Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([OH:12])=O)=[O:4].Cl.[NH2:14][CH2:15][C:16]#[N:17].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.C(N(CC)CC)C>CN(C)C=O>[C:15]([CH2:16][NH:17][C:10]([C@@H:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3]([O:2][CH3:1])=[O:4])=[O:12])#[N:14]
Reactant: COC(=O)C1CCCC1C(=O)O
Reactant: N#CCN
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)NCC#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Cyclopentane-1,2-dicarboxylic acid monomethyl ester (2.21 g, 12.8 mmol), 2-aminoacetonitrile hydrochloride (1.48 g, 16.0 mmol) and benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (7.34 g, 14.1 mmol) were dissolved in dimethylformamide (26 mL) and the reaction mixture was cooled to 0° C. Triethylamine (4.9 mL, 35 mmol) was added and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was partitioned between water (150 mL) and ethyl acetate (100 mL). The product was extracted into ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel with 3:2 ethyl acetate:hexanes eluent to give methyl trans-2-{[(cyanomethyl)amino]carbonyl}cyclopentanecarboxylate as a colorless solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].[CH2:14]=O>C(O)CCC>[CH3:11][N:12]([CH3:14])[CH2:13][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1
Reactant: C=O
Reactant: c1cnc2[nH]ccc2c1
Reactant: CNC
Agent: Cl
Solvent: CCCCO
Product: CN(C)Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine (59 g; 0.5 mol), dimethylamine hydrochloride (44.83 g; 0.55 mol) and paraformaldehyde (16.5 g; 0.55 mol) in n-butanol (700 mL) was heated at reflux for 20 minutes. The mixture was cooled to ambient temperature. The precipitated solid was collected by filtration and dried. The solid was then dissolved in water (800 mL), a few drops of HCl was added for complete solution. The aqueous solution was washed with diethyl ether. Solid potassium carbonate was then added to the aqueous phase until basic. The precipitated solid was collected, washed with water and dried to give 43.5 g (50% yield) of the title compound as an off-white solid, m.p. 161°-162° C. Anal. Calcd. for C10H13N3 : C, 68.54; H, 7.48; N, 23.95. Found: C, 68.28; H, 7.75; N, 23.99. Mass spectrum (DEI; M+) m/z 175. 1H-NMR (DMSO-d6 ; 400 MHz) δ 12.45 (br s, 1H), 8.14 (dd, 1H), 7.97 (dd, 1H), 7.32 (s, 1H), 7.01 (q, 1H), 3.51 (s, 2H), and 2.12 ppm (s, 6H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH2:13])=[C:5]([NH2:14])[CH:4]=1.[C:17](O)(=[O:21])[C:18](O)=[O:19]>Cl>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH:13][C:18](=[O:19])[C:17](=[O:21])[NH:14]2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Agent: Cl
Product: O=c1[nH]c2cc(C(F)(F)F)c(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A mixture of 102 mg (0.418 mmol) of 4,5-bis(trifluoromethyl)-1,2-phenylenediamine and 37 mg (0.411 mmol) of oxalic acid in 2 mL of 2N HCl was refluxed for 6 h and cooled to room temperature. The mixture was filtered and washed by water, CHCl3 and dried to leave a colorless solid (43 mg, 35%), mp >250° C. 1H NMR (DMSO-d6), 7.629 (s, 2) 12.293 (s, 2). 19F NMR (DMSO-d6), 62.185 (s).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:19](=O)[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:19](=[N:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)[CH2:20][CH3:21]
Reactant: CCC=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC=Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 4-trifluoromethylaniline (3.3 g, 20.5 mmol) and triethyl amine (8.3 g, 83 mmol) in 100 mL of dichloromethane, cooled in an ice/water bath, was added slowly titanium tetrachloride (11.4 mL of a 1.0M solution in dichloromethane, 11.4 mmol). After 25 min, propionaldehyde (1.8 g, 25.6 mmol) was added slowly as a solution in dichloromethane. After an additional hour of stirring in the ice/water bath, an aqueous potassium carbonate solution was added (~100 mL of a 1M solution). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude title product which was used without further purification. 1H NMR (CDCl3) δ 1.2 (t, 3H), 2.5 (dq, 2H), 7.05 (d, 2H), 7.56 (d, 2H), 7.84 (t, 1H, J=4.4 Hz).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.COCCOC>C(OCC)(=O)C>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(N3CCCC3)cc12
Temperature: 80 °C
Yield: 65.6 %

Procedure:
A vial was charged with 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (100 mg, 0.236 mmol), Pd-PEPPSI® (3 mg, 0.005 mmol), potassium tert-butoxide (40 mg, 0.354 mmol) and purged with argon for 15 min. Pyrrolidine (24 μl, 0.283 mmol) and dry 1,2-dimethoxyethane (1 ml) were added and the solution was heated at 80° C. for 18 hours. The mixture was diluted with ethyl acetate washed with a saturated aqueous solution of ammonium chloride, water and brine, dried over sodium sulfate and purified by flash chromatography over silica gel (cyclohexane/dichloromethane: 0-80%) to yield 2-isoquinolin-3-yl-6-(pyrrolidin-1-yl)-chromen-4-one O-tert-butyl oxime (64 mg, 65%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([C@H:19]1[C:27]2[C:22](=[C:23]([C:28]3[N:32]=[C:31]([C:33]4[S:34][C:35]([C:44]([F:47])([F:46])[F:45])=[C:36]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:37]=4)[O:30][N:29]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)C(=O)OC(C)(C)C)(C(C)(C)C)(C)C.Cl.CCOCC>C(Cl)Cl>[C:38]1([C:36]2[CH:37]=[C:33]([C:31]3[O:30][N:29]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[C:22]=4[CH2:21][CH2:20][C@H:19]5[NH:11][CH2:10][CH2:9][OH:8])[N:32]=3)[S:34][C:35]=2[C:44]([F:46])([F:47])[F:45])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: OCCN[C@@H]1CCc2c(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-63 (0.108 g, 0.16 mmol) dissolved in DCM (1.5 mL) was added 2N HCl in ether (1.45 mL, 2.9 mmol). The solution was stirred at room temperature for 12 h. The solvent was removed under a stream of nitrogen and the product dried under vacuum to afford 0.052 g (65%) of (R)-2-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylamino)ethanol 67 as the HCl salt. LCMS-ESI (m/z): calcd for C24H20F3N3O2S: 471.5; found 472.1 [M+H]+, tR=7.43 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 8.19 (d, J=7.6, 1H), 8.03 (d, J=7.5, 1H), 7.87 (t, J=1.5, 1H), 7.53-7.40 (m, 6H), 4.86 (d, J=4.8, 1H), 3.88 (s, 2H), 3.74-3.50 (m, 1H), 3.41 (ddd, J=13.3, 9.4, 4.4, 1H), 3.06 (m, 1H), 2.98 (m, 1H), 2.67-2.42 (m, 2H). 13C NMR (100 MHz, DMSO) δ 169.22, 168.07, 145.68, 144.75, 139.39, 135.43, 132.42, 129.42, 129.37, 129.25, 128.69, 128.27, 127.62, 126.41, 123.16, 122.37, 120.47, 61.10, 56.63, 46.54; 31.66, 27.80.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:12])=[C:5]([C:8]([F:11])=[CH:9][CH:10]=1)[C:6]#[N:7])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[F:11][C:8]1[C:5]([C:6]#[N:7])=[C:4]([CH3:12])[C:3]([CH:1]2[CH2:2][O:21]2)=[CH:10][CH:9]=1
Reactant: C=Cc1ccc(F)c(C#N)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C2CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-Ethenyl-6-fluoro-2-methylbenzonitrile (14.9 g, 92.0 mmol) was added to DCM (400 mL) at 0° C. then mCPBA (47.85 g, 277.5 mmol) was added and the mixture was stirred at RT for 72 h. The reaction mixture was washed with saturated aqueous Na2S2O3, then with 1N NaOH, and brine. The organic layer was separated, dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by chromatography through a 330 g Redi-sep column, eluting with 0-100% hexane/DCM solvent system to afford 6-fluoro-2-methyl-3-(oxiran-2-yl)benzonitrile. LC-MS: M+1=178.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Cl[CH2:23][CH:24]1[O:28][C:27](=[O:29])[NH:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:29]=[C:27]1[NH:26][CH2:25][CH:24]([CH2:23][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[O:28]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1NCC(CCl)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NCC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)O1
Temperature: 25 °C
Reaction time: 11 h
Yield: 30.1 %

Procedure:
A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.37 g, 4.89 mmol), 5-(chloromethyl)-1,3-oxazolidin-2-one (1.34 g, 5.38 mmol) and cesium carbonate (2.39 g, 7.34 mmol) in N,N-dimethylformamide (8.0 mL) was stirred at ambient temperature for 11 h and filtered. The solid was washed with ethyl acetate and the filtrate was washed with water (3×15 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography to afford 1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.56 g, 25%): mp 195-202° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.30 (m, 1H), 7.17-7.04 (m, 3H), 6.50 (s, 1H), 6.12 (s, 1H), 5.84 (s, 2H), 5.27 (br, 1H), 5.02-4.96 (m, 1H), 4.91-4.87 (m, 1H), 4.68-4.64 (m, 1H), 4.14-3.96 (m, 2H), 3.75-3.68 (m, 1H), 3.55-3.44 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 178.9, 158.5, 155.9, 149.0, 142.4, 142.2, 131.7, 129.4, 124.0, 123.9, 119.2, 109.6, 102.8, 101.6, 93.7, 80.3, 74.9, 58.1, 43.5, 43.1; MS (ES+) m/z 403.2 (M+23), 381.2 (M+1).
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:29][CH2:28][N:27]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][C:35]=4[CH3:36])[C:26]3=[O:37])[CH:23]=2)[CH2:18][CH2:17][C:16]1=[O:38])=O)(C)(C)C.C(OC(=O)C)C>CCCCCC>[CH3:36][C:35]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[N:27]1[CH2:28][CH2:29][N:25]([C:22]2[CH:23]=[C:24]3[C:19]([CH2:18][CH2:17][C:16](=[O:38])[NH:15]3)=[CH:20][CH:21]=2)[C:26]1=[O:37]
Reactant: Cc1ccncc1N1CCN(c2ccc3c(c2)N(C(=O)OC(C)(C)C)C(=O)CC3)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)NC(=O)CC3)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
Dioxane hydrochloride (3 mL) was added to 7-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-2-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.145 g, 0.00034 mol) at 0° C. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (40% ethylacetate in hexane). Purification by preparative HPLC, followed by column chromatography on silica gel (5% MeOH in CHCl3) afforded 48 mg of the product (35.47% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C1COCC1>[ClH:13].[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14](=[O:15])[NH:12][C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:7][CH:8]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(N2CCCC2)cc1
Solvent: C1CCOC1
Product: Cl
Product: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a stirred solution of 4.9 g (30.4 mmol) of 4-pyrrolidin-1-yl-phenylamine in 70 mL of anhydrous THF at room temperature, was added dropwise a solution of 6.4 g (32 mmol) of 4-nitrophenyl chloroformate in 16 mL of anhydrous THF. After the addition was complete, the mixture was stirred for 1 h and then filtered. The precipitate was washed first with anhydrous THF (2×10 mL) and then with anhydrous DCM (3×10 mL) and dried in vacuo to yield 10 g of an off-white solid. 1H-NMR (300 MHz, CD3OD): 10.39 (s, 1H), 8.32 (d, 2H), 7.73 (d, 2H), 7.60 (d, 2H), 7.48 (d, 2H), 3.86-3.68 (bs, 4H), 2.35-2.24 (bs, 4H). LC/MS (ESI): 328 (MH)+.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:25]3[CH2:24][CH2:23][N:22]([C:26]4[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21][CH2:20][C:19]=3[N:18]=[C:17]([CH:36]([CH3:38])[CH3:37])[N:16]=2)=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5]C)=[O:4].C1COCC1.O.[OH-].[Li+]>O>[CH3:7][C:2]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:25]3[CH2:24][CH2:23][N:22]([C:26]4[C:31]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21][CH2:20][C:19]=3[N:18]=[C:17]([CH:36]([CH3:38])[CH3:37])[N:16]=2)=[CH:12][CH:13]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)c1ccc(Nc2nc(C(C)C)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc2c(c(Nc3ccc(C(C)(C)C(=O)O)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 60 °C
Yield: 60 %

Procedure:
To a solution of methyl 2-methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate (Example 174; 63 mg, 0.12 mmol) in 1:2 THF:H2O (3 mL:6 mL) was added lithium hydroxide monohydrate (8.0 mg, 0.19 mmol). The mixture was heated at 60° C. for 5 h. The THF was removed under reduced pressure, and the resulting solution was acidified to neutral pH with 10% aq. HCl. The solution was then extracted with EtOAc. The organic layers were combined, dried, and concentrated. The crude residue was purified (FCC) to give the title compound (37 mg, 60%). MS (ESI): mass calcd. for C27H30F3N5O2, 513.24; m/z found, 514.1 [M+H]+. 1H NMR (CD3OD): 8.45-8.42 (m, 1H), 8.01 (dd, J=7.9, 1.7 Hz, 1H), 7.69-7.63 (m, 2H), 7.38-7.33 (m, 2H), 7.13-7.09 (m, 1H), 3.57-3.50 (m, 4H), 3.21-3.16 (m, 2H), 3.13-3.08 (m, 2H), 3.01-2.93 (m, 1H), 1.57 (s, 6H), 1.28 (d, J=6.9 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([I:17])=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2ccn3ccnc3c2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2ccn3c(I)cnc3c2)cc1
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a solution of 7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (13.0 g, 61.3 mmol) in N,N-dimethylformamide (100 mL) stirring under a nitrogen atmosphere at ambient was added N-iodosuccinimide (14.5 g, 64.4 mmol). The reaction mixture was stirred for 2 h and then poured into water (1 L) and stirred for a further 30 min. The solid obtained was collected by filtration, washed with water and air dried on the filter. The solid was triturated with ether, collected by filtration and dried under vacuum at 50° C. The solid obtained was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The solid thus obtained was partitioned between aqueous sodium thiosulphate solution and EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The product was triturated with EtOAc, collected by filtration and air-dried to afford 6.0 g (29%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, d), 7.91 (1H, s), 7.78 (1H, s), 7.67 (2H, dd), 7.28 (1H, d), 7.22 (2H, t). A further crop of product (11.0 g) containing minor impurities was obtained by evaporating the filtrates under reduced pressure, triturating with petrol/EtOAc and collection by filtration.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[CH2:7]([O:14][CH2:15][CH:16]1CC(=O)C1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH2:1]=[C:2]1[CH2:4][CH:16]([CH2:15][O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC(COCc2ccccc2)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C1CC(COCc2ccccc2)C1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In a 50 mL three-neck flask with t-BuOK (0.54 g, 4.8 mmol) and methyltriphenylphosphonium bromide (1.72 g, 4.8 mmol) inside, dry 1,4-dioxane was added under argon to give a yellow emulsion. This was heated to 40° C. for 30 min, after which time the mixture was cooled to 10° C. and a 1,4-dioxane solution of 3-(benzyloxymethyl)cyclobutanone (0.76 g, 4 mmol) was added drop by drop. The mixture was left stirring at 10° C. for 3 hr. Then the solvent was removed by rotary evaporator and the residue was dissolved in Et2O and H2O. The organic phase was separated and the aqueous phase was extracted with Et2O. The combined organic phase was dried over MgSO4 and the solvent was evaporated to dryness to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=20:1) to give a colorless oil (0.48 g, 63%, Rf=0.79 (Hexane:EtOAc=3:1)). 1H NMR (CDCl3, 400 MHz): δ 2.36-2.48 (m, 2H), 2.52-2.64 (m, 1H), 2.72-2.84 (m, 2H), 3.48-3.50 (d, J=7.2, 2H), 4.53 (s, 1H), 4.74-4.77 (m, 2H), 7.2-7.4 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 29.82, 35.06, 73.26, 74.60, 106.52, 127.77, 127.88, 128.60, 147.34. MS (FAB): expected for C13H16O (M+H)+ 189.27. Found 189.12748. IR (neat) νmax 2921, 2853, 1720, 1676, 1453, 1272, 1113, 1071, 1027, 875, 737, 713, 698.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][CH:52]([OH:64])[CH2:53][N:54]1[CH2:63][CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55]1>CN(C=O)C.O>[CH2:55]1[C:56]2[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:62][CH2:63][N:54]1[CH2:53][CH:52]([OH:64])[CH2:51][NH:50][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(OC2CCOCC2)cc1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccc(OC2CCOCC2)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To a solution of 4-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (150 mg, 0.67 mmol) in DMF (4 mL) was added DIEA (260 mg, 2.01 mmol), HATU (384 mg, 1.01 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (170 mg, 0.81 mmol). The reaction mixture was stirred at 22° C. for 16 h. The mixture was treated with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and the residue was was purified by prep-HPLC to give the title compound (206.1 mg, Yield 74.9%). 1H NMR (CD3OD, 400 MHz): δ 7.84 (d, J=8.8 Hz, 2H), 7.26-7.37 (m, 3H), 7.19-7.25 (m, 1H), 7.05 (d, J=8.8 Hz, 2H), 4.59-4.74 (m, 2H), 4.31-4.49 (m, 2H), 3.93-4.01 (m, 2H), 3.86 (brs, 1H), 3.63 (ddd, J=11.7, 8.8, 3.0 Hz, 2H), 3.53 (qd, J=14.0, 5.7 Hz, 3H), 3.37-3.44 (m, 1H), 3.11-3.32 (m, 3H), 2.02-2.12 (m, 2H), 1.69-1.81 (m, 2H). LCMS (m/z): 411.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].O=[C:15]([CH3:27])[CH2:16][O:17][C:18]1[C:19]([C:24]([NH2:26])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=1.[BH4-].[Na+].Cl>C(O)C>[CH3:27][CH:15]([NH:1][CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[CH2:16][O:17][C:18]1[C:19]([C:24](=[O:25])[NH2:26])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccccc1OCC(O)CN
Reactant: CC(=O)COc1cccnc1C(N)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1OCC(O)CNC(C)COc1cccnc1C(N)=O
Temperature: 25 °C

Procedure:
A solution of 4.5 g of 1-amino-3-(2-methyl-phenyloxy)-2-propanol and 4.85 g of 3-(2-oxo-propyloxy)-2-pyridinecarboxylic acid amide in 100 ml of ethanol is heated under reflux for 3 hours. After cooling to room temperature, 1.9 g of sodium borohydride are added whilst stirring; the temperature gradually rises to 45° C. After the reaction has subsided, the mixture is stirred for a further hour. The reaction mixture is then acidified with 2 N hydrochloric acid whilst cooling, and is extracted with 20 ml of ethyl acetate. The aqueous phase is rendered alkaline with a concentrated aqueous sodium hydroxide solution and is extracted with three times 50 ml of ethyl acetate. After drying over sodium sulphate and evaporation of the organic solution, only, crude 1-[1-methyl-2-(2-carbamoyl-3-pyridyloxy)-ethyl-amino]-3-(2-methyl-phenyloxy)-2-propanol is obtained, which forms a neutral fumaric acid salt, melting point 145°-161° C. after recrystallisation from a mixture of methanol and ethyl methyl ketone.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:7]2[C:2](=[O:1])[N:3]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=3)[C:4]3[N:5]([N:26]=[CH:27][N:28]=3)[C:6]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)#[N:22]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(=O)OC)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (5 g), methyl 4-(bromomethyl)benzoate (3.7 mL), potassium carbonate (2.3 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.8 g, 40%).