Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])[CH:14]=[CH2:15].C1(=O)C=CC(=O)C=C1>[N+]([O-])([O-])=O.[Ag+]>[C:10]([NH:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1/[CH:15]=[CH:14]/[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])(=[O:12])[CH3:11]
Reactant: COc1cccc(NC(C)=O)c1
Reactant: C=CC(=O)OCCCC
Agent: [Ag+]
Agent: O=C1C=CC(=O)C=C1
Agent: O=[N+]([O-])[O-]
Product: CCCCOC(=O)/C=C/c1ccc(OC)cc1NC(C)=O
Reaction time: 20 h
Yield: 82.4 %

Procedure:
N-(3-methoxy phenyl)acetamide (41 mg, 0.25 mmol), n-butyl acrylate (64 mg, 0.50 mmol), 1,4-benzoquinone (27 mg, 0.25 mmol), AgNO3 (85 mg, 0.5 mmol), and [Pd(MeCN)4](BF4)2 (11 mg, 0.025 mmol) were sequentially added under air to a reaction tube equipped with a stir bar and a septum. A degassed aqueous solution containing TPGS-M-PEG-750 (1.0 mL, 2 wt %) was added by syringe and the resulting mixture vigorously stirred for 20 h. After this time, the contents of the flask were quenched with aqueous NaHCO3 and extracted with EtOAc. The solution obtained was filtered through the plug of silica gel and anhydrous MgSO4, and then concentrated by rotary evaporation. The residue was purified by flash chromatography, eluting with 50% EtOAc/hexanes to afford the product as an off-white solid (60 mg, 83%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([N+:14]([O-])=O)([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:3]1>C1COCC1.[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([NH2:14])([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CN1CCCC(c2ccncc2)([N+](=O)[O-])C1
Agent: [Ni]
Solvent: C1CCOC1
Product: CN1CCCC(N)(c2ccncc2)C1
Temperature: 0 °C
Reaction time: 7 h
Yield: 100.1 %

Procedure:
To a 0° C. cooled solution of 52 mg (0.235 mmol) rac-1-Methyl-3-nitro-1,2,3,4,5,6-hexahydro-[3,4′]bipyridinyl in 2.0 ml THF were added 150 ul of Raney Nickel (50% in water). The mixture was stirred at 0° C. under a hydrogen atmosphere for 7 hours. The catalyst was filtered and the filtrate was concentrated in vacuo to provide 45 mg (88%) of the title compound as a light yellow oil. MS (m/e): 192.4 (M+H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([O:17][C:18](=[O:20])[CH3:19])[C:8]2([CH2:10][CH2:9]2)[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=O)[NH:34][C:33]=3[CH:39]=2)[CH:22]=1)(=[O:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:4][C@@H:5]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([O:17][C:18](=[O:20])[CH3:19])[C:8]2([CH2:10][CH2:9]2)[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][NH:34][C:33]=3[CH:39]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc3c(c2)NC(=O)CO3)c1
Agent: B
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc3c(c2)NCCO3)c1
Yield: 57.2 %

Procedure:
To a stirred solution of acetic acid (5S,6S,7R,8S)-6,7-diacetoxy-5-[4-chloro-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-4-oxa-spiro[2.5]oct-8-yl ester (100 mg, 0.18 mmol) in THF (6 mL) was added a solution of BH3-THF (2.2 ml, 1.8 mmol) and heated to reflux overnight. Reaction was quenched with the addition of ethyl acetate. The solvent was evaporated and the crude product was purified by silica gel column chromatography to furnish the acetic acid (5S,6S,7R,8S)-6,7-diacetoxy-5-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-4-oxa-spiro[2.5]oct-8-yl ester (56 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>CN(C=O)C.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Temperature: 100 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
A mixture of ethyl 5-bromothiophene-2-carboxylate (1.0 g, 4.25 mmol), 4-chlorophenylboronic acid (0.998 g, 6.38 mmol), 2.0 M aq NaHCO3 (6.38 ml, 12.76 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.492 g, 0.425 mmol) in DMF (40 ml) under nitrogen was stirred at 100° C. under nitrogen in a sealed tube for 18 hours as described in WO 2007/011284. The reaction was then cooled to RT, diluted with saturated aq NaHCO3 (40 ml) and extracted with EtOAc (40 ml). The EtOAc extracts were dried over Na2SO4 and concentrated. The crude product was purified by ISCO chromatography on a silica gel column (120 g) employing a 10 min gradient ranging from hexane to 30% EtOAc to elute ethyl 5-(4-chlorophenyl)thiophene-2-carboxylate (1.05 g, 3.94 mmol, 93% yield) as a white solid. LC MS at t=2.70 min. (m+H=267) Phenomenex S5 C18 4.6×30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. 1H NMR (400 MHz, CD3OD) δ ppm 1.39 (t, J=7.18 Hz, 3H), 4.37 (q, J=7.22 Hz, 2H), 7.43-7.51 (m, 3H), 7.71 (d, J=8.56 Hz, 2H), 7.78 (d, J=4.03 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:30][O:31][CH2:32]Cl.O>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:10][C@H:11]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[C@@H:12]([O:14][CH2:30][O:31][CH3:32])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)C[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCO[C@H]1C[C@@H](OCc2ccccc2)C[C@@H]1c1ccnn1C
Temperature: 40 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
To a solution of the (1S*,2R*,4S*)-4-benzyloxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (350 mg, 1.29 mmol) prepared in Example 98a and diisopropylethylamine (1.3 mL, 7.64 mmol) in dichloromethane (5.0 mL), chloromethyl methyl ether (0.48 mL, 6.32 mmol) was added, and the reaction solution was stirred at 40° C. for 5 hours. After allowing to cool, water (10 mL) was added to the reaction solution, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1:2) to yield the title compound (250 mg, 62%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([O:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)[C:5]=2[S:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncnc2c(Br)csc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c(Br)csc23)CC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To 7-bromo-4-chlorothieno[3,2-d]pyrimidine obtained in Step 1-3) of Preparation Example 1, t-butyl 4-hydroxypiperidine-1-carboxylate, K2CO3 and N,N-dimethylformamide were added, and stirred at 100° C. for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]1([OH:7])C=CC=CC=1.[OH:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.Cl.P(=O)(O)(O)O>CC(C)=O>[OH:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:1]=[O:7]
Reactant: Oc1ccccc1
Reactant: Oc1cc2ccccc2cc1O
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CC(C)=O
Product: O=Cc1c(O)c(O)cc2ccccc12

Procedure:
The procedure of Production Example 3 was repeated except that phenol was replaced with 2,3dihydroxynaphthalene, the 35% concentrated hydrochloric acid was replaced with 0.1 ml of phosphoric acid, and the reaction solution to be subjected to reflux was-added with 100 g of acetone and then was heated under reflux, to give a 2,3-dihydroxynaphthalene-formaldehyde condensate.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=2[C:5]([C:14]([OH:16])=O)=[CH:4][CH:3]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>O.CS(C)=O>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:14]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:11]([CH3:12])[CH3:13])[C:10]=2[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:16]
Reactant: Cc1ccc(C(=O)O)c2ccn(C(C)C)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2ccc(C)c3c2ccn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
Added 7-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (52 mg, 0.239 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (56.4 mg, 0.299 mmol), 1-hydroxy-7-azabenzotriazole (65.2 mg, 0.479 mmol), EDC (92 mg, 0.479 mmol) and N-methylmorpholine (0.105 mL, 0.957 mmol) to Dimethyl Sulfoxide (DMSO) (10 mL) and stirred at RT for 16 h. Added 25 ml of water and let stir for 10 minutes. Filtered off solids. Dissolved solids in DCM, washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (Biotage; 0% to 20% gradient MeOH:DCM; 10 g-HP-silica gel column) to give 55 mg of N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-7-methyl-1-(1-methylethyl)-1H-indole-4-carboxamide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (d, 6H), 2.24 (s, 3H), 2.44 (s, 3H), 2.75 (s, 3H), 4.63 (d, J=4.55 Hz, 2H), 5.17 (dt, J=13.20, 6.66 Hz, 1H), 5.97 (s, 1H), 6.91 (d, J=7.58 Hz, 1H), 7.01 (d, J=3.54 Hz, 1H), 7.29 (d, J=3.28 Hz, 1H), 7.39 (d, J=7.33 Hz, 1H), 7.69 (br. s., 1H), 12.59 (br. s., 1H). MS(ES) [M+H]+352.4.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CS(O)(=O)=O.[H][H]>[Pt]>[F:1][C:2]([F:11])([F:12])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Pt]
Agent: CS(=O)(=O)O
Product: CCOC(=O)CC(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h
Yield: 50.1 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (50 g), under a blanket of nitrogen gas, is heated to 40° C. and treated with platinum (0.1 g of 5% Pt/C, 0.01% load) and methanesulfonic acid (1.5 g, 2.9% load). Hydrogen is charged to a pressure of 5 bars, and the mixture agitated at 40° C. for 6h. After filtration to remove the catalyst, 25.3 g (50% yield) of ethyl 4,4,4-trifluoro-3-hydroxybutyrate is obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:20]1=2.[I-].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:29][C:26]4[CH:27]=[CH:28][C:20]5[O:19][CH2:24][CH2:23][O:22][C:21]=5[CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1cccnc1N1CCc2c(ncnc2Nc2ccc3c(c2)OCCO3)C1
Temperature: 150 °C
Yield: 81.7 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.095 g, 0.00034 mol), 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (0.10 g, 0.00068 mol) and sodium iodide (0.02 g, 0.0001 mol) in acetonitrile was heated at 150° C. by microwave in a sealed tube for 10 minutes. After cooling to r.t., the mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate and concentrated to leave an oil. Residue purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give 0.110 g of a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]2[CH:14]=1.[CH2:15]([S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1)[CH3:16].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.C(OCC)(=O)C.O1CCOCC1>[CH2:15]([S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]2[CH:14]=1)[CH3:16]
Reactant: FC(F)(F)c1ccc2nc(Br)cn2c1
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCSc1ccccc1-c1cn2cc(C(F)(F)F)ccc2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 89.1 %

Procedure:
A mixture of 526 mg of 2-bromo-6-trifluoromethyl-imidazo[1,2-a]pyridine, 576 mg of 2-ethylsulfanylphenylboronic acid pinacol ester, 50 mg of tris(dibenzylideneacetone) dipalladium(0), 201 mg of tricyclohexylphosphine (18% toluene solution), 1.26 g of tripotassium phosphate, 4.5 ml of 1,4-dioxane and 1.5 ml of water was stirred at 100° C. for 2.5 hours. Ethyl acetate and water were poured to the cooled reaction mixture, and the mixture was filtered. The aqueous layer of the filtrate was extracted with ethyl acetate, then combined with the organic layer of the filtrate, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 570 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-imidazo[1,2-a]pyridine (hereinafter, referred to as Compound of Present Invention 4).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:26]([CH3:29])([CH3:28])[CH3:27])(=O)=O>C1(C)C=CC=CC=1>[CH3:27][Si:26]([N:1]([Si:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)([CH3:29])[CH3:28]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N([Si](C)(C)C)[Si](C)(C)C)cc1
Yield: 92.6 %

Procedure:
About 9.24 g of ethyl 4-aminobenzoate, 14.88 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 32.68 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 8 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 4-[bis(trimethylsilyl)amino]benzoate (4-BTMSAEBz) as a yellow oil (16.04 g, 93% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 8.07 (doublet, 2H, aromatic protons), 6.76 (doublet, 2H, aromatic protons), 4.12 (quartet, 2H, CH2 protons), 1.00 (triplet, 3H, CH3 protons), 0.02 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]1)[CH3:2].N.[H][H]>[Ni].CO>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][NH2:24])[CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOCCn1c(CN2CCN(CC#N)CC2)nc2cccnc21
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOCCn1c(CN2CCN(CCN)CC2)nc2cccnc21
Yield: 52.1 %

Procedure:
A mixture of 41.8 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo-[4,5-b]pyridin-2-yl]methyl]-1-piperazineacetonitrile and 1100 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at room temperature with 20 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the (E)-2-butenedioate salt in 2-propanol. The salt was filtered off and crystallized from a mixture of acetonitrile and 2-propanol. The product was filtered off and dried, yielding 37.4 parts (52.1%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazineethanamine; mp. 159.8° C. (compound 128).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([C:24]([F:27])([F:26])[F:25])[CH:8]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:22]=[CH:23][C:7]([B:28]([OH:33])[OH:29])=[CH:8][C:9]=1[C:24]([F:27])([F:26])[F:25]
Reactant: FC(F)(F)c1cc(Br)ccc1OCCCOC1CCCCO1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCCCOC2CCCCO2)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
BuLi (2.5M, 19.1 ml) was added dropwise to a solution of 2-(3-(4-bromo-2-(trifluoromethyl)phenoxy)propoxy)tetrahydro-2H-pyran (16.6 g) in THF at −78° C. under N2 during 3 minutes. After stirring at −78° C. for another 10 minutes, triisopropyl borate (11 ml) was then added dropwise during 3 minutes at −78° C. The mixture was stirred at −78° C. for further 20 minutes, then warmed up to room temperature slowly and stirred at room temperature for 30 minutes. The mixture was then quenched with acetic acid (10% in water, 20 ml), extracted with EtOAc (200 ml), washed with brine (100 ml×5), dried over sodium sulphate, solvent removed under reduced pressure, the residue was taken in to toluene and then solvent removed under vacuum to take out trace of acetic acid (repeat 3 times, until no acetic acid smell). The product, as shown by NMR, contains 3 sets of product peaks assumed to be monomer, dimer and trimer.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:32][CH3:33])[N:3]=1.[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([NH2:41])=[O:40])#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:33][O:32][C:14]1[CH:15]=[C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([CH2:35][CH2:34][C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([NH2:41])=[O:40])[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=1
Reactant: C#Cc1cccc(C(N)=O)c1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I34) 0.098 g, 0.20 mmol), 3-ethynylbenzamide (I31) (0.038 g, 0.26 mmol), PdCl2(PPh3)2 (9 mg, 0.01 mmol), triphenylphosphine (0.010 g, 0.04 mmol) and copper(I) iodide (0.009 g, 0.05 mmol) in DMF (2 mL), that had been degassed with nitrogen for 10 minutes, was added triethylamine (0.090 mL, 0.65 mmol). The mixture was degassed with nitrogen then heated to 120° C. for 25 minutes under microwave irradiation. On cooling to room temperature the resulting mixture was left overnight, then an additional portion of 3-ethynylbenzamide (I26) (0.047 g, 0.32 mmol) was added. After degassing with nitrogen the reaction was heated at 120° C. for 25 minutes under microwave irradiation. The volatiles were evaporated under reduced pressure and the residue purified using silica gel column chromatography (20-70% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I35) (0.073 g, 61%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.04 (dd, J=1.4, 1.4 Hz, 1H), 8.02 (s, 1H), 7.93 (ddd, J=7.9, 1.8, 1.2 Hz, 1H), 7.80 (m, 1H), 7.53 (m, 1H), 6.88 (dd, J=8.3, 1.6 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.27 (m, 2H), 3.91 (s, 3H), 2.81 (m, J=12.2 Hz, 2H), 2.64 (tt, J=12.2, 3.4 Hz, 1H), 1.84 (m, 2H), 1.65 (m, 2H), 1.49 (s, 9H). LCMS Method C: rt 6.59 min; m/z 496.1 [(M-Boc)+H]+, 540.0 [(M-t-Bu)+H]+.
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2].Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1>>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2]
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(O)ccc12
Reactant: ClCc1cccnc1
Agent: Cl
Product: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCc3cccnc3)ccc12

Procedure:
The title compound was prepared starting from the title product of Example 16 and 3-picolyl chloride hydrochloride using a procedure analogous to that outlined for Example 2. Product was isolated by flash chromatography eluting with 25% ethyl acetate in methylene chloride. Mass spectrum: m/e 430 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][CH2:41][CH:40]1[CH2:49][NH2:50]>CN(C=O)C>[O:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][CH2:41][CH:40]1[CH2:49][NH:50][CH2:15][CH2:14][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Reactant: NCC1COc2ccccc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]cc(CCCCNCC3COc4ccccc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
5-methoxyindole-3-butyric acid (1.5 g, 6.4 mmole), 1-hydroxybenzotriazole hydrate (1.0 g, 7.7 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.4 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.3 g, 6.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of TBF to remove a by-product and to give 1.8 g (74%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(5-1H-indole-3-yl)-butanamide, as an oil.