Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][N:73]([C:76](=[O:84])[C@@H:77]([NH2:83])[CH2:78][C:79]([F:82])([F:81])[F:80])[CH2:72][CH2:71]1)=[O:69])[CH2:65][CH3:66].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][N:73]([C:76](=[O:84])[C@@H:77]([NH:83][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH2:78][C:79]([F:80])([F:82])[F:81])[CH2:72][CH2:71]1)=[O:69])[CH2:65][CH3:66]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCOC(=O)N1CCN(C(=O)[C@@H](N)CC(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOC(=O)N1CCN(C(=O)[C@H](CC(F)(F)F)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 100 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 3 ml DMF were added 92 mg HATU, 82 l DIPEA and 75 mg 4-((S)-2-Amino-4,4,4-trifluoro-butyryl)-piperazine-1-carboxylic acid propyl ester. After stirring for 3 h saturated NaHCO3 solution (1.5 ml) was added and the mixture passed through a Chem Elute® cartridge eluting with DCM. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[CH:17]=[CH:16][C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[CH:9]=1.C([Li])CCC.[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[S:35][C:34]1=[O:64])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[S:35][C:34]1([C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]3[O:12][CH2:13][CH2:14][O:15][C:10]=3[CH:9]=2)[CH:18]=1)[OH:64])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc2c(c1)OCCO2
Reactant: O=C1S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 6-(5-bromo-2-chlorobenzyl)-2,3-dihydrobenzo[b][1,4]dioxine (124, 384 mg, 1.1 mmol) in tetrahydrofuran (5 mL) at −78° C. under an atmosphere of nitrogen was added dropwise n-butyllithium (2.5 M in hexane, 0.45 mL, 1.1 mmol), and the mixture was stirred for 0.5 h at the same temperature. Then a solution of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-one (123, 300 mg, 0.54 mmol, This compound was synthesized by reference to H. Driguez and B. Henrissat, Tetrahedron Lett. 1981, 22, 5061-5062, Kakinuma, H., et al., J. Med. Chem. 2010, 53, 3247-3261) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred for 15 min at the same temperature. The reaction mixture was quenched by addition of saturated ammonium chloride solution. After complete addition, the solution was gradually raised to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (silica gel, 3 to 30% tetrahydrofuran in hexane) to yield (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)phenyl)tetrahydro-2H-thiopyran-2-ol (125, 416 mg, 0.51 mmol, 95%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.CCOCC.O>CN(C=O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)=[CH:23][CH:22]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCCOc1ccc2c(ccn2Cc2ccc(Br)cc2)c1
Yield: 53.6 %

Procedure:
130 mg (0.5 mmol) Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine in 1 ml DMF were treated with 67 mg (0.6 mmol) potassium tert. butylate and 150 mg (0.6 mmol) 4-bromobenzylbromide at 45° C. for 1 h. Ether and water were added and the organic phase was washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2: MeOH 9:1 yielded 115 mg (53%) {4-[1-(4-Bromo-benzyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine as colorless oil, MS: 429 (MH+, 1Br).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1ccc2c(=O)[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(=O)n(Cc3cccc(C(F)(F)F)c3)cnc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.100 g, 0.49 mmol) in DMF (5 mL) was added potassium carbonate (0.135 g, 0.98 mmol) and 3-(trifluoromethyl)benzyl bromide (0.11 mL, 0.74 mmol). The reaction mixture was heated to 60° C. and stirred overnight. The mixture was then cooled to rt and concentrated. Water was added and the reaction mixture was extracted with DCM (15 mL, 3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford methyl 4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-dihydroquinazoline-7-carboxylate. LC-MS: (FA) ES+ 363.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[C:13]=3[C:26]=2[CH3:27])=O)=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[C:13]=3[C:26]=2[CH3:27])=[CH:30][CH:31]=1
Reactant: Cc1ccc(C2c3c(C)c(NC(=O)c4ccc(F)cc4)c(C)c(C)c3OC2(C)C)cc1
Solvent: CO
Product: Cc1ccc(C2c3c(C)c(NCc4ccc(F)cc4)c(C)c(C)c3OC2(C)C)cc1
Yield: 39 %

Procedure:
By using 4-fluoro-N-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 39%. Melting point: 92-94° C. (Methanol)
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:14](=O)[CH2:15][S:16][C:17]3[NH:18][CH2:19][CH2:20][N:21]=3)[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:14]3[N:21]4[CH2:20][CH2:19][N:18]=[C:17]4[S:16][CH:15]=3)[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(CSC1=NCCN1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Br
Solvent: CC(=O)O
Product: Clc1ccc(C2(C3=CSC4=NCCN34)CCC2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
A stirred suspension of 1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(2-imidazolin-2-ylthio)ethanone hydrobromide (5 g) in acetic acid (20 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The solvent was removed in vacuo, the residue was allowed to stand at ambient temperature for 24 hours, and the resulting solid was triturated with ether (50 ml), collected by filtration, washed with ether (50 ml) and dried in vacuo at 50° C. for 3 hours to give 3-[1-(3,4-dichlorophenyl)cyclobuty]-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide as a white solid (4.5 g), m.p. 241-244° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[ClH:16].[N:17]1(C(=N)N)[CH:21]=[N:20]C=N1.CCOCC>CN(C)C=O>[ClH:16].[N:1]1([C:21](=[NH:17])[NH2:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: N=C(N)n1cncn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCCCC1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A mixture of piperidine (4.95 ml, 50 mmol), diisopropylethylamine (8.73 ml, 50.0 mmol) and 1H-1,2,4-triazole-1-carboximidamide hydrochloride (6.11 g, 55.0 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature over the weekend. Ether (50 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. The ether layer was separated and DMF layer was stirred with ether (50 ml) at 5° C. (ice water bath) for 10 minutes and the ether layer was separated from the residue. Ether (30 ml) was added to the residue and the mixture was stirred at 5° C. The resulting solid was triturated with ether, collected, washed with ether and dried to give the title compound as a colourless solid (3.55 g, 43%). LC/MS [M+H]+=128.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:28]=[C:27]5[C:22]([C:23]([CH3:33])([CH3:32])[CH2:24][CH2:25][N:26]5C(=O)C)=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:28]=[C:27]5[C:22]([C:23]([CH3:33])([CH3:32])[CH2:24][CH2:25][NH:26]5)=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCC(C)(C)c2ccc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)CCNc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Temperature: 90 °C
Yield: 77 %

Procedure:
A mixture of 1-(7-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,4-dihydro-4,4-dimethylquinolin-1(2H)-yl)ethanone (10 mg), acetonitrile (2 mL), and 5 N HCl (0.5 mL) was heated at 90° C. for 3 h. The cooled solution was treated with sat. aq. NaHCO3, extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried, and evaporated. The residue was purified by TLC to give an off-white solid (7 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)=[CH:2]1.ClN1C(=[O:21])CCC1=O>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]2=[O:21])=[CH:2]1
Reactant: c1ccc2c(c1)ccn2-c1ccsc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: O=C1Cc2ccccc2N1c1ccsc1
Temperature: 70 °C
Yield: 62.5 %

Procedure:
A solution of the above 1-(thien-3-yl)-1H-indole (6.10 g, 30.6 mmol), N-chlorosuccinimide (4.30 g, 32.2 mmol) and dichloromethane (230 mL) is stirred for 2 hr at room temperature. The solvent is then removed, the residue is dissolved in acetic acid (127 mL) and heated to 70° C. Then 85% phosphoric acid is added and the reaction mixture is heated at gentle reflux for 24 hr. After cooling to room temperature, the reaction is concentrated to about its volume, poured onto ice and water and extracted with ethyl acetate. The combined extract is washed with water, with brine, dried, filtered and concentrated. The black residue is purified by chromatography eluting with dichloromethane-0 to 5% methanol. Product containing fractions are combined and concentrated to afford 1-(thien-3-yl)-1H-indol-2-one (4.12 g, 63% yield) as a brown solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:36][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[O:29][CH3:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: COc1ccccc1N
Product: COc1ccccc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 2-methoxyphenylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=385.3 [M+H]+.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[C:20]1([C:26]2[C:34]3[C:33]([N:35]4[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]4)=[N:32][CH:31]=[N:30][C:29]=3[S:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:16][CH:15]([CH2:17][NH:41][CH:38]1[CH2:39][CH2:40][N:35]([C:33]2[C:34]3[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:27][S:28][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:36][CH2:37]1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Product: Oc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)cc1
Yield: 21 %

Procedure:
Synthesis followed SP6 (3 h), using 220 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) with 21% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 70% yield.
Reaction SMILES: Br[CH:2]1[CH:10]([F:11])[CH2:9][C:8]2[C:7](=[O:12])[N:6]([C:13]3[CH:18]=[C:17]([O:19][CH2:20][C:21]#[CH:22])[C:16]([Cl:23])=[CH:15][C:14]=3[F:24])[C:5](=[O:25])[C:4]=2[CH2:3]1.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Cl:23][C:16]1[C:17]([O:19][CH2:20][C:21]#[CH:22])=[CH:18][C:13]([N:6]2[C:7](=[O:12])[C:8]3[CH2:9][CH:10]([F:11])[CH2:2][CH2:3][C:4]=3[C:5]2=[O:25])=[C:14]([F:24])[CH:15]=1
Reactant: C#CCOc1cc(N2C(=O)C3=C(CC(Br)C(F)C3)C2=O)c(F)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: C#CCOc1cc(N2C(=O)C3=C(CC(F)CC3)C2=O)c(F)cc1Cl
Yield: 77.4 %

Procedure:
A mixture of 526 mg (1.22 mmol) of 5-bromo-2-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-6-fluoro4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione, 822 mL of n-tributyltin hydride (3.06 mmol), and a catalytic amount of AIBN (2,2'-azobis[2-methylpropanenitrile]) in 20 mL of benzene was warmed under reflux for 1h. The mixture was then concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel eluting with a 1:4 v:v mixture of ethyl acetate and n-hexane to give 332 mg of the title product of Example 5, a compound of the invention, as a colorless oily film. 1H NMR (CDCl3, 300 MHz) δ 1.8-2.0 (m, 2H), 2.3-2.9 (m, 5H), 4.8 (d, 2H), 5.22 (dm, J=50 Hz, 1H), 7.0 (d, 1H), 7.3 (d,1H).
Reaction SMILES: [CH3:1][C:2]1([C:13]([O:15]C(C)(C)C)=[O:14])[C:6](=[CH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH:4]([CH3:12])[O:3]1.[H][H]>C(OCC)(=O)C.CO>[CH3:1][C:2]1([C:13]([OH:15])=[O:14])[CH:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH:4]([CH3:12])[O:3]1
Reactant: COC(=O)C=C1CC(C)OC1(C)C(=O)OC(C)(C)C
Reactant: [H][H]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CC1CC(C)OC1(C)C(=O)O
Yield: 93.8 %

Procedure:
2,5-Dimethyl-3-methoxycarbonylmethylene-2-tetrahydrofuroic acid, t-butyl ester (28 mg, obtained from Step A) was dissolved in 0.25 mL of ethyl acetate and 0.25 mL of methanol. This mixture was hydrogenated under a balloon of hydrogen at room temperature for 1.25 h. The reaction mixture was filtered over a pad of celite, and the crude product obtained after removal of volatiles was purified via a silica gel SepPak, providing 21 mg of the desired compound cleanly (75% yield), homogeneous by TLC (Rf=0.2 in 10/1 hexane/ethyl acetate)
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]4[CH:22]=[C:23]([C:25]([NH:27][CH:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)=[O:26])[N:24]=[C:18]4[CH:17]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[ClH:43]>O1CCOCC1>[ClH:43].[ClH:43].[NH:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:23]2[N:24]=[C:18]3[CH:17]=[C:16]([O:15][CH:12]4[CH2:13][CH2:14][N:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:41])[F:42])=[CH:4][CH:5]=5)[CH2:10][CH2:11]4)[CH:21]=[CH:20][N:19]3[CH:22]=2)=[O:26])[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cn3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)c1cn2ccc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of tert-butyl 4-(7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)imidazo[1,2-a]pyridine-2-carboxamido)piperidine-1-carboxylate (0.13 g, 0.22 mmol) and 4N hydrochloric acid in dioxane (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and washed with diethyl ether (2×3 mL) and then dried under reduced pressure to afford N-(piperidin-4-yl)-7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)imidazo[1,2-a]pyridine-2-carboxamide dihydrochloride salt as a brown solid (0.13 g, 98%). 1H NMR (CD3OD, 300 MHz) δ 8.72 (m, 1H), 8.56 (m, 1H), 7.64 (m, 2H), 7.45 (m, 2H), 7.31 (m, 1H), 7.26 (m, 1H), 4.97 (m, 1H), 3.64 (m, 5H), 3.01 (m, 2H), 2.14 (m, 10H) ppm; MS (ES) 488.1 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:37]O>C(OCC)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([O:25][CH3:37])=[O:24])=[CH:26][CH:27]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCn1c(=O)c2nc(C(CC)c3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCn1c(=O)c2nc(C(CC)c3ccc(OCC(=O)OC)cc3)[nH]c2n(CCC)c1=O
Temperature: 60 °C

Procedure:
Dissolve 2-[4-[1-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid (85.6 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: C([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23]CC3C=CC(OC)=CC=3)[N:14]=[C:13]([NH2:33])[C:12]=2[CH2:34][OH:35])=[CH:9][CH2:8][CH2:7][N:6]=1)(C)(C)C.[ClH:36]>O1CCOCC1>[ClH:36].[NH2:33][C:13]1[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[CH:16]=[C:11]([C:10]2[CH2:5][NH:6][CH2:7][CH2:8][CH:9]=2)[C:12]=1[CH2:34][OH:35]
Reactant: COc1ccc(COc2ccccc2-c2cc(C3=CCCN=C3C(C)(C)C)c(CO)c(N)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(-c2ccccc2O)cc(C2=CCCNC2)c1CO
Yield: 87 %

Procedure:
tert-butyl 2′-amino-3′-(hydroxymethyl)-6′-{2-[(4-methoxybenzyl)oxy]phenyl}-5,6-dihydro-3,4′-bipyridine-[(2H)-carboxylate (25.0 mg, 0.05 mmol) was treated with 2N HCl in dioxane (4.0 mL) overnight at room temperature. The resulting solid was collected by filtration, washed with ether and dried under reduced pressure to give 2-[6′-amino-5′-(hydroxymethyl)-1,2,5,6-tetrahydro-3,4′-bipyridin-2′-yl]phenol hydrochloride. (14 mg, yield 87%)
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1C
Yield: 98.6 %

Procedure:
A mixture of 5,6-dimethyl-1H-benzo[d]imidazole (500 mg, 3.42 mmol), trityl chloride (1.05 g, 3.76 mmol) and TEA (524 μL, 3.76 mmol) in 5 mL DMF was stirreds at rt for 3 h. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 1.31 g of Intermediate 415.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][S:3]1.[C:8]([NH:15][CH2:16][CH2:17][C:18](O)=[O:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl.C1CCCCC1.CCOC(C)=O>[CH3:1][C:2]1([CH3:7])[N:6]([C:18](=[O:19])[CH2:17][CH2:16][NH:15][C:8](=[O:9])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:5][CH2:4][S:3]1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC1(C)NCCS1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCSC1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.2 %

Procedure:
To a mixture of 2,2-dimethylthiazolidine (234.4 mg; 2 mmol; 1 eq) and boc-beta-alanine (416.3 mg; 2.20 mmol; 1.10 eq) in DCM (30 ml), are added triethylamine (832 μl; 6 mmol; 3 eq) and 2-chloro-1-methylpyridinium iodide (1533 mg; 6 mmol; 3 eq). The mixture is stirred 2 days at RT. The reaction is followed by TLC (cyclohexane/EtOAc 1:1). The reaction mixture is then washed twice with NH4Cl sat. solution and twice with NaHCO3 sat. solution. The organic layer is dried over Na2SO4, filtered and concentrated to give 497 mg of an orange oil, which is purified by flash chromatography (cyclohexane/EtOAc gradient, from 9/1 to 1/1 over 30 min). The title product is isolated as a white-off solid (45.5 mg; 8%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:13]=[CH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:2]2[C:3]3[N:4]([CH:13]=[CH:14][N:15]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: Fc1ccc2nc(Cl)c3nccn3c2c1
Product: Fc1ccc2nc(NC3CCCCC3)c3nccn3c2c1

Procedure:
By reacting 4-chloro-8-fluoroimidazo[1,2-a] quinoxaline (example 25) with cyclohexylamine, following a procedure that is similar to that described in example 3, there is obtained 4-cyclohexylamino-8-fluoroimidazo[1,2-a]quinoxalin. m.p. (DSC)=157.6° C.(onset); IR (KBr): 3415, 2927, 1556 cm-1 ; 1H-NMR (CDCl3): δ7.8 (1H,dd, J=2 Hz), 7.7÷7.35 (1H,dd, JHF =16 Hz), 7.55 (1H,d, J=2 Hz), 7.55÷7.25 (1H,dd, JHF =16 Hz), 7.05 (1H,dd), 6.0 (1H,d), 4.25 (1H,m), 2.35÷1.2 (10H,m); UV (EtOH): λmax =226, 239, 285, 297, 323, 337 nm. Elementary analysis for C16H17FN4 (m.w. 284.33): calcd. C 67.59, H 6.03, N 19.71%; found C 67.31, H 6.04, N 19.70%.