K+].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:23][C@H:21]([C:20]1[N:19]=[C:18]2[CH:24]=[CH:25][N:26]([CH3:27])[C:17]2=[CH:16][C:15]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 40 %

Procedure:
To a 50 mL pear flask were added tert-butyl piperazine-1-carboxylate (2.44 g, 12.7 mmol) and (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (1.54 g, 6.06 mmol) in 1,4-dioxane (15 mL). To this solution was added potassium 2-methylpropan-2-olate (1 M in THF) (13.3 mL, 13.3 mmol), and the resulting mixture was heated to 90° C. for 45 minutes. After cooling for 10 minutes, the red mixture was poured into saturated NaHCO3 (300 mL) and then extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give crude product, which was purified by preparative HPLC (acid mode, 25-65% ACN/water gradient). The product-containing fractions were combined, concentrated in vacuo, and then partitioned between saturated NaHCO3 and EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound (872 mg, 40.0%). ESI-MS m/z [M+H]+ calc'd for C19H29N5O2, 360. found 360.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].CC1(C)C(C)(C)OB(C2C=C(CNC(=O)CCCC)C=CC=2)O1>>[CH:30]1([C:29]([NH:28][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:11][CH2:10]3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH2:33][CH2:32][CH2:31]1
Reactant: CCCCC(=O)NCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Agent: CCCCC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(=O)C5CCC5)c4)cc23)CC1
Yield: 8 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1H-indole-7-carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}cyclobutanecarboxamide (45 mg, 0.144 mmol) for N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Mass Directed Auto Prep HPLC to give 4.3 mg of the title compound (8%).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[SH:12])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28]Br>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][S:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[N:2]=[CH:3][CH:4]=[CH:5]2
Reactant: Sc1cccc2cccnc12
Reactant: COC(=O)c1ccccc1CBr
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CSc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4.0 eq. of quinoline-8-thiol hydrochloride (39, Aldrich, cat. no. 35,978-5) was dissolved in DMF. To this was added 32.0 eq. of potassium carbonate. The mixture was stirred at room temperature for 20 minutes and 1.0 eq of 2-bromomethyl-benzoic acid methyl ester (40, J. Org. Chem, 2002, 67, 2160) was added. The mixture was stirred at room temperature for a time sufficient enough for reaction completion. The mixture was diluted with 0.1 M citric acid and extracted with EtOAc. The organic layer was washed with brine and dried with Na2SO4, filtered, and concentrated. The product was purified by flash chromatography on silica gel using a mixture of EtOAc-hexanes as eluant to give 41.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[C:16]3([CH:31]=[CH:30][C:29](=[O:32])[CH:28]=[CH:27]3)[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[C:16]3([CH:31]=[CH:30][C:29](=[O:32])[CH:28]=[CH:27]3)[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=CC(N3CCN(Cc4ccccc4)CC3)=NC23C=CC(=O)C=C3)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C1C=CC2(C=C1)N=C(N1CCN(Cc3ccccc3)CC1)C=C2c1ccc(O)cc1
Temperature: 20 °C
Yield: 62.4 %

Procedure:
2-(4-Benzyl-1-piperazinyl)-4-(4-hydroxyphenyl)-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one can be obtained in the following manner: 2-(4-benzyl-1-piperazinyl)-4-(4-methoxyphenyl)-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (6.3 g) dissolved in acetic acid (150 cc) and a 48% strength solution of hydrobromic acid (100 cc) are heated for 12 hours to a temperature of about 100° C. After being cooled to a temperature of about 20° C., the solution is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. Crushed ice (200 g) is added to the residue, followed by 11N aqueous ammonia solution (500 cc). The aqueous solution is washed with chloroform (2×300 cc). The organic fractions are combined, washed with distilled water (200 cc), dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in chloroform (200 cc) and the solution is poured into silica (120 g) contained in a column 3.2 cm in diameter. Elution is performed first with chloroform (1 liter) and the corresponding eluate is rejected. Elution is then performed with a mixture of chloroform and methanol (95:5 by volume) (1 liter) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. 2-(4-Benzyl-1-piperazinyl)-4-(4-hydroxyphenyl)-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (3.8 g) is thereby obtained in the form of a brown cake.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[Li]CCCC.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C([O:36][C:37](=O)[C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([N:45]2[CH:49]=[C:48]([C:50]3[N:51]([CH3:55])[CH:52]=[N:53][CH:54]=3)[CH:47]=[N:46]2)[CH:39]=1)C>C1COCC1.CO>[C:8]([C:6]1[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:37](=[O:36])[C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([N:45]3[CH:49]=[C:48]([C:50]4[N:51]([CH3:55])[CH:52]=[N:53][CH:54]=4)[CH:47]=[N:46]3)[CH:39]=2)[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CCOC(=O)c1ccc(C)c(-n2cc(-c3cncn3C)cn2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cncn4C)cn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A solution of N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (81 mg, 0.261 mmol) in THF (4 mL) was stirred in a bath cooled to −78° C., and n-BuLi (0.22 mL, 0.548 mmol) was added slowly. The cold bath was removed, and the reaction was allowed to stir for 30 min. LHMDS (0.261 mmol) was then added slowly. The suspension was transferred dropwise to a stirring solution of compound 4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzoic acid ethyl ester (81 mg, 0.261 mmol) in THF at 0° C. After 30 min cole MeOH was added and the mixture was partitioned between saturated NH4Cl and EtOAc, then extracted with EtOAc (3×). The organic combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated, and chromatographed (1% MeOH (with 5% NH4OH)/CH2Cl2 to 5% MeOH (with 5% NH4OH)/CH2Cl2) to afford N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzamide (47 mg, 33%) as an orange foam: ESI MS m/z=537 [C27H32N6O4S+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[S:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[N:20]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27]>N1C=CC=CC=1>[N:20]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[S:13][C:12]=1[C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:24]=[C:23]([O:22][CH3:21])[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)c1cc(N)cc(-c2nc3ccncc3s2)c1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)cc(-c2nc3ccncc3s2)c1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Methyl 3-amino-5-(thiazolo[5,4-c]pyridin-2-yl)benzoate (150 mg, 0.526 mmol) was mixed together with 3,4,5-trimethoxybenzoyl chloride (121 mg, 0.526 mmol) in 1 mL of pyridine. The reaction mixture was reacted in a Biotage microwave reactor at 160 degrees for 10 min. It was then cooled to room temperature and concentrated. The resulting residue was purified by chromatography using a 9:1 mixture of CH2Cl2 to MeOH to afford 90 mg of methyl 3-(thiazolo[5,4-c]pyridin-2-yl)-5-(3,4,5-trimethoxybenzamido)benzoate (36% yield) (MS, M++H=480).