Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1.C[Mg+].[Br-]>C1COCC1.O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]([NH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH3:21])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)c1cccc(C=O)c1OCc1ccccc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1NC(C)c1cccc(C(C)(C)C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 21 (1.88 g, 7 mmol, 1.0 equiv), o-anisidine (0.86 g, 0.79 mL, 7 mmol, 1.0 equiv), toluene (35 mL) and a crystal of p-toluenesulfonic acid was refluxed for 4 hr with H2O removal (Dean-Stark trap). The mixture was cooled to room temperature and concentrated under reduced pressure to give crude imine 22 as a yellow-brown oil. Crude 22 was dissolved in THF (25 mL) and the solution cooled to ˜2° C. 3M MeMgBr in THF (5 mL, 15 mmol, 2.15 equiv) was added dropwise via syringe. A green color developed followed by a yellow-brown color. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to ˜10° C., quenched by the slow, dropwise addition of saturated NH4Cl solution (10 mL) then partitioned between EtOAc (100 mL) and H2O (20 mL). The organic phase was washed with brine (2×40 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a brown oil. The crude product was absorbed onto silica gel using dichloromethane and dry-loaded onto a column of silica gel (30 g) packed in heptanes. The column was eluted with heptanes (100 mL), 2% EtOAc/heptanes (200 mL) and 3% EtOAc/heptanes (200 mL). Product fractions were concentrated under reduced pressure to give 2.3 g (85%) 23 as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[S:7]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:8].CN1C=NN=C1S(CC1C=CC(C(O)=O)=CC=1)(=O)=O.[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][C:40]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>>[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH:43][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH2:9][S:7]([C:3]3[N:2]([CH3:1])[CH:6]=[N:5][N:4]=3)=[O:8])=[CH:18][CH:17]=2)=[CH:41][C:40]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1
Reactant: Cn1cnnc1S(=O)Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: Cn1cnnc1S(=O)(=O)Cc1ccc(C(=O)O)cc1
Product: Cn1cnnc1S(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 4-methyl-4H-1,2,4-triazole-3-thiol via Procedure Q. 804 mg of methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylthio)methyl)benzoate was subsequently reacted via Procedure R to give an approximate 1:9 mixture of methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoate and methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoate. The mixture of 740 mg was hydrolyzed via Procedure M to give 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid. 114 mg of the mixture of 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was separated on reverse phase HPLC to give N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzamide. MS (Q1) 452.3 (M)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19](CC(NCC4C=CC=CC=4)=O)=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.BrC1C=CC(OCCN2CCOCC2)=CC=1.B(O)(O)C1C=CC([F:56])=NC=1>>[F:56][C:19]1[N:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Reactant: OB(O)c1ccc(F)nc1
Agent: Brc1ccc(OCCN2CCOCC2)cc1
Product: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1

Procedure:
In another aspect, the invention relates to the process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide comprising the steps of coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; and reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH:8]=[C:7]3[O:13][C:14]([CH3:18])([CH3:17])[CH:15]=[CH:16][C:6]3=[CH:5][C:4]=2[N:3]=1.CN1C=CN=C1.Cl[O-].[Na+].S([O-])([O-])(=[O:30])=S.[Na+].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH:8]=[C:7]3[O:13][C:14]([CH3:18])([CH3:17])[C@H:15]4[O:30][C@H:16]4[C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: O=S([O-])([O-])=S
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)C=C3
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H]1O[C@@H]31
Yield: 94 %

Procedure:
To a solution of 7-chloro-2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline (200 mg, 0.77 mmol) in ethyl acetate (3.0 mL), N-methyl imidazole (0.012 mL, 0.154 mmol) and ent-Ph,Ph salen manganese complex (8.0 mg, 0.0077 mmol) were added at room temperature and sodium hypochlorite aqueous solution (1.0 g, 1.513 mol/kg, 1.54 mmol) was added dropwise in water bath, and the resulting mixture was stirred in water bath for 40 minutes. In water bath, sodium hypochlorite aqueous solution (1.0 g, 1.513 mol/kg, 1.54 mmol) was added dropwise, and the resulting mixture was further stirred in water bath for 30 minutes. Upon the completion of the reaction, sodium thiosulfate aqueous solution was added to the reaction solution, the resulting solution was filtered through celite and extracted. The organic phase was washed with sodium hydrogencarbonate aqueous solution and then with sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=10/1) to obtain (3S*,4S*)-7-chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline (yield: 94%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].Cl.[C:9]([N:12]1[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[S:14][CH:13]1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[O:30][CH2:31][CH2:32][CH2:33][N:34](CCO)[CH:35]([CH3:37])[CH3:36])(=[O:11])[CH3:10].N1C=CC=CC=1>C(=O)([O-])O.[Na+]>[ClH:21].[C:5]([O:4][CH2:1][CH2:2][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:23]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=1[CH:13]1[N:12]([C:9](=[O:11])[CH3:10])[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[S:14]1)[CH:35]([CH3:36])[CH3:37])(=[O:7])[CH3:6]
Reactant: COc1ccc(OCCCN(CCO)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(OCCCN(CCOC(C)=O)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 171.3 %

Procedure:
Acetic anhydride (0.26 ml, 2.91 mmol) was added to a solution of 3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline hydrochloride (300 m g, 0.58 mmol) in pyridine (0.47 ml, 5.80 mmol) under ice-cooling, and then the mixture was stirred at room temperature for two hours. A saturated aqueous sodium hydrogencarbonate solution (50 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated brine (50 ml) and dehydrated with anhydrous magnesium sulfate, and ethyl acetate was evaporated under reduced pressure. The obtained oily matter was dissolved in ethyl acetate (1 ml), and then a 4 N solution (0.5 ml) of hydrogen chloride in ethyl acetate. The mixture was concentrated under reduced pressure to give 277 mg (92%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[C:8]1=[O:28].I.[CH2:37]([O:39][C:40]([CH2:42][N:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=[C:44]1[NH:52][CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:41])[CH3:38].C(N(CC)CC)C>C(#N)C.ClCCl>[CH3:35][O:34][C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:56]2[CH2:57][CH2:58][CH:53]([NH:52][C:44]3[N:43]([CH2:42][C:40]([O:39][CH2:37][CH3:38])=[O:41])[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=4[N:45]=3)[CH2:54][CH2:55]2)([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:8]1=[O:28]
Reactant: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: CCOC(=O)Cn1c(NC2CCNCC2)nc2ccccc21
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)Cn1c(NC2CCN(CCCC3(Cc4ccc(F)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine (0.35 g, 0.68 mmol), (1-(ethoxycarbonylmethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (0.38 g, 0.68 mmol), and triethylamine (0.276 g, 2.72 mmol) in acetonitrile (15 mL). Heat to reflux. After 12 hours, cool the reaction mixture, dilute with dichloromethane, and extract with brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5% methanol/0.5% concentrate aqueous ammonium hydroxide/dichloromethane to give the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH2:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[C:21]([Cl:26])[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:26][C:21]1[CH:22]=[C:23]([O:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:15]=[CH:14][O:13][CH:12]=3)=[CH:9][CH:10]=2)[C:2]([F:1])([F:16])[F:17])[N:24]=[C:19]([NH2:18])[N:20]=1
Reactant: OC(c1ccc(-c2ccoc2)cc1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(OC(c2ccc(-c3ccoc3)cc2)C(F)(F)F)n1
Temperature: 110 °C
Yield: 82.6 %

Procedure:
The mixture of 2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethanol (100 mg, 0.4 mmol), 2-amino-4,6-dichloro-pyrimidine (60 mg, 0.36 mmol), cesium carbonate (468 mg, 1.44 mmol) and 1,4-dioxane (1 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 110 mg of 4-chloro-6-[2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine, yield: 72%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=CC=1.IC1C=C2C(=CC=1)C(=[O:41])NC(=O)C2=COC.NCC1C=CC(C2C=COC=2)=C(O)C=1>>[O:41]1[CH:27]=[CH:28][CH:29]=[C:24]1[C:3]1[CH:4]=[CH:5][C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])=[CH:7][C:2]=1[OH:1]
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Agent: NCc1ccc(-c2ccoc2)c(O)c1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccco2)c(O)c1
Yield: 53 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (80 mg, 0.24 mmol) and 5-Aminomethyl-2-furan-3-yl-phenol (50 mg, 0.26 mmol) in 53% yield: MS (ESI): 485.1 (M−1)−1.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][C:12]1=[O:25])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>ClCCl>[C:1]([O:5][CH2:6][CH:7]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][C:12]1=[O:25])[C:8]([NH:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=1)=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1OC1=CC(=O)N(C(COC(C)(C)C)C(=O)O)C1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1OC1=CC(=O)N(C(COC(C)(C)C)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
A solution of 3-t-butoxy-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (100 mg, 0.29 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (45 mg, 0.29 mmol) and 1-hydroxybenzotriazole (40 mg, 0.30 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 50 mg, 0.32 mmol). The reaction mixture was then stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 3-t-butoxy-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (45 mg, 32%) as an off-white solid: LR-ES-MS m/z calculated for C25H34N4O6 [M]+ 486, observed [M+H]+ 487; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 6H) 1.12 (s, 9H) 3.64-3.78 (m, 2H) 3.81 (s, 3H) 3.89 (s, 2H) 4.15 (d, J=18.4 Hz, 1H) 4.45 (d, J=18.4 Hz, 1H) 4.67 (s, 1H) 4.73 (s, 1H) 4.80 (dd, J=7.1, 4.7 Hz, 1H) 6.43 (d, J=2.2 Hz, 1H) 6.94-7.09 (m, 1H) 7.13-7.39 (m, 3H) 7.53 (d, J=2.2 Hz, 1H) 10.64 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:6]=2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C:3]1=[O:34].[Li+].CC([N-]C(C)C)C.[CH3:43][CH:44]([CH3:48])[CH2:45][CH:46]=[O:47]>C1COCC1.C(Cl)Cl.O>[OH:47][CH:46]([C:11]1[C:6]2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C:3](=[O:34])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1)[CH2:45][CH:44]([CH3:48])[CH3:43]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccc(C(F)(F)F)c3)cnc21
Reactant: CC(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(O)c1c(Oc2cccc(C(F)(F)F)c2)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 50.5 %

Procedure:
To a solution of 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethyl) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.21 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 0.4 mL, 0.82 mmol) dropwise. The reaction was stirred at −78° C. for 40 min then 3-methylbutanal (35.9 mg, 0.42 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 30 min then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 5:1) to give 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 50.8% yield) as a solid. LCMS: [M+-THP-OH] 465 and TR=2.180 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16]O)=[CH:10][CH:9]=2)[CH:2]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[ClH:20].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][Cl:20])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: OCCCc1ccc(Cc2cccnc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCCCc1ccc(Cc2cccnc2)cc1

Procedure:
In 10 ml of methylene chloride was dissolved 2.04 g of 3-[4-(pyridin-3-ylmethyl)phenyl]propanol, and 3.26 ml of thionyl chloride was added dropwise to the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction under reflux for one hour. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure to obtain oily 3-[4-(pyridin-3-ylmethyl)phenyl]propyl chloride hydrochloride.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH3:12])=[N:8][CH:9]=2)[N:4]([CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)[N:3]=1.B(O)(O)[C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1.P(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOC(C)=O.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.O>[CH3:12][NH:11][C:7]1[N:6]=[C:5]2[N:4]([CH2:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]3)[N:3]=[C:2]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[C:10]2=[CH:9][N:8]=1
Reactant: CNc1ncc2c(Br)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CNc1ncc2c(-c3ccc(C)cc3)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 88.8 %

Procedure:
A 30 mL microwave tube was charged with tert-butyl 4-((3-bromo-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.070 g, 0.16 mmol), p-tolylboronic acid (0.065 g, 0.48 mmol), potassium phosphonate (0.10 g, 0.48 mmol), tetrakis(triphenylphosphine)palladium (0.018 g, 0.016 mmol), dioxane (2 mL) and water (0.5 mL). After stirring for 5 min, the reaction was heat at 150° C. for 10 min in microwave. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), concentrated, and purified by Isco to provide tert-butyl 4-((6-(methylamino)-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.064 g, 89%) as a white solid.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[NH:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[C:44]1[C:52]([O:54][CH2:55][CH3:56])=[O:53]>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]3[C:27]=2[CH2:26][N:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=[C:44]2[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:37][CH:38]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CCOC(=O)c1cc2ccccc2n1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and ethyl 1H-indole-2-carboxylate. M/e+ 430 for C25H21ClN3O2 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ 8.13 (d, J=6.6 Hz, 1H), 7.70 (dd, J=8.4, 2.2 Hz, 2H), 7.55 (d, J=9.1 Hz, 1H), 7.42 (d, J=8.4, 2.5 Hz, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.25 (t, J=6.6 Hz, 1H), 7.10 (t, J=6.6 Hz, 1H), 6.79 (m, 1H), 6.67 (m, 1H), 6.61 (m, 2H), 5.03 (s, 2H), 4.44 (q, J=6.9 Hz, 2H), 1.39 (t, J=6.9 Hz, 3H) ppm.
Reaction SMILES: Br.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][S:3]2(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][Cl:20].O>CN(C=O)C.CCOC(C)=O>[Cl:20][CH2:19][CH2:18][N:6]1[CH2:7][C@@H:2]2[CH2:8][C@H:5]1[CH2:4][S:3]2(=[O:10])=[O:9]
Reactant: ClCCBr
Reactant: O=S1(=O)C[C@@H]2C[C@H]1CN2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)C[C@@H]2C[C@H]1CN2CCCl
Temperature: 25 °C
Reaction time: 30 h
Yield: 32.6 %

Procedure:
To a solution of (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, hydrobromide (0.5 g, 2.192 mmol) in DMF (25 mL) was added potassium carbonate (0.397 mL, 6.58 mmol) followed by 1-bromo-2-chloroethane (0.927 mL, 10.96 mmol). The reaction mixture was stirred at rt. After 30 h, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to viscous light brown oil. The crude material was loaded onto a silica gel column, eluted with 1:2 hex:EtOAc to give (1S,4S)-5-(2-chloroethyl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide (150 mg, 32.6% yield) of a clear glass material. LC/MS: m/e 210.0 (M+H)+, 0.240 min (method 3).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[C:22]1[C:23]([CH2:28][CH3:29])=[N:24][O:25][C:26]=1[CH3:27])=[O:12]>O1CCCC1>[CH3:30][N:8]([CH3:7])[CH2:9][CH2:10][CH:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[C:22]1[C:23]([CH2:28][CH3:29])=[N:24][O:25][C:26]=1[CH3:27])[OH:12]
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCN(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(O)CCN(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 816 mg. (0.022 mole) of lithium aluminum hydride in 125 ml. tetrahydrofuran is cooled to 5° and treated by the dropwise addition of 3.5 g. (0.011 mole) of 3-dimethylamino-1-[2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indol-3-yl]-1-propanone in 125 ml. tetrahydrofuran maintaining the temperature between 5°-8° C. The resulting mixture is then stirred for 4 hours at 0°-5°, then cooled to -50° and quenched by the addition of 10 ml. saturated magnesium sulfate solution. The mixture is warmed to room temperature and filtered and the filtrate is evaporated in vacuo. The resulting residue is dissolved in methylene chloride, washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is crystallized from ether to give 3-dimethylamino-1-[2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indol-3-yl]-1-propanol, m.p. 166°-169° C.