Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:44][Si](CC)(CC)CC)[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:43]=[CH:42][C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)=[CH:11][C:10]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54])C1C=CC=CC=1.[F-].C([NH3+])(C)(C)C>O1CCCC1>[CH2:34]([NH:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:23]2[CH:42]=[CH:43][C:20]([CH2:19][CH2:18][NH:17][CH2:16][C@H:15]([OH:44])[C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:11]=3)=[CH:21][CH:22]=2)[CH2:26][CH2:27]1)=[O:32])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O[Si](CC)(CC)CC)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)CC1
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
4-{4-[2-({(2R)-2-{4-(Benzyloxy)-3-[(methylsulfonyl)amino]phenyl}-2-[(triethylsilyl)oxy]ethyl}amino)ethyl]anilino}-N-octyl-1-piperidinecarboxamide was dissolved in anhydrous tetrahydrofuran and tert-butylammonium fluoride (1 M in tetrahydrofuran) added. The reaction was stirred at ambient temperature for 4 days. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel Merck-60 (eluant: 20:1 going to 10:1 chloroform-methanol containing 2% triethylamine) to furnish the title compound (0.36 g, 0.519 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:19])[CH2:14][CH2:15][C:16]([NH2:18])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][NH2:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(C)CCC(N)=O)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCN(C)CCCN)cc1OC
Temperature: 0 °C
Yield: 60.9 %

Procedure:
1.5 g (5.6 mmol) 3-[[2-(3,4-Dimethoxyphenyl)ethyl]methylamino]propanamide (D1) in dry tetrahydrofuran were added dropwise to a suspension of 0.64 g (1.7 mmol) lithium aluminium hydride in 20 ml dry diethylether whilst stirring. The mixture was heated under reflux for 2 hours then cooled with a bath of ice water before carefully adding dropwise 0.65 ml water, 0.65 ml 15% aqueous NaOH, then 1.95 ml water. The mixture was dried over MgSO4, concentrated in vacuo and the residue was purified twice by chromatography on basic alumina using methylene chloride/methanol: 95/5 then methylene chloride/methanol/30% aqueous ammonia: 90/10/0.1 to yield 0.86 g (60.8%) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:15][CH2:14][C@@:13]([C:17](=[O:19])[NH2:18])([CH3:16])[C:12]3([CH3:21])[CH3:20])=[C:8]([C:22]([NH2:24])=[O:23])[CH:7]=[N:6][N:5]2[CH:25]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:17]([C@@:13]1([CH3:16])[CH2:14][CH2:15][C@@H:11]([NH:10][C:9]2[C:4]3[N:5]([CH:25]=[C:2]([C:31]4[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)[CH:3]=3)[N:6]=[CH:7][C:8]=2[C:22]([NH2:24])=[O:23])[C:12]1([CH3:21])[CH3:20])(=[O:19])[NH2:18]
Reactant: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@]1(C)C(N)=O
Reactant: COc1ccc(B(O)O)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(N[C@@H]4CC[C@](C)(C(N)=O)C4(C)C)c(C(N)=O)cnn3c2)cn1
Temperature: 90 °C
Yield: 20.5 %

Procedure:
A solution of 6-bromo-4-((1R,3S)-3-carbamoyl-2,2,3-trimethylcyclopentylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (50 mg, 0.122 mmol) in DMF (816 μl) was added into a reaction vial charged with 6-methoxypyridin-3-ylboronic acid (37.5 mg, 0.245 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (5.88 mg, 0.012 mmol) and palladium (II) acetate (2.75 mg, 0.012 mmol), followed by addition of a 2.0 M aqueous potassium phosphate, dibasic solution (184 μl, 0.367 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 90° C. for 2 hrs. The reaction was cooled to room temperature and diluted with ethyl acetate (10 ml). The ethyl acetate solution was washed with water (3×5 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding a light yellow oil. The crude product was chromatographed using reverse-phase HPLC (Column: LUNA 5u C18 21×100). The collected fractions were combined and concentrated under reduced pressure. The product was taken up in ethyl acetate and neutralized with (sat.) sodium carbonate. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (11.3 mg, 0.025 mmol, 20.08% yield) as a white solid. LC/MS found [M+H]+=437.3. 1H NMR (400 MHz, MeOD) δ ppm 8.42-8.48 (1 H, m), 8.11-8.18 (1 H, m), 7.96-8.04 (1 H, m), 7.89-7.96 (1 H, m), 7.10-7.19 (1 H, m), 6.84-6.91 (1 H, m), 4.66-4.74 (1 H, m), 3.94 (3 H, s), 2.53-2.65 (1 H, m), 2.41-2.53 (1 H, m), 1.69-1.81 (1 H, m), 1.57-1.69 (1 H, m), 1.34-1.42 (3 H, m), 1.11-1.18 (3 H, m), 1.02-1.11 (3 H, m). HPLC Retention Time=2.790 (HPLC conditions: column: Phenominex Synergy, 4.6×50 mm, Mobile phase A: 90:10 water/methanol with 0.2% H3PO4; Mobile Phase B: 90:10 methanol/water with 0.2% H3PO4; Wavelength: 220 nm; Gradient: 0-100% B over 4 minutes, then a 1-minute hold at 100% B; Flow: 4 mL/min.)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[NH:15][C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:27]I.O>CN(C=O)C>[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[N:15]([CH3:27])[C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)OCc2ccccc2)c2cc(OCCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a suspension of NaH (0.959 mmol, 0.038 g, 60% in mineral oil, rinsed twice with hexanes) in 5 mL of DMF at 0° C. under N2 was added a solution of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.873 mmol, 0.300 g, Example 1, Step A) in 3.73 mL of DMF. The ice bath was removed and the solution was stirred for 2 hours at room temperature. Methyl iodide (0.959 mmol, 0.060 mL, Aldrich) was added dropwise via syringe and the solution was stirred for 20 hours. Water (10 mL) was added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered off, the filtrate was extracted with ether (3×10 mL), and the extracts were washed with water (2×10 mL), brine (1×10 mL), dried over MgSO4, and concentrated. The residue was combined with the solid and purified by silica gel flash column chromatography (30% ethyl acetate/hexanes) to give a white solid (0.216 g, 69%): 1HNMR (400 MHz, DMSO-d6) δ 2.67 (s, 3H, ArCH3), 3.66 (s, 3H, NCH3), 3.87-3.89 (m, 2H, CH2Cl), 4.09-4.12 (m, 2H, CH2OAr), 5.29 (s, 2H, CO2CH2Ph), 6.80-6.83 (m, 1H, ArH), 7.21-7.50 (m, 7H, ArH); MS(APCI+): m/z 358.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1.C(N(CC)CC)C.O>CS(C)=O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(CO)cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g (71.9 mMol) of 2-methoxy-5-hydroxymethylpyridine (preparation see Heterocycl. Commun. 1999, 5, 257) are dissolved in 160 ml of DMSO and 30 ml (215 mMol) of triethylamine. At RT (exothermic-cool!), 34.3 g (215 mMol) of sulfur trioxide pyridine complex in 160 ml DMSO are added dropwise, and the mixture is stirred 1 h at RT. The mixture is poured into water and extracted three times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and evaporated to yield the title compound: HPLC(Grad5-40) tRet=12.9.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1.Cl.Cl[CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33].[H-].[Na+]>CN(C=O)C>[CH3:33][N:32]([CH3:34])[CH2:31][CH2:30][CH2:29][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1
Reactant: CN(C)CCCCl
Reactant: CN1C(=O)C(c2c[nH]c3ccccc23)=C(c2c[nH]c3ccccc23)C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)N(C)C2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41 %

Procedure:
Sodium hydride (60 to 72%, oily, 50 mg) was washed with pentane and then suspended into DMF (0.3 mL). A DMF solution (1.2 mL) of 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (150 mg, 0.44 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 1887, 1988) was added thereto, and the whole was stirred at room temperature for 45 minutes. On the other hand, DMF (1.2 mL) was added at 0° C. to a mixture of (3-chloropropyl)dimethylamine hydrochloride (70 mg, 0.44 mmol) and sodium hydride (60 to 75%, oily, 18 mg) washed with pentane, and the whole was stirred for 5 minutes and then warmed to room temperature with standing. The supernatant was added to the solution of sodium salt of 2,3-bis(1H-indol-3-yl)-N-methylmaleimide. The resulting mixture was stirred at 40° C. for 1.5 hours, and then DMF was removed under reduced pressure. To the residue were added dichloromethane and saturated aqueous sodium chloride solution, and the organic layer was separated. The water layer was further extracted with dichloromethane. The resulting organic layers were combined and dried over sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by column chromatography over silica gel (chloroform saturated with ammonia:methanol=10:1) to obtain 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-N-methylmaleimide (77 mg, 41%) as dark red solids.
Reaction SMILES: Cl.[CH2:2]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[C:4]([OH:6])=[O:5].[O-2].[Mg+2].[CH3:13][O:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][O:20][C:21](N=[N+]=[N-])=[O:22])=[CH:17][CH:16]=1>O.O1CCOCC1>[CH2:2]=[C:3]([CH2:7][CH2:8][CH2:9][NH:10][C:21]([O:20][CH2:19][C:18]1[CH:26]=[CH:27][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:22])[C:4]([OH:6])=[O:5]
Reactant: C=C(CCCN)C(=O)O
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Agent: Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: C=C(CCCNC(=O)OCc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 116.8 %

Procedure:
To a solution of 8.8 g of 2-methylene-5-aminopentanoic acid hydrochloride in 100 ml of water is added with stirring 6.36 g of magnesium oxide, followed by a solution of 12.2 g of p-methoxybenzyloxycarbonyl azide in 100 ml of dioxane, and the resulting mixture is stirred at room temperature for two days. The reaction mixture is filtered, and the filtrate diluted with 200 ml of ethyl acetate, two equivalents of Dowex 50 ion exchange resin is added, and the mixture is stirred at room temperature for two hours. The resin is then filtered off and washed with water. The layers in the filtrate are separated and the aqueous layer is extracted twice with ethyl acetate. The combined organic layers are dried and concentrated in vacuo to give 18.2 g of 2-methylene-5-(p-methoxybenzyloxycarbonyl)aminopentanoic acid as an amber oil which crystallizes on standing. This is used without further purification.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:10]2[N:17]=[C:16](C)[C:15]([N+]([O-])=O)=[CH:14][C:11]=2[C:12]#[N:13])[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:25](OCC)[N:26]([CH3:28])[CH3:27])C.[H-].[Na+].IC>CN(C=O)C.CO.CCOC(C)=O.O>[CH:1]1([CH2:6][N:7]([C:10]2[N:17]=[C:16]3[CH:15]=[CH:27][N:26]([CH3:28])[C:25]3=[CH:14][C:11]=2[C:12]#[N:13])[CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(OCC)N(C)C
Reactant: CCN(CC1CCCC1)c1nc(C)c([N+](=O)[O-])cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCN(CC1CCCC1)c1nc2ccn(C)c2cc1C#N
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-[N-(cyclopentylmethyl)-N-ethylamino]-6-methyl-5-nitronicotinonitrile (1.22 g, 4.23 mmol) in DMF (10 mL) is added N,N-dimethylformamide diethyl acetal (1.09 mL, 6.35 mmol). After stirring at 85° C. for 30 min, the reaction mixture is cooled to room temperature and then H2O is added. The mixture is extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo. The resulting solid is rinsed with MeOH to give an orange solid. The solid is dissolved in MeOH (200 mL) and EtOAc (200 mL) and treated with Palladium-activated carbon ethylenediamine complex (Pd/C(en), 470 mg). The mixture is stirred under H2 atmosphere for 2.5 hours at room temperature. The reaction mixture is filtered, and the filtrate is concentrated in vacuo. The residue is dissolved in EtOAc/Hexane and passed through a silica-gel pad. The resulting mixture is concentrated in vacuo, and the residue is dissolved in DMF (10 mL). To this mixture, NaH (0.54 g, 13.5 mmol) is added at 0° C., and after 30 min, iodomethane (0.28 mL, 4.50 mmol) is added. After stirring for 1 hour, the reaction is quenched with H2O. The mixture is extracted with EtOAc and washed with brine. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica-gel column chromatography to give 5-[N-(cyclopentylmethyl)-N-ethylamino]-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)=[O:4].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][NH:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:4]
Reactant: CNC(=O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CNC(=O)[C@H]1CCCN1c1ccc(N)cc1
Yield: 95 %

Procedure:
(R)-1-(4-Nitro-phenyl)-pyrrolidine-2-carboxylic acid methylamide (Method 56; 1.2 g, 4.8 mmol) was dissolved in MeOH (50 ml), to this was added ammonium formate (1.5 g, 24 mmol) and palladium (0.1 g). The reaction was heated at reflux for 60 minutes; reaction decolourised. MeOH was removed in vacuo and saturated ammonium chloride (50 ml) was added, the system was extracted with DCM (2×100 ml), dried and solvent removed in vacuo to yield the title compound as a brown gum (1.0 g, 95%). Product rapidly turned black on exposure to air. The product was used immediately without any purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[F:9][C:4]1[C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Fc1ncccc1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cccnc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
3-(bromomethyl)-2-fluoropyridine, 6-methyl-2-sulfanylpyrimidin-4-ol (1.42 g, 10 mmol) and triethylamine (1.54 mL, 11 mmol) were mixed in ethanol (50 mL). The mixture was stirred at room temperature for 2 hours. After evaporation, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (1.8 g, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 3H), 4.35 (s, 2H), 6.00 (br, 1H), 7.28 (m, 1H), 8.05 (m, 1H), 8.11 (m, 1H); M+252.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])(=O)C.[K+].[N:15]([O-])=O.[Na+]>CC(O)=O.O>[Cl:9][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[N:15][NH:1][C:2]=12
Reactant: Cc1ccnc(Cl)c1N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1nccc2cn[nH]c12
Temperature: 25 °C
Reaction time: 66 h
Yield: 45.7 %

Procedure:
To a cooled (internal temperature of <13° C.) mixture of 3-amino-2-chloro-4-methylpyridine (10.14 g, 71.1 mmol, Matrix) and potassium acetate (9.02 g, 92 mmol) in AcOH (200 mL) was added a solution of sodium nitrite (7.36 g, 107 mmol) in water (30 mL) dropwise while maintaining an internal temperature <13° C. The reaction was allowed to warm slowly to rt and stirred for 66 h. The mixture was concentrated under reduced pressure and the residue was basified with saturated NaHCO3. The solid was filtered and washed with water. The solid was stirred over EtOAc overnight and filtered. The filtrate was combined with the organic extracts, evaporated onto silica gel and purified by flash chromatography (Isco (120 gram)) eluting with EtOAc:hexanes (0:1→1:1) to give a white crystalline solid (4.99 g, 46%). MS m/z=153.9, 155.9 [M+H]+. Calculated for C6H4ClN3: 153.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11]C)=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[O:27])=[CH:21][CH:20]=2)[N:3]=1.[OH-].[Na+].CCOCC.Cl>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[O:27])=[CH:23][CH:24]=2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(N2CCCC2)c1CC(=O)O
Temperature: 60 °C
Reaction time: 13 h
Yield: 31.2 %

Procedure:
A solution of methyl {4-methyl-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetate (0.018 g, 0.04 mmol) in THF (1 mL) at room temperature was treated with 1N NaOH (0.5 mL) and the resulting biphasic mixture was stirred at 60° C. for 13 hours. After cooling to room temperature, Et2O was added and the organic layer siphoned off. The remaining aqueous layer was acidified with 6N HCl and the separated solids were collected by suction, rinsed with water, and dried under high vacuum for 4 hours to give {4-methyl-2-[4-(2-naphthoyl-amino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetic acid (0.006 g, 37% yield) as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1Cl.O>C(OCC)C>[C:23]1([CH3:32])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: Cc1cc(C)c(Cl)c(C)c1
Reactant: COC(=O)c1ccc(CCCCO)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCCc2c(C)cc(C)cc2C)cc1
Temperature: 0 °C

Procedure:
To a mixture of 65.07 g (1.0 eq) of methyl 4-(4-hydroxybutyl)benzoate and 33.20 (1.05 eq) of triethylamine in 350 mL of anhydrous ethyl ether, stirred under nitrogen and cooled to 0° C., are added in a dropwise fashion, 37.58 g (1.05 eq) of mesityl chloride. A solid forms and the reaction mixture is gradually brought to room temperature and stirred under nitrogen for 4 hours. Four hundred milliliters of water are then added and the organic layer is separated, washed with water, dried over magnesium sulfate, and concentrated to yield methyl 4-(4-mesitylbutyl)benzoate, m.p. 52°-53° C.; IR (KBr) vmax 3010, 2930, 2850, 1700, 1603, 1432, 1334, 1323, 1165, 1104, 937, 822, and 700 cm-1 ; 1H NMR (CDCl3) delta 7.92 (d, J=8.2 Hz, 2H, Ar), 7.22 (d, J=8.2 Hz, 2H, Ar), 4.18-4.22 (m, 2H, CH2OMs), 3.86 (s, 3H OCH3), 2.96 (s, 3H, SO2CH3), 2.65-2.68 (m, 2H, benzyl), 1.72-1.74 (m, 4H, 2° aliphatic).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH2:40]([N:44]([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:45][CH2:46][CH2:47][NH2:48])[CH2:41][CH2:42][CH3:43]>C1COCC1>[CH2:40]([N:44]([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:45][CH2:46][CH2:47][NH:48][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:39])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCN(CCCC)CCCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: CCCCN(CCCC)CCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 66 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in THF(3 mL) was added N,N-dibutyl-1,3-propanediamine (0.041 mL, 0.182 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (16 mg, 66%). LC-MS m/z 674 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 6H), 1.30 (m, 4H), 1.40 (m, 4H), 1.50 (m, 2H), 2.34 (s, 3H), 2.43 (m, 6H), 3.10 (m, 2H), 4.13 (s, 2H), 7.15(m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:10][C:11]([F:29])([F:28])[C:12]1[C:13]([NH2:27])=[N:14][CH:15]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:17]=1.C([O-])([O-])=O.[K+].[K+].N#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[F:29][C:11]([F:10])([F:28])[C:12]1[C:13]([NH2:27])=[N:14][CH:15]=[C:16]([C:2]2[S:6][C:5]3=[N:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:17]=1
Reactant: Brc1nn2ccnc2s1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ncc(-c2nn3ccnc3s2)cc1C(F)(F)F
Temperature: 110 °C
Yield: 37.2 %

Procedure:
A solution of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (0.469 g, 2.3 mmol, 1 eq), 3-(trifluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.7 g, 3.5 mmol, 1.5 eq), dioxane (8 mL) and a sat. aq. solution of K2CO3 (1 mL) was degassed (N2, 5 min) at RT. Pd(Ph3P)2Cl2 (0.404 g, 0.250 mmol, 1 eq) was added, and the reaction mixture was heated at 110° C. under N2 for 2 h. The solvent was evaporated, and the residue was taken up in AcOEt and n-BuOH and washed with water. The organic phase was separated, dried (Na2SO4), filtered and concentrated. The residue was treated with MeOH, filtered off and dried to give the desired product (0.244 g, 37%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=3.61 min, [M+H]+ m/z 286.0.