Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[C:13]([O:17][C:18](=[O:40])[CH:19]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH:20]([CH3:22])[CH3:21])([CH3:16])([CH3:15])[CH3:14]>ClCCl.CN(C)C1C=CN=CC=1>[C:13]([O:17][C:18]([CH:19]([NH:23][S:24]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([O:11][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)=[O:12])=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)(=[O:25])=[O:26])[CH:20]([CH3:22])[CH3:21])=[O:40])([CH3:15])([CH3:16])[CH3:14]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 23.9 %

Procedure:
To benzofuran-2-carboxylic acid (0.401 g, 2.47 mmol, 1 equiv.) dissolved in dry dichloromethane (50 mL) was added dicyclohexylcarbidiimide (1.019 g, 4.94 mmol, 2 equiv) and the mixture was stirred under nitrogen for 15 minutes. Then 2-(4′-hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (1.0 g, 2.47 mmol, 1 equiv., Example 134, Step 1) was introduced to the reaction mixture, followed by the addition of 4-dimethylamino pyridine (0.050 g, 0.41 mmol). The mixture was allowed to stir at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with water and brine. The organic layer was dried over magnesium sulfate and the solvent was concentrated in vacuo. The residue was dissolved in ethyl acetate and purified by column chromatography on silica gel eluting with 20% ethyl acetate/hexane to afford 325 mg of benzofuran-2-carboxylic acid 4′-(1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester in 31% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 1.03 (d, J=6.82 Hz, 3 H) 1.21 (s, 9 H) 2.07 (m, 1 H) 3.68 (dd, J=9.85, 4.55 Hz, 1 H) 5.15 (d, J=9.85 Hz, 1 H) 7.37 (m, 3 H) 7.53 (t, J=7.83 Hz, 1 H) 7.66 (m, 5 H) 7.77 (m, 2 H) 7.92 (d, J=8.34 Hz, 2 H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=O)=O.[Br-:26].[Mg+2].[Br-]>CCOCC>[CH2:6]([Br:26])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: [Br-]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCOS(C)(=O)=O
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCBr
Reaction time: 48 h

Procedure:
A mixture of arachidonyl methane sulfonate (1.0 g, 2.7 mmol) and magnesium bromide (2.2 g, 12 mmol) in anhydrous ether (40 mL) was stirred under argon for two days. The resulting suspension was filtered and the solid washed with ether (2×10 mL). The filtrate and wash were combined and solvent evaporated. The resulting residual was treated with hexanes (50 mL). The solid was filtered and solvent evaporated resulting in an oily residual. The crude product was purified by column chromatography on silica gel (230-400 mesh, 30 mL) eluted with hexanes. This gave 1 g of arachidonyl bromide (II) as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH:13]([CH3:15])[CH3:14])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].[CH:22]([C:24]([CH3:26])=[O:25])=[CH2:23]>O1CCCC1>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:13]([CH3:14])[CH3:15])([CH2:23][CH2:22][C:24](=[O:25])[CH3:26])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C(C)C)C2
Reactant: C=CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CCC(C)=O)(C(C)C)C2
Temperature: 25 °C

Procedure:
Methyl [(6,7-dichloro-2-isopropyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetate (16.5 gm., 0.05 mole) is suspended in dry tetrahydrofuran (100 ml.) containing triton-B (1 ml.). The suspension is stirred at ambient temperature and methyl vinyl ketone (5.02 gm., 0.072 mole) is added. The solution which becomes warm initially, is stirred at ambient temperature for 4 hours. Then, the stirring solution is treated with methyl vinyl ketone (0.3 ml.) and triton-B (0.6 ml.) every 4 hours for the next twenty hours.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)OC)cc1
Yield: 86.2 %

Procedure:
Into a flask were introduced methyl 4-hydroxybenzoate (251.0 g, 1.65 mol), potassium carbonate (276.37 g, 1.99 mol) and 1200 g of acetone. This was refluxed for 45 min followed by the drop-wise addition of 1-octylbromide (386.17 g, 1.99 mol) over a 1 hour period. The reaction mixture was refluxed for two days. Filtration of the cooled reaction mixture and evaporation of the filtrate gave an oil. This was taken up in ethyl acetate and extracted with 5% NaOH (2×100 ml) followed by water (2×100 ml). The organic layer was dried (MgSO4), concentrated, and transferred to a pre-weighed 1L three-necked flask. The contents of the flask were subjected to high vacuum distillation to remove the excess 1-octylbromide. The pot residue gave 376 g (86% yield) of methyl 4-octoxybenzoate.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:22]=[N:23][NH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].Cl[CH2:34][C:35]#[N:36]>>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:22]=[N:23][N:24]([CH2:34][C:35]#[N:36])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2ccc3c(cc(-c4cn[nH]c4)n3Cc3ccccc3)n12
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4cnn(CC#N)c4)n3Cc3ccccc3)n12
Reaction time: 0.17 h

Procedure:
A solution of 6-benzyl-1-methyl-7-(1H-pyrazol-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (14 mg, 0.043 mmol, from Example 63) in DMF (0.56 mL, 7.2 mmol) was treated with NaH (5.1 mg, 0.21 mmol). After 10 minutes, the mixture was treated with chloroacetonitrile (8.1 μL, 0.13 mmol, Fluka). After 10 minutes, the reaction was quenched by the addition of water. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (7.0 mg, 45%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21].Cl>C1COCC1>[OH:22][CH:20]([CH3:21])[CH2:19][NH:18][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: CC(O)CN
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCC(C)O
Temperature: 0 °C
Yield: 63.5 %

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (2.80 g, 10 mmol) in 100 ml of THF was cooled in an ice-bath and stirred while a solution of 1-amino-2-propanol (1.65 g, 22 mmol) in 10 ml of THF was added dropwise over a period of 50 minutes. After stirring an additional 30 minutes in the ice-bath, the reaction mixture was acidified by the addition of 3 ml of 1.2 N HCl. The THF was evaporated under reduced pressure and the residue taken up in 100 ml of ethyl acetate. After extracting with 4×20 ml of saturated NaCl solution, the ethyl acetate solution was dried over Na2SO4 and the solvent evaporated. The residue was crystallized from a mixture of ethyl acetate and hexane to give 2.02 g (63.5%) of yellow crystalline product, m.p., 93.5°-95°.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:28][OH:29]>C(O)C.N1C=CC=CC=1>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:10]=2)=[N:28][OH:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1

Procedure:
A solution of 15.9 g (46 mmol) of 4-(quinolin-2-yl-methoxy)phenyl cyclohexyl ketone in 100 ml of ethanol and 33 ml of pyridine is stirred at room temperature for 18 h after addition of 4.77 g (68.6 mmol) of hydroxylamine hydrochloride. For working up, the mixture is concentrated in vacuo and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over sodium sulphate and concentrated to dryness in vacuo.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([C:16](OC)=[O:17])[CH2:15][CH:14]=[CH:13][CH2:12]1)=O>O1CCCC1.C1(C)C=CC=CC=1>[OH:8][CH2:9][C:11]1([CH2:16][OH:17])[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: COC(=O)C1(C(=O)OC)CC=CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCC1(CO)CC=CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The desired diol 2 was prepared via LAH reduction of the corresponding diester 1. To a flame dried round-bottomed flask was placed lithium aluminum hydride (LAH, Aldrich 95%, 6.99 g, 175 mmol) and anhydrous tetrahydrofuran (THF, 235 mL). The resulting suspension was cooled to 0° C. and then a solution of the dimethyl diester 1 in 58 mL of anhydrous THF was added dropwise via an additional funnel. The resulting mixture was allowed to stir at ° C. for 4 hours while monitored by TLC. The reaction mixture was then carefully quenched by sequential addition of 6 mL of water, 6 mL of 3 N aqueous solution of NaOH and 17.5 mL of water. The resulting mixture was allowed to slowly come to room temperature and then filtered through a bed of Celite. The resultant solid cake was washed repeatedly with refluxing THF (total of 250 mL). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a light yellow oil which was dissolved in 150 mL of refluxing toluene and the water was azeotropically removed. Removal of the remaining toluene gave an off-white solid, which was recrystallized from refluxing toluene. The desired diol 2 was obtained as white needles in 86.2% yield. Mp (DSC) 81.21° C., 1H-NMR (CDCl3, 300 MHz) δ5.59 (s, 2H), 3.73 (s, 2H), 3.63 (s, 4H), 2.16 (S, 4H); 13C-NMR (CDCl3, 300 MHz) δ128.69, 69.19, 47.53, 38.61; FT-IR (CH2Cl2) (cm−1) 3323, 3055, 2918, 2846, 1619, 1442, 1419, 1357, 1266 1114, 1093, 1025, 955, 909, 896.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[Cl:15][C:4]1[C:5]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Oc1ncnc2cccnc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ncnc2cccnc12
Temperature: 25 °C

Procedure:
To a stirred solution pyrido[3,2-d]pyrimidin-4-ol (B-2) (16 g, 109 mmol, 1.0 eq) in DCM (200 mL) and DMF (0.4 mL) at RT, oxalyl chloride (23.2 mL, 272 mmol, 2.5 eq) is added dropwise (over 5 min) and the resulting mixture is stirred at reflux overnight. The mixture is allowed to cool to RT and concentrated in vacuo. The residue is diluted with water (200 mL), neutralized with saturated aqueous NaHCO3 solution below 10° C. to adjust the pH to 8-9 and then extracted with ethyl acetate (4×100 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (16-50% ethyl acetate-petroleum ether) to afford the product, 4-chloropyrido[3,2-d]pyrimidine (B-3).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.[Cl:30][CH2:31]I>C1COCC1>[Cl:30][CH2:31][C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14][N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCI
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(CCl)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.75 h
Yield: 51.4 %

Procedure:
To a solution of diisopropylamine (22.6 mL, 159 mmol) in anhydrous THF (140 mL) in an oven-dried round-bottomed flask was added n-BuLi (65.4 mL, 163 mmol, 2.50 M in hexanes) dropwise at 0° C. The solution was stirred for 45 minutes and 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (20 g, 80 mmol) in THF (60 mL) was added dropwise at 0° C. and the mixture was stirred at 0° C. for 1 hour. Chloroiodomethane (17.9 mL, 239 mmol) was added dropwise and the mixture was stirred for 1 h. The mixture was quenched with 250 mL of saturated aqueous NaHCO3 followed by extraction with ethyl acetate (3×250 mL). The combined organic layers were washed (brine, 250 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil that was purified by silica chromatography using a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.) system to give 1-tert-butyl 4-methyl 4-(chloromethyl)piperidine-1,4-dicarboxylate (12 g, 52%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.10-2.17 (m, 4H), 2.97 (br s, 2H), 3.56 (s, 2H), 3.74 (s, 3H), 3.83 (br s, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[CH:6][CH:5]=1.[CH2:15]1COCC1>IC>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH3:15])=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: CC(C)(CO)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Sodium hydride (1.664 g, 41.6 mmol, 60% dispersion in mineral oil) was suspended in dry THF (18 ml) under N2 and 2-(4-fluorophenyl)-2-methylpropan-1-ol (3.500 g, 20.8 mmol) in dry THF (18 ml) was slowly added to the suspension at 0° C. After complete addition the reaction was warmed to r.t. and left for 1 h. Iodomethane (6.5 ml, 0.104 mmol) was slowly added at r.t. and the reaction left for 3 h. The reaction was quenched by slow addition of H2O (35 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3×35 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% heptane to 10% EtOAc:90% heptane as eluent to give the product as a colourless oil (2.991 g, 79%): LC purity 98% (ret. time, 2.16 min); 1H NMR (500 MHz, CDCl3) δH 7.40-7.32 (m, 2H), 7.11-6.96 (m, 2H), 3.39 (s, 2H), 3.33 (s, 3H), 1.33 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][NH:20]2)=[CH:16][CH:15]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]([C:13]([F:12])([F:23])[F:24])[CH:22]=3)[CH2:18][CH2:19]2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: FC(F)(F)c1ccc2c(c1)NCC2
Solvent: CCCCO
Product: FC(F)(F)c1ccc2c(c1)N(c1nc(Cl)nc3[nH]cnc13)CC2
Reaction time: 23 h
Yield: 92.4 %

Procedure:
756 mg of 2,6-dichloropurine, 8 ml of butanol and 897 mg of 6-(trifluoromethyl)indoline are mixed and brought to a temperature of 90° C. for approximately 23 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum at 50° C. are carried out, and 1.256 g of expected product are obtained, in the form of beige crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[N:14]=2)=[CH:9][CH:8]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:24]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:15]3[N:14]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:12][CH:11]=4)[CH:18]=[CH:17][N:16]=3)=[CH:28][CH:27]=2)=[O:25])[CH2:40][CH2:41]1)=[O:35]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(SCCCCO)cc3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc(Nc2nccc(-c3ccc(SCCCCO)cc3)n2)cc1)N1CCN(C(=O)c2ccco2)CC1
Reaction time: 12 h
Yield: 8.8 %

Procedure:
4-{4-[4-(4-Hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}benzoic acid (0.34 g, 0.86 mmol) was dissolved in THF (5 mL). To this solution was added 1-furoylpiperazine (0.170 g), EDCI (0.180 g), and HOBt (0.127 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparatory HPLC (30-80 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(Furan-2-carbonyl)-piperazin-1-yl]-(4-{4-[4-(4-hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}phenyl)methanone (0.042 g, 9%): HPLC Retention Time; 10.07 min. (Method B) M+H=558.3.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[CH3:20])[CH:3]=1.[N:34]1([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[CH:15][C:14]=1[NH:13][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([NH:48][C:45]3[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:43][CH:44]=3)[N:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nccn1-c1cc(Cl)ncn1
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nccn1-c1cc(Nc2ccc(CCN3CCOCC3)cc2)ncn1

Procedure:
A Smith vial (2-5 mL) is charged with N-{3-[1-(6-chloro-pyrimidin-4-yl)-1H imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (16.8 mg, 0.035 mmol), 4-(2-morpholin-4-yl-ethyl)-phenylamine (22 mg, 0.11 mmol), p-toluenesulfonic acid monohydrate (4.4 mg, 0.023 mmol) and DMSO (0.5 mL). After purging with Argon, the vial is sealed and irradiated at 100° C. for 1.5 hours in a Smith Synthesizer. The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound. 1H NMR 600 MHz (DMSO-d6) δ 11.00 (s, 1H), 10.54 (s, 1H), 10.09 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.97 (d, J=6.6 Hz, 1H), 7.79 (t, J=8.4 Hz 1H), 7.64 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.28 (m, 3H), 7.06 (s, 1H), 6.95 (s, 1H), 4.03 (d, J=12.6 Hz, 2H), 4.03 (d, J=12.6 Hz, 2H), 3.69 (t, J=12.6 Hz, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H), 3.13 (br, 2H), 2.98 (t, J=7.8 Hz, 2H), 2.33 (s, 3H); MS m/z 643.4 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:29][C:28]3[C:27](=[O:30])[N:26]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]5(O)[CH2:42][C:41]([F:44])([F:43])[CH2:40]5)=[C:33]([O:46][CH3:47])[CH:32]=4)[CH:25]=[N:24][C:23]=3[CH:22]=2)=[CH:17][CH:16]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH3:10])[C:11]([O:13][C:39]1([CH2:38][O:37][C:34]2[CH:35]=[CH:36][C:31]([N:26]3[C:27](=[O:30])[C:28]4[S:29][C:21]([C:18]5[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=5)=[CH:22][C:23]=4[N:24]=[CH:25]3)=[CH:32][C:33]=2[O:46][CH3:47])[CH2:40][C:41]([F:44])([F:43])[CH2:42]1)=[O:12])=[O:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(O)CC(F)(F)C1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)CC(F)(F)C1
Temperature: 40 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
A mixture of Boc-alanine (94 mg, 0.495 mmol), 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (50 mg, 0.099 mmol) from Example 2,4-pyrrolidinopyridene (14.68 mg, 0.099 mmol) and N,N′-diisopropylcarbodiimide (0.077 mL, 0.495 mmol) in CH2Cl2 (4 mL) was stirred at 40° C. in a sealed tube for 18 hours. After cooling to RT and removal of the volatiles under vacuum, the crude product was subjected to gradient chromatography (silica gel/EtOAc/hexane 0 to 30%) to afford (S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-(tert-butoxycarbonylamino)propanoate (59 mg, 0.087 mmol, 88% yield) as off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1 H, s), 7.66 (2 H, d), 7.54 (1 H, s), 7.46 (2 H, d), 6.87-7.06 (3 H, m), 4.96 (1 H, br. s.), 4.34-4.48 (2H, m), 4.20-4.34 (1 H, m), 3.87 (3 H, s), 3.09-3.24 (2 H, m), 2.97 (2 H, broad s.), 1.45 (9 H, s), 1.38 (3 H, d, J=7.30 Hz). LC-MS: 2.72 min 677 (M+H). Luna 5 u C18 30×4.6 mm ID, flow rate=4 ml/min., gradient=0% A to 100% B in 2 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA).
Reaction SMILES: Br[CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[OH:16])[O:12][C:11]([CH3:18])([CH3:17])[CH2:10][C:9]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC)=O>[CH2:2]1[CH2:3][O:16][C:15]2[CH:14]=[C:13]3[C:8]([C:9](=[O:19])[CH2:10][C:11]([CH3:17])([CH3:18])[O:12]3)=[CH:7][C:6]=2[O:5]1
Reactant: CC1(C)CC(=O)c2cc(O)c(O)cc2O1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)CC(=O)c2cc3c(cc2O1)OCCO3
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a stirred mixture of 100 ml of methyl-ethyl-ketone and 2.6 ml (30 millimoles) of 1,2-dibromo ethane heated to 60° C. 4.2 g (20 millimoles) of 6,7-dihydroxy-2,2-dimethyl-4-chromanone and a suspension of 8.3 g (60 millimoles) of potassium carbonate and 0.5 g of potassium iodide in 100 ml of methyl-ethyl ketone are added dropwise within 3 hours. The reaction mixture is heated to boiling for 5 hours. The inorganic salt is filtered off, washed twice with 20 ml of acetone each and the solvent is removed. The residue is crystallized from 70% ethanol. Thus 3.75 g of the desired compound are obtained, yield 80%. Mp.: 118°-119° C.