Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N:22]([C:24](=[O:34])[CH2:25][NH:26][C:27](=[O:33])[C@@H:28]4[CH2:32][CH2:31][CH2:30][NH:29]4)[CH3:23])[C:16]=3[Cl:35])[C:7]2=[N:6][C:5]=1[CH3:36].[C:37](OC(=O)C)(=[O:39])[CH3:38].N1C=CC=CC=1>C(Cl)Cl>[C:37]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:27]([NH:26][CH2:25][C:24]([N:22]([C:17]1[C:16]([Cl:35])=[C:15]([C:20]([Cl:21])=[CH:19][CH:18]=1)[CH2:14][O:13][C:12]1[C:7]2[N:8]([C:4]([Br:3])=[C:5]([CH3:36])[N:6]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:23])=[O:34])=[O:33])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)[C@@H]4CCCN4)c3Cl)cccn2c1Br
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H]1C(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-[N-(L-prolylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine dihydrochloride (40 mg), acetic anhydride (0.01 ml), pyridine (0.03 ml) and methylene chloride (2 ml) was stirred for 2 hours at ambient temperature. The mixture was washed with water twice, dried over magnesium sulfate, and concentrated in vacuo to give 8-[3-[N-(acetyl-L-prolylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (31 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23]CC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[OH-].[Na+]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)CC(C(=O)OC)c1cc(O)cc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
10% Pd/C (Aldrich cat no 205699, 0.55 g) was added to a stirred solution of 2-(3,5-bis-benzyloxyphenyl)-4-methyl-pent-4-enoic acid methyl ester (14.1 g, 33.8 mmol) and NaOH (1.50 g, 37.5 mmol) in MeOH (180 mL) at room temperature. Stirring was continued for 1 h under H2 (1 atm.) then the mixture was filtered through Celite, concentrated in vacuo, suspended in water (100 mL) and adjusted to pH 2 with 1M HCl. The mixture was extracted with EtOAc (2×180 mL); the combined organic layer was washed with brine (50 mL), dried (MgSO4), concentrated in vacuo and purified by flash chromatography (silica, 0-30% EtOAc in petroleum ether) to give the title product as a yellow oil (7.40 g, 67%) 1H-NMR (400 MHz, CDCl3): δ 7.41-7.25 (m, 5H), 6.54 (s, 1H), 6.43 (s, 1H), 6.38 (s, 1H), 5.01 (s, 3H), 4.74 (s, 1H), 4.67 (s, 1H), 3.70 (t, 1H), 3.65 (s, 3H), 2.78 (dd, 1H), 2.38 (dd, 1H), 1.71 (s, 3H); Mass spectrum (ESI, m/z) 325 (M−1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][CH2:41][NH2:42].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][CH2:41][NH:42][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:19]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccccc4Br)cc3)c(Cl)cc21
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (200 mg, 0.531 mmol) was diluted with DCM (3 mL) followed by the addition of oxalyl chloride in DCM (2M) (292 μl, 0.584 mmol) and DMF (1 drop). After stirring for 20 minutes, 2-(2-bromophenyl)ethanamine (117 mg, 0.584 mmol) and DIEA (203 μl, 1.17 mmol) were added and the reaction was stirred at ambient temperature for 12 hours. The reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 7-(4-(2-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (268 mg, 0.480 mmol, 90.3% yield).
Reaction SMILES: FC(C1C=CC=CC=1N1C2NCNC=2C(C(N)=[O:21])=NC1)(F)F.[NH2:23]/[C:24](/[C:40]#[N:41])=[C:25](\[NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39])=[O:30])/[C:26]#[N:27].[F:42][C:43]([F:54])([F:53])[O:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH:48]=O>>[CH3:39][O:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:31]1[C:29](=[O:30])[NH:28][C:25]2[C:26]1=[N:27][C:48]([C:47]1[CH:50]=[CH:51][CH:52]=[C:45]([O:44][C:43]([F:42])([F:53])[F:54])[CH:46]=1)=[N:23][C:24]=2[C:40]([NH2:41])=[O:21]
Reactant: COc1ccccc1NC(=O)N/C(C#N)=C(\N)C#N
Reactant: NC(=O)C1=NCN(c2ccccc2C(F)(F)F)C2=C1NCN2
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(-c3cccc(OC(F)(F)F)c3)nc21
Yield: 22 %

Procedure:
9-(2-Methoxyphenyl)-8-oxo-2-(3-(trifluoromethylphenyl)-8,9-dihydro-7H-purine-6-carboxamide. (Z)-1-(2-Amino-1,2-dicyanovinyl)-3-(2-methoxyphenyl)urea (See Example 2.A) (0.50 g, 1.9 mmol) and 3-(trifluoromethoxy)benzaldehyde (0.52 g, 2.0 mmol) were reacted according to General Procedure B. The resultant heterogeneous mixture was filtered, and triturated with methanol/diethyl ether while sonicating. The brown solid, recovered by filtration, was triturated a second time using methanol/diethyl ether to afford a yellow powder that was subsequently dried under high vacuum at 60° C. to afford the title compound (0.19 g, 0.43 mmol, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.66 (s, 1H), 8.40 (s, 1H), 8.34 (d, J=8.2, 1H), 8.01 (s, 1H), 7.53-7.60 (m, 2H), 7.50 (dd, J=7.6, 1.4, 1H), 7.44 (d, J=8.2, 1H), 7.30 (d, J=8.2, 1H), 7.16 (t, J=7.4, 1H), 3.75 (s, 3H); MS (ESI) m/z 446.1 [M+1]+; mp 269-272° C.
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[OH:22])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CC(NP(OC1C=CC(Cl)=CC=1Cl)(OC)=S)C>[C:23]([O:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][C:14]=2[OH:22])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)c1ccc(C2(O)C(=O)c3ccccc3C2=O)c(O)c1
Agent: COP(=S)(NC(C)C)Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C2(OC(=O)c3ccccc3)C(=O)c3ccccc3C2=O)c(O)c1
Yield: 60 %

Procedure:
2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37 mmol) was completely dissolved in anhydrous methylene chloride (20 ml). This solution was added with benzoyl chloride (0.94 g, 6.74 mmol), triethylamine (0.41 g, 4.04 mmol), and DMPA (0.01 g), followed by heating 24 hrs under reflux. After the reaction mixture was concentrated, extracted with dichloromethane, and the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.81 g, 14%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14](O)[CH3:15]>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]([Cl:3])[CH3:15]
Reactant: COc1ccc(C(C)O)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(C)Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.9 ml) was added to a solution of 1-(2-chloro-4-methoxy-phenyl)-ethanol (2 g) in DCM (5 ml) at 0° C. The mixture was allowed to warm to room temperature and then stirred for 1 h. The mixture was concentrated to an oil and filtered over SiO2 (1 g) to give the title compound (2 g) as a light brown oil. 1H NMR (300 MHz, CDCl3) δ 7.5 (1H, d), 6.8-6.9 (2H, m), 5.5 (1H, q), 3.8 (3H, s), 1.8 (3H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:20]=3[O:31][CH3:32])=[N:16]2)=[CH:11][CH:10]=1.[O:33]1[CH2:36][C:35](=O)[CH2:34]1.C([BH3-])#N.[Na+].N1N2C=CC=C2C=NC=1>CN(C)C=O.C(O)(=O)C.CO>[CH3:32][O:31][C:20]1[CH:21]=[C:22]([CH:25]2[CH2:30][CH2:29][N:28]([CH:35]3[CH2:36][O:33][CH2:34]3)[CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: O=C1COC1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: c1cc2cncnn2c1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C2CCN(C3COC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 0 °C
Reaction time: 10 h
Yield: 58.8 %

Procedure:
To [7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(2-methoxy-4-piperidin-4-yl-phenyl)-amine (60.00 mg, 0.140 mmol) in N,N-dimethylformamide (0.52 mL)/Methanol (2.00 mL)/Acetic acid (0.26 mL) was added oxetan-3-one (30.06 mg, 0.417 mmol) and the reaction mixture was cooled to 0° C. Sodium cyanoborohydride (43.64 mg, 0.695 mmol) was added and the reaction was heated at 60° C. overnight, and then at room temperature in air for 10 h to re-aromatize the pyrrolo[2,1-f][1,2,4]triazine core, which underwent partial reduction. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane/1N sodium carbonate, washed with brine, dried over sodium sulfate, and concentrated. The product was isolated by flash chromatography (ISCO, SIlicagel, MeOH/DCM 0-10%) to afford [2-methoxy-4-(1-oxetan-3-yl-piperidin-4-yl)-phenyl]-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a yellow solid (40 mg, 59%). MP: 78-85° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.30 (d, J=8.7 Hz, 1H), 7.99 (dd, J=7.6 ; 1.4 Hz, 1H), 7.42 (m, 2H), 7.12 (m, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.02 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 6.74 (m, 2H), 4.68 (m, 4H), 3.88 (s, 3H), 3.84 (s, 3H), 3.51 (m, 1H), 2.88 (m, 2H), 2.47 (m, 1H), 1.90 (m, 6H); LC/MS (ESI+): 485.9 (M+H).
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([O:16][CH3:24])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Boc-Asp(OBn)-OH 2.4 g (1 equiv, 7.45 mmol) was dissolved in 17 mL of dry DMF in a 100 mL round-bottom flask. Finely ground K2CO3 (1.5 g, 11 mmol) was added to the solution to form a suspension. The mixture was cooled to 0° C. in an ice-bath over five minutes. MeI (1 mL, 15 mmol) was then added to the mixture over 20 seconds under a positive flow of nitrogen. A yellow color developed within 30 min. The resulting mixture was stirred for 3 hours. The ice-bath was removed and 25 mL of water were added and the mixture left standing at room temperature 2 hours. The mixture was then treated with 30 mL of water and extracted with 3×25 mL AcOEt. The organics were washed with saturated NaHCO3 1×, brine 3×, dried over Na2SO4 filtered and concentrated to yield a yellow oil. This material was passed through a short silica column (eluting w/ AcOEt), after concentration of the pure fractions 2.42 g of Boc-Asp(OBn)-OMe as a yellow oil was obtained (98% yield). 1H NMR (DMSO d6, 500 mHz): δ 7.36 (m, 5H), 5.10 (s, 2H), 4.40 (q, 1H), 3.6 (s, 3H), 2.80 (dd, 1H), 2.72 (dd, 1H), 1.38 (s, 9H). LCMS (C18, 2-98% CH3CN in 0.1% TFA/H2O over 6 min); Calculated mass for C17H23NO6 (M+H)+ 338.23. found by LC-MS 338.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:5]([F:20])=[CH:4][C:3]=1[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23].C(N(CC)CC)C.[CH3:34][C:35]1([O:38][C:39](ON2C(=O)CCC2=O)=[O:40])[CH2:37][CH2:36]1>ClCCl>[CH3:25][N:24]([CH3:26])[C:22](=[O:23])[CH2:21][C:3]1[C:2]([F:1])=[CH:7][C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:39]([O:38][C:35]3([CH3:34])[CH2:37][CH2:36]3)=[O:40])[CH2:18][CH2:19]2)=[C:5]([F:20])[CH:4]=1
Reactant: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Reactant: CC1(OC(=O)ON2C(=O)CCC2=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2,5-difluoro-4-{2-[(1S,2R)-2-piperidin-4 ylcyclopropyl]ethoxy}phenyl-)-N,N-dimethylacetamide (40.0 mg, 0.109 mmol) in 1 ml anhydrous dichloromethane at 0° C. was added triethylamine (0.0300 ml, 0.218 mmol) and 1-({[(1-methylcyclopropyl)oxy]carbonyl}oxy)pyrrolidine-2,5-dione (27.9 mg, 0.131 mmol). The reaction was stirred at RT for 2 hours. The solvent was evaporated, and the residue was purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 25-85% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 465.4 (M+H)+. Human EC50: 2.2 nM
Reaction SMILES: C([O:3][C:4](=[O:41])[CH:5]([C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24](=[O:40])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:18][CH:17]=1)[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])C.O[Li].O>CO.O>[C:36]([O:35][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:24](/[CH:23]=[CH:22]/[C:19]1[CH:18]=[CH:17][C:16]([CH:5]([CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:4]([OH:41])=[O:3])=[CH:21][CH:20]=1)=[O:40])=[O:34])([CH3:38])([CH3:37])[CH3:39]
Reactant: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCO[Si](C)(C)C(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.8 %

Procedure:
To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid ethyl ester (2.63 g, 4.52 mmol) in MeOH/H2O (30 mL/10 mL) was added LiOH.H2O (556 mg, 13.56 mmol). This mixture was stirred for about 5 h at room temperature, and then evaporated to remove most of the MeOH. The aqueous layer was acidified with concentrated HCl to pH 5-6. The acidified aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain 2.0 g (80%) of a yellow solid product. MS: calc'd 555 (MH+), exp 555 (MH+).
Reaction SMILES: C[C:2]([CH3:5])([O-:4])[CH3:3].[K+].[I-].[CH3:8][S+](C)(C)=O.[CH3:13][O:14][C:15]1[CH:56]=[CH:55][C:18]([CH2:19][N:20]2[C:48](=[O:49])[C:23]3=C(C4CO4)[CH:25]=[C:26]([N:29]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)[C:30]4[CH:35]=[CH:34][N:33]=[CH:32][N:31]=4)[C:27](=[O:28])[N:22]3[C:21]32[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)=[CH:17][CH:16]=1>C(O)(C)(C)C.CS(C)=O>[CH3:13][O:14][C:15]1[CH:56]=[CH:55][C:18]([CH2:19][N:20]2[C:48](=[O:49])[C:23]3=[C:3]([CH:2]4[CH2:5][CH2:8][O:4]4)[CH:25]=[C:26]([N:29]([CH2:36][C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)[C:30]4[CH:35]=[CH:34][N:33]=[CH:32][N:31]=4)[C:27](=[O:28])[N:22]3[C:21]32[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)=[CH:17][CH:16]=1
Reactant: CC(C)(C)[O-]
Reactant: C[S+](C)(C)=O
Reactant: COc1ccc(CN(c2ccncn2)c2cc(C3CO3)c3n(c2=O)C2(CCCCC2)N(Cc2ccc(OC)cc2)C3=O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: COc1ccc(CN(c2ccncn2)c2cc(C3CCO3)c3n(c2=O)C2(CCCCC2)N(Cc2ccc(OC)cc2)C3=O)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Potassium tert-butoxide (0.23 g, 2.02 mmol) is added to a solution of trimethylsulfoxonium iodide (0.44 g, 2.02 mmol) in tert-butanol (10 mL) at room temperature. After 15 min, a solution of 2′-(4-methoxybenzyl)-6′-(4-methoxybenzyl)(pyrimidin-4-yl)amino)-8′-(oxiran-2-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (5, 1 g, 1.68 mmol) in dimethylsulfoxide (5 mL) is added dropwise. The reaction is stirred at 50° C. overnight. The resulting mixture is quenched with brine and extracted with ethyl acetate. The combined extracts are dried over magnesium sulfate. After filtration and concentration, the residue is purified by flash column to afford 2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8′-(oxetan-2-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (6).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[C:25]([CH3:37])[CH:24]=1)=[O:10])=[O:4].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:37][C:25]1[CH:24]=[C:23]([NH:22][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:13]=3)[N:18]=[CH:17][N:16]=2)[CH:28]=[CH:27][C:26]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCCNC(=O)CCl)cc34)cc2C)cn1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCCNC(=O)CN5CCOCC5)cc34)cc2C)cn1
Temperature: 100 °C
Yield: 38 %

Procedure:
0.07 g of the compound obtained in Example 108 dissolved in 5 ml of N,N′-dimethylformamide was reacted with 0.02 ml of morpholine and 0.04 g of potassium carbonate for 10 hours while heating to 100° C. The reacted solution was diluted with distilled water, extracted with ethylacetate, washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (0.03 g, 38%).
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[NH2:13]/[C:14](/[CH3:18])=[CH:15]\[C:16]#[N:17]>C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:10]([CH:11]2[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[NH:13][C:2]([CH3:10])=[C:3]2[C:4]#[N:5])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: C/C(N)=C/C#N
Reactant: O=Cc1ccc2[nH]ncc2c1F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]ncc3c2F)C(C#N)=C(C)N1
Temperature: 25 °C
Yield: 104.1 %

Procedure:
250 mg (1.52 mmols) 4-fluoro-1H-indazole-5-carbaldehyde (Synthetic Preparation 11) and 250.1 mg (3.05 mmols) 3-aminocrotononitrile were dissolved in 1.74 mL acetic acid and refluxed for 1.5 hours. The mixture was allowed to cool to room temperature, filtered and washed with a little amount of acetic acid. The product was dried under vacuum at 40° C. to yield a first crop. The mother liquors were diluted with ethyl acetate, washed with water and saturated sodium hydrogen carbonate solution and dried over sodium sulfate to yield a second crop. Together 232 mg (51, 9%) 4-(4-fluoro-1H-indazol-5-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarbonitrile were obtained (Cpd. No. 311). 1H-NMR (DMSO-d6): δ=13.42 (br s, 1H), 9.58 (br s, 1H), 8.21 (s, 1H), 7.44 (d, 1H), 7.32 (dd, 1H), 4.86 (s, 1H), 2.04 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.CN1CCCN(C)C1=[O:22]>O1CCCC1>[C:7]1([CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:3]([O:22][CH:8]([CH3:9])[CH3:7])([CH3:4])[CH3:2]
Reactant: [Li]CCCC
Reactant: CN1CCCN(C)C1=O
Reactant: BrCCCCCCBr
Solvent: C1CCOC1
Product: CC(C)OC(C)C
Product: Cc1ccccc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of 3.33 g of 3,4-bis-(tetrahydropyranyl-2'-oxy)-phenylacetylene in 20 ml of absolute tetrahydrofuran were added dropwise over 45 minutes at -78° to -70° C., while stirring in an atmosphere of dry nitrogen, 6.9 ml of n-butyllithium solution, and after one hour stirring at the same temperature 5.1 ml of 1,6-dibromohexane followed by 7 ml of absolute 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone were added dropwise. The mixture was stirred for 20 hours, allowed to warm to 0° C. and then worked up as described in Example 5e. By column chromatography with toluene/diisopropyl ether (10:1) 3.55 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:29])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1COCC1.O.[OH-].[Li+].Cl>O>[F:29][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)=[N:15]2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 23 °C
Reaction time: 39 h
Yield: 95.9 %

Procedure:
In a 250 mL round bottom flask equipped with an overhead stirrer, thermocouple, and nitrogen inlet was added methyl 4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (11.1 g, 26.9 mmol) and THF (100 mL). To this yellow suspension was added water (10 mL) and lithium hydroxide monohydrate (3.4 g, 81 mmol). There was no change in reaction appearance and temperature (20.5° C.). The reaction was stirred at 23° C. for 39 h during which it became a yellow solution. A heating mantle was attached to the reaction flask and the flask was heated to an internal temperature of 60° C. for 2.5 hrs. The reaction was then cooled to 4° C. in an ice bath and water (100 mL) was added, providing a light yellow solution. Concentrated HCl (8.0 g) was added (note: exothermic) which gave a thick white precipitate. The white suspension was stirred at 5° C. for 30 min and then the solid was collected by vacuum filtration and washed with water (2×25 mL). The white wet cake was allowed to dry in air for 3 h, and was then placed into a vacuum oven (50° C., 700 mm Hg vacuum, 16 h). This gave the title compound as a white solid (10.3 g, 96%): mp 227-229° C.; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.32 (d, J=8.4 Hz, 2H), 8.23 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.9 Hz, 1H), 7.42 (d, J=8.9 Hz, 2H).
Reaction SMILES: [I:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].F[C:13]1[C:18]2[CH:19]=[C:20]([C:22]#[N:23])[S:21][C:17]=2[C:16](O)=[CH:15][CH:14]=1>C1COCC1>[I:1][CH2:2][CH2:3][C@@H:4]([O:5][C:13]1[C:18]2[CH:19]=[C:20]([C:22]#[N:23])[S:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O[C@@H](CCI)c1ccccc1
Reactant: N#Cc1cc2c(F)ccc(O)c2s1
Solvent: C1CCOC1
Product: N#Cc1cc2c(O[C@H](CCI)c3ccccc3)cccc2s1
Reaction time: 18 h
Yield: 96.8 %

Procedure:
4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenyl phosphonium (498 mg, 1.12 mmol) was added in one portion to a stirred solution of (S)-3-iodo-1-phenyl-1-propanol (Molander, Gary A.; Shakya, Sagar R.; J. Org. Chem.; 1994, 59; 12; 1994; 3445–3452) (237 mg, 0.84 mmol) and 4-fluoro-7-hydroxy-benzothiophene-2-carbonitrile (144 mg, 0.70 mmol) in dry THF (12 mL) under an inert atmosphere on nitrogen. The resulting suspension was allowed to stir for a further 18 hrs before the solvent was removed in vacuo. The residue was purified by flash chromatography with a gradient of 0–4% diethyl ether in hexane to give the title compound as a colourless oil (284 mg, 72%); δH (300 MHz, CDCl3) 7.83 (1H, s, 3-ArH), 7.36–7.12 (5H, m, ArH), 6.85–6.75 (1H, m, ArH), 6.65–6.57 (1H, m, ArH), 5.40–5.30 (1H, m, CHO), 3.47–3.28 (1H, m, CH2CHHI), 3.23–3.12 (1H, m, CH2CHHI), 2.60–2.42 (1H, m, CHHCH2I) and 2.34–2.19 (1H, m, CHHCH2I).