Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]([CH3:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]([CH3:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[N:34]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A mixture of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.536 g) and 7-(2-ethoxycarbonyl-1-methyl-ethyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (396 mg, Reference Example 19) in tetrahydrofuran (10 ml) containing 4 Angström molecular sieves (0.5 g) was treated with triethyl amine (638 μl), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (518 mg) and 4-dimethyl-aminopyridin (14 mg). After stirring for 5 hours further aliquots of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.178 g) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (172 mg) were added and stirring was continued for a further 18 hours. The reaction mixture was filtered through a celite and the filter pad was washed with ethyl acetate (50 ml). The combined filtrate and washings were washed three times with aqueous saturated ammonium chloride (20 ml), then dried over magnesium sulfate and then evaporated (40° C., 40 mbar). The residue (1.2 g) was submitted to chromatography (36 g silica, 0.040-0.063 mm particle size) eluting with a mixture of cyclohexane and ethyl acetate (70:30, v/v) to afford the title compound as a white powder (379 mg). TLC: RF=15/65 (cyclohexane:ethyl acetate, 1:1). 1H NMR (400 HMz, (CD3)2SO, at room temperature, we observe a mixture of rotamers): δ1.14 (t, J=7 Hz, 31); 1.24 (d, J=7 Hz, 3H); 1.48 (s, 9 H); 2.26 (s, 3H); 2.58 (d, J=7.5 Hz, 2H); 3.17 (m, 1H); 3.64 (m, 2H); from 3.75 to 3.90 (m, 7H); 4.04 (q, J=7 Hz, 2H); from 6.55 to 6.85 (very broad band, 2H); 6.96 (t, J=7.5 Hz, 1H); 7.00 (broad d, J=8 Hz, 1H); from 7.10 to 7.20 (m, 2H); 7.46 (broad band, 1H); 7.64 (broad s, 1H); 7.78 (d, J=8 Hz, 1H); 8.01 (d, J=8 Hz, 1H); 8.48 (s, 1H); 8.54 (broad s, 1H). MS (EI): 644 (M+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C@@H:43]([CH2:51][CH3:52])[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:45])(=O)=O.O>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C@H:43]([CH2:51][CH3:52])[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:45])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: CCCCOC(=O)[C@H](CC)OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCOC(=O)[C@@H](CC)Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1
Reaction time: 0.17 h
Yield: 104.4 %

Procedure:
To a solution of N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydrox ybenzylamine (530 mg) in acetonitrile (10 mL), potassium carbonate (272 mg) in a powder form was added at room temperature, and the resulting mixture was stirred for 10 minutes. The solution of n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate (587 mg) in acetonitrile (10 mL) prepared in Preparative Example 6 was added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, the mixture was extracted with toluene, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain a colorless oil (748 mg, 100%).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]([O:17][CH:18]([CH3:20])[CH3:19])(=[O:16])[CH2:9][C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11].Br[CH2:22][C:23]([O:28][CH3:29])([O:26][CH3:27])[CH2:24]Br>O>[CH:18]([O:17][C:8]([C:9]1([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[CH2:24][C:23]([O:28][CH3:29])([O:26][CH3:27])[CH2:22]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Reactant: COC(CBr)(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Temperature: 145 °C

Procedure:
Following the procedure of Pigou and Scheisser (J. Org. Chem. 1988, 53, 3841), a 500 mL, 3-neck flask, fitted with a reflux condenser and thermocouple, was charged with NaH (60% in mineral oil, 4 g, 0.210 mol). DMF (100 mL) was added via syringe and the slurry was stirred under N2. Diisopropyl malonate was added at a rate so that the internal temperature did not rise above 70° C. After the H2 evolution had ceased, the flask was briefly opened and 1,3-dibromo-2,2-dimethoxypropane was added. The bath temperature was raised to 145° C. The reaction mixture was maintained at this temperature for 48 h. After this time the dark brown mixture was allowed to cool to rt. Water (50 mL) was added and the solvents were removed in vacuo. The residue was partitioned between ether (200 mL) and sat'd aq NH4Cl (200 mL) and the mixture filtered through a pad of Celite to remove solid impurities. The aqueous layer was extracted with ether (2×100 mL). The combined ether extracts were washed with brine, dried over Na2SO4, filtered and evaporated. Flash chromatography (SiO2, O-25% EtOAc in hexanes) gave semi-pure diisopropyl-3,3-dimethoxycyclobutane-1,1-dicarboxylate (28.5 g), which was used in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:11]=2[C:12]([O:14]C)=O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:22]([Li])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:11]=2[C:12](=[O:14])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: [Li]C(C)(C)C
Reactant: COC(=O)c1cc(CO)ccc1-c1cc(OC)ncc1F
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(CO)cc2C(=O)C(C)(C)C)c(F)cn1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of methyl 2-(5-fluoro-2-methoxypyridin-4-yl)-5-(hydroxymethyl)benzoate T37.3 (0.307 g, 1 mmol) in THF (11 mL) at −78° C. was added tert-butyl lithium (2 mL, 3 mmol). The reaction mixture was stirred for one hour and then quenched with a saturated solution of ammonium chloride and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield T37.4 as a colorless solid (0.28 g, 84% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[S:22]([O:12][CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:13])(=[O:24])(=[O:23])[CH3:21]
Reactant: C[C@@H](CCO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CCOS(C)(=O)=O)NC(=O)OC(C)(C)C

Procedure:
The product of example 22 (a) (1.06 g, 5.6 mmol) was dissolved in CH2Cl2 (10 ml) and cooled in an ice bath while stirring under argon. Triethylamine (0.667 g, 6.6 mmol) was added followed by the dropwise addition of methanesulfonyl chloride (0.687 g, 6 mmol). After 10 minutes the ice bath was removed and the mixture stirred at rt for 2 h. The solvent was stripped off and the title compound was isolated as a yellow oil. ES (+) MS m/e=268 (MH+), 290 (MNa+)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.B1([C:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH:42]=2)OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[N:29]1[CH:30]=[CH:31][C:26]([NH:25][S:22]([C:19]2[CH:20]=[CH:21][C:13]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[C:41]4[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH:42]=4)[CH2:17][CH2:16][O:15][C:14]=3[CH:18]=2)(=[O:24])=[O:23])=[N:27][CH:28]=1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Nc4ccncn4)ccc32)CC1
Temperature: 115 °C

Procedure:
A 5-mL glass microwave reaction vessel was charged with 4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.075 g, 0.159 mmol), (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.123 mL, 0.398 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.017 g, 0.024 mmol), potassium phosphate (0.053 mL, 0.637 mmol) and sealed with a septa cap. The reaction head space was flushed with nitrogen and dioxane (0.6 mL) and water (0.2 mL) were added. The mixture was sparged with nitrogen for 5 min. The reaction mixture was stirred and heated in a microwave reactor at 115° C. for 3 h. The reaction mixture was diluted with EtOAc and the organic layer was decanted from the aqueous layer at the bottom of the vial by pipet. The organic layer was concentrated and absorbed onto a 5 g loading cartridge and passed through a silica gel column (12 g) using a gradient from 0% to 70% EtOAc in Heptanes to provide tert-butyl 4-(2-(7-(N-(pyrimidin-4-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2 H)-carboxylate. This product was taken up in 0.5 mL DCM and 0.5 mL of trifluoroacetic acid was added and the solution was maintained at rt for 10 min. The solution was concentrated to dryness and then triturated with ether and IPA to give N-(pyrimidin-4-yl)-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide 2,2,2-trifluoroacetate (0.005 g, 7.92 μmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.13-3.25 (m, 3 H) 3.57-3.64 (m, 3 H) 3.65-3.72 (m, 3 H) 4.24-4.40 (m, 2 H) 5.82-5.94 (m, 1 H) 6.42-6.55 (m, 1 H) 7.01-7.14 (m, 1 H) 7.24-7.38 (m, 2 H) 7.53-7.67 (m, 2 H) 7.72-7.82 (m, 1 H) 8.32-8.47 (m, 1 H) 8.63-8.72 (m, 1 H) 8.73-8.86 (m, 2 H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][N:10]([CH2:25][CH2:26][NH:27][C:28]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:34])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2CCNC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
Ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (125 mg, 0.541 mmol) was dissolved in DMF (10 mL), followed by addition of potassium tert-butoxide (79 mg, 0.703 mmol). After stirring for 15 minutes, 1,1-dimethylethyl (2-bromoethyl)carbamate (121 mg, 0.541 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness. The crude residue was diluted with water (50 mL) and acidified with acetic acid. The contents were extracted with DCM (4×50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0 to 50% EtOAc:Hex). The final product was obtained as 0.114 g (56%). LCMS E-S (M+H)=375.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.14 (m, 4H), 1.15-1.20 (m, 2H), 1.27 (s, 7H), 1.41 (t, J=7.07 Hz, 3H), 2.36-2.45 (m, 1H), 3.31-3.41 (m, 3H), 4.36-4.50 (m, 5H), 6.84 (t, J=5.81 Hz, 1H), 7.65 (s, 1H), 8.24 (s, 3H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:23]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]2)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([Cl:31])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:31][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:23]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]2)=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1

Procedure:
A mixture of 6-bromo-9H-purine (0.0234 g, 0.118 mmol), (3S)-1-[7-(1-aminoethyl)-5-chloroquinolin-8-yl]piperidin-3-ol (0.018 g, 0.059 mmol), and N,N-diisopropylethylamine (0.0205 mL, 0.118 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the products. First peak retention time 1.482 minutes, LCMS calculated for C21H23ClN7O (M+H)+: m/z=424.2; Found: 424.0. Second peak retention time 1.583 minutes, LCMS calculated for C21H23ClN7O (M+H)+: m/z=424.2; Found: 424.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:18][CH2:19][C:20]2([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH2:12]OS(C)(=O)=O)[C:8]2[C:4](=[CH:5][N:6]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:7]=2)[CH:3]=1.[C-:48]#[N:49].[Na+].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:18][CH2:19][C:20]2([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]2)[CH2:12][C:48]#[N:49])[C:8]2[C:4](=[CH:5][N:6]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:46])[CH3:47])[N:7]=2)[CH:3]=1
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(COC(COS(C)(=O)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COC(CC#N)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-(methylsulfonyloxy)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (155 mg, 0.218 mmol) in DMF was added NaCN (21.37 mg, 0.436 mmol) and the reaction was stirred at R.T for 1 h. LC/MS showed no reaction. The reaction was heated at 50 C for another hour, LC/MS showed no reaction either. The reaction was again heated at 80 C for another hour, no reaction was observed. It was stirred at 80 C over the weekend. LC/MS showed product along with staring material. It was stirred at 80 C for 6 h, LC/MS showed the reaction was complete. The reaction was then partitioned between Et2O and H2O, the phase was separated and the aqueous phase was extracted with Et2O, the combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. It was purified by Biotage LC (30% EtOAc/Hex) to title compound (52.2 mg, 0.081 mmol, 37.3% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.0 (s, 1H),), 7.53 (m, 1H), 7.32 (m, 2H), 7.05 (m, 2H), 6.63 (s, 1H), 5.61 (s, 2H), 5.04 (m, 1H), 3.68 (m, 2H), 3.57 (t, J=8.05 Hz, 2H), 3.45 (m, 2H), 3.05-2.96 (m, 3H), 2.74 (m, 1H), 2.28 (m, 1H), 1.98 (m, 1H), 1.96 (m, 1H), 1.83 (m, 1H), 1.42 (s, 9H), 0.9 (t, J=8.42 Hz, 2H); 13C-NMR (CDCl3, 126 MHz) δ 161.63 (d, J=245.7 Hz), 155.0, 144.8, 129.9, 128.9, 128.0, 124.0, 122.8, 119.3, 117.2, 115.5, 115.4, 81.9, 79.5, 79.0, 73.4, 67.8, 42.5, 41.4, 32.4, 28.6, 25.3, 17.9, 1.35. LC/MS (HPLC method 3): tR=4.16 min, 643.1 (MH)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([Br:9])=[C:7]([CH3:10])[NH:6][C:5](=[S:11])[N:4]=1.[OH-].[K+].I[CH2:15][C:16]([NH2:18])=[O:17]>>[C:16]([CH2:15][S:11][C:5]1[N:6]=[C:7]([CH3:10])[C:8]([Br:9])=[C:3]([CH3:2])[N:4]=1)(=[O:17])[NH2:18]
Reactant: NC(=O)CI
Reactant: Cc1nc(=S)[nH]c(C)c1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(SCC(N)=O)nc(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
4,6-Dimethyl-5-bromopyrimidine-2-thione HCl salt (5 mmol) was added to ethanolic (60 ml) KOH (11.4 mmol), the solution stirred for 10 min at room temperature, iodoacetamide (5.7 mmol) added, the stirring continued for 20 min at room temperature and for 100 min at 70° C. (pH 8). The warm reaction mixture was filtered, the filtrate evaporated, the residue extracted with chloroform (150 ml), the chloroform solution washed and the dried (MgSO4) solution evaporated to leave the sulfide; yield 72%, m.p. 175°-177° C. (iPrOH). 1H NMR (DMSO-d6): δ2.50 (Me), 3.80 (SCH2).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][CH3:15])[NH:10][C:9]=2[C:8](=O)[NH:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].O>N1C=CC=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][CH3:15])[NH:10][C:9]=2[C:8](=[S:19])[NH:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCn1c(=O)[nH]c(=O)c2[nH]c(CC)nc21
Solvent: c1ccncc1
Solvent: O
Product: CCCCn1c(=O)[nH]c(=S)c2[nH]c(CC)nc21
Temperature: 25 °C

Procedure:
11.8 g (50 mM.) of 3-butyl-8-ethyl-xanthine (mp 304°-9° C., and 18.2 g (82 nM.) of phosphorus pentasulfide were refluxed in 170 ml of pyridine for 2 hrs. The solution was cooled to ambient temperature and treated slowly with 110 ml. of water (exothermic). The suspension was concentrated to 100 ml. in vacuo at 60° C., further diluted with 140 ml. of water, and concentrated again to about 120 ml. The crude product was collected and washed with ice water. The dried material (11.1 g.) was dissolved in about 100 ml. of chloroform, and the solution filtered through 55 g. of silicagel. The chloroform was evaporated and the residue crystallized from acetone-ether: 7.2 g. (57.5%) of 3-butyl-8-ethyl-6-thioxanthine, mp. 206°-7° C. From the mother liquor, a second crop of 2.1 g. (16.3%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[Br:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[CH:37]=O.N1CCCCC1>CO>[Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9]/[C:8](=[CH:37]\[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([Br:27])[CH:29]=4)[NH:33][N:32]=3)/[C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2n[nH]c4ccc(Br)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.261 mmol) synthesized in Example B13, Step 2 in methanol (1 mL) was added with 5-bromo-1H-indazole-3-carbaldehyde (0.0587 g, 0.261 mmol) synthesized in Example B10, Step 3, and piperidine (0.00222 g, 0.0261 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (4 mL), and suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({5-chloro-2-[(5-bromo-1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.110 g, 71%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
A solution of anthranilic acid (50 g, 364.6 mmol) in a mixture of anhydrous DMF (125 mL) and dioxane (125 mL) in a 1 L morton flask equipped with a mechanical stirrer and a constant addition funnel was cooled with an ice-bath to 0° C. Distilled bromoacetyl bromide (73.6 g, 31.77 mL, 364.6 mmol) was added dropwise keeping the internal temperature between 0°-1.5° C. over a 2.5 h period. After the addition was completed, the ice-bath was removed and stirring was continued for 5 h at ft. The reaction mixture was cooled in an ice-bath and water (300 mL) was slowly added. A white precipitate formed, which was filtered, washed sequentially with 5% HBr solution (500 mL) and water (500 mL), and then dried in a vacuum desiccator. Further drying in a vacuum oven at 60° C. afforded 82.61 g (87.8%) of the title compound as a white powder: mp 164.6°-167.6° C. (lit. 165.5°-172° C. (Hoffman LaRoche U.S. Pat. No. 3,244,698)); 1H NMR (DMSO-d6) δ13.7 (bs, 1H), 11.60 (s, 1H), 8.44 (d, J=8.0, 1H), 8.00 (dd, J=8.0, J=1.6, 1H), 7.62 (dt, J=8.0, J=1.6, 1H), 7.21 (t, J=8.0, 1H); 4.26 (s, 2H); 13C NMR (DMSO-d6) δ169.20, 165.05, 139.95, 134.08, 131.13, 123.46, 120.02, 117.09, 30.67; MS (EI, m/z) 256.9 (M+), 258.9 (M+ 2+). HRMS (EI) calcd for C9H8NO3Br 256.9686, found 256.9695.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:24]([O:23][C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)=[CH:29][CH:28]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 81.1 %

Procedure:
A solution of compound D (31.5 g; 0.1278 mol), tert-butyl 4-aminobenzoate (48 g; 0.248 mol), N,N-diisopropylethylamine (50.3 g; 0.39 mol) in 400 mL of dioxane was refluxed for 72 h under magnetic stirring. The reaction mixture was filtered, concentrated and taken up with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulphate and concentrated. The crude mixture was purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate=9/1) to yield compound E (41.8 g; 81%).