Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22]Br)=[CH:20][C:19]3[C:18]([CH3:25])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:27])([CH3:26])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1>CN1CCCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:21]([CH2:22][N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:20][C:19]3[C:18]([CH3:25])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:27])([CH3:26])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2CBr)C(C)(C)CCC3(C)C)cc1
Agent: CN1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(C=Cc2cc3c(cc2Cn2cccn2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of 2.0 g (4.5 mmol) of (E)-methyl-4-[2-(3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate and 0.65 g (9.5 mmol) of pyrazole in 15 mL of N-methyl pyrrolidine was heated at 100°. After 2 hours, the reaction mixture was cooled to room temperature, poured into brine and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was stirred with hexane and the product was filtered off, washed with hexane and dried to give 1.6 g (83%) of methyl-4-[2-(5,5,8,8-Tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate (M+=429).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:27][C:28]([F:45])([F:44])[C@H:29]([O:31][C:32](=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1)[CH3:30]>>[F:27][C:28]([F:45])([F:44])[C@H:29]([O:31][C:32]([N:23]1[CH2:24][CH2:25][CH:20]([C@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:33])[CH3:30]
Reactant: C[C@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: C[C@@H](OC(=O)N1CCC([C@@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (R)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described in Example 1. LC (method 2): tR=1.00 min; Mass spectrum (ESI+): m/z=513 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH2:28]([C:30]1[N:35]=[C:34]([NH2:36])[CH:33]=[N:32][CH:31]=1)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1.CO.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].CC(C)=O.CO.CCO>[CH2:28]([C:30]1[N:35]=[C:34]([NH:36][C:2]2[CH:7]=[C:6]([CH2:8][O:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:12][CH:11]=3)[CH:5]=[CH:4][N:3]=2)[CH:33]=[N:32][CH:31]=1)[CH3:29]
Reactant: CCc1cncc(N)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCc2ccnc(Cl)c2)c2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1cncc(Nc2cc(COc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)ccn2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 28 %

Procedure:
A mixture of tert-butyl (4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate (Intermediate C) (1050 mg, 2.73 mmol), 6-ethylpyrazin-2-amine (437 mg, 3.55 mmol), and cesium carbonate (1333 mg, 4.09 mmol) in 1,4-dioxane (15 mL) was degassed with nitrogen for 5 min. A solution of Pd2(dba)3 (125 mg, 0.136 mmol) and BINAP (170 mg, 0.273 mmol) in 1,4-dioxane (5 mL) was added, and the reaction mixture stirred at 90° C. for 6 h. The reaction mixture was allowed to cool and was stirred at room temperature for 16 h, then diluted with 10% MeOH/DCM (25 mL) and filtered through a plug of Celite, washing with additional 10% MeOH/DCM (15 mL). The solvent was removed in vacuo and the crude product was combined with MeOH (15 mL) and slurried for 3 h. The resulting orange solid was isolated by filtration, then combined with MeOH/EtOH (5 mL) solution and stirred for 72 h. Again the resulting orange solid was isolated by filtration, then acetone (20 mL) was added and the mixture was slurried for 2 h. The residual solid was filtered off, and the filtrate was evaporated to give the subtitle compound tert-butyl (4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate (360 mg, 27%); Rt 2.6 min (Method 2); m/z 472 (M+H)+ (ES+); 1H NMR δ: 1.18 (3H, t), 1.47 (9H, s), 2.63 (2H, q), 5.36 (2H, s), 6.99 (1H, d), 7.06 (1H, d), 7.36 (1H, d), 7.53-7.63 (2H, m), 7.90-8.06 (3H, overlapping m), 8.29 (1H, d), 8.36 (1H, m), 8.91 (1H, s), 8.96 (1H, s), 10.06 (1H, s).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([CH3:49])[CH:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:50][C:37]1[CH:38]=[C:39]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([CH3:49])[CH:44]=2)[CH:40]=[C:41]([CH3:42])[C:36]=1[C:19]1[CH:20]=[CH:21][C:22]([F:24])=[C:23]2[C:18]=1[CH2:17][CH2:16][C@H:15]2[O:14][C:12]1[CH:11]=[CH:10][C:9]2[C@H:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:6][O:7][C:8]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cc(C)c(Br)c(C)c2)ccn1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: Cc1cc(-c2cc(C)c(-c3ccc(F)c4c3CC[C@H]4Oc3ccc4c(c3)OC[C@H]4CC(=O)O)c(C)c2)ccn1

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-2-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. Saponification of the methyl ester following a procedure analogous to that described for Example 4 gives the title compound; if the title compound does not precipitate from the aqueous solution, the crude title compound is purified by HPLC. LC (method 9): tR=0.95 min; Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.CO.[ClH:29]>C1(C)C=CC=CC=1>[ClH:29].[ClH:29].[N:14]1([C:13]2[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2N2CCC(O)CC2)CC1
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: OC1CCN(c2ncccc2N2CCNCC2)CC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 99.47 %

Procedure:
Add t-Butyl 4-(2-(4-hydroxypiperidin-1-yl)pyridin-3-yl)piperazine-1-carboxylate (306.5 g, 0.846 mol) to a 12-liter flask, followed by methanol (613 ml) and toluene (3.06 L). Stir the mixture to give a solution and then add the methanolic HCl solution (579 mL). Heat the solution to 35° C. for 2 hr. followed by 4 hr. at ambient temperature. Filter off the resulting crystalline product, wash the crystals with toluene, and then dry in a vacuum oven at 40-45° C. to provide 1-(3-(piperazin-1-yl)pyridin-2-yl)piperidin-4-ol dihydrochloride as a crystalline solid (283.5 g, 99.47%). 1H NMR 300 MHz (DMSO) δ 9.624 (bs, 2H) 7.890 (dd, J=6.4 Hz, 1H), 7.633 (d, J=7.75 Hz, 1H), 7.137 (m, 1H), 3.916 (bm, 2H), 3.727 (bm, 1H), 3.236 (bs, 9H), 1.877 (bm, 2H), 1.515 (bm, 2H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][C:8](=[CH:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16]O)[CH3:14])[CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:16][CH2:15][CH:13]([CH2:12][CH2:11][CH:10]=[C:8]([CH3:9])[CH3:7])[CH3:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)=CCCC(C)CCO
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCC(C)CCC=C(C)C
Temperature: 150 °C

Procedure:
24 g of methacrylic acid, 31 g of citronellol and 1.5 g of p-toluenesulfonic acid in 500 mL of toluene were heated to reflux at a oil temperature of 150° C. for 19 h. Subsequently, the reaction mixture was quenched by the addition of salt saturated sodium bicarbonate solution. The mixed solution was extracted with ether. The organic layers were combined and washed with salt saturated sodium bicarbonate solution, an aqueous solution of sodium hydride, and then salt saturated ammonium chloride solution, and then dried over salt saturated brine and sodium sulfate anhydrous. Finally, the resultant oily product was evaporated under reduced pressure to obtain citronellyl methacrylate.
Reaction SMILES: [CH3:1][C@@H:2](OS(C)(=O)=O)[C:3]#[CH:4].[Cl:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])=[O:13].C([Zn]CC)C.Cl>O1CCCC1.C1(C)C=CC=CC=1.[Pd](Cl)Cl.CC(CC#N)=N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:10][CH2:11][C@@:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])([OH:13])[C@@H:3]([CH3:4])[C:2]#[CH:1]
Reactant: C#C[C@@H](C)OS(C)(=O)=O
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: CC(=N)CC#N
Agent: CC[Zn]CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#C[C@H](C)[C@](O)(CCl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 115.3 %

Procedure:
16.33 mg (0.0630 mmol) of palladium(II)-dichloride-diacetonitrile were dissolved in 6.00 ml of tetrahydrofuran. 41.29 ml (0.157 mmol) of triphenylphoshine were added. The reaction mixture turned yellow and was stirred for 10 minutes at room temperature. 419.8 mg (2.833 mmol) of (R)-methanesulfonic acid 1-methyl-prop-2-ynylester and 300.0 mg (1.574 mmol) of 2-chloro-1-(2,4-difluorophenyl)-ethanone were added, also 4.293 ml (4.722 mmol) of diethylzinc solution in toluene (1.1 M) within 5 min. at 25–35° C., the latter dropwise with intermittent cooling of the reaction mixture. Stirring was continued for 45 min. at room temperature. The reaction mixture was added to 10 ml of ice-cold water and 5 ml of 25% aqueous hydrochloric acid, extracted twice with each 25 ml of ethyl acetate, the organic phases washed once with 15 ml of water, combined, dried over sodium sulfate and evaporated to dryness. 444 mg of (2R,3S)-1-chloro-2-(2,4-difluoro-phenyl)-3-methyl-pent-4-yne-2-ol were obtained as a yellow oil with purity 78.6%, which contained 77% of the stated diastereomer. Yield 90.6%.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH2:12][CH2:13][C:4]=2[N:3]=[C:2]1[NH2:14].I[CH2:16][CH2:17][CH3:18].[BH4-].[Na+].Cl>C(O)C>[CH2:16]([N:10]1[CH:11]2[C:6]([C:5]3[S:1][C:2]([NH2:14])=[N:3][C:4]=3[CH2:13][CH2:12]2)=[CH:7][CH2:8][CH2:9]1)[CH2:17][CH3:18]
Reactant: CCCI
Reactant: Nc1nc2c(s1)-c1cccnc1CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCN1CCC=C2c3sc(N)nc3CCC21
Reaction time: 1 h

Procedure:
The free base of 4,5-dihydrothiazolo[5,4-f]quinolin-2-amine, 5.0 g (20 mmol), is refluxed in 250 ml ethanol with 6.8 g (40 mmol) of 1-iodopropane for 20 hours. The solvent is removed in-vacuo and the 2-amino-4,5-dihydrothiazolo[5,4-f]quinolinium iodide which remains is dissolved in 200 ml methanol and treated with 1.7 g (50 mmol) of sodium borohydride in small portions, at 0° C. After 1 hour, 50 ml of 10% hydrochloric acid is added dropwise and the volatile components are removed in-vacuo. The residue is made basic with ammonium hydroxide and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, evaporated and the residue is chromatographed to yield (±)-4,5,5a,6,7,8-hexahydro-6-propylthiazolo-[5,4-f]quinolin-2-amine.
Reaction SMILES: [CH3:1][C:2]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=1)([CH3:7])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>CO.C1COCC1.O>[CH3:7][C:2]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)Oc1cc(C(F)(F)F)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Oc1cc(C(F)(F)F)ccn1)C(=O)O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 2-methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionate (Step B, 7.5 g, 29 mol) in 50 mL MeOH, 50 mL THF and 50 mL water was added sodium hydroxide (2.3 g, 57 mmol). After stirring at 50° C. for 5 h, the reaction mixture was partially concentrated, and was added 2 M hydrochloric acid to pH>2. The resulting mixture was extracted with EtOAc (2×200 mL), and the combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.28 (d, 1H), 7.17 (d, 1H), 7.05 (s, 1H), 1.70 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[CH2:47]([C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1)[CH3:48]>>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:38]=[C:2]([C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([CH2:47][CH3:48])[CH:50]=3)[CH:3]=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:20][CH:19]=1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1cccc(-c2cccc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)c1
Yield: 97.7 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-ethyl phenyl boronic acid (0.145 mg, 0.69 mmol) by following general procedure D yielding the title compound (101 mg, 85%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H:27]1[CH2:32][CH2:31][CH2:30]C[C@H:28]1[NH2:33].BrC1C=NC=CC=1>[Cu]I.O1CCOCC1>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:27]3[CH:28]=[N:33][CH:30]=[CH:31][CH:32]=3)[C:6]=2[N:14]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Brc1cccnc1
Solvent: C1COCCO1
Product: NC(=O)c1cc2c3ccccc3n(-c3cccnc3)c2nc1N
Temperature: 110 °C
Yield: 164.8 %

Procedure:
To a stirred mixture of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 100 mg, 0.44 mmol), Copper(I) iodide (8 mg, 0.045 mmol) and potassium phosphate (190 mg, 0.88 mmol) under dry nitrogen was added (±)-trans-1,2-diaminocyclohexane (5 μL, 0.04 mmol) and 3-bromopyridine (43 μL, 0.442 mmol), followed by 1,4-dioxane (2 mL). The mixture was heated at 110° C. for 2 days. The reaction mixture was cooled to room temperature, extracted with methylene chloride (3×30 ml) and washed with water. The extracts were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (12 g silica, methylene chloride to 90/10 methylene chloride/methanol gradient) to yield 2-amino-9-pyridin-3-yl-9H-pyrido[2,3-b]indole-3-carboxamide (67, 20 mg, 10%). NH4OAc standard conditions. DAD Retention time =5.99 min. M+H=310. 1H NMR (300 MHz, MeOD): δ 8.86 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.66-8.63 (m, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.96 (d, J=7.0 Hz, 1H), 7.70 (dd, J=4.7, 8.2 Hz, 1H), 7.36-7.28 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(OC2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]2[C:3]=1[N:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]2[OH:20]
Reactant: CCOC(=O)C(=CNc1ccc(C#N)cc1Br)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(Br)cc(C#N)cc2c1O
Temperature: 25 °C
Yield: 130.3 %

Procedure:
100 mL of diphenyl ether was heated to reflux followed by addition of 5.00 g (13.6 mmol) diethyl 2-((2-bromo-4-cyanophenylamino)methylene)malonate in portions in 30 minutes. The resulting brown solution was reflux for another hour and then cooled down to room temperature. The precipitate was collected and washed with hexanes (15 mL×3) to give 5.69 g of a light brown solid as the desired product. MS ESI (m/z) 321 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][O:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)(=O)=O>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][O:23][CH:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)OCCOC1CCc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOC2CCc3ccccc3C2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with rac.-2-(1,2,3,4-tetrahydro-2-naphthalenyloxy)ethyl methanesulfonate (1.08 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and extracted with dichloromethane. The organic layers were dried (Na2SO4), filtered and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 1:1 plus 2% ethyl acetate) to provide, after crystallization from diethyl ether-hexane, 0.79 g of rac.-alpha-oxo-4-[[2-(1,2,3,4-tetrahydro-2-naphthalenyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 86°-87° C.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][OH:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH:28]=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CN(c2nc(C=O)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 91.5 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (3.88 g, 9.15 mmol) (obtained as described in Reference Example 2(2)) in anhydrous methylene chloride (194 ml) were added activated manganese dioxide (19.4 g) and the mixture was stirred at room temperature for 7 hours. After checking the completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-formyl-1,3-thiazol-2-yl)azetidine (3.54 g, yield 92%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+](=[CH:16][Si](C)(C)C)=[N-].CCCCCC.C(O)(=O)C>CO>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(O)c(C(=O)O)cc1Br
Solvent: CO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(OC)cc1O
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2-hydroxy-4-methoxybenzoic acid (2.00 g) in methanol (10.0 mL) was added 0.6M (diazomethyl)trimethylsilane/hexane solution (14.8 mL) under ice-cooling, and the mixture was stirred for 3 hr. To the reaction mixture was added acetic acid (0.12 mL), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.08 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[C:22]3[C:17](=[C:18]([NH:23][C:24]([C:26]4[N:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]5=[N:28][CH:27]=4)=[O:25])[CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:35][CH3:36])=[N:15]2)[N:8]=1)(=O)=O.[B-](F)(F)(F)[CH:40]=[CH2:41].[K+].C(N(CC)CC)C>CC(O)C.C1COCC1>[CH2:35]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[N:28][CH:27]=2)=[O:25])[N:14]([CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH:40]=[CH2:41])[N:8]=2)[N:15]=1)[CH3:36]
Reactant: CCc1nn(Cc2cccc(OS(=O)(=O)C(F)(F)F)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=Cc1cccc(Cn2nc(CC)c3c(NC(=O)c4cnc5ccccn45)cccc32)n1
Temperature: 80 °C
Yield: 92.6 %

Procedure:
To 6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yl trifluoromethanesulfonate (100 mg, 0.184 mmol) in IPA/THF (3 mL/1 mL) was added potassium trifluoro(vinyl)borate (36.9 mg, 0.275 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (15.0 mg, 0.0184 mmol) and triethylamine (37.2 mg, 0.367 mmol). The reaction mixture was sealed and heated to 80° C. for 16 hours. The mixture was cooled to ambient temperature and concentrated under reduce pressure. The residue was filtered through a plug of silica gel washing with EtOAc. The solution was concentrated to give the product (72 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>>[OH:9][CH2:8][CH:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:3][CH2:4]1
Reactant: O=C(O)c1ccncc1
Reactant: NC1CCC(CO)CC1
Product: O=C(NC1CCC(CO)CC1)c1ccncc1

Procedure:
Prepared as in Example 24a from (4-Aminocyclohexyl)methanol and isonicotinic acid as a yellow oil (100%). MS 235 (MH+).