Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH3:35])=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:22]=1[CH:23]=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][Mg]Br>O1CCCC1>[C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH3:35])=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:22]=1[CH:23]([OH:24])[CH3:37])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C=O)c1OCc1cccc(C#N)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C(C)O)c1OCc1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 5-(3-cyano-benzyloxy)-4-formyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (109) (1.4 g, 2.9 mmol) in anhydrous tetrahydrofuran (50 mL) was slowly added methyl magnesium bromide (4 mL, 1.0 M, 4.0 mmol) at −78° C. under nitrogen atmosphere and stirred for 30 minutes. The reaction mixture was quenched with a solution of saturated aqueous sodium bicarbonate, and the crude product extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using a gradient mixture of ethyl acetate:hexane (0:1 to 3:2) as an eluant to give [5-(3-cyano-benzyloxy)-4-(1-hydroxy-ethyl)-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (112) (1.04 g, 72% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>CS(C)=O>[C:14]([O:13][C:12](=[O:18])[NH:11][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH:2]=[O:1])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(CCO)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CC=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of 1.63 g of tert-butyl 3-hydroxy-1-phenylpropylcarbamate (Formula 11) in 15 mL of dimethyl sulfoxide (DMSO) was added 2.72 mL of triethylamine. The solution was cooled to 0° C. and 3.1 g of sulfur trioxide pyridine complex in 15 mL of DMSO was added. The reaction mixture was stirred at room temperature for 1 hour then poured onto ice-water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 10% acetic acid, water, 5% sodium bicarbonate, and brine, dried over sodium sulfate and concentrated. Column chromatography (40% ethyl acetate/hexane) gave 1.2 g (74%) of tert-butyl-3-oxo-1-phenylpropylcarbamate (Formula 12) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 2.89-2.96 (m, 2H), 5.23 (br, 1H), 5.32 (br, 1H), 7.27-7.37 (m, 5H), 9.74 (m, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=O)[CH2:2][CH3:3].[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[CH2:2][CH3:3]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: CCCc1ccccc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1ccccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 26.8 %

Procedure:
A solution of (2-propyl-phenoxy)-acetic acid (180 mg, 0.93 mmol), and benzoic acid N′-isopropyl-hydrazide (150 mg, 0.842 mmol) in DMF (5 ml), was treated with triethylamine (0.352 ml, 2.52 mmol), HOBT (136 mg, 1.00 mmol), and EDCI (194 mg, 1.00 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed with 1N NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 10% ethyl acetate/hexanes to afford the product as a white solid (80 mg, 25%). MS m/e 355.35 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15]([OH:21])([CH3:20])[CH2:16][C:17](=[NH:19])[NH2:18].C(=O)(O)[O-].[K+].Br[CH2:28][C:29](=O)[C:30]([CH3:33])([CH3:32])[CH3:31]>O1CCCC1.O>[C:30]([C:29]1[N:19]=[C:17]([CH2:16][C:15]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=3)=[CH:7][C:2]=2[F:1])([OH:21])[CH3:20])[NH:18][CH:28]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(O)(CC(=N)N)c1ccc(-c2ccc(F)cn2)cc1F
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1c[nH]c(CC(C)(O)c2ccc(-c3ccc(F)cn3)cc2F)n1

Procedure:
A solution of the di(trifluoroacetate) salt of (±)-3-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (50 mg, 0.10 mmol), potassium bicarbonate (19 mg, 0.19 mmol) and 1-bromo-3,3-dimethylbutan-2-one (52 mg, 0.29 mmol) in tetrahydrofuran (1 mL) and water (0.25 mL) were stirred at ambient temperature overnight. Volatiles were removed in vacuo and the residue was purified by HPLC (Gilson; KR100-5C18 100×21.2 mm column; 10-100% MeCN/H2O) over 12 min to afford the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, J=2.8 Hz, 1H), 7.90 (dd, J=4.3, 8.8 Hz, 1H), 7.76-7.58 (m, 4H), 6.99 (s, 1H), 3.45 (AB, J=14.9 Hz, 2H), 3.30 (bs, 1H), 1.732 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH:17][C:18](=[O:30])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:11]=1>C1COCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:10]1[CH:15]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[N:13]=[C:12]([NH:17][C:18](=[O:30])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:11]=1
Reactant: OCC(F)(F)F
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.3 %

Procedure:
Sodium hydride (272 mg, 6.8 mmol, 60% in mineral oil) was added to a solution of 2,2,2-trifluoroethanol (1.5 g, 15 mmol) in anhydrous THF (15 mL) at 0° C. and the mixture stirred for 20 min. To this mixture was added N′-[4,6-dichloropyrimidin-2-yl]-N-[4-(trifluoromethyl)phenyl]urea (1.14 g, 3.24 mmol) and stirred at 0° C. for 1 h. The cooling bath was removed and the mixture allowed to warm to room temperature. The mixture was warmed to 45° C. and stirred for additional 18 h. The mixture was poured into water and stirred for 10 min and filtered to afford 1 (1.4 g, 68% yield): m.p. 167-168° C.; 1H NMR (DMSO-d6) δ 10.44 (bs, 1H), 10.28 (bs, 1H), 7.76 (d, J=6 Hz, 2H), 7.69 (d, J=6 Hz, 2H), 6.29 (s, 1H), 5.13 (q, J=9.0 Hz, 4H); ESI/MS 476.92 (M−H), 478.95 (M+H)
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1>>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([C:21]4[NH:29][C:28]5[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=5[CH:22]=4)[CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:4]=1
Reactant: Oc1cccnc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5cccnc5)nc34)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.3 %

Procedure:
Prepared according to Example 103, using NaH as a 60% dispersion in mineral oil (153 μl, 3.53 mmol, Sigma Aldrich), pyridin-3-ol (335 mg, 3.53 mmol, Sigma Aldrich), and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 150 mg, 0.504 mmol) and stirring at 25° C. for 6 h. Purification by column chromatography (silica gel, 0 to 9% MeOH/DCM) followed by trituration with MeOH provided 2-(2-(3-pyridinyloxy)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (49 mg, 27.3%). 1H NMR (400 MHz, CDCl3) δ ppm 11.07-11.15 (1H, m) 8.72-8.76 (2H, m) 8.68 (1H, d, J=1.00 Hz) 8.26 (1H, d, J=1.00 Hz) 8.04-8.09 (1H, m) 7.61-7.70 (2H, m) 7.45-7.57 (2H, m) 7.09-7.14 (1H, m) 5.38 (1H, br. s) 3.52-3.59 (2H, m) 2.54 (2H, t, J=1.00 Hz). m/z (ESI, +ve) 357.0 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:9]=1[CH2:10]Br)=[O:4].[Li+].[OH-:30].[Na+].[Cl-].Cl>C1COCC1.O.C1COCC1>[OH:30][CH2:10][C:9]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=2)=[C:7]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[S:6][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1CBr
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)sc(C(=O)O)c2CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 400 mg of the product of Step 6, 10 g of n-Bu4NOAcin 10 mL of THF were stirred at room temperature for 2 h. The reaction mixture was diluted with 50 mL of 3:2 THF/H2O and treated with 10 mL of 1N LiOH for 8 h. The reaction mixture was poured into a mixture of 20 mL of sat. NaCl and 10 mL of 2N HCl, and then extracted with 100 mL of EtOAc. The extract was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography and eluted with 19:1 EtOAc/AcOH to yield 250 mg of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:12][CH3:13])=[N:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[C:8]#[N:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][OH:22]>C(O)C>[CH2:1]([C:3]1[C:4]([O:12][CH3:13])=[N:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[C:8]([NH:21][OH:22])=[NH:9])[CH3:2]
Reactant: NO
Reactant: CCc1cc(C#N)c(C)nc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCc1cc(C(=N)NO)c(C)nc1OC
Temperature: 90 °C

Procedure:
To a mixture of 5-ethyl-6-methoxy-2-methylnicotinonitrile (300 mg, 1.705 mmol), potassium carbonate (1.174 g, 8.51 mmol) and hydroxylamine hydrochloride (591 mg, 8.50 mmol) is added absolute ethanol (15 mL). The reaction mixture is heated at 90° C. under a reflux condenser for 22 hr. LC/MS shows the reaction is incomplete, and 2 products are observed, one consistent with the desired compound and the other consistent with the corresponding primary nicotinamide. More potassium carbonate (1.174 g, 8.51 mmol) and hydroxylamine hydrochloride (591 mg, 8.50 mmol) are added and the reaction is heated at 90° C. for a further 15 hr. The mixture is allowed to cool, filtered and the filtrate is evaporated to give a sticky, cream colored residue that is used in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[CH2:22]([NH:29][CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:22]([N:29]([CH2:30][CH3:31])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.296 g, 1.00 mmol) and N-benzyl-N-ethylamine (0.149 g, 1.10 mmol) in methylene chloride (10 mL) were added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.353 g, 1.10 mmol) and the reaction mixture was stirred at room temperature for three days. The resulting solution was diluted with methylene chloride (90 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 0.129 g (31%) of a whitish oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Br(O)(=O)=O.Br(O)(=O)=O.[CH2:42]([N:49]1[CH2:54][C@@H:53]2[CH2:55][C@H:50]1[CH2:51][NH:52]2)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH2:42]([N:49]1[CH2:54][C@@H:53]2[CH2:55][C@H:50]1[CH2:51][N:52]2[CH2:32][C:29]1[CH:30]=[N:31][C:26]([C:24]2[NH:25][C:21]([CH:13]([C:10]3[CH:11]=[CH:12][C:7]([S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[CH:8][CH:9]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:22][CH:23]=2)=[CH:27][CH:28]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [O-][Br+2]([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CN4C[C@@H]5C[C@H]4CN5Cc4ccccc4)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (5 mL) were added (1S,4S)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane dibromate (350 mg) and triethylamine (310 μL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (280 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (172 mg, yield 63%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). MS: 637 (MH+).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([N:22]([CH3:24])[CH3:23])=[C:17]([CH3:25])[CH:16]=1>C(O)(=O)C.O>[CH3:24][N:22]([CH3:23])[C:18]1[C:17]([CH3:25])=[CH:16][C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:20][C:19]=1[CH3:21]
Reactant: COC(=O)c1cc(C)c(N(C)C)c(C)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C(=O)CS(C)(=O)=O)cc(C)c1N(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of 24.5 g. of dimethylsulfone and 9.1 g. of sodium hydride (50% dispersion in oil) in 50 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for 3 hours. Then, it was treated with 16 g. of 4-(dimethylamino)-3,5-dimethyl-benzoic acid methyl ester. The mixture was stirred at 80° C. for 45 minutes, cooled and dissolved in 300 ml. of water. The solution was neutralized with glacial acetic acid. The precipitate was removed by filtration with suction, washed with water and recrystallized from alcohol, whereby there was obtained 4'-(dimethylamino) 3',5'-dimethyl-2-(methylsulfonyl)-acetophenone having a melting point of 132°-133° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([B:35]4[O:39]C(C)(C)C(C)(C)[O:36]4)=[C:31]([CH2:44][O:45][CH2:46][O:47][CH3:48])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.Cl.I([O-])(=O)(=O)=O.[Na+]>CO.O1CCCC1>[CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([B:35]([OH:36])[OH:39])=[C:31]([CH2:44][O:45][CH2:46][O:47][CH3:48])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B4OC(C)(C)C(C)(C)O4)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
The crude 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-((methoxymethoxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (215 mg, 0.317 mmol) was dissolved in methanol (1.0 mL) and tetrahydrofuran (4.0 mL). HCl (4.0 mL, 4.00 mmol) was added followed by addition of sodium periodate (542 mg, 2.54 mmol). The mixture was stirred at room temperature overnight. It was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×). The organic phase was washed with 10% aq. Na2S2O3, brine, dried over Na2SO4. Concentrated under reduced pressure, the residue was purified by reversed phase HPLC (10-100 MeCN/H2O with 0.05% TFA) to give product (54 mg, 29%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (q, J=4.36 Hz, 1H) 8.07 (s, 1H) 7.97 (dd, J=8.88, 5.37 Hz, 2H) 7.31-7.53 (m, 5H) 7.14-7.20 (m, 1H) 4.65 (s, 2H) 4.59 (s, 2H) 3.37 (s, 2H) 3.24 (s, 2H) 2.83 (d, J=4.68 Hz, 3H) 2.11-2.26 (m, 1H) 1.01 (br. s., 1H) 0.84 (br. s., 2H) 0.52 (br. s., 1H). LCMS (m/z, ES+)=597 (M+H+).
Reaction SMILES: [C:1]1(N=C=O)[CH:6]=[CH:5][CH:4]=CC=1.[CH2:10]([NH:12][C:13](=[O:31])[O:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[N:18]([O:23][C:24](=[O:28])[NH:25][CH2:26][CH3:27])[C:17]([CH3:30])([CH3:29])[CH2:16]1)[CH3:11]>>[C:10]1([NH:12][C:13](=[O:31])[O:14][CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[N:18]([O:23][C:24](=[O:28])[NH:25][C:26]3[CH:4]=[CH:5][CH:6]=[CH:1][CH:27]=3)[C:17]([CH3:29])([CH3:30])[CH2:16]2)[CH:1]=[CH:6][CH:5]=[CH:4][CH:11]=1
Reactant: CCNC(=O)OC1CC(C)(C)N(OC(=O)NCC)C(C)(C)C1
Reactant: O=C=Nc1ccccc1
Product: CC1(C)CC(OC(=O)Nc2ccccc2)CC(C)(C)N1OC(=O)Nc1ccccc1
Yield: 64 %

Procedure:
The compound 118 is prepared using phenyl isocyanate in a procedure similar to that for preparing the compound 117, and is obtained in a 64% yield as colourless crystals; melting point: 188-190° C.
Reaction SMILES: [O:1]=[C:2]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.N1CCCCC1.C1C=CC=CC=1.C(O)(=O)C>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[C:3](/[C:2]([C:8]2[S:9][C:10]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[CH:11][CH:12]=2)=[O:1])\[C:4]([O:6][CH3:7])=[O:5])=[CH:22][CH:21]=1
Reactant: COC(=O)CC(=O)c1ccc(-c2ccncc2)s1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)/C(=C\c1ccc(Cl)cc1)C(=O)c1ccc(-c2ccncc2)s1
Temperature: 92 °C
Yield: 65.8 %

Procedure:
To a 100 mL round bottom flask was added a solution of methyl 3-oxo-3-(5-pyridin-4-yl-2-thienyl)propanoate (0.150 g, 0.574 mmol), 4-chlorobenzaldehyde (0.097 g, 0.689 mmol) and piperidine (0.006 mL, 0.057 mmol) in anhydrous benzene (10.00 mL, 111.9 mmol). Acetic acid (0.023 mL, 0.401 mmol) was added and the reaction mixture was fitted with a Dean-Stark trap and the bath was heated to 92° C. and allowed to reflux for 18 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using ISCO (12 g cartridge, gradient hexanes to 100% EtOAc over 30 min) to afford the title compound (0.145 g, 63%) as a white solid. LC/MS (AA) ES+ 384, 386. 1H NMR (dmso-d6, 400 MHz): δ 8.66-8.65 (m, 2H), 8.00 (d, 1H), 7.84-7.75 (m, 4H), 7.47-7.46 (m, 4H), 3.76 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]2[N:14]3[C:15]4[C:20]([N:21]=[C:22]([NH:23][CH2:24][CH2:25][CH2:26][O:27]C5CCCCO5)[C:13]3=[N:12][CH:11]=2)=[CH:19][C:18]([C:34]([F:37])([F:36])[F:35])=[CH:17][CH:16]=4)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:5]1[CH:9]=[C:8]([C:10]2[N:14]3[C:15]4[C:20]([N:21]=[C:22]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[C:13]3=[N:12][CH:11]=2)=[CH:19][C:18]([C:34]([F:36])([F:35])[F:37])=[CH:17][CH:16]=4)[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(-c2cnc3c(NCCCOC4CCCCO4)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)(C)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a solution of 1-(3-tert-butyl-1H-pyrazol-5-yl)-N-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-amine (11 mg, 0.021 mmol) in methanol (0.2 mL) cooled at 0° C. was added para-toluenesulfonic acid (9 mg, 0.047 mmol). The mixture was stirred at room temperature under argon for 5 h and then concentrated in vacuo. The residue is diluted in ethyl acetate and water. The aqueous layer is basified to pH 8 with a saturated aqueous solution of sodium hydrogenocarbonate and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 20/1) to afford the title compound (7 mg, 78%) as a colourless gum.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]([CH:29]=[CH:30][CH:31]=1)[CH2:12][S:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]2[C:26]([Cl:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[CH:17]=[CH:18][CH:19]=1.Cl>COCCO.C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:27][C:26]1[CH:25]=[N:24][C:23]2[NH:8][C:9]3[CH:31]=[CH:30][CH:29]=[C:11]([CH:10]=3)[CH2:12][S:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]=1[N:22]=2)[CH:17]=[CH:18][CH:19]=3
Reactant: Nc1cccc(CSc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: CCO
Solvent: COCCO
Solvent: O=C(O)C(F)(F)F
Product: Clc1cnc2nc1Nc1cccc(c1)SCc1cccc(c1)N2
Temperature: 150 °C
Yield: 27.6 %

Procedure:
A solution of N-{3-[(3-aminobenzyl)thio]phenyl}-2,5-dichloropyrimidin-4-amine trifluoroacetate (33 mg, 67 μmol) in 2-methoxyethanol (6.6 mL) was treated with 3.5 M HCl in ethanol (3 mL) and heated in the microwave at 150° C. for 5 min. The reaction mixture was degassed to remove the HCl and concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (8.4 mg, 27%) as a TFA salt. LCMS for C17H14ClN4S (M+H)+: m/z=341.0. 1H NMR (300 MHz, DMSO-d6): δ 9.59 (s, 1H), 9.20 (s, 1H), 8.17 (s, 2H), 7.93 (s, 1H), 7.21-7.15 (m, 3H), 7.08-7.05 (m, 1H), 7.00-6.97 (m, 1H), 6.91-6.88 (m, 1H), 4.03 (s, 2H).